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ABSTRACT: Hypertension and chronic kidney disease are more common in men than in premenopausal women at the same age. In animal models, females are relatively protected against genetic or pharmacological procedures that produce high blood pressure and renal injury. Over-activation or dysfunction of the ET system modulates the progression of hypertension or kidney diseases with the ET(A) receptor primarily mediating vasoconstriction, injury and anti-natriuresis, and ET(B) receptors having opposite effects. The purpose of this review is to examine the role of the ET system in the kidney with a focus on the inequality between the sexes associated with the susceptibility to, and progression of hypertension and kidney diseases. In most animal models, males have higher renal ET-1 mRNA expression, greater ET(A) -mediated responses, including renal medullary vasoconstriction, and increased renal injury. These differences are reduced following gonadectomy suggesting a role for sex hormones, mainly testosterone. In contrast, females are relatively protected from high blood pressure and kidney damage via increased ET(B) versus ET(A) receptor function. Furthermore, ET(A) receptors may have a favorable effect on sodium excretion and reducing renal damage in females. In human studies, the genetic polymorphisms of ET system are more associated with hypertension and renal injury in women. However, the knowledge of sex differences in the efficacy or adverse events of ET(A) antagonists in the treatment of hypertension and kidney disease are poorly described. Increased understanding how the ET system acts differently in the kidneys between sexes, especially with regard to receptor subtype function, could lead to better treatments for hypertension and renal disease. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
British Journal of Pharmacology 02/2012; · 4.41 Impact Factor
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ABSTRACT: Activation of endothelin receptor-A (ET(A)) increases glomerular permeability to albumin (P(alb)) and elevates pro-inflammatory markers in hyperglycaemic rats.
Male Sprague-Dawley rats were given streptozotocin (n = 32) or saline (sham; n = 32). Half of the animals in each group received the ET(A)-selective antagonist, ABT-627 (atrasentan; orally), beginning immediately after hyperglycaemia was confirmed. Glomeruli were isolated by sieving techniques and P(alb) determined from the change in glomerular volume induced by oncotic gradients of albumin. Glomerular nephrin levels were assessed by immunofluorescence, whereas urinary nephrin was measured by immunoassay.
At 3 and 6 weeks after streptozotocin injection, proteinuria was significantly increased compared with sham controls and significantly reduced by ABT-627 treatment. P(alb) was also increased at 3 and 6 weeks post-streptozotocin. ABT-627 had no effect on P(alb) or protein excretion in sham control rats. In glomeruli isolated from hyperglycaemic rats, incubation with BQ-123, a selective ET(A) antagonist, reduced P(alb), whereas BQ-788, a selective endothelin receptor-B antagonist had no effect (n = 6 rats per group, 5-8 glomeruli per rat). Glomerular and plasma content of soluble intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 were significantly increased 6 weeks after streptozotocin (ELISA). ABT-627 attenuated these increases. After 6 weeks of hyperglycaemia, glomerular nephrin content was decreased with a concurrent increase in urinary nephrin excretion. ABT-627 prevented glomerular nephrin loss in hyperglycaemic rats (n = 5-8 rats per group; eight groups).
These observations support the hypothesis that endothelin-1, via the ET(A) receptor, directly increases P(alb), possibly via nephrin loss, as well as early inflammation in the hyperglycaemic rat.
Diabetologia 12/2010; 54(4):979-88. · 6.81 Impact Factor
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ABSTRACT: Our laboratory and others have shown that endothelin (ET)-1 directly stimulates nitric oxide (NO) production in inner medullary collecting duct (IMCD) cells. The goal of this study was to determine which NO synthase (NOS) isoforms in IMCD are sensitive to ET-1, and the role of ET(A) and ET(B) receptor activation in vivo and in vitro.
