ArticleLiterature Review

Potassium Channel Conductance as a Control Mechanism in Hair Follicles

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Abstract

The opening of intracellular potassium channels is a common mechanism of action for a set of anti-hypertensive drugs that includes the hair-growth-inducing agent minoxidil. Recent work suggests potassium channel openers (PCOs) also influence hair growth. Correlative studies demonstrate that a series of PCOs including minoxidil, pinacidil, P-1075, an active pinacidil analog, RP-49,356, cromakalim, and nicorandil maintain hair growth in cultured vibrissa follicles. Studies using balding stumptail macaques verify that minoxidil, P-1075, and cromakalim but not RP-49,356 stimulate hair growth. The definition of potassium channels and documentation of drug effects on these channels is classically done using electrophysiologic techniques. Such studies require the identification and isolation of target cells. Both these are among the unsolved problems in the area of hair biology. Estimating K+ flux using 86Rb+ as a K+ tracer is an accepted method of assessing potassium channel conductance in other organ systems. Both pinacidil and RP-49,356 induce measurable Rb+ flux in isolated vibrissa follicles and a hair epithelial cell line whereas neither minoxidil nor minoxidil sulfate had measurable effects. Potassium channels have been studied successfully in other organ systems using specific pharmacologic blockers for the various channel subtypes. Blockers including glyburide, tetraethylammonium, and procaine failed to inhibit minoxidil stimulation of cultured follicles. The current explosion of knowledge on potassium channel biology, cloning of channels, and continued progress in hair biology promise to clarify the role of K+ ions in the control of hair follicles.

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... Potassium channel openers promote hair growth by a direct effect on hair follicles, and by improving blood supply to follicles [150,151]. In particular minoxidil stimulates DNA synthesis in epidermal keratinocytes and whole-hair follicles enhancing proliferation and differentiation of the epithelial hair shaft and increase hair density by induction of anagen or an increase in anagen duration. ...
... In particular minoxidil stimulates DNA synthesis in epidermal keratinocytes and whole-hair follicles enhancing proliferation and differentiation of the epithelial hair shaft and increase hair density by induction of anagen or an increase in anagen duration. [150,151]. Topical minoxidil maintain and stimulate new hair growth and helps stop the loss of hair in men with androgenic alopecia and women with female pattern hair loss [150][151][152][153]. The increase in hair growth, measured by hair counts or hair weight is evident within 6-8 weeks of starting treatment and generally peaks by 12-16 weeks [153]. ...
... [150,151]. Topical minoxidil maintain and stimulate new hair growth and helps stop the loss of hair in men with androgenic alopecia and women with female pattern hair loss [150][151][152][153]. The increase in hair growth, measured by hair counts or hair weight is evident within 6-8 weeks of starting treatment and generally peaks by 12-16 weeks [153]. ...
Article
The family of potassium channel openers regroups drugs that share the property of activating adenosine triphosphate-sensitive potassium (K(ATP)) channels, metabolic sensors responsible for adjusting membrane potential-dependent functions to match cellular energetic demands. K(ATP) channels, widely represented in metabolically-active tissue, are heteromultimers composed of an inwardly rectifying potassium channel pore and a regulatory sulfonylurea receptor subunit, the site of action of potassium channel opening drugs that promote channel activity by antagonizing ATP-induced pore inhibition. The activity of K(ATP) channels is critical in the cardiovascular adaptive response to stress, maintenance of neuronal electrical stability, and hormonal homeostasis. Thereby, K(ATP) channel openers have a unique therapeutic spectrum, ranging from applications in myopreservation and vasodilatation in patients with heart or vascular disease to potential clinical use as bronchodilators, bladder relaxants, islet cell protector, antiepileptics and promoters of hair growth. While the current experience in practice with potassium channel openers remains limited, multitude of ongoing investigations aims at defining the benefit of this emerging family of therapeutics in diverse disease conditions associated with metabolic distress.
... CCS KATP channels display quite distinct properties from ventricular cardiomyocyte channels, including reduced inhibition by cytosolic ATP, lower single channel conductances, and increased sensitivity to diazoxide activation 69 Kir6.1-and SUR2-containing KATP channels are also found elsewhere, including in the dermal papilla and sheath of human hair follicles where they may act to control cell proliferation and hair growth [75][76][77] ; and in microglia, astrocytes and neurons in the brain 78 . Potassium channels sensitive to ATP, KCOs and sulfonylurea inhibitors which regulate salt and fluid reabsorption are found in renal epithelial cells, but these channels are formed of Kir1.1 and CFTR complexes [79][80][81][82][83] . ...
Article
Kir6.1 and SUR2 are subunits of ATP-sensitive potassium (K ATP ) channels expressed in a wide range of tissues. Extensive study has implicated roles for these channel subunits in diverse physiological functions. Together they generate the predominant K ATP conductance in vascular smooth muscle and are the target of vasodilatory drugs. Roles for Kir6.1/SUR2 dysfunction in disease have been suggested based on studies of animal models and human genetic discoveries. In recent years, it has become clear that gain-of-function (GoF) mutations in both genes result in Cantu Syndrome (CS) - a complex, multi-system disorder. There is currently no targeted therapy for CS, but studies of mouse models of the disease reveal that pharmacological reversibility of cardiovascular and gastrointestinal pathologies can be achieved by administration of the K ATP channel inhibitor, glibenclamide. Here we review the function, structure, and physiological and pathological roles of Kir6.1/SUR2B channels, with a focus on CS. Recent studies have led to much improved understanding of the underlying pathologies and the potential for treatment, but important questions remain: Can the study of genetically defined CS reveal new insights to Kir6.1/SUR2 function? Do these reveal new pathophysiological mechanisms that may be important in more common disease? And is our pharmacological armoury adequately stocked.
... Minoxidil은 체내에서 sulpho-transferase의 촉매작용으로 빠르게 Minoxidil sulphate로 전환됨으로서 vascular smooth muscle의 빠른 이 완작용을 유발하여 혈압강하의 효과를 유발한다고 보고되 었다[3]. Minoxidil 이외에 다른 potassium channel opener 를 대상으로 한 발모실험[4]에서 Cromakalin 및 P-1075 (Pinacidil analog)도 발모효과가 입증되어 potassium channel 이 발모효과의 중요한 표적으로 인식되었다. 그러나 근래에 Minoxidil에 대한 연구가 다양하게 이루어지면서 potassium channel opener 뿐만 아니라, 세포기능에 다양한 효과를 보 인다고 밝혀졌다. ...
Article
In order to explore structural features of minoxidil analogs with a view of enhancing lysyl hydroxylase (LH) inhibitory activity, molecular holographic QSAR (HQSAR) and CoMSIA (comparative molecular similarity indices analysis) were performed. The results from the atomic contributions with optimized the HQSAR 6-2 model indicated that, in case of pyrimidine-1-N-oxide substituent, C2 atom of pyrimidine ring and C'3-C'4 bond of 4-piperidinol group showed the highest impact on the inhibitory activity towards LH enzyme. It was also evident from the information of the optimized CoMSIA F5 model that the inhibitory activity mainly depended on the hydrophobic field contribution (36%) and the hydrogen bond (H-bond) field contribution (49.2%) of substrate molecule. Particularly, it is predicted that the functional groups which disfavor H-bond acceptors in large space around the piperidinol group and also the functional groups which favor the H-bond acceptors at C'4 (& C'5) atom in R_5 group play a role for increased inhibitory activity. With this in mind, it is likely that a novel candidate having more improved inhibitory activity on hair growth could be designed in the future.
... Both tolbutamide (Fig 8) and another potassium channel inhibitor, glibenclamide (10 mM) (Fig 10) , completely abolished the stimulatory effects of minoxidil (10 mM) in phenol red-free media. This contrasts with a previous report where tolbutamide (5–500 mM) or glibenclamide (0.5–50 mM) had no effect on minoxidil (1 mM)-induced 35 S-cysteine incorporation into neonatal mouse vibrissae follicles (Buhl et al, 1993). Although these differences may indicate variations in the action of minoxidil (Buhl et al, 1990) between adult deer follicles and the neonatal, specialized mouse vibrissae follicles , the effects are more likely to be due to methodological differences between the studies. ...
Article
Although ATP-sensitive potassium (K(ATP)) channel openers, e.g., minoxidil and diazoxide, can induce hair growth, their mechanisms require clarification. Improved drugs are needed clinically. but the absence of a good bioassay hampers research. K(ATP) channels from various tissues contain subtypes of the regulatory sulfonylurea receptor, SUR, and pore-forming, K(+) inward rectifier subunits, Kir6.X, giving differing sensitivities to regulators. Therefore, the in vitro effects of established potassium channel openers and inhibitors (tolbutamide and glibenclamide), plus a novel, selective Kir6.2/SUR1 opener, NNC 55-0118, were assessed on deer hair follicle growth in serum-free median without streptomycin. Minoxidil (0.1-100 microM, p<0.001), NNC 55-0118 (1 mM, p<0.01; 0.1, 10, 100 microM, p<0.001), and diazoxide (10 microM, p<0.01) increased growth. Tolbutamide (1 mM) inhibited growth (p<0.001) and abolished the effect of 10 microM minoxidil, diazoxide and NNC 55-0118; glibenclamide (10 microM) had no effect, but prevented stimulation by 10 microM minoxidil. Phenol red stimulated growth (p<0.001), but channel modulator responses remained unaltered. Thus, deer follicles offer a practical, ethically advantageous in vitro bioassay that reflects clinical responses in vivo. The results indicate direct actions of K(ATP) channel modulators within hair follicles via two types of channels, with SUR 1 and SUR 2, probably SUR2B, sulfonylurea receptors.
... Despite several studies over the last 30 years, we still have not understood minoxidil's mode of action in hair growth induction. Studies to date have focused on its ability to open K ATP channels (6)(7)(8)(9)(10), and indeed minoxidil shares this capacity with other hypertrichotic agents, e.g. pinacidil and diazoxide (11,12). ...
Article
Minoxidil induces new hair growth in approximately one-third of patients with androgenetic alopecia after 1 year of treatment. With several conflicting reports in the literature based on small-scale studies, the current study aimed to clarify whether organ culture of human scalp anagen VI hair follicles is a suitable in vitro test system for reproducing, and experimentally dissecting, the recognized in vivo hair-growth-promoting capacity of minoxidil. Hair shaft elongation was studied in terminal anagen VI hair follicles microdissected from the occipital scalp of 36 healthy adults. A total of 2300 hair follicles, approximately 65 per individual, were tested using modifications of a basic organ culture protocol. It is shown here that minoxidil does not significantly increase hair shaft elongation or the duration of anagen VI in ex vivo culture despite several enhancements on the conventional methodology. This disparity to what is seen clinically in minoxidil responders may be explained by the following: (i) use of occipital (rather than frontotemporal or vertex) hair follicles; (ii) use of, already maximally growing, anagen VI hair follicles; (iii) a predominance of hair follicles from minoxidil unresponsive-donors; (iv) use of minoxidil rather than its sulfate metabolite; and/or (v) use of a suboptimal minoxidil dosage. This disparity questions the usefulness of standard human hair follicle organ culture in minoxidil research. Unexpectedly, minoxidil even inhibited hair shaft elongation in the absence of insulin, which may indicate that the actual hair-growth-modulatory effects of minoxidil depend on the concomitant local presence/absence of other growth modulators.
