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K Y Chan, L Edvinsson,
S Eftekhari,
P O Kimblad,
S A Kane,
J Lynch,
R J Hargreaves,
R de Vries,
I M Garrelds,
A J van den Bogaerdt,
A H J Danser,
A Maassenvandenbrink
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ABSTRACT: The sensory neuropeptide calcitonin gene-related peptide (CGRP) plays a role in primary headaches, and CGRP receptor antagonists are effective in migraine treatment. CGRP is a potent vasodilator, raising the possibility that antagonism of its receptor could have cardiovascular effects. We therefore investigated the effects of the antimigraine CGRP receptor antagonist telcagepant (MK-0974) [N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxamide] on human isolated coronary arteries. Arteries with different internal diameters were studied to assess the potential for differential effects across the coronary vascular bed. The concentration-dependent relaxation responses to human alphaCGRP were greater in distal coronary arteries (i.d. 600-1000 microm; E(max) = 83 +/- 7%) than proximal coronary arteries (i.d. 2-3 mm; E(max) = 23 +/- 9%), coronary arteries from explanted hearts (i.d. 3-5 mm; E(max) = 11 +/- 3%), and coronary arterioles (i.d. 200-300 microm; E(max) = 15 +/- 7%). Telcagepant alone did not induce contraction or relaxation of these coronary blood vessels. Pretreatment with telcagepant (10 nM to 1 microM) antagonized alphaCGRP-induced relaxation competitively in distal coronary arteries (pA(2) = 8.43 +/- 0.24) and proximal coronary arteries and coronary arterioles (1 microM telcagepant, giving pK(B) = 7.89 +/- 0.13 and 7.78 +/- 0.16, respectively). alphaCGRP significantly increased cAMP levels in distal, but not proximal, coronary arteries, and this was abolished by pretreatment with telcagepant. Immunohistochemistry revealed the expression and colocalization of the CGRP receptor elements calcitonin-like receptor and receptor activity-modifying protein 1 in the smooth muscle cells in the media layer of human coronary arteries. These findings in vitro support the cardiovascular safety of CGRP receptor antagonists and suggest that telcagepant is unlikely to induce coronary side effects under normal cardiovascular conditions.
Journal of Pharmacology and Experimental Therapeutics 09/2010; 334(3):746-52. · 3.83 Impact Factor
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ABSTRACT: Calcitonin gene related peptide (CGRP) has a key role in migraine and recently CGRP receptor antagonists have demonstrated clinical efficacy in the treatment of migraine. However, it remains unclear where the CGRP receptors are located within the CGRP signaling pathway in the human trigeminal system and hence the potential antagonist sites of action remain unknown. Therefore we designed a study to evaluate the localization of CGRP and its receptor components calcitonin receptor-like receptor (CLR) and receptor activity modifying protein (RAMP) 1 in the human trigeminal ganglion using immunohistochemistry and compare with that of rat. Antibodies against purified CLR and RAMP1 proteins were produced and characterized for this study. Trigeminal ganglia were obtained at autopsy from adult subjects and sections from rat trigeminal ganglia were used to compare the immunostaining pattern. The number of cells expressing CGRP, CLR and RAMP1, respectively, were counted. In addition, the glial cells of trigeminal ganglion, particularly the satellite glial cell, were studied to understand a possible relation. We observed immunoreactivity for CGRP, CLR and RAMP1, in the human trigeminal ganglion: 49% of the neurons expressed CGRP, 37% CLR and 36% RAMP1. Co-localization of CGRP and the receptor components was rarely found. There were no CGRP immunoreactions in the glial cells; however some of the glial cells displayed CLR and RAMP1 immunoreactivity. Similar results were observed in rat trigeminal ganglia. We report that human and rat trigeminal neurons store CGRP, CLR and RAMP1; however, CGRP and CLR/RAMP1 do not co-localize regularly but are found in separate neurons. Glial cells also contain the CGRP receptor components but not CGRP. Our results indicate, for the first time, the possibility of CGRP signaling in the human trigeminal ganglion involving both neurons and satellite glial cells. This suggests a possible site of action for the novel CGRP receptor antagonists in migraine therapy.