NOS enzymatic activity and NOS isoform protein expression were examined in cultured IMCD-3 cells and isolated renal inner medulla. ET(B) receptor-deficient homozygous rats (sl/sl) have elevated levels of circulating ET-1 and lack a functional ET(B) signalling pathway in kidneys, and furthermore provides a unique model to study ET(A) receptor signalling in the renal inner medulla in vivo.
Incubation of IMCD-3 cells with exogenous ET-1 (50 nm) resulted in ET(A)-dependent increased NOS1 protein expression in IMCD-3 cells with no effect on NOS2 or NOS3 expression. ET(B) receptor antagonism has no effect on NOS expression in IMCD-3 cells. Consistent with in vitro results, cytosolic NOS1 protein expression was significantly greater in the renal inner medulla of sl/sl rats compared with heterozygous (sl/+) controls, with no alteration in NOS3 expression. In contrast to protein expression data, NOS1- and NOS3-specific enzymatic activities decreased in the cytosolic fraction from the renal inner medulla of sl/sl compared with sl/+.
These results provide evidence that both ET(A) and ET(B) receptors regulate NOS isoform activity in the renal inner medulla and specifically support the hypothesis that ET(A) receptor activation increases NOS1 expression.
Acta Physiologica 01/2008; 191(4):329-36. · 3.09 Impact Factor
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ABSTRACT: Aim: Our laboratory and others have shown that endothelin (ET)-1 directly stimulates nitric oxide (NO) production in inner medullary collecting duct (IMCD) cells. The goal of this study was to determine which NO synthase (NOS) isoforms in IMCD are sensitive to ET-1, and the role of ETA and ETB receptor activation in vivo and in vitro.Methods: NOS enzymatic activity and NOS isoform protein expression were examined in cultured IMCD-3 cells and isolated renal inner medulla. ETB receptor-deficient homozygous rats (sl/sl) have elevated levels of circulating ET-1 and lack a functional ETB signalling pathway in kidneys, and furthermore provides a unique model to study ETA receptor signalling in the renal inner medulla in vivo.Results: Incubation of IMCD-3 cells with exogenous ET-1 (50 nm) resulted in ETA-dependent increased NOS1 protein expression in IMCD-3 cells with no effect on NOS2 or NOS3 expression. ETB receptor antagonism has no effect on NOS expression in IMCD-3 cells. Consistent with in vitro results, cytosolic NOS1 protein expression was significantly greater in the renal inner medulla of sl/sl rats compared with heterozygous (sl/+) controls, with no alteration in NOS3 expression. In contrast to protein expression data, NOS1- and NOS3-specific enzymatic activities decreased in the cytosolic fraction from the renal inner medulla of sl/sl compared with sl/+.Conclusion: These results provide evidence that both ETA and ETB receptors regulate NOS isoform activity in the renal inner medulla and specifically support the hypothesis that ETA receptor activation increases NOS1 expression.
Acta Physiologica 11/2007; 191(4):329 - 336. · 3.09 Impact Factor
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ABSTRACT: Hypertension is associated with increased reactive oxygen species (ROS). Renal ROS production and their effects on renal function have never been investigated in mineralocorticoid hypertensive rats. In this study we hypothesized that increased ROS production in kidneys from deoxycorticosterone (DOCA)-salt rats contributes to adverse renal morphological changes and impaired renal function in DOCA-salt hypertensive rats. We also determined whether ROS-induced renal injury was dependent on blood pressure. DOCA-salt hypertensive rats exhibited a marked increase in blood pressure, renal ROS production, glomerular and tubular lesions, and microalbuminuria compared to sham rats. Treatment of DOCA-salt hypertensive rats with apocynin for 28 days resulted in attenuation of systolic blood pressure and improvement of renal morphology. Renal superoxide level in DOCA-salt rats was 215% of sham-operated rats and it was significantly decreased to 140% with apocynin treatment. Urinary protein level was decreased from 27 +/- 3 mg/day in DOCA-salt hypertensive rats to 9 +/- 2 mg/day. 28 days of Vitamin E treatment also reduced renal injury in regard to urinary protein level and renal morphology but had no effect on blood pressure in DOCA-salt rats. Increased urinary 8-isoprostane, a marker for oxidative stress, in DOCA-salt hypertensive rats (55 +/- 8 ng/day) was diminished by vitamin E treatment (24 +/- 6 ng/day). These data suggest that renal injury characteristic of mineralocorticoid hypertension is associated with oxidative stress and is partly independent of blood pressure.