... Key words: apoptosis/MEK/phospholipids/transforming growth factor b. J Invest Dermatol 121:448 ^456, 2003 N umerous researchers have investigated scienti¢cally proven hair growth stimulants with respect to the mechanisms of action of how they exert hair-growing activity. One of these compounds, minoxidil (Rogaine s , Upjohn, Kalamazoo, MI), originally synthesized as a potassium channel opener (Buhl et al, 1993) and initially prescribed for hypertension, is an FDA-approved topical medication for treating male pattern baldness (Kulick, 1988; Olsen, 1989). Minoxidil is known to possess growthpromoting e¡ects on hair epithelial cells (Tanigaki-Obana and Ito, 1992) and stimulates anagen induction of the hair cycle in animal models (Uno et al, 1985). ...
Article
Phospholipids have recently been discovered to play an important role in cellular regulation. In this study, we focused on phosphatidic acid and lysophosphatidic acid, which are phospholipids known to possess growth-hormonal effects on several types of cells, and examined their growth-promoting effects on murine hair epithelial cells. We discovered that phosphatidic acid possesses intensive growth-promotional effects on hair epithelial cells and epidermal keratinocytes. In contrast, lyso-phosphatidic acid showed lower growth-promoting effects on hair epithelial cells relative to phosphatidic acid and showed minimal or no growth-promoting activity on epidermal keratinocytes. Phosphatidic acid was also shown to have hair-growing activity to induce the anagen phase of the hair cycle in the in vivo murine model. For the purpose of examining the hair-growing mechanisms of phosphatidic acid, we examined its relationship to the mitogen-activated protein kinase cascade linked to cell proliferation and the transforming growth factor beta signal pathway known to be a regulator of catagen induction. We confirmed that phosphatidic acid activates MEK-1/2 and upregulates the expression of MEK-1/2 in cultured murine hair epithelial cells. Addition of transforming growth factor beta1 to hair epithelial cell cultures concentration-dependently decreased cell growth and induced apoptosis; however, addition of phosphatidic acid to the culture neutralized the growth-inhibiting effects of transforming growth factor beta1 and protected the cells from apoptosis. We speculate that the hair-growing activity of phosphatidic acid is at least linked to its growth-promoting effects on hair epithelial cells that follow mitogen-activated protein kinase/extracellular signal-regulated kinase kinase activation and its protective action on transforming-growth-factor-beta1-induced apoptosis that is assumed to trigger catagen induction in the hair cycle.
... There is growing evidence that K + channels may serve functions necessary for cell proliferation [33,39], and specific openers of inwardly rectifying Kir6/SUR (K ATP ) channels (pinacidil, minoxidil and cromakalim) are used clinically to stimulate hair growth in patients with alopecia [2,5]. Recently, it has been shown that these K ATP channel openers increase the mitogen-induced proliferation and DNA synthesis of liver cells [21]. ...
Article
Full-text available
Kir channel subunit expression during development of the rat collecting-duct epithelium was quantified by RT-PCR of primary monolayer cultures. mRNAs of the vascular-type K(ATP) (K(NDP)) channel-forming subunits Kir6.1/SUR2 were highly expressed in early ureteric bud generations (embryonic day E14) and downregulated thereafter, while Kir1.1b (ROMK2) mRNA increased fourfold during cortical collecting duct (CCD) maturation. As assessed by immunohistochemistry, Kir6.1 protein was abundant in the apical and basolateral plasma membranes of early ureteric buds and trunks (E15 to postnatal day P1), downregulated thereafter and not detectable in CCD and outer medullary collecting ducts (OMCD) (P7). During nephron development, Kir6.1 protein was expressed ubiquitously on plasma membranes of early nephron stages from mesenchymal condensations to S-shaped bodies. After fusion of nephron and CCD, Kir6.1 protein was restricted to the apical membrane of proximal tubule. The Kir6/SUR2 channel opener, pinacidil (100 microM/2 days), increased tubulogenesis in organ culture by a factor of 3. Cell proliferation of human embryonic kidney cells (HEK 293) which endogenously express Kir6.1/SUR2 mRNA was stimulated by pinacidil in a dose-dependent manner, an effect that was partially abolished by glibenclamide (3 microM). In summary, Kir6.1/SUR2 channel subunits are highly expressed during early development of ureteric bud and nephron epithelia where Kir6.1/SUR2 activity regulates cell proliferation.
... Potassium channel openers, including MXD, stimulates DNA synthesis [8] or protein synthesis [9] in whole-organ cultures of mouse vibrissa hair follicles . However, MXD or MXD sulfate failed to activate potassium channel current in hair follicles [10,11] . For the purpose of discovering natural products which possess hair growing activity, we examined about 1000 kinds of plant extracts and found proanthocyanidins from grape seeds and procyanidin oligomers [12,13] promoted proliferation of mouse HBCs in vitro and activated hair follicle growth in vivo. ...
Article
KF19418, a newly synthesized compound, stimulated proliferation of cultured hair bulb cells from new born mice in concentration-dependent manner in the range under 10 microM. In the culture system of whole skin pieces from 4-week-old mice which we earlier established, KF19418 promoted hair follicle elongation as in the case of minoxidil. After topical application for 2 weeks of KF19418 or minoxidil to dorsal skin of hair-clipped mouse alopecia model, KF19418 at 1% suspension accelerated hair regrowth at a rate comparable to 1% minoxidil solution. Thus, it was shown that KF19418 directly stimulated hair follicle in vitro and had hair growth promoting activities in vivo.
... Although minoxidil has been used as hair-regrowing therapy for more than 20 years, its mechanism of action is not fully understood. Many mechanisms of action have been proposed such as vasodilatation [76,77], angiogenesis [78], enhanced cell proliferation [79,80], and K channel opening [81,82]. In animal studies, topical minoxidil increased the proportion of anagen hairs, reduced the number of telogen hairs, and increased the hair follicle size [83]. ...
Article
Full-text available
Androgenetic alopecia (AGA) or male pattern hair loss is a very common condition that has a significant psychosocial impact for patients. Many advances in the pathogenesis and treatment of AGA have been discovered recently. We discuss the pathogenesis and treatment of AGA. Wide genome analysis showed an association of AGA and chromosome 20pll in addition to androgen-receptor gene. Also, a locus on chromosome 3q26 was found to have a linkage with AGA. Dutasteride has been shown to be more effective than finasteride in the treatment of AGA but is not yet a recommended therapy. In an in-vitro study, a new topical liposomal finasteride formulation showed more than five-fold higher deposition of drug in skin than the corresponding plain drug solution. These recent developments in the field of AGA hold some promise and may play a role in the future management.
... These results indicate that DPC themselves possess multiple adenosine-dependent signaling pathways. The opening of K ATP channels has been considered to be a common mechanism for the action of minoxidil and a set of potassium channel openers (Buhl et al, 1993). Several investigators have described a bene®cial effect of the K ATP channel on cardioprotective vasorelaxation associated with adenosine receptors (Kato et al, 2000; Roscoe et al, 2000). ...
Article
The mechanism by which minoxidil, an adenosine-triphosphate-sensitive potassium channel opener, induces hypertrichosis remains to be elucidated. Minoxidil has been reported to stimulate the production of vascular endothelial growth factor, a possible promoter of hair growth, in cultured dermal papilla cells. The mechanism of production of vascular endothelial growth factor remains unclear, however. We hypothesize that adenosine serves as a mediator of vascular endothelial growth factor production. Minoxidil-induced increases in levels of intracellular Ca(2+) and vascular endothelial growth factor production in cultured dermal papilla cells were found to be inhibited by 8-sulfophenyl theophylline, a specific antagonist for adenosine receptors, suggesting that dermal papilla cells possess adenosine receptors and sulfonylurea receptors, the latter of which is a well-known target receptor for adenosine-triphosphate-sensitive potassium channel openers. The expression of sulfonylurea receptor 2B and of the adenosine A1, A2A, and A2B receptors was detected in dermal papilla cells by means of reverse transcription polymerase chain reaction analysis. In order to determine which of the adenosine receptor subtypes contribute to minoxidil-induced hair growth, the effects of subtype-specific antagonists for adenosine receptors were investigated. Significant inhibition in increase in intracellular calcium level by minoxidil or adenosine was observed as the result of pretreatment with 8-cyclopentyl-1,3-dipropylxanthine, an antagonist for adenosine A1 receptor, but not by 3,7-dimethyl-1-propargyl-xanthine, an antagonist for adenosine A2 receptor, whereas vascular endothelial growth factor production was blocked by both adenosine A1 and A2 receptor antagonists. These results indicate that the effect of minoxidil is mediated by adenosine, which triggers intracellular signal transduction via both adenosine A1 and A2 receptors, and that the expression of sulfonylurea receptor 2B in dermal papilla cells might play a role in the production of adenosine.
... Minoxidil actions as an anti-hypertension agent have been mainly attributed to its potassium channel-opening effect, which has been linked to the hypertrichosis phenomenon associated with minoxidil [37]. However, this mechanism is not compatible with certain findings, including the observations that potassium channel antagonists are unable to block minoxidil effects and potassium channels are not expressed in hair follicle cells [38, 39]. Although a specific subtype of potassium channel has been identified in human hair follicles [31, 34], our data suggest that minoxidil modulation of AR activity does not involve this pathway. ...
Article
Full-text available
Although minoxidil has been used for more than two decades to treat androgenetic alopecia (AGA), an androgen-androgen receptor (AR) pathway-dominant disease, its precise mechanism of action remains elusive. We hypothesized that minoxidil may influence the AR or its downstream signaling. These tests revealed that minoxidil suppressed AR-related functions, decreasing AR transcriptional activity in reporter assays, reducing expression of AR targets at the protein level, and suppressing AR-positive LNCaP cell growth. Dissecting the underlying mechanisms, we found that minoxidil interfered with AR-peptide, AR-coregulator, and AR N/C-terminal interactions, as well as AR protein stability. Furthermore, a crystallographic analysis using the AR ligand-binding domain (LBD) revealed direct binding of minoxidil to the AR in a minoxidil-AR-LBD co-crystal model, and surface plasmon resonance assays demonstrated that minoxidil directly bound the AR with a Kd value of 2.6 µM. Minoxidil also suppressed AR-responsive reporter activity and decreased AR protein stability in human hair dermal papilla cells. The current findings provide evidence that minoxidil could be used to treat both cancer and age-related disease, and open a new avenue for applications of minoxidil in treating androgen-AR pathway-related diseases.
... Other potassium channel openers, like diazoxide [39, 40] and pinacidil [41] can cause hypertrichosis in humans as well as minoxidil. In balding macaques minoxidil, cromakalin and P-1075 (a pinacidil analogue) stimulate hair growth in about 20 weeks of topical treatment, whereas a fourth potassium channel opener, called RP49356, is not effective [42]. Harmon et al. suggested that minoxidil, diazoxide, cromakalin and pinacidil increased uptake of thymidine in hair growth cultures of mouse vibrissae follicles [43]. ...