Neuroscience 08/2010; 169(2):683-96. · 3.38 Impact Factor
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ABSTRACT: The role of nitric oxide (NO) in migraine has been studied in the experimental glyceryl trinitrate (GTN)-infusion headache model. We hypothesized that GTN-induced headache may activate the trigeminovascular system and be associated with increased levels of sensory neuropeptides, including calcitonin gene-related peptide (CGRP). CGRP, vasoactive intestinal peptide (VIP), neuropeptide Y (NPY) and somatostatin plasma levels were measured before and after placebo/sumatriptan injection and during GTN-induced headache. Following a double-blind randomized cross-over design, 10 healthy volunteers received subcutaneous sumatriptan 6 mg or placebo. This was succeeded by 20 min of GTN (0.12 µg kg(-1) min(-1)) infusion. At baseline no subject reported headache (using verbal rating scale from 0 to 10) and the jugular CGRP-like immunoreactivity (-LI) level was 18.6 ± 2.5 pmol/l. After a 20-min intravenous infusion of GTN 0.12 µg kg(-1) min(-1), median peak headache intensity was 4 (range 2-6) (P < 0.05), while jugular CGRP-LI levels were unchanged (19.0 ± 2.8 pmol/l; P > 0.05). There were no changes in VIP-, NPY- or somatostatin-LI. In conclusion, the NO donor GTN appears not to induce headache via immediate CGRP release.
Cephalalgia 09/2009; 30(4):467-74. · 3.43 Impact Factor
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Pharmacology & Toxicology 03/2009; 59(s7):116 - 118.
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ABSTRACT: To examine the ascending projections from the headache-related trigeminocervical complex in rats, biotinylated dextran amine (BDA) was injected into the ventrolateral dorsal horn of segments C1 and C2, a region previously demonstrated to receive input from sensory nerves in cranial blood vessels. Following injections into laminae I-II, BDA-labelled terminations were found bilaterally in several nuclei in the pons and the midbrain, including the pontine reticular nucleus, the parabrachial nuclei, the cuneiform nucleus and the periaqueductal grey. In the diencephalon, terminations were confined to the contralateral side and evident foremost in the posterior nuclear group, especially its triangular part, and in the ventral posteromedial nucleus. Following injections extending through laminae I-IV, anterograde labelling was more extensive. Some of the above regions are likely to be involved in the central processing of noxious signals of craniovascular origin and therefore putatively involved in mechanisms associated with primary headaches.
Cephalalgia 03/2009; 29(9):935-48. · 3.43 Impact Factor
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ABSTRACT: Salient aspects of the anatomy and function of the blood-barrier barrier (BBB) are reviewed in relation to migraine pathophysiology and treatment. The main function of the BBB is to limit the access of circulating substances to the neuropile. Smaller lipophilic substances have some access to the central nervous system by diffusion, whereas other substances can cross the BBB by carrier-mediated influx transport, receptor-mediated transcytosis and absorptive-mediated transcytosis. Studies of drugs relevant to migraine pathophysiology and treatment have been examined with the pressurized arteriography method. The drugs, given both luminally and abluminally, provide important notions regarding antimigraine site of action, probably abluminal to the BBB. The problems with the BBB in animal models designed to study the pathophysiology, acute treatment models and preventive treatments are discussed with special emphasize on the triptans and calcitonin gene-related peptide (CGRP). The human experimental headache model, especially the use of glycerol trinitrate (the nitric oxide model), and experiences with CGRP administrations utilize the systemic administration of the agonists with effects on other vascular beds also. We discuss how this can be related to genuine migraine attacks. Our view is that there exists no clear proof of breakdown or leakage of the BBB during migraine attacks, and that antimigraine drugs need to pass the BBB for efficacy.