Journal of physiology and pharmacology: an official journal of the Polish Physiological Society 10/2006; 57(3):343-57. · 2.27 Impact Factor
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ABSTRACT: Several disease states, including hypertension, are associated with elevations in plasma endothelin-1 (ET-1) and variable changes in vascular contraction to ET-1. The spotting lethal (sl) rat carries a deletion of the endothelin-B (ET(B)) receptor gene that prevents expression of functional ET(B) receptors, resulting in elevated plasma ET-1. On a normal diet, these rats are normotensive and thus provide an opportunity to study the vascular effects of chronically elevated ET-1 in the absence of hypertension. Studies were performed in rats homozygous for the ET(B) deficiency (sl/sl; n = 8) and in transgenic rats heterozygous for the ET(B) deficiency (sl/+; n = 8). Plasma ET-1 was elevated in sl/sl rats (3.85 +/- 0.55 pg/ml) compared with sl/+ rats (0.31 +/- 0.11 pg/ml). Mean arterial blood pressure in conscious unrestrained sl/sl and sl/+ rats was 101 +/- 5 and 107 +/- 6 mmHg, respectively. Concentration-dependent contractions to ET-1 (10(-11)-10(-8) M) were reduced in mesenteric small arteries (150-250 microm) from sl/sl rats, as indicated by an approximately 10-fold increase in EC(50). A selective ET(A) antagonist, A-127722 (30 nM), abolished contraction to ET-1 in both groups, whereas a selective ET(B) antagonist had no effect. Also, ET(B) agonists (IRL-1620 and sarafatoxin 6c) produced neither contraction nor relaxation in either group, indicating that contraction to ET-1 in this vascular segment was exclusively ET(A) dependent. Despite increased plasma ET-1, protein expression of ET(A) receptors in membrane protein isolated from mesenteric small arteries was increased in sl/sl compared with sl/+ rats, as shown by Western blotting. These results indicate that, in ET(B)-deficient rats, ET(A)-induced contraction is reduced in vessels normally lacking ET(B)-mediated effects. Reduced contraction may be related to elevated plasma ET-1 and occurs in the presence of increased ET(A) receptor protein expression, suggesting an uncoupling of ET(A) receptor expression from functional activity.
AJP Heart and Circulatory Physiology 01/2002; 281(6):H2680-6. · 3.71 Impact Factor
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ABSTRACT: The relationship between urinary vasoactive factors and sodium excretion has not been adequately addressed in humans.
Excretion rates of sodium, nitrates/nitrites (NOx), cGMP, and endothelin-1 (ET-1) were measured before and after ingestion of a mixed electrolyte solution (8 oz Gatorade) while undergoing a routine cardiovascular evaluation in a sample of 51 normotensive young adults.
Significant correlations were detected for changes in excretion between all four variables, r ranged from 0.50 to 0.86 (P < .001). Correlations were higher in African Americans than white Americans.
The association of renal ET-1 and NO activity with sodium excretion supports the hypothesis that these factors play a role in the physiologic response to acute changes in sodium intake, particularly in African Americans.