Article
Full-text available
Minoxidil, a vasodilator medication known for its ability to slow or stop hair loss and promote hair regrowth, was first introduced, exclusively as an oral drug, to treat high blood pressure. It was however discovered to have the important side-effect of increasing growth or darkening of fine body hairs; this led to the development of a topical formulation as a 2% concentration solution for the treatment of female androgenic alopecia or 5% for treating male androgenic alopecia. Measurable changes disappear within months after discontinuation of treatment. The mechanism by which it promotes hair growth is not fully understood. Minoxidil is a potassium channel opener, causing hyperpolarization of cell membranes and it is also a vasodilator, it is speculated that, by widening blood vessels and opening potassium channels, it allows more oxygen, blood and nutrients to the follicle. This can also cause follicles in the telogen phase to shed, usually soon to be replaced by new, thicker hairs in a new anagen phase. It needs to be applied regularly, once or twice daily, for hair gained to be maintained, and side effects are common. The most common adverse reactions of the topical formulation are limited to irritant and allergic contact dermatitis on the scalp. There have been cases of allergic reactions to the nonactive ingredient propylene glycol, which is found in some topical solution especially if they are galenic. Increased hair loss which can occur during Minoxidil use, is due to the synchronization of the hair cycle that the treatment induces. In this review, we described its mechanism of action, use in dermatology and some patents related to alternative treatment of allergic reactions due to its use.
... 1 These most common forms of hair loss in men and women, affecting *50% of the adult population, are nonstop processes that flow toward a definite pattern of alopecia in genetically predisposed individuals. Although clinically different, the pathogenic pathways leading to this type of hair loss are thought to be similar in both sexes. 2 Minoxidil, which was originally synthesized as a potassium channel opener 3 and initially prescribed for hypertension, is an FDA-approved topical medication for curing male pattern baldness. 4,5 Recently, finasteride, which is a type II 5a-reductase inhibitor and was initially used for curing prostatic hypertrophy, 6,7 has been approved by the FDA as an oral drug for male hair loss therapy. ...
Article
Several pharmaceutical products have been formulated over the past decades for the treatment of male and female alopecia, and pattern baldness, but relatively few metadata on their efficacy have been published. For these reasons, the pharmaceutical and medical attention has recently focused on the discovery of new and safer remedies. Particularly, great interest has been attracted by oligomeric procyanidin bioactivity, able to promote hair epithelial cell growth as well as to induce the anagen phase. Specifically, the procyanidin B2, a dimeric derivative extracted from apples, has demonstrated to be one of the most effective and safest natural compounds in promoting hair growth, both in vitro and in humans by topical applications. By evaluating the polyphenolic content of different apple varieties, we have recently found in the apple fruits of cv Annurca (AFA), native to Southern Italy, one of the highest contents of oligomeric procyanidins, and, specifically, of procyanidin B2. Thus, in the present work we explored the in vitro bioactivity of AFA polyphenolic extract as a nutraceutical formulation, named AppleMets (AMS), highlighting its effects on the cellular keratin expression in a human experimental model of adult skin. Successively, testing the effects of AMS on hair growth and tropism in healthy subjects, we observed significant results in terms of increased hair growth, density, and keratin content, already after 2 months. This study proves for the first time the impact of apple procyanidin B2 on keratin biosynthesis in vitro, and highlights its effect as a nutraceutical on human hair growth and tropism.
... Androgenic alopecia (AGA) is a common form of hair loss (HL), affecting men and women at different ages [1,2]. In AGA, androgens are involved in the reduction of anagen phase, inducing an increment of the number of hair follicles (HF) in the catagen and telogen phases as well as delaying the telogen-to-anagen transition [3]. ...
Article
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Abstract: Hair loss is a disorder in which the hair falls out from skin areas such as the scalp and the body. Several studies suggest the use of herbal medicine to treat related disorders, including alopecia. Dermal microcirculation is essential for hair maintenance, and an insu�cient blood supply can lead to hair follicles (HF) diseases. This work aims to provide an insight into the ethnohistorical records of some nutritional compounds containing flavonoids for their potential beneficial features in repairing or recovering from hair follicle disruption. We started from a query for “alopecia” OR “hair loss” AND “Panax ginseng C.A. Mey.“ (or other six botanicals) terms included in Pubmed and Web of Sciences articles. The activities of seven common botanicals introduced with diet (Panax ginseng C.A. Mey., Malus pumila Mill cultivar Annurca, Co�ea arabica, Allium sativum L., Camellia sinensis (L.) Kuntze, Rosmarinum o�cinalis L., Capsicum annum L.) are discussed, which are believed to reduce the rate of hair loss or stimulate new hair growth. In this review, we pay our attention on the molecular mechanisms underlying the bioactivity of the aforementioned nutritional compounds in vivo, ex vivo and in vitro studies. There is a need for systematic evaluation of the most commonly used plants to confirm their anti-hair loss power, identify possible mechanisms of action, and recommend their best adoption.
... Minoxidil also promotes hair regrowth through its action to open potassium channels [15]. The effect on the cell cycle is to initiate the onset of anagen (and thereby shorten telogen duration) and to prolong the duration of anagen by delaying initiation of catagen [5]. ...
... 24 Minoxidil also promotes hair regrowth through its action to open potassium channels. 25 The effect on the cell cycle is to initiate the onset of anagen (and thereby shorten telogen duration) and to prolong the duration of anagen by delaying initiation of catagen. 15 Several studies have shown the effect of topical minoxidil in promoting hair growth. ...
Article
Background: Androgenetic alopecia (AGA) is a common form of hair loss in Asian men. Although AGA is often regarded as a relatively minor dermatological condition, hair loss can impact self-image and is a main cause for anxiety and depression in some men. We have treated patients with AGA for seven years. Objective: The goal of this study was to evaluate the effectiveness of our combination therapy in Asian men with AGA. Participants: Between the years 2011 and 2017, 18,918 male patients were treated in our center. Our combination therapy consists of oral finasteride once daily, oral and topical minoxidil twice daily, and an injectable treatment of lidocaine and an AGA treatment solution comprising minoxidil, arginine, aspartic acid, caffeine, copper tripeptide, lysine, niacin, panthenol, propanediol, propylen glycol, retinyl palmitate, pyridoxine, sodium hyaluronate, and ubiquinone once monthly for more than six months. Measurements: Digital photographs were taken pre- and post-treatment, and patient assessments were recorded after six and 12 months post-treatment. Results: Significant improvement was observed in all patients in the digital photographs. Ninety-six and 80 percent of the patients reported satisfaction with the results of the treatment after six and 12 months post-treatment. Minor complications were observed in 802 (4.2%) patients, characterized by slight pain and bleeding due to injection, swelling, dizziness, itching, and erythema of the scalp. Slight pain was reported in 651 patients (3.4%), and slight bleeding was reported in 56 patients (0.3%). Sexual dysfunctions were uncommon. These minor complications resolved spontaneously. No treatment-related adverse events were observed. Conclusion: A combination of these therapeutic options offers safe and highly efficacious treatment for AGA with minimal complications.
... Although it is being used for the treatment of male androgenetic alopecia (AgA) and female pattern hair loss (fPHl) for approximately three decades, but our understanding of its mechanisms of action on the hair follicle is still very limited (1,2). Due to the blood pressure lowering effect of oral minoxidil through relaxing the vas-cular smooth muscle by the action of its sulphated metabolite, as an opener of sarcolemmal adenosine triphosphate sensitive potassium channels (K AtP ), it is postulated that its stimulatory effect on hair growth is also related with the opening of potassium channels (1,3,4). Cutaneous blood flow was observed to increase 10-15 minutes after the application of topical minoxidil (5). ...
Article
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Although more than three decades have passed since the first use of minoxidil in androgenetic alopecia (AGA), its mechanisms of action have still not been comprehensively understood. 5α-reductase (5α-R) has an active role as the predominant enzyme in both AGA and female pattern hair loss (FPHL), which are also the main therapeutic indications of topical minoxidil. But there is insufficient literature data regarding the interaction of minoxidil and the enzyme 5α-R. Herein, we studied the in vitro expression levels of 5α-R type 2 (5α-R2) in a minoxidiltreated human keratinocyte cell line (HaCaT) in order to elucidate the relation of these two parameters. Cell proliferation assay was performed by a XTT reagent (a yellow tetrazolium salt). After determination of non-cytotoxic concentration, HaCaT cells were treated with minoxidil. Ribonucleic acid (RNA) isolations were carried out from both non-treated and treated cell groups using a TRI reagent (an RNA, DNA, and protein isolation reagent). Gene expressions of 5α-R2 as study material and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as the control were determined by real time-quantitative polymerase chain reaction (RT-qPCR) analysis. Results were represented as 5α-R2/GAPDH fold change. Minoxidil treatment resulted in a 0.22 fold change for 5α-R2 (p < 0.0001). This antiandrogenic effect of minoxidil, shown by significant downregulation of 5α-R2 gene expression in HaCaT cells, may be one of its mechanisms of action in alopecia. © 2017, Croatian Dermatovenerological Society. All rights reserved.
... [2] Orally administered minoxidil lowers blood pressure by relaxing vascular smooth muscles through the action of its sulfated metabolite, as an opener of sarcolemmal adenosine triphosphate-sensitive potassium channels (K ATP ); it is postulated that the stimulatory effect of topical minoxidil on hair growth is due to the opening of K ATP by minoxidil sulfate. [2][3][4][5] One hypothesis of the mechanism of action of minoxidil concerns its vasodilatory properties. Cutaneous blood flow increases 10-15 min after application of topical minoxidil. ...
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Introduction: Minoxidil has been used topically to stimulate hair growth for male androgenetic 13 alopecia (AGA) for more than 3 decades. It is currently being used for female AGA and alopecia 14 areata (AA) as well. Although much time has passed since its first use, our understanding of its 15 mechanism of action is highly limited. Therefore, we examined the inflammatory properties of AGA 16 and AA, two entities in which minoxidil is being used as a therapeutic agent. We investigated the 17 in vitro expression levels of cytokine interleukin‐1 alpha (IL‐1α), a potent inhibitor of hair growth, 18 in minoxidil‐treated human keratinocyte (HaCaT) cells to determine whether this molecule exerts 19 anti‐inflammatory effects. Materials and Methods: Cellular proliferation was examined using 20 the Cell Proliferation Kit II (XTT) reagent. After determining a noncytotoxic concentration, HaCaT cells were treated with minoxidil. RNA was isolated from both untreated and treated cells with TRI 21 Reagent®. Expression of the IL‐1α gene was determined by reverse transcription quantitative 22 polymerase chain reaction analysis and is reported relative to glyceraldehyde‐3‐phosphate 23 dehydrogenase (GAPDH), which served as a control. Results: Results are presented as 24 IL‐1α/GAPDH fold change. Minoxidil treatment downregulated IL‐1α expression by 0.3433‐fold compared with untreated cells (P = 0.001). Conclusion: This anti‐inflammatory effect of 25 minoxidil, as evidenced by significant downregulation of IL‐1α gene expression in HaCaT cells, 26 may represent one of its mechanisms of action in alopecia.