Cephalalgia 09/2008; 28(12):1245-58. · 3.43 Impact Factor
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ABSTRACT: Previous studies have shown that endothelin type B (ETB) and 5-hydroxytryptamine type 1B (5-HT1B) receptors are upregulated following subarachnoid hemorrhage (SAH). The purpose of the present study was to test whether
extracellular signal-regulated kinase (ERK1/2) inhibition could alter the degree of SAH induced receptor upregulation in addition
to prevent the cerebral blood flow (CBF) reduction. The ERK1/2 inhibitor SB386023-b was injected intra cisternally in conjunction
with and after the induced SAH in rats. Two days after SAH cerebral arteries were harvested and the contractile response to
endothelin-1 (ET-1) and 5-carboxamidotryptamine (5-CT) were investigated with a myograph. The contractile responses to ET-1
and 5-CT were increased after SAH compared to sham. Administration of SB-386023-b prevented the upregulated contraction elicited
by application of ET-1 and 5-CT in cerebral arteries. Regional CBF evaluated by an autoradiographic technique, revealed a
reduced CBF by 50% after SAH this was prevented by treatment with SB-386023-b. The results indicate that an ERK1/2 mechanism
is involved in cerebral vasospasm and ischemia associated with SAH.
12/2007: pages 65-67;
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ABSTRACT: A new concept for the inhibition of CGRP signalling has been developed by interaction with the CGRP molecule per se by using a CGRP antibody or a CGRP binding RNA-Spiegelmer (NOX-C89). We have compared these CGRP scavengers with two known receptor antagonists (CGRP8-37 and BIBN4096BS) on CGRP-induced relaxations in the rat middle cerebral artery (MCA). Furthermore, the role of the endothelial barrier has been studied.
We used the luminally perfused MCA in an arteriograph, pressurized to 85 mm Hg and myograph studies of isolated ring segments of the MCA.
In myograph studies and in the perfusion system during abluminal application, alphaCGRP and betaCGRP induced concentration-dependent dilatation of the MCA. Given luminally neither peptide was significantly vasodilator. Adrenomedullin and amylin induced weak dilatations. In myograph experiments, relaxation induced by alphaCGRP was prevented by the four CGRP blockers (CGRP8-37, BIBN4096BS, the CGRP antibody and NOX-C89.). In abluminal perfusion experiments, the relaxant response to alphaCGRP was prevented by these agents to a varying degree. Dilatation induced by abluminal application of alphaCGRP was inhibited by luminal CGRP8-37 but not by luminal BIBN4096BS, CGRP antibody or NOX-C89.
alpha or betaCGRP acted on smooth muscle cell CGRP receptors in rat MCA and were effectively prevented from reaching these receptors by the endothelial barrier. The CGRP blockers significantly inhibited alphaCGRP induced relaxation but were also prevented from reaching the CGRP receptors by the arterial endothelium.
British Journal of Pharmacology 04/2007; 150(5):633-40. · 4.41 Impact Factor
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ABSTRACT: Calcitonin gene-related peptide (CGRP) and related peptides may be involved in migraine pathogenesis. To understand their vasomotor role in the cerebral circulation, we performed two studies, a pressurized arteriography study of the middle cerebral artery (MCA) and a genuine closed cranial window (gCCW) in vivo study. Using the pressurized arteriography model rat MCAs were mounted on micropipettes, pressurized to 85 mmHg and luminally perfused. The diameter responses to luminally and abluminally applied rat-alphaCGRP, rat-betaCGRP, amylin and adrenomedullin were compared with the resting diameter. Only abluminally applied CGRP induced dilation of the cerebral arteries; E(max) for alphaCGRP and betaCGRP were 35 +/- 0.5% and 10.8 +/- 0.2%. These responses were blocked by CGRP(8-37). The gCCW model allowed videomicroscopic visualization of the pial vessels in anaesthetized rats. Changes in vessel diameter to intravenously administered alphaCGRP and betaCGRP were compared with pre-infusion baseline. Intravenous infusion of alphaCGRP and betaCGRP in the highest dose induced dilation of the cerebral cortical pial arteries/arterioles of 40.3 +/- 7.5% and 49.1 +/- 8.4%, respectively. However, this was probably secondary to a decrease in blood pressure of 44.8 +/- 3.3 mmHg and 49.2 +/- 3.3 mmHg. Our results suggest that CGRP receptors are probably functional on the smooth muscle cells and not on the endothelium of rat cerebral arteries.