American Journal of Hypertension 10/2001; 14(10):1003-6. · 3.18 Impact Factor
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ABSTRACT: Recent evidence indicates that endothelin-1 (ET-1) might be a principal vasoconstrictor in the penis. We report that ET-1 injection into the cavernous sinuses before erection sharply reduced the magnitude of subsequent erections. Corpus cavernosum pressure-to-mean arterial pressure ratios (CCP/MAP), with maximal ganglionic stimulation, were 0.62 +/- 0.05 before ET-1 injection and 0.31 +/- 0.05 after, indicating that ET-1 acted as a vasoconstrictor. When ET-1 was injected during a maximal neurally induced erection, the ability of ET-1 to attenuate subsequent erections was diminished (CCP/MAP 0.75 +/- 0.02 before ET-1, 0.61 +/- 0.03 after). At submaximal stimulation voltages, injection of ET-1 during erection also attenuated its vasoconstrictive effect. Similarly, when ET-1 was injected during erection induced by intracavernosal injection of the nitric oxide (NO) donor NOR-1, subsequent erections were not significantly suppressed (CCP/MAP 0.53 +/- 0.04 before ET-1, 0.45 +/- 0.04 after). These findings that ET-1-induced vasoconstriction is attenuated during erection are consistent with the hypothesis that NO mediates erection both by initiating pathways that cause smooth muscle relaxation and by inhibiting the vasoconstrictive actions of ET-1.
AJP Regulatory Integrative and Comparative Physiology 09/2001; 281(2):R476-83. · 3.34 Impact Factor
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ABSTRACT: Recent evidence suggests that endothelin-1 (ET-1), perhaps through the ET(B) receptor, may participate in blood pressure regulation through the control of sodium excretion. Mean arterial pressure (MAP) was continuously measured via telemetry implants in male Sprague-Dawley rats. After 1 wk of baseline measurements, rats were given either high (10%) or low (0.08%) NaCl in chow for the remainder of the experiment (n = 5 in each group). MAP was significantly increased in rats on a high-salt diet (115 +/- 2 mmHg) compared with rats on the low-salt diet (103 +/- 2 mmHg; P < 0.05). All rats were then treated with the ET(B) receptor antagonist A-192621 mixed with the food and adjusted daily to ensure a dose of 30 mg x kg(-1) x day(-1). ET(B) blockade produced an increase in MAP within a few hours of treatment and was significantly higher in rats on the high-salt diet over a 1-wk period (170 +/- 3 vs. 115 +/- 3 mmHg, P < 0.01). To determine whether the increase in MAP during A-192621 treatment was due to increased ET(A) receptor activation, all rats were then given the ET(A)-selective antagonist ABT-627 in the drinking water while a low-salt/high-salt diet and ET(B) blockade were continued. ABT-627 decreased MAP within a few hours in rats on either the high-salt (113 +/- 3 mmHg) or low-salt (101 +/- 3 mmHg) diet. These results support the hypothesis that endothelin, through the ET(B) receptor, participates in blood pressure regulation in the response to salt loading.
American journal of physiology. Renal physiology 07/2001; 281(1):F144-50. · 3.68 Impact Factor
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D M Pollock
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ABSTRACT: Renal clearance studies were conducted to determine the role of ET(B) receptors in the renal response to big endothelin-1 (big ET-1). Two series of experiments were conducted on Inactin-anesthetized rats to contrast acute pharmacological blockade of ET(B) receptors vs. genetic ET(B) receptor deficiency. In the first series, Sprague-Dawley rats were given either ET(B)-selective antagonist, A-192621, or vehicle (0.9% NaCl) prior to infusion of big ET-1 (10 pmol.kg(-1).min(-1)) for 60 min. A-192621 significantly increased baseline mean arterial pressure (MAP; 102 +/- 4 vs. 141 +/- 6 mmHg, P < 0.05) and urine flow rate (0.5 +/- 0.1 vs. 1.3 +/- 0.2 microl/min, P < 0.05) without any effect on glomerular filtration rate (GFR) or effective renal plasma flow (ERPF). Big ET-1 significantly increased MAP in both groups but to a higher level in rats given antagonist (120 +/- 6 vs. 169 +/- 6 mmHg, P < 0.05). Big ET-1 increased urine flow in control rats but decreased in rats given antagonist. GFR and ERPF were decreased in rats given big ET-1, an effect that was exaggerated by ET(B) blockade. Another series of experiments examined the response to big ET-1 in rats lacking functional renal ET(B) receptors, known as spotting lethal (sl) rats. Surprisingly, rats heterozygous (sl/+) for ET(B) receptor deficiency had a significantly higher baseline MAP compared with homozygous (sl/sl) rats (134 +/- 6 vs. 112 +/- 7 mmHg, P < 0.05), although other variables were similar. Big ET-1 produced no significant change in MAP in either group. Urine flow, GFR, and ERPF were significantly decreased in both groups, although these changes were much larger in sl/sl rats. These experiments indicate that the ET(B) receptor plays an important role in limiting the renal hemodynamic response to big ET-1. Furthermore, the diuretic actions of big ET-1 require a functional ET(B) receptor.