... 1 These most common forms of hair loss in men and women, affecting *50% of the adult population, are nonstop processes that flow toward a definite pattern of alopecia in genetically predisposed individuals. Although clinically different, the pathogenic pathways leading to this type of hair loss are thought to be similar in both sexes. 2 Minoxidil, which was originally synthesized as a potassium channel opener 3 and initially prescribed for hypertension, is an FDA-approved topical medication for curing male pattern baldness. 4,5 Recently, finasteride, which is a type II 5a-reductase inhibitor and was initially used for curing prostatic hypertrophy, 6,7 has been approved by the FDA as an oral drug for male hair loss therapy. ...
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Exercise enhances mitochondrial biogenesis in skeletal muscle. Increased mitochondrial function and content can contribute to the improvement in skeletal muscle function and the benefits of exercise by increasing the response to energy demands. The effect of standardized Kaempferia parviflora extract (KPE) on exercise performance was accessed in L6 myotubes and C57BL/6J mice. KPE significantly activated peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and increased mitochondrial density in L6 myotubes. KPE also upregulated the expression of transcription factors for mitochondrial biogenesis (estrogen-related receptor-α [ERRα], nuclear respiratory factor-1 [NRF-1], and mitochondrial transcription factor A [Tfam]) through activation of PGC-1α in L6 myotubes. In vivo models including normal diet mice and high-fat diet obese mice showed that KPE effectively enhanced running endurance and increased the skeletal muscle weight/body weight ratio. Furthermore, these observations were associated with a significant upregulation of mitochondrial biogenesis regulatory genes in skeletal muscle tissue. KPE enhanced the protein expression of the sirtuin 1 (SIRT1)/adenosine monophosphate (AMP)-activated protein kinase (AMPK)/PGC-1α/peroxisome proliferator-activated receptor-δ (PPARδ) signaling pathway components in vitro and in vivo, acting as an exercise metabolism regulator. These results suggest that KPE has the potential to enhance exercise performance through mitochondrial biogenesis and the SIRT1/AMPK/PGC-1α/PPARδ signaling pathways.
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Unlabelled: Male and female pattern hair loss affects a large percentage of the population, and patients frequently present for treatment of this to their dermatologist. Here we review the many treatments available for hair loss. We review the evidence for each, and outline the most effective treatment strategies for both men and women. Learning objective: At the conclusion of this article, the reader should be able to describe the most effective treatments for hair loss, understand their mechanism(s) of action, and explain which treatments are the best in different settings.
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The hair follicle bulge possesses putative epithelial stem cells. Characterization of these cells has been hampered by the inability to target bulge cells genetically. Here, we use a Keratin1-15 (Krt1-15, also known as K15) promoter to target mouse bulge cells with an inducible Cre recombinase construct or with the gene encoding enhanced green fluorescent protein (EGFP), which allow for lineage analysis and for isolation of the cells. We show that bulge cells in adult mice generate all epithelial cell types within the intact follicle and hair during normal hair follicle cycling. After isolation, adult Krt1-15-EGFP-positive cells reconstituted all components of the cutaneous epithelium and had a higher proliferative potential than Krt1-15-EGFP-negative cells. Genetic profiling of hair follicle stem cells revealed several known and unknown receptors and signaling pathways important for maintaining the stem cell phenotype. Ultimately, these findings provide potential targets for the treatment of hair loss and other disorders of skin and hair.
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Androgenetic alopecia (AGA) is the most common type of hair loss in men. The relative strong concordance of the degree of baldness in fathers and sons is not consistent with a smiple Mendelian trait and a polygenic basis is considered to be most likely. So far the predisposing genes for AGA are unknown and we do not understand the molecular steps involved in androgen-dependent beard growth versus androgen-dependent hair loss, but AGA can be defined as a DHT-dependent process with continuous miniaturization of sensitive hair follicles. The type 2 5aR plays a central role by the intrafollicular conversion of T to DHT. Due to the inceasing knowledge in this field, this article shall privide an critical overwiew of recent discoveries.
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The length and size of hair are depend on the anagen term in its hair cycle. It has been reported that the some cell growth factors, such as VEGF, FGF-5S, IGF-1 and KGF, induce the proliferation of cells in the matrix, dermal papilla and dermal papillary vascular system and increase the amount of extra cellular matrix in dermal papilla and then maintain follicles in the anagen phase. On the other hand, negative factors, like FGF-5, thrombospondin, or still unknown ones, terminate the anagen phase. If the negative factors become dominant against cell proliferation factors according to fulfilling some time set by the biological clock for hair follicles, TGF beta induced in the matrix tissues evokes apoptosis of matrix cells and shifts the follicles from anagen to catagen. Androgenetic alopecia is caused by miniaturizing of hair follicles located in the frontal or crown part of scalp and are hereditarily more sensitive to androgen. In their hair cycles, the androgen shortens the anagen phase of follicles and shifts them to the catagen phase earlier than usual. The mode of action of hair growth effect of minoxidil is not completely elucidated, but the most plausible explanation proposed here is that minoxidil works as a sulfonylurea receptor (SUR) activator and prolongs the anagen phase of hair follicles in the following manner: minoxidil (1) induces cell growth factors such as VEGF, HGF, IGF-1 and potentiates HGF and IGF-1 actions by the activation of uncoupled SUR on the plasma membrane of dermal papilla cells, (2) inhibits of TGF beta induced apoptosis of hair matrix cells by opening the Kir 6.0 channel pore coupled with SUR on the mitochondrial inner membrane, and (3) dilates hair follicle arteries and increases blood flow in dermal papilla by opening the Kir 6.0 channel pore coupled with SUR on the plasma membrane of vascular smooth muscle cells.
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The conversion of nitriles to amides is generally considered to be a hydrolytic process that does not involve redox chemistry. We demonstrate here that cytochrome P450 (CYP) is responsible for the conversion of the cyano group of pinacidil to the corresponding amide. The reaction in human liver microsomes was NADPH-dependent and was nearly completely inhibited by an anti-CYP3A4 antibody. Incubations of pinacidil with recombinant CYP enzymes confirm that CYP3A4 is the principal catalyst of this reaction. The kinetics of pinacidil amide formation by CYP3A4 yielded an apparent K(m) of 452 +/- 33 microM and k(cat) of 0.108 min(-1) (k(cat)/K(m) = 0.238 mM(-1).min(-1)). Incubation of pinacidil with CYP3A4 in the presence of (18)O(2) or H(2)(18)O showed that the amide carbonyl oxygen derived exclusively from molecular oxygen. The CYP3A4-mediated reaction also was supported by hydrogen peroxide when incubations were carried out in the absence of cytochrome P450 reductase and NADPH. The reaction can be explained by a nucleophilic attack of a deprotonated ferric peroxide intermediate (Fe(3+)-O-O(-)) on the carbon atom of the -C triple bond N triple bond to form an Enz-Fe(III)-O-O-C(=NH)R intermediate, followed by cleavage of the O-O bond to give pinacidil amide. This nucleophilic addition of an Fe(3+)-O-O(-) intermediate to a -C=N pi-bond in a P450 system resembles the analogous reaction catalyzed by the nitric oxide synthases.
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Potassium (K(+)) channel openers (KCOs) define a class of chemically diverse agents that share a common molecular target, the metabolism-regulated ATP-sensitive K(+) (K(ATP)) channel. In view of the unique function that K(ATP) channels play in the maintenance of cellular homeostasis, this novel class of ion channel modulators adds to existent pharmacotherapy with potential in promoting cellular protection under conditions of metabolic stress. Indeed, experimental studies have demonstrated broad therapeutic potential for KCOs, including roles as cardioprotective agents, vasodilators, bronchodilators, bladder relaxants, anti-epileptics, insulin secretagogues and promoters of hair growth. However, clinical experience with these drugs is limited and their place in patient management needs to be fully established.
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We have previously reported that proanthocyanidins extracted from grape seeds possess growth-promoting activity toward murine hair epithelial cells in vitro and stimulate anagen induction in hair cycle progression in vivo. This report constitutes a comparison of the growth-promoting activity of procyanidin oligomers and the target cells of procyanidins in the skin. Results show that procyanidin dimer and trimer exhibit higher growth-promoting activity than the monomer. The maximum growth-promoting activity for hair epithelial cells with procyanidin B-2, an epicatechin dimer, reached about 300% (30 microM) relative to controls (= 100%) in a 5 d culture. Optimum concentration of procyanidin C-1, an epicatechin trimer, was lower than that of procyanidin B-2; the maximum growth-promoting activity of procyanidin C-1 was about 220% (3 microM). No other flavonoid compounds examined exhibit higher proliferative activities than the procyanidins. In skin constituent cells, only epithelial cells such as hair keratinocytes or epidermal keratinocytes respond to procyanidin oligomers. Topical application of 1% procyanidin oligomers on shaven C3H mice in the telogen phase led to significant hair regeneration [procyanidin B-2, 69.6% +/- 21.8% (mean +/- SD); procyanidin B-3, 80.9% +/- 13.0%; procyanidin C-1, 78.3% +/- 7.6%] on the basis of the shaven area; application of vehicle only led to regeneration of 41.7% (SD = 16.3%). In this paper, we demonstrate the hair-growing activity of procyanidin oligomers both in vitro and in vivo, and their potential for use as agents to induce hair growth.
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Objectives : The experiment was performed to investigate promotive effects of haeae-tang (HET) extract, a traditional Korean medicinal recipe, on hair growth, protein and gene expression in hair-removed C57BL/6. Methods : In experiment, animals were divided into 3 groups including normal (vehicle), HET ethanol extract and 5% minoxidil-treated groups (Minoxidil, positive control). The vehicle or testing samples were daily treated with 0.2ml per on hair-shaved dorsal skin of C57BL/6mice for 15 days. Effects of testing samples on hair growth was monitored through phototrichogram analysis by folliscope on the initial, 5^{th}, 10^{th}, 15^{th} day, respectively. Also, gene and protein expressions of vascular endothelial growth factor (VEGF) and Insulin like growth factor-1 (IGF-1), relevant to hair growth, were examined. Results : Hair density and hair thickness of Minoxidil treated-group was significantly increased compared to that of vehicle application on the 15^{th}day, respectively. Dorsal hair density of HET treated-group was significantly increased compared to that of vehicle application on the 15^{th}day. In addition, the Minoxidil group significantly increased the expression of cutaneous IGF-1 protein and mRNA compared to that of the vehicle-applied group on the 15^{th} day. And HET-treated group significantly increased the expression of dorsal VEGF protein compared to that of the vehicle-applied group on the 15^{th} day. Conclusions : These results suggest that this Korean medicinal recipe, HET has promoting activity on hair growth in an Alopecia animal model thus it can be used as a material of agent or products for improvement or prevention of alopecia.