Cephalalgia 07/2005; 25(6):424-32. · 3.43 Impact Factor
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ABSTRACT: The genuine closed cranial window model, in which the thinned parietal bone constitutes the covering of the preparation, has contributed to a better understanding of the pathophysiological mechanisms in migraine. In its present form, only measurements of the middle meningeal artery (MMA) are performed. The aim of this study was, in addition, to measure pial artery/arteriole (PA) diameter and cortical cerebral blood flux in the same cranial window. The model was evaluated by studying the effects of hypotension and changes in arterial carbon dioxide pressure (PaCO2), because these parameters might influence the interpretation of pharmacological experiments. Out of 23 successful experiments it was possible to measure all three parameters in 19 animals. In four, PA diameter could not be measured, while MMA diameter and local cortical cerebral blood flux (LCBF(Flux)) always could. Haemorrhage-induced hypotension (-64+/-0.8 mmHg) caused an increase of MMA diameter of 11.8+/-8.4%, PA diameter of 61.2+/-7.7% and a decrease in LCBF(Flux) of -36.4+/-2.5%. The decrease in blood pressure did not significantly change the MMA (P=0.38); however, the PA diameter and the LCBF(Flux) were affected (P<0.001). All three parameters were sensitive to hypo- and hypercapnia. In conclusion, we have shown that not only MMA but also PA diameter and LCBF(Flux) can be measured in the same cranial window. Tight control of PaCO2 is essential in pharmacological experiments. If test substances possess hypotensive actions, it may be difficult to interpret whether the PA dilation is caused by the induced hypotension per se or is a direct pharmacological action or a combination. In contrast, the MMA does not autoregulate and MMA diameter changes in pharmacological studies may exclusively be due to direct pharmacological effects.
Cephalalgia 02/2005; 25(1):23-9. · 3.43 Impact Factor
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L Edvinsson
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ABSTRACT: In primary headaches, there is a clear association between the headache and the release of calcitonin gene-related peptide (CGRP) but not with any of the other neuronal messengers. The purpose of this review is to describe the role of CGRP in the intracranial circulation and to elucidate a possible role for a specific CGRP receptor antagonist in the treatment of primary headaches. Acute treatment with a 5-HT(1B/1D) agonist (triptan) results in alleviation of the headache and normalization of the cranial venous CGRP levels, in part due to a presynaptic inhibitory effect on sensory nerves. The central role of CGRP in migraine and cluster headache pathophysiology has led to the search for small molecule CGRP antagonists with few cardiovascular side-effects. The initial pharmacological profile of such a group of compounds has recently been disclosed. One of these compounds has been found to be efficacious in the relief of acute attacks of migraine.
Cephalalgia 09/2004; 24(8):611-22. · 3.43 Impact Factor
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ABSTRACT: The pulmonary and vascular effects of endothelin-1 receptor activation were studied in isolated perfused and ventilated lung preparations from rat. The responses to endothelin-1 (ET-1) and the endothelin B (ET(B)) receptor agonist sarafotoxin 6c (S6c) were characterized using the endothelin A (ET(A))-receptor antagonist FR 139317, the ET(B)-receptor antagonist BQ 788 and the combined ET(A)/ET(B)-receptor antagonist Bosentan. The respiratory parameter airway conductance (G(aw)) and the vascular parameter perfusion flow were analysed simultaneously.