Physiological Genomics 06/2001; 6(1):39-43. · 2.73 Impact Factor
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D M Pollock
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ABSTRACT: The degree to which ET-1 participates in the pathogenesis of renal dysfunction remains poorly understood. In the kidney, ET-1 not only produces vasoconstriction, but also vasodilation in the renal medulla, stimulation of sodium reabsorption in the proximal tubule, and inhibition of reabsorption in a variety of nephron segments. It is clear that ET-1 production is increased in most forms of renal failure, although the cause of this increase is not known. Endothelin receptor antagonists, as therapeutic agents, have been investigated in a large variety of animal models, and even though there have been some promising results, there are many conflicting reports. While there is little known about the therapeutic utility of endothelin receptor antagonists in human renal failure, progress is most likely to be slow due to the complex nature of ET-1 actions and the less than promising initial studies in humans.
Current opinion in investigational drugs (London, England: 2000) 05/2001; 2(4):513-20. · 3.31 Impact Factor
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ABSTRACT: Hyperinsulinemia, a primary feature of insulin resistance, is associated with increased endothelin-1 (ET-1) activity. This study determined the vascular response to ET-1 and receptor binding characteristics in small mesenteric arteries of insulin-resistant (IR) rats. Rats were randomized to control (C) (n = 32) or IR (n = 32) groups. The response to ET-1 was assessed (in vitro) in arteries with (Endo+) and without (Endo-) endothelium. In addition, arteries (Endo+) were pretreated with the ET(B) antagonist A-192621 or the ET(A) antagonist A-127722. Finally, binding characteristics of [(125)I]ET-1 were determined. Results showed that in Endo+ arteries the maximal relaxation (E(max)) to ET-1 was similar between C and IR groups; however, the concentration at 50% of maximum relaxation (EC(50)) was decreased in IR arteries. In Endo- arteries, the E(max) to ET-1 was enhanced in both groups. Pretreatment with A-192621 enhanced the E(max) and EC(50) to ET-1 in both groups. In contrast, A-127722 inhibited the ET-1 response in all arteries in a concentration-dependent manner; however, a greater ET-1 response was seen at each concentration in IR arteries. Maximal binding of [(125)I]ET-1 was increased in IR versus C arteries although the dissociation constant values were similar. In conclusion, we found the vasoconstrictor response to ET-1 is enhanced in IR arteries due to an enhanced expression of ET receptors and underlying endothelial dysfunction.
AJP Heart and Circulatory Physiology 03/2001; 280(2):H522-7. · 3.71 Impact Factor
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ABSTRACT: The aim of this study was to determine the response of inflammatory and vasoactive mediators to 3 consecutive days of exercise in African-American women with and without sickle cell anemia (SCA). Circulating inflammatory mediators [C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha)] were measured before, and vasoactive mediators [endothelin-1 (ET-1), nitric oxide metabolites (NOx)] before and after each exercise bout in ten subjects with SCA and ten controls. Exercise did not affect ET-1, IL-6 or CRP concentrations (p >.05). TNFalpha was higher in SCA than controls (p < or = .0005) at all times; however, the response pattern was similar for the groups: no change from day 1 to day 2, but a decrease from day 2 to day 3 (p < or = .05). NOx increased significantly after exercise (p < or = .0001) but returned to baseline by 24 h afterward. On the 3rd day, NOx increased after exercise in SCA but not in the controls (p < or = .05). In conclusion, exercise did not cause a harmful inflammatory response in these individuals with SCA. However, NOx increased after exercise on all 3 days in SCA but appeared attenuated after 2 days in controls.