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Objectives: In the present study we investigated the role of adenosine triphosphate (ATP)-sensitive potassium (KATP) channel in chronic morphine tolerance. Materials and methods: Male Institute of Cancer Research (ICR) mice were intrathecally injected with KATP channel opener cromakalim (CRO), morphine or the saline respectively (each in 10▒μL). Different doses of CRO (0.3▒μg, 1▒μg or 3▒μg/10▒μL/mouse) were administered at 15 minutes before morphine (10▒μg/10▒μL/mouse) challenge daily for consecutive 7 days. Half an hour after morphine injection, tail-flick latency was measured to evaluate the antinociceptive effect of morphine. At 7 day, mice were terminally sacrificed with sodium pentobarbital (100▒mg/kg) at 1 hour after morphine injection and their spinal cords were removed for western blot, Immunofluorescence and quantitative real-time polymerase chain reaction. Results: Opening of KATP channel attenuates chronic morphine tolerance, suppresses astrocyte activation in the spinal cord (SC) following chronic morphine treatment, inhibits morphine-induced increase of interleukin (IL)-1β at transcriptional and translational levels, reduces morphine-induced up-regulation of phosphorylated c-Jun N-terminal kinase (p-JNK) mitogen-activated protein kinase (MAPK), moreover, transcriptional levels of spinal cord astrocyte KATP channel subunits, named inwardly rectifying potassium (Kir) 6.1 and sulfonylurea receptor (SUR1) are decreased in morphine tolerant mice. Discussion: Cromakalim significantly suppresses morphine-induced astrocyte activation through suppressing JNK pathway, resulting in reduced release of IL-1β and attenuation of morphine chronic antinociceptive tolerance.
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Die Ionenkanäle des renalen Tubulus- und Sammelrohrsystems bestimmen die Funktion der adulten Säugetierniere. Sie müssen mit der Entwicklung der permanenten Niere (Metanephrogenese) erworben werden und können auch entwicklungsspezifische Aufgaben haben. Ziel dieser Arbeit ist die erstmalige systematische Beschreibung der Expression und entwicklungsspezifischen Rolle von Ionenkanälen während der Metanephrogenese. Methoden: Die ontogenetische mRNA-Expression der Kir Kalium-Kanal-Untereinheiten Kir6.1, SUR2 und ROMK1-3 (Kir1.1a-c) wurde mittels RT-PCR von Primärkulturen im Sammelrohrepithel quantifiziert, die ontogenetische Kir6.1- und ROMK-Protein-Expression mittels Immunhistochemie in Sammelrohr- und Nephron-Epithelien untersucht. Der Effekt von cAMP auf die ROMK-mRNA-Expression wurde gemessen und der Einfluss von Kalium-Kanalmodulatoren auf das Wachstum von Nephron-Kulturen in vitro und von HEK293 Nierenepithel-Zellen bestimmt. Ferner wurde die ontogenetische mRNA-Expression des ENaC-Natrium-Kanals und der Chlorid-Kanäle CFTR, CLC-2 und ICLn mittels RT-PCR im Sammelrohrepithel quantifiziert. Alle Experimente wurden an Ratten oder Mäusen durchgeführt. Ergebnisse: (i) Die mRNA der KDNP-(KATP)-Kanaluntereinheiten Kir6.1/SUR2 war in frühen Ureterknospen-Generationen (embryonaler Tag E14) hoch exprimiert und nach der Geburt herunterreguliert. In gleicher Weise war Kir6.1-Protein im embryonalen Sammelrohrepithel und Nephron ubiquitär apolar exprimiert. Im Gegensatz hierzu war Kir6.1 im adulten Nephron ausschließlich im Proximalen Tubulus nachweisbar (apikal > basolateral). Die spezifische Aktivierung von KNDP-(KATP)-Kir6.1/SUR2-Kanälen in Nephronkulturen und HEK293-Zellen steigerte die Zellproliferation, was auf eine wachstumsregulierende Rolle der frühen Kir6.1/SUR2-Expression hinweist. Somit könnten zelluläre Entwicklungsprogramme der Niere die Wachstumsrate über die Expression von Kalium-Kanälen regulieren. (ii) Die mRNA des apikalen sekretorischen Sammelrohr-Kalium-Kanals ROMK2(Kir1.1b) war von Beginn der Entwicklung an in Ureterknospen/Sammelrohrepithelien exprimiert und stieg während der Reifung des Kortikalen Sammelrohrs um den Faktor 4 an (postnatale Tage P7-28). Diese Zunahme spiegelt den Erwerb der adulten Natrium-retinierenden Funktion des Sammelrohrepithels wider. Die Protein-Expression von ROMK war in embryonalen Nierenepithelien ubiquitär und apolar nachweisbar, jedoch postnatal auf die apikale Plasmamembran des aufsteigenden Teils der Henle'schen Schleife und des Sammelrohrs beschränkt. Die ROMK-mRNA-Expression in embryonalen Sammelrohrepithelien war durch cAMP stimulierbar. (iii) Während der frühen Genese des Sammelrohrsystems wurden die mRNAs der Chlorid-Kanäle CFTR, CLC-2 und ICLn exprimiert, die sehr wahrscheinlich an der aus Ureterknospen bekannten hohen fraktionellen Chlorid-Leitfähigkeit beteiligt sind. Während der postnatalen Sammelrohrepithel-Reifung wurde die mRNA des apikalen Natrium-Kanals ENaC transkriptionell hochreguliert. So kann rechtzeitig die NaCl-resorbierende Funktion der Niere des Neugeborenen sicher gestellt werden (zusammen mit der Heraufregulation von ROMK).
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The hair follicle, hair shaft, and sebaceous gland collectively form what is recognized as the pilosebaceous unit. This complex, three-dimensional structure within the skin possesses a unique biochemistry, metabolism and immunology. Recent studies have focused on the hair follicle as a potential pathway for both localized and systemic drug delivery. Greater understanding of the structure and function of the hair follicle may facilitate rational design of drug formulations to target follicular delivery. Targeted drug delivery may enhance current therapeutic approaches to treating diseases of follicular origin. Presented here is a review of follicular drug delivery and a discussion of the feasibility of the pilosebaceous unit as a target site. Peer Reviewed http://deepblue.lib.umich.edu/bitstream/2027.42/41442/1/11095_2004_Article_307277.pdf
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Androgenetic alopecia affects up to 80% of males by the age of 80. The synonym 'male-pattern hair loss' highlights the fact that hair loss occurs in a defined and reproducible pattern. Hair loss results in reduced self esteem, loss of confidence and anxiety in affected men. An effective treatment for hair baldness would be desirable. In androgenetic alopecia, hair follicles undergo progressive miniaturization. Genetic factors and androgens play a major role in the pathogenesis of the disease. Polymorphism of the androgen receptor gene was first identified in association with androgenetic alopecia. Identification of new susceptibility genes on chromosomes 3q26 and 20p11 suggest that non-androgen-dependent pathways also are involved. Topical monoxidil and oral finasteride are commonly in use and have FDA approval for the treatment of male androgenetic alopecia; dutasteride, a type I and II 5-alpha-reductase inhibitor, is on hold in Phase III trials. A combination of medical treatment and hair transplant surgery has shown superior efficacy. Androgenetic alopecia is a progressive condition and although the current available treatments are effective in arresting the progression of the disease, they allow only partial regrowth of hair at its best. Early treatment achieves the best desirable outcome.
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Hair has psychological and sociological importance throughout the ages in framing the personality and general appearance of an individual. Significant progress is being made on discovering an effective and safe drug for hair growth. Angiogenesis, androgen antagonism, vasodilation, potassium channel opening and 5-alpha reductase inhibition are the major non-surgical therapeutic strategies of hair growth promotion. In spite of a flood of drugs claiming to be useful as hair growth promoters, more rational strategies, which can target the problem areas or stages of the hair growth cycle effectively, are still awaited. This article highlights the developments in hair rejuvenation strategies and reviews the potential of herbal drugs as safer and effective alternatives.
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Objective: Hair loss and greying affect men and women of all ages, often causing psychosocial difficulties. Dickkopf-1 (DKK1), a major hair loss factor secreted from dermal papilla (DP) cells in response to the secretion of dihydrotestosterone (DHT), has been reported to induce and accelerate androgenetic alopecia (AGA). In addition, DKK1 acts as a potent suppressor of melanogenesis and is closely related to hair colour. R-spondin 1 (RSPO1) is a secretory agonist of Wnt signalling known to antagonize the effects of DKK1, including DKK1-mediated hair follicle suppression. In this study, we investigated the effect of watercress extract (WCE) on the secretion of RSPO1 and DKK1 from DP cells as well as its anti-hair loss effect in human hair follicles and patients. Methods: The in vitro secretion of RSPO1 and DKK1 was measured by ELISA. Human hair follicles were collected from the scalp of a female donor and used for ex vivo organ culture to investigate the effects of WCE on human hair loss. Finally, a 6-month human clinical trial was conducted to examine the effect of WCE-containing lotion on hair growth in a male panel. Results: WCE significantly upregulated RSPO1 secretion and suppressed DKK1 secretion in a dose-dependent manner, even in the presence of DHT. WCE-treated hair follicles elongated 1.6-fold compared to the control, and the level of RSPO1 production in DP as well as RSPO1 bound to the outer root sheath (ORS) increased. In the clinical trial, the hair lotion containing 2% WCE increased hair thickness and density to improve against hair loss symptoms. Conclusion: WCE exhibited a strong anti-androgenic effect through its ability to suppress DKK1 secretion and antagonize DKK1 via RSPO1. These findings highlighted the potential use of WCE for the treatment of hair loss. These results also showed that WCE might have an effect on hair colour since DKK1 is a suppressor of melanogenesis.
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Minoxidil sulfate and pinacidil are K channel openers and are considered to promote hair growth. However, there have been no studies on the single channel current of isolated cells from hair follicles. Therefore, we characterized the single K channel current of outer root sheath cells and dermal papilla cells and the effect of K channel openers on K currents by patch clamp. We also carried out86Rb efflux studies to observe macroscopic K channel currents. In physiological saline, these two cells showed two types of K channels, large and small conductance Ca2+-activated K channels, both intact cell-attached and excised inside-out patches. In symmetrical 150 mM K solution, unitary conductances were 246 and 70 pS, respectively. Intracellular ATP (up to 5 mM) or glibenclamide (20 nM), a specific ATP-sensitive K channel blocker, did not block these channels. Minoxidil sulfate (5 μg/ml) or pinacidil (10 μM) did not open these two types of K channels or increase86Rb efflux. These results suggest that minoxidil sulfate or pinacidil did not activate K channel current in hair follicles, and that the drug effect on hair growth might be mediated by other mechanisms such as increased blood flow.
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Introduction: Hair care, color and style play an important role in physical appearance and self-perception. Hair loss or alopecia is a common dermatological and affective disorder. Factors contributing to alopecia include genetic predisposition, hormonal factors, disease status, side effects of chemotherapeutic agents and stress. To keep pace with the demand for drugs for alopecia, attempts are being made to explore drugs with hair-growth-promotion activity. To explore and evaluate these, it is necessary to be familiar with the basics and the availability and suitability of techniques and experimental models of hair growth activity assessment. Areas covered: Basic and advanced techniques and models for assessing hair growth activity. A variety of pharmacological models of hair growth are reviewed. This review will help in selecting a suitable, relevant, inexpensive, easy and reliable model for hair growth assessment. Expert opinion: There is a need to identify the genes involved in hair follicle growth for the production of more effective animal models of the disorder. Standardization of pharmacological models will also be essential for better comparison and validation of results. Recently developed hair follicle organ culture models are a suitable, relevant and inexpensive alternative to traditional whole-animal pharmacological models and will, largely, replace whole-animal systems in the future.