Concentration-response curves for ET-1 administered intra-arterially revealed that its most potent effect was on the vascular side while S6c had a more potent effect on airway conductance. ET-1, given as a bolus dose intra-arterially (100 microL of 0.2 nM), induced a strong- and long-lasting contraction of the vasculature while only a less pronounced contraction was seen in the airways. Neither of the antagonists had a significant effect per se on G(aw) or perfusion flow. FR 139317 reduced the effect of ET-1 on perfusion flow by about 50%, while airway conductance was augmented. BQ 788 enhanced the decrease in perfusion flow by ET-1 while G(aw) was not influenced. The combined ET(A)/ET(B) antagonist Bosentan powerfully prevented the ET-1-induced decrease in G(aw) but did not alter its reduction in perfusion flow.
The potent effect of ET-1 on the vascular side of the lung is mediated mainly through ET(A) receptors, whereas both ET(A) and ET(B) receptors are involved in G(aw) in the rat lung.
Acta Physiologica Scandinavica 07/2004; 181(2):259-64. · 2.55 Impact Factor
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ABSTRACT: The central projections of the rat superior sagittal sinus (SSS) sensory innervation were studied by transganglionic tract tracing techniques. Cholera toxin subunit b (CTb) or wheat germ agglutinin-horseradish peroxidase conjugate (WGA-HRP) was applied on the overlying dura of the SSS and labeled terminations in the brainstem and cervical spinal cord were examined under the light microscope. Labeled cell bodies were seen bilaterally in the trigeminal ganglia and in the C2 dorsal root ganglia following both CTb and WGA-HRP applications. In the brainstem, labeled terminations were mainly found in the caudal and interpolar parts of the spinal trigeminal nucleus. In the CTb cases, terminations were also found in the dorsolateral part of the cuneate nucleus. In the spinal cord, labeled terminations were primarily located in the most ventrolateral part of the C1-C3 spinal dorsal horns on both sides. WGA-HRP labeled terminations were mainly located in laminae I and II, whereas CTb-labeled terminations located in laminae III and IV. These results indicate that the sensory information from the SSS is transmitted through both trigeminal and cervical spinal nerve branches to a primary sensory nervous center that extends from the C3 dorsal horn until to the interpolar part of the spinal trigeminal nucleus.
Neuroscience 02/2004; 129(2):431-7. · 3.38 Impact Factor
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ABSTRACT: 5-HT1D (but not 5-HT1B)-receptor immunoreactivity (i.r.) can be detected on trigeminal fibres within the spinal trigeminal tract of the human brainstem. The present study used immunohistochemical and morphometric techniques to determine the proportions of trigeminal fibres expressing substance P, CGRP or 5-HT1D-receptor immunoreactivities. Co-localization studies between 5-HT1D-receptor and substance P- or CGRP-i.r. were also performed. Brainstem material was obtained with consent (four donors) and the total number of immunoreactive fibres within the trigeminal tract was estimated using random field sampling. A greater proportion of fibres (>1 microm diameter) expressed CGRP-i.r. (80 +/- 6%) compared with substance P-i.r. (46 +/- 7%) or 5-HT1D-receptor-i.r. (25 +/- 1%). 5-HT1D-receptor-i.r. was co-localized on some CGRP- or substance P-i.r. fibres. This suggests that 5-HT1D-receptors can regulate the release of CGRP and substance P and may be relevant to the clinical effectiveness of 5-HT1B/1D-receptor agonists in the treatment of migraine and other cranial pain syndromes.