Endothelium 01/2001; 8(2):147-55. · 1.65 Impact Factor
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ABSTRACT: The spotting lethal rat carries a naturally occurring deletion of the endothelin-B- (ET(B)) receptor gene that prevents expression of functional ET(B)-receptors. Gariepy and colleagues used tissue-specific ET(B) transgene expression to support normal enteric nervous system development. To determine functional consequences of ET(B)-receptor deficiency, studies were conducted to characterize the pressor response to endothelin-1 (ET-1) and the ET(B) agonist, sarafotoxin 6c (S6c) in transgenic rats homozygous for the ET(B)-deficiency (sl/sl). Similar transgenic rats heterozygous for the ET(B) deficiency were used as controls (sl/+). All rats were anesthetized with Inactin (100 mg/kg, i.p.) and a tracheostomy performed. The right carotid artery and right jugular veins were catheterized for measuring mean arterial pressure (MAP) and infusion of peptides, respectively. Following baseline measurement of MAP, hexamethonium was infused (10 mg/kg) to block sympathetic reflex responses. After a 10-15 min stabilization period, ET-1 or S6c was infused at 0, 1, 0.3 and 1.0 nmol/kg at 10 min intervals. MAP in the two groups of anesthetized rats was similar during the baseline period. The sl/+ rats showed a classic dose-dependent pressor response to ET-1; a transient vasodilation followed by prolonged vasoconstriction. In contrast, the vasodilation was absent in sl/sl rats. Furthermore, ET-1 was more potent in sl/sl compared to the sl/+ rats. The response to S6c was qualitatively similar to ET-1 in the sl/+ rats. However, the sl/sl rats also had a significant pressor response to the ET(B) agonist, S6c. These studies provide in vivo evidence that the rescued ET(B)-deficient rat lacks functional vasodilatory ET(B) responses in response to ET-1 but retains the vasoconstrictor response to ET(B)-receptor agonists.
Journal of Cardiovascular Pharmacology 12/2000; 36(5 Suppl 1):S82-5. · 2.29 Impact Factor
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ABSTRACT: Recent evidence suggests that nitric oxide (NO) within the inner medullary collecting duct (IMCD) functions to regulate sodium and water reabsorption. Because fluid shear stress has been shown to increase NO production in endothelial and vascular smooth muscle cells, experiments were designed to determine whether a similar mechanism exists in IMCD cells. Cultured IMCD-3 cells derived from murine IMCD were subjected to 60 min of pulsatile shear stress. Nitrite production (2,3-diaminonaphthalene fluorometric assay) increased 12-, 16-, and 23-fold at 3.3, 10, and 30 dyn/cm(2), respectively, compared with static control cultures. Preincubation with the non-isoform-specific NO synthase inhibitor nitro-L-arginine methyl ester reduced nitrite production by 83% in response to 30 dyn/cm(2). Western blotting and immunofluorescence analysis of static IMCD-3 cell cultures revealed the expression of all three NO synthase isoforms (NOS-1 or neuronal NOS, NOS-2 or inducible NOS, and NOS-3 or endothelial NOS) in IMCD-3 cultures. These results indicate that NO production is modulated by shear stress in IMCD-3 cells and that fluid shear stress within the renal tubular system may play a role in the regulation of sodium and water excretion by control of NO production in the IMCD.