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Die androgenetische Alopezie ist bei Frauen und Mnnern die hufigste Form von Haarverlust. Wenngleich sich der Haarausfall bei Frau und Mann klinisch unterschiedlich manifestiert, so sind dennoch die zugrunde liegenden, zur Alopezie fhrenden Pathomechanismen dieselben. Es kann davon ausgegangen werden, dass aufgrund genetischer Prgung bestimmte Haarfollikel am Kapillitium eine verstrkte Sensitivitt gegenber Androgenen aufweisen. Die Forschungsergebnisse der letzten Jahre haben eine Vielzahl pathophysiologisch, diagnostisch und therapeutisch bedeutsamer Erkenntnisse hervorgebracht, deren klinisch relevante Aspekte und Neuerungen in dieser bersicht dargestellt werden.Androgenetic alopecia is the most common form of hair loss in men and women. Although the clinical manifestations are different in men and women, the pathogenetic pathways leading to this type of hair loss are similar in both sexes. In short genetically predestined hair follicles show an increased sensitivity to androgens. In recent years, much new data concerning the pathophysiology, management and therapy of androgenetic alopecia has been gathered. This article gives a critical overview of these new findings and assesses their practical relevance.
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We have known for over 30 years that minoxidil stimulates hair growth, yet our understanding of its mechanism of action on the hair follicle is very limited. In animal studies, topical minoxidil shortens telogen, causing premature entry of resting hair follicles into anagen, and it probably has a similar action in humans. Minoxidil may also cause prolongation of anagen and increases hair follicle size. Orally administered minoxidil lowers blood pressure by relaxing vascular smooth muscle through the action of its sulphated metabolite, minoxidil sulphate, as an opener of sarcolemmal KATP channels. There is some evidence that the stimulatory effect of minoxidil on hair growth is also due to the opening of potassium channels by minoxidil sulphate, but this idea has been difficult to prove and to date there has been no clear demonstration that KATP channels are expressed in the hair follicle. A number of in vitro effects of minoxidil have been described in monocultures of various skin and hair follicle cell types including stimulation of cell proliferation, inhibition of collagen synthesis, and stimulation of vascular endothelial growth factor and prostaglandin synthesis. Some or all of these effects may be relevant to hair growth, but the application of results obtained in cell culture studies to the complex biology of the hair follicle is uncertain. In this article we review the current state of knowledge on the mode of action of minoxidil on hair growth and indicate lines of future research.
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This article reviews the different treatments of alopecia areata (AA). The information includes both a review of the literature as well as practical aspects regarding the use of the most commonly used therapies for AA. These modalties are summarized in a practical algorithm that can be used as a guide. For patients less than 10 years of age, the options are topical corsticosteroids, topical minoxidil, and anthralin. For adults with less than 50% scalp involvement, the first option is usually the use of intralesional corticosteroids, followed by topical corticosteroid creams, minoxidil solution, or anthralin cream. For adults with more than 50% scalp involvement, topical immunotherapy and phototherapy are added to the other options. Other modalities such as cyclosporine, tacrolimus, interferon, dapsone, and cosmetic coverups are also discussed.
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Eyebrow hair serves many important biologic and aesthetic functions. This article reviews the structure and function of the hair follicle, as well as hair follicle morphogenesis and cycling. Eyebrow hair follicles share the same basic structure as hair follicles elsewhere on the body, but are distinguished by their shorter anagen (growing) phase. Knowledge of the hair follicle structure and cycle is important for understanding the pathophysiology of alopecia, as diseases affecting the stem cell portion of the hair follicle in the bulge region may cause permanent hair loss. Furthermore, therapeutic agents that target distinct phases and hormones involved in the hair cycle may be useful for promoting hair growth. J Drugs Dermatol. 2014;13(suppl 1):s12-s16.
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Minoxidil (2, 6-diamino-4-piperidinopyrimidine 1-oxide) is a systemic antihypertensive agent, the topical application of which has been shown to produce hair growth. Topical minoxidil solution (5% minoxidil, propylene glycol, alcohol, water) has generally been well-tolerated, but allergic contact dermatitis has been reported. When allergic contact dermatitis to minoxidil solution is suspected, evaluation of ingredients of minoxidil solution should be performed because allergic contact dermatitis due to propylene glycol in minoxidil solution has been frequently reported. A 34-year-old male presents with a diffuse erythematous patch on the scalp. He has applied minoxidil solution for 7 days due to androgenic alopecia. A Patch test with Korean standard series and the ingredients of used topical agents showed positive reactions to 1%, 2% and 5% minoxidil solution.
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Hair disorders cause psychological distress but are generally poorly controlled; more effective treatments are required. Despite the long-standing use of minoxidil for balding, its mechanism is unclear; suggestions include action on vasculature or follicle cells. Similar drugs also stimulate hair, implicating ATP-sensitive potassium (K(ATP)) channels. To investigate whether K(ATP) channels are present in human follicles, we used organ culture, molecular biological, and immunohistological approaches. Minoxidil and tolbutamide, a K(ATP) channel blocker, opposed each other's effects on the growing phase (anagen) of scalp follicles cultured in media with and without insulin. Reverse transcriptase-polymerase chain reaction identified K(ATP) channel component gene expression including regulatory sulfonylurea receptors (SUR) SUR1 and SUR2B but not SUR2A and pore-forming subunits (Kir) Kir6.1 and Kir6.2. When hair bulb tissues were examined separately, epithelial matrix expressed SUR1 and Kir6.2, whereas both dermal papilla and sheath exhibited SUR2B and Kir6.1. Immunohistochemistry demonstrated similar protein distributions. Thus, human follicles respond biologically to K(ATP) channel regulators in culture and express genes and proteins for two K(ATP) channels, Kir6.2/SUR1 and Kir6.1/SUR2B; minoxidil only stimulates SUR2 channels. These findings indicate that human follicular dermal papillae contain K(ATP) channels that can respond to minoxidil and that tolbutamide may suppress hair growth clinically; novel drugs designed specifically for these channels could treat hair disorders.
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The K+ channel openers, including cromakalim, pinacidil, minoxidil sulfate, diazoxide, and nicorandil, form a chemically heterogeneous group of compounds, which relax smooth muscle by opening plasmalemmal K+ channels. At present it is not known whether these drugs elicit their effects by binding to the same target, presumably the K+ channel. In order to address this question, a binding assay for K+ channel openers has been developed in vascular smooth muscle. The novel tritiated K+ channel opener, [3H]P1075, an analogue of pinacidil, binds with high affinity (KD = 6 +/- 1 nM) to endothelium-denuded rings of rat aorta. Inhibition studies indicate that the different families of K+ channel openers bind to a common target. Evidence is presented to suggest that the binding site for the sulfonylurea, glibenclamide, the major blocker of the K+ channel openers, is coupled in a negative allosteric manner to the binding site(s) for the openers. The binding assay described here may open the way to the biochemical characterization of the drug receptor for the K+ channel openers.
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Sulfonylureas are powerful hypoglycemic drugs that have been used for decades to treat diabetic patients. This paper describes a 86Rb+ flux technique that permits one to study easily the properties of ATP-modulated K+ channels in RINm5F insulinoma cells. Sulfonylureas inhibit this type of K+ channel under conditions of intracellular ATP depletion. The most potent sulfonylureas (glibenclamide, glipizide, and gliquidone) are acting in the nanomolar range of concentration. Inhibition of the single ATP-modulated K+ channels by low concentrations of sulfonylureas was also observed using the patch-clamp technique. The sulfonylurea receptor has been biochemically identified with [3H]glibenclamide. For 10 different sulfonylureas (or sulfonylurea analogs) there was an excellent correlation between efficacy of blockade of ATP-modulated K+ channels and efficacy of binding to the sulfonylurea receptors using the 3H-ligand.
Article
Voltage-gated potassium channels make up a large molecular family of integral membrane proteins that are fundamentally involved in the generation of bioelectric signals such as nerve impulses. These proteins span the cell membrane, forming potassium-selective pores that are rapidly switched open or closed by changes in membrane voltage. After the cloning of the first potassium channel over 3 years ago, recombinant DNA manipulation of potassium channel genes is now leading to a molecular understanding of potassium channel behavior. During the past year, functional domains responsible for channel gating and potassium selectivity have been identified, and detailed structural pictures underlying these functions are beginning to emerge.
Article
Forty-four patients with severe hypertension who were resistant to treatment with more conventional hypotensive drugs or could not tolerate the side effects were treated with minoxidil, a potent peripheral vasodilator. A beta-blocking drug and a diuretic were used routinely to control, respectively, the tachycardia and fluid retention caused by minoxidil. During treatment the outpatient supine blood pressure fell from a mean of 221/134 mm Hg to 162/98 mm Hg. Eleven patients required additional or alternative hypotensive agents before blood pressure was adequately controlled. Side effects were minor, although the invariable hirsuties caused by minoxidil was unacceptable to three women. The possibility of cardiotoxic effects, raised by early studies in dogs, has not been excluded, and therefore this drug should be used only in patients with severe hypertension. In such patients minoxidil appears to be most effective.
Article
The opening of intracellular potassium channels has been suggested as a mechanism regulating hair growth. Enhancing the flux of potassium ions is a mechanism shared by several structurally diverse antihypertensive agents including minoxidil sulfate (the active metabolite of minoxidil), pinacidil, P-1075 (a potent pinacidil analog), RP-49,356, diazoxide, cromakalim, and nicorandil. Of these drugs, minoxidil, pinacidil, and diazoxide have been reported to elicit hypertrichosis in humans. This potassium channel hypothesis was examined by testing these drugs for effects on hair growth both in vitro and in vivo. For the in vitro studies, mouse vibrissae follicles were cultured for 3 d with drug and the effects on hair growth were measured by metabolic labeling. All drugs, except diazoxide, enhanced cysteine incorporation into the hair shafts of the cultured vibrissae. Diazoxide was poorly soluble and thus was tested only at low doses. Minoxidil, P-1075, cromakalim, and RP-49,356 were also evaluated in vivo by measuring hair growth effects in balding stumptail macaque monkeys. The drugs were administered topically to defined sites on balding scalps once per day for 4-5 months and the amount of hair grown was determined by monthly measurements of shaved hair weight. Three of the drugs produced significant increases in hair weight whereas, the RP-49,356 had no effect. These studies provide correlative evidence that the opening of potassium channels is an important regulatory mechanism for hair growth. This provides the impetus for further studies on this potentially important mechanism affecting hair biology.
Article
To identify minoxidil target cells in hair follicles we followed the uptake of radiolabeled drug in mouse vibrissae follicles both in vitro and in vivo. Autoradiography showed that both 3H-minoxidil and 3H-minoxidil sulfate accumulated in the differentiating epithelial matrix cells superior to the dermal papilla, a distribution similar to that of pigment. Minoxidil localized in melanocytes, melanocyte processes, and areas of greater melanin concentrations within the epithelial cells. Although uptake of minoxidil was significantly less in unpigmented follicles, the drug stimulated proliferation and differentiation of both pigmented and unpigmented follicles. Labeled minoxidil bound to Sepia melanin and was displaced with unlabeled minoxidil and other electron donor drugs. This interaction with melanin acts as a targeting mechanism of minoxidil to pigmented hair follicles but has no apparent functional significance in hair growth. This work illustrates how measurement of drugs in hair may be biased by pigmentation.