Cephalalgia 07/2002; 22(6):424-31. · 3.43 Impact Factor
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ABSTRACT: There is a considerable literature to suggest that adenosine A1 receptor agonists may have anti-nociceptive effects, and we sought to explore the role of adenosine A1 receptors in a model of trigeminovascular nociceptive transmission. Cats were anaesthetized (alpha-chloralose 60 mg/kg, intraperitoneally), and prepared for physiological monitoring. The superior sagittal sinus (SSS) was stimulated electrically, and linked units were recorded in the trigeminocervical complex. Post-stimulus histograms were constructed to analyse the responses and the effect of drug administration. Blood was sampled from the external jugular vein to determine levels of calcitonin gene-related peptide (CGRP) release before and after drug administration. Intravenous administration of the highly selective adenosine A1 receptor agonist, GR79236 (3-100 microg/kg) had a dose-dependent inhibitory effect on SSS-evoked trigeminal activity. The maximal effect (80 +/- 6% reduction in probability of firing) was seen at 100 microg/kg. The neuronal inhibitory effect of GR79236 could be inhibited by the selective adenosine A1 receptor antagonist DPCPX (300 microg/kg; P < 0.05). SSS stimulation increased cranial CGRP levels from 33 +/- 2 pmol/l (n = 6) to 64 +/- 3 pmol/l, an effect substantially reduced by pre-treatment with GR79236 (30 microg/kg; P < 0.01). The selective low efficacy adenosine A1 receptor agonist, GR190178 (30-1000 microg/kg i.v.), also inhibited SSS-evoked neuronal activity in a dose-dependent fashion. In this model of trigeminovascular nociception, adenosine A1 receptor activation leads to neuronal inhibition without concomitant vasoconstriction, suggesting a novel avenue for the treatment of migraine and cluster headache.
Brain 07/2002; 125(Pt 6):1392-401. · 9.46 Impact Factor
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ABSTRACT: The vascular effects of endothelins (ET) are in mammals mediated via two receptor subtypes, endothelin A (ET(A), mainly constrictive) and endothelin B (ET(B), mainly dilating) receptors. We have examined the presence of ET(A) and ET(B) receptor mRNA using the reverse transcription polymerase chain reaction (RT-PCR) in both normal human cerebral arteries and cerebral arteries from patients with cerebrovascular disease. Two vessel preparations were studied: macroscopic arteries and microvessels, the latter obtained through a sensitive separation method. In endothelial cells both ET(A) and ET(B) receptor mRNA was detected. In almost all samples from normal cerebral arteries only ET(A) receptor mRNA was detected, whereas in vessel samples from patients with cerebrovascular disease as well as cerebral neoplasms, additional ET(B) receptor mRNA was detected significantly more frequently. The pathophysiological significance of this difference is at present speculative, but does point to a vascular involvement of this receptor in cerebrovascular disease.
British Journal of Neurosurgery 05/2002; 16(2):149-53. · 0.88 Impact Factor
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ABSTRACT: Extracellular nucleotides have been shown to induce vasodilatation of conductance arteries by release of the endothelium-derived hyperpolarizing factor (EDHF). As small resistance arteries are of greater importance for blood pressure regulation, a whole rat mesenteric arterial bed preparation was used in the present study when evaluating the physiological relevance for EDHF in mediating nucleotide dilatation. Dilatory responses were examined after pre-contraction with noradrenaline in the presence of 10 mM indomethacin. Adenosine-5'-O-thiodiphosphate (ADPbetaS), adenosine triphosphate (ATP) and uridine triphosphate (UTP) induced vasodilatation (pEC50=6.5-7 and E(max)=40-70%), while uridine diphosphate (UDP) was ineffective. Endothelium-derived hyperpolarizing factor was studied in the presence of 0.5 mM Nvarpi-nitro-L-arginine (L-NOARG). ADPbetaS and UTP induced strong and potent EDHF-dilatations, while ATP only had a weak effect (E(max)=25%). After P2X1 receptor desensitization with 10 microM alphabeta-methylene-adenosine triphosphate, the ATP response was significantly increased (E(max)=65%). Putatively, this could be because of simultaneous activation of both endothelial P2Y receptors and P2X1 receptors on smooth muscle cells, which resulted in the release of EDHF and subsequent hyperpolarization, and depolarization, respectively. Nitric oxide (NO) was studied in the presence of 60 mM K+. ADPbetaS, ATP and UTP induced weak NO dilatations, suggesting a minor role for NO as compared with EDHF. In conclusion, extracellular nucleotides stimulate dilatation by activating P2Y(1) and P2Y(2)/P2Y(4) receptors, but not P2Y(6) receptors. The dilatory responses are mediated primarily by EDHF in the peripheral vascular bed.