American journal of physiology. Renal physiology 09/2000; 279(2):F270-4. · 3.68 Impact Factor
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ABSTRACT: Specific receptor antagonists were used to examine the role of endothelin-1 (ET-1) in the erectile response of the rat. In these studies, intact rats were cannulated to permit the continuous recording of mean arterial pressure (MAP) and intracavernosal pressure (CCP). Erection was induced by electrical stimulation of the autonomic ganglion, which regulates blood flow to the penis. The animals were subjected to intracavernosal injection with vehicle only (Cont) or with an antagonist to the endothelin-A receptor (ET(A)) or to the endothelin-B receptor (ET(B)). Blockade of the ET(A) or the ET(B) had no effect on the erectile response (CCP/MAP) during maximal ganglionic stimulation. When ET-1 was injected into Cont rats, there was a marked vasoconstriction with a sharp rise in MAP and a decline in CCP as the cavernosal arterioles constricted and limited inflow. The injection of the ET(A) antagonist prevented the vasoconstriction after ET-1 injection into Cont rats, whereas blockade of the ET(B) had no effect on the vasoconstrictive effect to ET-1. Similar results were obtained during submaximal ganglionic stimulation. With minimal levels of ganglionic stimulation, ET-1 injection led to a moderated degree of vasodilation in the presence of the ET(A) antagonist. The ET(B) antagonist failed to alter the CCP response during minimal stimulation, but it did have a marked effect on the MAP response to ET-1 injection. The results of these studies confirm that cavernosal tissue of the rat penis is highly responsive to ET-1. However, the failure of the ET-1 antagonists to affect penile erection in response to ganglionic stimulation reflects a minimal role of ET-1 in the erectile response in the rat.
AJP Regulatory Integrative and Comparative Physiology 08/2000; 279(1):R25-30. · 3.34 Impact Factor
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ABSTRACT: Several recent studies have provided evidence that many of the hemodynamic and mitogenic actions of angiotensin II (Ang II) are mediated by endothelin-1 (ET-1). We hypothesized that Ang II and ET-1 act synergistically to promote a decline in renal function and the development of renal fibrosis in the deoxycorticosterone acetate (DOCA)-salt model of malignant hypertension and renal dysfunction. Experiments were conducted to determine the effects of ET(A) receptor antagonism (A-127722) and AT(1) receptor antagonism (candesartan cilexetil) on the development of renal fibrosis and the decline of renal function. Surgery was conducted on male, Sprague-Dawley rats to remove the right kidney and implant subcutaneously a time-release pellet containing DOCA. DOCA-treated rats were also given 0.9% NaCl to drink. After recovery from surgery, rats received one of four treatments via the drinking solution: (1) candesartan cilexetil (10 mg/kg/day), (2) A-127722 (10 mg/kg/day), (3) candesartan cilexetil plus A-127722, or (4) untreated controls. Over the course of a 3-week treatment period, systolic arterial pressure in all groups were elevated. However, this increase was significantly attenuated in the group given combined A-127722 and candesartan, but not with candesartan alone. Creatinine clearance, used as a measure of GFR, was significantly higher in rats treated with either or both drugs. At the end of the study, renal medullary tissue was harvested for determination of TGF-beta and fibronectin content (ELISA). TGF-beta levels were not reduced by either ET(A), AT(1), or combined ET(A) and AT(1) receptor blockade. Likewise, fibronectin content was similar among groups. These studies indicate that combined ET(A) and AT(1) receptor blockade may produce some improvement on hemodynamics, but have no effect on progression of renal damage in this non-renin-dependent model of hypertension.
General Pharmacology 06/2000; 34(5):337-42.