Article
We have generated a transgenic mouse line by microinjection of a chimeric DNA fragment (KER-CAT) containing a hair-specific, murine ultra-high-sulfur keratin promoter (KER) fused to the coding region of the bacterial chloramphenicol acetyltransferase (CAT) gene. A 671-base pair (bp) stretch of the 5' promoter region was used to direct the expression of the CAT gene in this construct. Of the tissues tested for CAT activity in these transgenic animals only skin with growing hair, isolated hair follicles, and microdissected vibrissae showed substantial levels of activity. These are the same tissues where the endogenous ultra-high-sulfur keratin gene is expressed as shown by in situ hybridization. Furthermore, analysis of the CAT activity during the developmental stages of the hair growth cycle shows that the chimeric gene is expressed during the anagen phase of the hair growth cycle; this is the expected time during development for its expression. From these results we conclude that 671 bp of the promoter sequence from the ultra-high-sulfur keratin gene is sufficient to direct the correct development-specific and tissue-specific expression of the reporter gene construct in transgenic mice. The appropriate expression of the KER-CAT construct in transgenic mice is an important step in understanding the regulation of this gene during hair organogenesis.
Article
Cromakalim, pinacidil, nicorandil, diazoxide and RP-49356 belong to the class of drugs termed potassium channel openers. In rat portal vein diazoxide, like cromakalim, abolished spontaneous mechanical and electrical activity and in rat aorta caused an increase in 86Rb efflux and inhibited KCl(20 mM)-induced contractions. However, in contrast to cromakalim, diazoxide (greater than 100 microM) also inhibited mechanical responses evoked by 80 mM KCl in rat aorta suggesting that it possesses pharmacological properties in addition to K channel opening. Since glibenclamide can attenuate the effects of cromakalim and diazoxide in vascular tissues, it is possible that a channel resembling the ATP-sensitive K channel found in pancreatic beta-cells may be involved in the vasorelaxant effects of these agents. However, differences exist in the order of potency of cromakalim and diazoxide for producing smooth muscle relaxation and for decreasing insulin secretion in pancreatic beta-cells. Furthermore galanin (which opens ATP-sensitive K channels in beta-cells) increases mechanical activity in rat portal vein. It is anticipated that new chemical developments will produce K channel opening molecules with greater potency and tissue selectivity.
Article
Potassium (K) channel openers comprise a diverse group of molecules capable of opening K channels in excitable cells. These agents exhibit their greatest potency in the smooth muscle system but K channels in cardiac muscle, neurones and in secretory cells are also affected. The development of tissue selectivity is currently one major focus of research and evidence is starting to emerge that this can be achieved. The profound effects of the K channel openers in vivo has led to the suggestion that an endogenous K channel opener might exist and exert an important role in blood pressure homeostasis. The discovery of such a substance--endothelium-derived hyperpolarizing factor--has many implications and its role in cardiovascular regulation is currently under investigation. In vivo, initial studies with the K channel openers emphasized their antihypertensive properties. However, later studies have concentrated on the improvement to coronary blood flow produced by these substances together with their protective effect on the ischaemic myocardium, the basis of which is not fully understood. In spite of great efforts, the K channel which forms the target of these agents in smooth muscle is a matter of controversy. The ability of glibenclamide to antagonize the actions of the K channel openers initially led to the suggestion that an ATP-dependent K channel was their site of action in smooth muscle although the most recent data have implicated a smaller conductance K channel.
Article
We analyzed the effect of minoxidil on hair follicles isolated from transgenic mice. These transgenic animals synthesize the reporter enzyme CAT in their hair follicles only during the active phases of hair growth. The recombinant gene used to generate these mice contained the bacterial enzyme CAT under the control of the promoter from the gene of UHS protein. Studies using in situ hybridization showed that UHS proteins are expressed specifically in the matrix cells of the hair follicle during the terminal stages of hair differentiation. Hence the expression of the UHS proteins is a clear sign of active hair growth. With other in situ hybridization studies we demonstrated that CAT mRNA is expressed in differentiating matrix cells of the hair shaft in a location similar to that in which mRNA encodes UHS proteins. Thus we can use the levels of CAT activity as a measure of hair growth. We have confirmed that expression of the transgene is found in hair that is high in anagen and low in catagen follicles. The usefulness of our model was further demonstrated by showing that minoxidil, a drug that stimulates hair growth, increased the expression of CAT in cultured hair follicles. Thus we have demonstrated that expression of this reporter gene is sensitive, hair specific, and also useful for monitoring effects in cultured hair follicles. Hence these transgenic mice provide a model system for studying the biology of hair growth.
Article
The effects of the K+ channel opening drugs minoxidil sulphate and cromakalim, on 42K+ and 86Rb+ efflux and on vasorelaxation in rat isolated aorta, were compared. In rat aortic rings precontracted with noradrenaline (100 nmol/l), minoxidil sulphate and cromakalim concentration-dependently inhibited induced tension by up to 90%, with pD2 values of 7.35 +/- 0.1 and 7.17 +/- 0.1, respectively. Glibenclamide (300 nmol/l), produced 2200- and 19-fold rightward shifts in the concentration-relaxation curves to minoxidil sulphate and cromakalim, respectively, without an effect on the maximum relaxation. Both minoxidil sulphate and cromakalim increased the efflux of 42K+ and 86Rb+ from aorta in a concentration-dependent manner, with midpoints in the mumol/l range; the maximum efflux induced by minoxidil sulphate being approximately one tenth of that induced by cromakalim. The ratio of stimulated 86Rb+/42K+ efflux increased from 0.22 to 0.48 with increasing cromakalim concentrations, but was approximately constant (approximately 0.39) when the minoxidil sulphate concentration was varied. In the presence of minoxidil sulphate, the effects of cromakalim on 42K+ and 86Rb+ efflux were inhibited in a concentration-dependent manner, by up to 60%. In the continuing presence of cromakalim (300 nmol/l), minoxidil sulphate (10 mumol/l)-induced increases in 42K+ and 86Rb+ efflux were inhibited by 45%, whereas conditioning with cromakalim (1 mumol/l) inhibited the 86Rb+ efflux stimulated by additional superfusion of cromakalim (1 mumol/l) by 85%. Glibenclamide inhibited minoxidil sulphate (10 mumol/l)- and cromakalim (1 mumol/l)-induced increases in 42K+ and 86Rb+ efflux in a concentration-dependent manner with IC50 values of approximately 80 nmol/l.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
The precise biochemical mechanism and site(s) of action by which minoxidil stimulates hair growth are not yet clear. Minoxidil sulfate is the active metabolite of minoxidil, with regard to smooth muscle vasodilation and hair growth. Formation of minoxidil sulfate is catalyzed by specific PAPS-dependent sulfotransferase(s) and minoxidil-sulfating activities have been previously reported to be present in liver and hair follicles. One of these minoxidil-sulfating enzymes has been purified from rat liver (rat minoxidil sulfotransferase, MST) and a rabbit anti-MST antibody has been prepared. Using this anti-MST antibody, we have immunohistochemically localized minoxidil sulfotransferase in the liver and anagen hair follicles from rat. In rat pelage and vibrissa follicles, this enzyme is localized within the cytoplasm of epithelial cells in the lower outer root sheath. Although the immunolocalization of MST might not necessarily correlate with the MST activity known to be present in anagen follicles, the results of this study strongly suggest that the lower outer root sheath of the hair follicle may serve as a site for the sulfation of topically applied minoxidil.
Article
Immunohistochemistry with a minoxidil antibody suggested that minoxidil-immunoreactivity is associated with the root sheaths, laterally orientated differentiating matrix cells, and dividing epithelial cells of cultured vibrissa follicles of pigmented and albino neonatal mice. The dermal papilla and connective tissue sheath were devoid of minoxidil-immunoreactivity. To verify that minoxodil-immunoreactivity in the follicles was specific, immunostaining was conducted with dissected whisker pads, formalin-fixed "dead" follicles, and sections of spleen, liver and kidney (non-haired organs) cultured with minoxidil. Microscopic examination revealed minoxidil-immunoreactivity in all of these tissues. Follicles and whisker pads cultured with minoxidil, then washed for one h in media were devoid of minoxidil-immunoreactivity. These data suggest that minoxidil-immunoreactivity in cultured vibrissa follicles is probably non-specific. Sections of skin from C3H and CF1 mice which were topically dosed with minoxidil (in vivo) showed no minoxidil-immunoreactivity. Autoradiography demonstrated that tritiated minoxidil was bound in vivo and in vitro only to melanin granules in pigmented follicles of rodent and human tissue. This is probably non-specific binding since melanin is known to accumulate several chemically and pharmacologically unrelated drugs. It is reasonable to conclude that, under the conditions of these experiments, minoxidil is not specifically localized in any cells of whisker, pelage or, scalp follicles.
Article
1. The actions of diazoxide and minoxidil sulphate have been compared with those of cromakalim in rat aorta and portal vein. 2. Diazoxide and minoxidil sulphate hyperpolarized the rat portal vein in a similar manner to cromakalim. 3. Cromakalim, diazoxide and minoxidil sulphate increased 42K and 86Rb efflux from rat portal vein, although minoxidil sulphate had only a small effect on 86Rb efflux. 4. Cromakalim, diazoxide and minoxidil sulphate increased 42K efflux from rat aorta but only cromakalim and diazoxide increased 86Rb efflux from this tissue. 5. Glibenclamide inhibited the relaxant actions of cromakalim, diazoxide and minoxidil sulphate on rat aorta and the increase in 42K efflux produced by these agents in this tissue. 6. Diazoxide relaxed an 80 mM KCl-induced contraction of rat aorta, whilst cromakalim and minoxidil sulphate were without effect. 7. Cromakalim, diazoxide and minoxidil sulphate had no effect on cyclic AMP or cyclic GMP concentrations in rat aorta. 8. It is concluded that diazoxide and minoxidil sulphate like cromakalim exhibit K+ channel opening properties in vascular smooth muscle. Diazoxide exerts an additional inhibitory action not related to the production of cyclic AMP or cyclic GMP. The action of minoxidil sulphate may be primarily located at a K+ channel which is relatively impermeable to 86Rb.
Article
An important step in understanding minoxidil's mechanism of action on hair follicles was to determine the drug's active form. We used organ-cultured vibrissa follicles to test whether it is minoxidil or its sulfated metabolite, minoxidil sulfate, that stimulates hair growth. Follicles from neonatal mice were cultured with or without drugs and effects were assessed by measuring incorporation of radiolabeled cysteine in hair shafts of the treated follicles. Assays of minoxidil sulfotransferase activity indicated that vibrissae follicles metabolize minoxidil to minoxidil sulfate. Dose-response studies showed that minoxidil sulfate is 14 times more potent than minoxidil in stimulating cysteine incorporation in cultured follicles. Three drugs that block production of intrafollicular minoxidil sulfate were tested for their effects on drug-induced hair growth. Diethylcarbamazine proved to be a noncompetitive inhibitor of sulfotransferase and prevented hair growth stimulation by minoxidil but not by minoxidil sulfate. Inhibiting the formation of intracellular PAPS with chlorate also blocked the action of minoxidil but not of minoxidil sulfate. Acetaminophen, a potent sulfate scavenger blocked cysteine incorporation by minoxidil. It also blocked follicular stimulation by minoxidil sulfate apparently by directly removing the sulfate from the drug. Experiments with U-51,607, a potent minoxidil analog that also forms a sulfated metabolite, showed that its activity was inhibited by both chlorate and diethylcarbamazine. These studies show that sulfation is a critical step for hair-growth effects of minoxidil and that it is the sulfated metabolite that directly affects hair follicles.