Acta Physiologica Scandinavica 05/2002; 174(4):301-9. · 2.55 Impact Factor
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ABSTRACT: In migraine and other primary headaches there is a strong vascular component. Besides the trigeminovascular components some of the associated symptoms point to the involvement of brain stem regions. The central limb of the trigeminal vascular pathway is its projection to the trigeminal nucleus caudalis (TNC) and to the C1-C2 levels of the spinal cord. The aim of the present study was to demonstrate the occurrence of some neurotransmitters in these regions in man. In both the TNC and in the Rexed's laminae I and II of the dorsal horns at the C1 and C2 levels there were numerous substance P immunoreactive fibres. Fibres containing calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating peptide (PACAP) were moderately dense in number. Fibres containing vasoactive intestinal peptide (VIP) or nitric oxide synthase (NOS) were not seen in the TNC or at the C1 and C2 levels of the spinal cord.
Cephalalgia 04/2002; 22(2):112-6. · 3.43 Impact Factor
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ABSTRACT: Extracellular nucleotides have been shown to induce vasodilatation of conductance arteries by release of the endothelium-derived hyperpolarizing factor (EDHF). As small resistance arteries are of greater importance for blood pressure regulation, a whole rat mesenteric arterial bed preparation was used in the present study when evaluating the physiological relevance for EDHF in mediating nucleotide dilatation. Dilatory responses were examined after pre-contraction with noradrenaline in the presence of 10 mM indomethacin. Adenosine-5′-O-thiodiphosphate (ADPβS), adenosine triphosphate (ATP) and uridine triphosphate (UTP) induced vasodilatation (pEC50=6.5–7 and Emax=40–70%), while uridine diphosphate (UDP) was ineffective. Endothelium-derived hyperpolarizing factor was studied in the presence of 0.5 mM Nϖ-nitro-L-arginine (L-NOARG). ADPβS and UTP induced strong and potent EDHF-dilatations, while ATP only had a weak effect (Emax=25%). After P2X1 receptor desensitization with 10 μMαβ-methylene-adenosine triphosphate, the ATP response was significantly increased (Emax=65%). Putatively, this could be because of simultaneous activation of both endothelial P2Y receptors and P2X1 receptors on smooth muscle cells, which resulted in the release of EDHF and subsequent hyperpolarization, and depolarization, respectively. Nitric oxide (NO) was studied in the presence of 60 mM K+. ADPβS, ATP and UTP induced weak NO dilatations, suggesting a minor role for NO as compared with EDHF. In conclusion, extracellular nucleotides stimulate dilatation by activating P2Y1 and P2Y2/P2Y4 receptors, but not P2Y6 receptors. The dilatory responses are mediated primarily by EDHF in the peripheral vascular bed.
Acta Physiologica Scandinavica 03/2002; 174(4):301 - 309. · 2.55 Impact Factor
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ABSTRACT: Isolated segments (1-2 mm) of small subcutaneous arteries (diameter 0.1-0.9 mm) and veins (0.1-1.0 mm) from patients with hypertension (essential n = 13, renovascular n = 6) and controls (n = 17) were examined. The relaxant responses to the sensory transmitters calcitonin gene-related peptide (CGRP) and substance P, and the contractile responses to potassium and noradrenaline were studied. Enhanced dilatory responses (E(max)) but no change in sensitivity (pEC50) were demonstrated in the arteries but not in the veins to CGRP in hypertensives (P < 0.01) as compared with normotensives, and in the hypertensive subgroups (essential hypertension, P < 0.05; renovascular hypertension, P< 0.05). The relaxant responses to substance P were not altered either in arteries or in veins of hypertensives. Furthermore, there were no differences in the contractile responses to 60 mM potassium or to 10 microM noradrenaline between the groups. The results suggest that the enhanced vasodilator response to CGRP in hypertension is an adaptive reaction. The elevated blood pressure may be augmented by vasodilatory activity since different subgroups of hypertensives showed the same results. However, other common characteristics of hypertension (eg, medication, metabolic disturbances) may have also influenced the results.
Journal of Human Hypertension 02/2002; 16(1):53-9. · 2.80 Impact Factor