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D M Pollock
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ABSTRACT: Due to the potent vasoconstrictor action of endothelin-1 and its synthesis throughout the vasculature and other tissues, most investigators believe that it is an active participant in the pathogenesis of hypertension. However, the autocrine and paracrine nature of the endothelin system has made its role difficult to define. In recent years, it has become apparent that endothelin-1 contributes to the regulation of renal salt and water excretion and that it is a major contributor to the hypertension associated with salt-dependency. Evidence suggests that endothelin-1 within the renal medulla is activated in conditions of salt loading and inhibits reabsorption of sodium in a nitric oxide-dependent manner. Blockade of endothelin A receptors lowers arterial pressure in animal models of salt-dependent hypertension. Furthermore, circulating levels of endothelin-1 are generally higher in African-Americans compared to white Americans as is the prevalence of salt-dependent hypertension. Therefore, it would appear that use of endothelin A-selective receptor antagonists should be targeted to those individuals at risk for salt-dependent hypertension. Blockade of endothelin B receptors would not be desirable because of their important role in eliminating a salt load.
Current Opinion in Nephrology and Hypertension 04/2000; 9(2):157-64. · 4.33 Impact Factor
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ABSTRACT: Experiments were designed to elucidate the role of endothelin B receptors (ET(B)) on arterial pressure and renal function in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Male Sprague-Dawley rats underwent uninephrectomy and were treated with either DOCA and salt (0.9% NaCl to drink) or placebo. DOCA-salt rats given the ET(B)-selective antagonist, A-192621, for 1 wk (10 mg. kg(-1). day(-1) in the food) had significantly greater systolic arterial pressure compared with untreated DOCA-salt rats (208 +/- 7 vs. 182 +/- 4 mmHg) whereas pressure in placebo rats was unchanged. In DOCA-salt, but not placebo rats, A-192621 significantly decreased sodium and water excretion along with parallel decreases in food and water intake. To determine whether the response in DOCA-salt rats was due to increased expression of ET(B) receptors, endothelin receptor binding was performed by using membranes from renal medulla. Maximum binding (B(max)) of [(125)I]ET-1, [(125)I]ET-3, and [(125)I]IRL-1620 increased from 227 +/- 42, 146 +/- 28, and 21 +/- 1 fmol/mg protein, respectively, in placebo rats to 335 +/- 27, 300 +/- 38, and 61 +/- 6 fmol/mg protein, respectively, in DOCA-salt hypertensive rats. The fraction of receptors that are the ET(B) subtype was significantly increased in DOCA-salt (0.88 +/- 0.07) compared with placebo (0.64 +/- 0.01). The difference between [(125)I]ET-3 and [(125)I]IRL-1620 binding is consistent with possible ET(B) receptor subtypes in the kidney. These results indicate that ET(B) receptors in the renal medulla are up-regulated in the DOCA-salt hypertensive rat and may serve to maintain a lower arterial pressure by promoting salt and water excretion.
American journal of physiology. Renal physiology 03/2000; 278(2):F279-86. · 3.68 Impact Factor
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ABSTRACT: Blacks exhibit greater vasoconstriction-mediated blood pressure (BP) increases in response to stress than do whites. Endothelin-1 (ET-1), a potent vasoconstrictive peptide, has been proposed as having a role in racial differences in stress reactivity. We evaluated the hemodynamic and plasma ET-1 levels of 41 (23 whites, 18 blacks, mean age 18.6 years) normotensive adolescent males at rest and in response to a video game challenge and forehead cold stimulation. Measurements were performed at catheter insertion and before and immediately after the 2 stressors, which were separated by 20-minute rest periods. Blacks exhibited higher absolute levels of diastolic blood pressure, total peripheral resistance index, or both in response to catheter insertion and to the video game challenge and during recovery from video game challenge and cold stimulation (P<0. 05 for all). Blacks exhibited higher absolute levels of ET-1 at every evaluation point (P<0.05 for all) and greater increases in ET-1 in response to both stressors (ps<0.05). These findings suggest that altered endothelial function may be involved in racial differences in hemodynamic reactivity to stress and possibly in the development of essential hypertension.
Hypertension 03/2000; 35(3):722-5. · 6.21 Impact Factor