Article
Potassium channel openers comprise a diverse group of chemical agents which open plasma-lemmal K-channels. They show selectivity for smooth muscle, although K-channels in cardiac and skeletal muscle, neurones and the pancreatic beta-cell are also affected at relatively high concentrations. In addition, at least one endogenous K-channel opener of vascular origin--endothelium-derived hyperpolarizing factor--exists and in man plays a role in modulating blood vessel tone. The type of K-channel involved in the actions of both exogenous and endogenous K-channel openers is still uncertain, although a prime candidate in smooth muscle seems similar to the [ATPi]-modulated K-channel in the pancreatic beta-cell. This review focuses attention on the action of these agents in vascular smooth muscle and on the possible clinical exploitation of their powerful vasorelaxant properties.
Article
On the basis of electrophysiological analysis of Shaker mutants, the Shaker locus of Drosophila melanogaster has been proposed to encode a structural component of a voltage-dependent potassium channel, the A channel. Unlike sodium channels, acetylcholine receptors, and calcium channels, K+ channels have not been purified biochemically. To facilitate biochemical studies of a K+ channel, genomic DNA from the Shaker locus has been cloned. Rearrangements in five Shaker mutants have been mapped to a 60-kilobase segment of the genome. Four complementary DNA clones have been analyzed. These clones indicate that the Shaker gene contains multiple exons distributed over at least 65 kilobases of genomic DNA in the region where the mutations mapped. Furthermore, the gene may produce several classes of alternatively spliced transcripts. Two of the complementary DNA clones have been sequenced and their sequences support the hypothesis that Shaker encodes a component of a K+ channel.
Article
Minoxidil, a potent vasodilator, stimulates the growth of terminal hair from vellus or miniaturized follicles in balding scalp. To study minoxidil's action on isolated follicles we developed and validated an organ culture system using mouse whisker follicles. Control follicles cultured without minoxidil showed macroscopic changes including kinking of the hair shafts and bending of the follicles. Necrosis was evident in the differentiating epithelial elements forming the cuticle, cortex, and inner root sheath. These abnormalities were eliminated or greatly reduced in minoxidil-treated follicles. The morphology of these follicles was consistent with the production of new hair during culture. Direct measurement demonstrated that minoxidil-treated follicles grew significantly longer than control follicles during the 3-d culture. Minoxidil increased the incorporation of radiolabeled cysteine and glycine in follicles compared with control treatment. Doses of minoxidil up to 1 mM caused increased cysteine incorporation, while higher doses were inhibitory. Experiments with labeled thymidine indicated that minoxidil induced proliferation of hair epithelial cells near the base of the follicle. Autoradiography also showed that cysteine accumulated in the keratogenous zone above the dermal papilla. These studies demonstrate that organ cultured follicles are suitable for determining minoxidil's mechanism of action and may be useful for studying other aspects of hair biology. The results also show that minoxidil's effect on hair follicles is direct. This suggests that minoxidil's action in vivo includes more than just increasing blood flow to hair follicles.
Article
The clinical pharmacology of potassium channel openers has been reviewed using pinacidil as a prototype drug. When administered acutely or chronically, the hemodynamic and neuroendocrine profile is that of a peripheral arterial vasodilator. The drug produces decreases in peripheral vascular resistance, and subsequent blood pressure decreases are associated with reflex increments in heart rate. When studied, plasma catecholamines increased about twofold during chronic therapy. Plasma renin activity, however, was not increased during chronic therapy with pinacidil monotherapy. When patients were treated with pinacidil doses ranging from 12.5 to 75 mg b.i.d., 66.9% of patients had a decrease in supine diastolic blood pressure to below 91 mm Hg and 10 mm Hg less than baseline, whereas only 23.9% of patients had similar falls during placebo treatment. During maintenance therapy with pinacidil, the average blood pressure during the daytime dosing interval was 137.8 +/- 1.2/83.4 +/- 0.7 mm Hg (mean +/- SEM). Titration of pinacidil as monotherapy resulted in a characteristic adverse event profile dominated by the presence of dose-related edema. Other characteristic events included tachycardia, palpitations and headache. When pinacidil was given to patients unresponsive to hydrochlorothiazide (25 mg b.i.d.), similar efficacy relative to placebo was noted with a change of post-dose supine diastolic blood pressure in the pinacidil group of 13.5 +/- 0.8 mm Hg and 7.3 +/- 0.9 mm Hg in the placebo group.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
The distribution of antidiabetic sulfonylurea [( 3H]glibenclamide) binding sites is heterogeneous in rat brain. Pyramidal and extrapyramidal motor system contain the highest densities of sites, particularly in the substantia nigra and in the globus pallidus. Only low levels are present in the hypothalamic nuclei and the main medulla oblongata regions. In hippocampal formation the stratum lucidum and the stratum lacunosum moleculare of CA3 show an important density of glibenclamide binding sites. Electrophysiological studies with hippocampal slices show that glibenclamide blocks hyperpolarization induced by anoxia, suggesting the involvement of adenosine triphosphate-sensitive K+ channel in this early hyperpolarization event.
Article
The electrophysiological and mechanical properties of the vasodilator minoxidil sulfate (MNXS) were examined in isolated smooth muscle cells and strips from rabbit portal vein. At micromolar concentrations, MNXS inhibited norepinephrine (0.1-1.0 microM)-induced contractions in isolated muscle strips. In isolated cells, norepinephrine caused a dose-dependent depolarization of the resting membrane potential, which was significantly attenuated by MNXS (5 microM); MNXS alone caused a hyperpolarization of the membrane potential. This hyperpolarization was insensitive to Na+-K+ pump blockade by ouabain, but was inhibited by the K+ channel antagonist, tetraethylammonium (20 mM). In voltage-clamp experiments, a resting (background) conductance associated with the resting membrane potential was identified. This conductance, which previously has been shown to be reduced by Ba2+ as well as tetraethylammonium, was increased by MNXS (2 microM). In additional experiments, whole-cell L-type Ca2+ currents were inhibited by micromolar concentrations of MNXS. These experiments show that concentrations of MNXS that inhibit norepinephrine-induced contractions promote K+ conductance and inhibit Ca2+ entry through voltage-dependent Ca2+ channels in vascular smooth muscle cells. These electrophysiological effects of MNXS may be responsible for the vasorelaxant effects of the drug observed in vitro and in vivo.
Article
The topical agents developed thus far to treat male-pattern baldness have provided encouraging results, but with continued efforts other new, more effective compounds are certain to be developed in the future in this promising new area of dermatologic research.
Article
The mechanism of smooth muscle relaxing effect of minoxidil sulfate (MxSO4) was investigated in isolated rabbit superior mesenteric artery. MxSO4 (5 X 10(-6) M) was found to effectively relax maximal norepinephrine (NE; at 5 X 10(-6) M) contraction, but failed to relax 80 mM K+-induced contraction. MxSO4-induced relaxation was endothelium independent. When the tissues were exposed to increased extracellular K+ (10-25 mM), and then contracted with NE, the relaxation response to MxSO4 was significantly attenuated. Tetraethylammonium (5-10 mM) pretreatment caused pronounced inhibition of MxSO4-induced relaxation. Pretreatment with ouabain (0.5-5 microM) also significantly inhibited MxSO4 relaxation. This effect of ouabain was found to be due to its effect on K+ gradient. These data suggested a role of K+ permeability during MxSO4 relaxation which was further confirmed when it was found that MxSO4 can cause a significant stimulation of 42K efflux from the mesenteric artery preloaded with 42K. It is suggested that MxSO4 may act as a K+ channel agonist to affect the plasmalemmal Ca++ permeability during agonist activation. Consistent with this, MxSO4 was demonstrated to cause an inhibition of NE-stimulated 45Ca influx in this tissue. Such a strong dependence on K+ permeability makes MxSO4 a unique vasodilator among the clinically used vasodilators.
Article
Potassium transport has frequently been assessed by measurement of 86Rb. However, recent reports indicated that the K ion channels are selective to K over Rb. Therefore, the purpose of this study was to evaluate whether the basal and stimulated fluxes of Rb and K were equivalent in rat aorta in the absence of endothelium. The ouabain-sensitive (active) uptake of 86Rb and 42K was similar. However, the basal 86Rb efflux was only 80% of the 42K efflux. Norepinephrine and KCl depolarization stimulated 86Rb and 42K effluxes via a calcium-dependent process. The stimulated 86Rb efflux ranged from 56 to 74% of the 42K efflux. Diltiazem reduced the KCl-stimulated 86Rb and 42K effluxes. The 86Rb efflux was 82% of the 42K efflux in the presence of KCl plus diltiazem, similar to that under basal conditions. Substitution of Rb for K in the incubation solution was associated with a marked increase in spontaneous contractile activity. There was no change in the norepinephrine concentration required for a 50% stimulation of contraction or 86Rb efflux from Rb-loaded tissues. We conclude from these studies that the basal and calcium-activated potassium channels are selective for K over Rb and therefore 86Rb fluxes quantitatively underestimate that of 42K. However, 86Rb is an appropriate substitute for the measurement of active K transport.
Article
Minoxidil applied topically on the bald scalp of stumptailed macaques seems to have a favorable effect in enlarging some hair follicles that then produce thicker hairs. It also seems to prevent hair follicles from becoming smaller during the peri-adolescence period in these animals. A novel method, the folliculogram, revealed that minoxidil accelerates the cyclic turnover of vellus follicles and simultaneously induces enlargement of regrowing follicles during early anagen phases. Minoxidil appears to enhance a proliferation of follicular cells in the secondary bud, thus producing a larger follicle than that of the previous cycle. The study revealed that 'transformed vellus follicles' in the bald scalp have a potential to recover their ability to produce thick hair. However, recovery from baldness may take as long as the time it takes for baldness to develop. Thus, treatment in early stages of baldness should be more effective than treatment at advanced stages.
Article
The 100,000 g supernatant fraction of rat liver homogenate contains a sulfotransferase activity which catalyzes the sulfation of minoxidil. Synthetic minoxidil N-O sulfate and the enzyme synthesized product had identical chromatographic characteristics on high pressure liquid chromatography. Minoxidil sulfate, which yields minoxidil when treated with sulfatase, was slowly hydrolyzed in water. Several N-oxides of other heterocycles, including several other pyrimidines, triazines and imidazoles, were also substrates for this sulfotransferase.
Article
Voltage-gated potassium channels make up a large mo- lecular family of integral membrane proteins that are fundamentally involved in the generation of bioelectric signals such as nerve impulses. These proteins span the cell membrane, forming potassium-selective pores that are rapidly switched open or closed by changes in mem- brane voltage. After the cloning of the first potassium channel over 3 years ago, recombinant DNA manipula- tion of potassium channel genes is now leading to a molecular understanding of potassium channel behavior. During the past year, functional domains responsible for channel gating and potassium selectivity have been iden- tiffed, and detailed structural pictures underlying these functions are beginning to emerge.
AW: Comparison of 86rubidium and 42potassium fluxes in rat aorta
  • Smith
  • Sanchez
  • Jones Aa