Neurogenic vasodilation in rabbit basilar isolated artery: involvement of calcitonin-gene related peptide.
Neurogenic vasodilation in cranial arteries may be an important mechanism in the pathogenesis of migraine headache. We describe a novel, in vitro assay to characterise neurogenic vasodilator responses in endothelium-denuded segments of rabbit isolated basilar artery, with particular focus on calcitonin-gene related peptide (CGRP). In arterial segments precontracted with prostaglandin F(2alpha), relaxations evoked by exogenously applied alphaCGRP (EC(50)=2.9 nM) were inhibited by alphaCGRP-(8-37) (pA(2)=6.49) or by desensitisation resulting from prior exposure to alphaCGRP. Relaxations evoked by exogenously applied vasoactive intestinal polypeptide (VIP) (EC(50)=2.5 nM) were inhibited by VIP-(7-28) 1 microM. The 5-HT(1) receptor agonists L-771,331 ((3S)-3[N-(S)-alpha-methylbenzyl]aminomethyl-(S)-1-[2-(5-(2-oxo-1, 3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl]pyrrolidine) and sumatriptan exerted contractile effects (EC(50)=293 and 95 nM, respectively). In neurogenic experiments, vasodilation evoked by electrical field stimulation was markedly attenuated by pre-treatment with capsaicin (10 microM) or by prior CGRP receptor desensitisation and to a lesser extent by pre-treatment with VIP-(7-28) 1 microM. L-771,331 (100 nM) exerted a weak inhibitory effect, marked only by a short reduction in the recovery time (post-electrical stimulation) and sumatriptan (30 nM) had no effect. The neurogenic response was potentiated by alphaCGRP-(8-37) 1 microM (reversible on wash-out). Short application (5-10 min) of capsaicin (10 microM) produced vasodilation that was inhibited by alphaCGRP-(8-37) 1 microM. These data suggest that electrically evoked neurogenic vasodilation in rabbit basilar artery has a large component resulting from the release of sensory neuropeptides in particular CGRP and a smaller component involving the release of VIP.
Olivar
T
T
Department of Pharmacology, Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Harlow, UK.
Razzaque
Z
Z
Nwagwu
M
M
Longmore
J
J
D000818:Animals; D001488:Basilar Artery / Q000187:drug effects* / Q000294:innervation / Q000502:physiology; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology / Q000502:physiology; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002211:Capsaicin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D010080:Oxazoles / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D011817:Rabbits; D018005:Receptors, Vasoactive Intestinal Peptide / Q000037:antagonists & inhibitors; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D018170:Sumatriptan / Q000494:pharmacology; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
C409724:3-(N-alpha-methylbenzyl)aminomethyl-1-(2-(5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl)ethyl)pyrrolidine; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D010080:Oxazoles; D010446:Peptide Fragments; D011759:Pyrrolidines; D018005:Receptors, Vasoactive Intestinal Peptide; D017366:Serotonin Receptor Agonists; D014662:Vasoconstrictor Agents; C058636:calcitonin gene-related peptide (8-37); D014660:Vasoactive Intestinal Peptide; D018170:Sumatriptan; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin