Nonadrenergic and noncholinergic arterial dilatation and venoconstriction are mediated by calcitonin gene-related peptide1 and neurokinin-1 receptors, respectively, in the mesenteric vasculature of the rat after perivascular nerve stimulation.
In the present study, selective calcitonin gene-related peptide (CGRP) and neurokinin (NK) agonists and antagonists were used to characterize the receptors mediating the nerve-induced arterial vasodilation and venous vasoconstriction in the rat mesenteric vasculature. In guanethidine-pretreated preparations, perivascular nerve stimulation (PNS) induced a frequency-dependent vasodilation in the arterial vasculature (precontracted with methoxamine), yet only induced an atropine-resistant contraction in the venous mesenteric vasculature (precontracted with U46619) of the rat. hCGRP alpha induced a marked dose-dependent relaxation of the arterial side, whereas only a slight vasodilation was seen at a high dose on the precontracted venous side. The PNS or hCGRP alpha-induced arterial dilatation was markedly reduced by the antagonist hCGRP8-37, whereas the venoconstrictive response to PNS was not. Furthermore, [acetamidomethyl-Cys2,7]hCGRP was inactive on either side of the rat mesenteric vasculature. A selective NK-1 nonpeptidic antagonist (CP-96,345) reduced the response of the venous vasculature to PNS by 70% without affecting the response of the arterial side to the same stimulus. Furthermore, a selective NK-3 receptor antagonist ([Trp7,beta-Ala8]-NKA (4-10)) did not affect the venoconstriction induced by PNS, yet markedly reduced the pressor response induced by a selective NK-3 receptor agonist, [MePhe7]-NKB. Hence, PNS induces the release of CGRP which activates specifically CGRP1 receptors and induces relaxation on the arterial vasculature. On the venous side, the nerve stimulation activates transmural NK-1 receptors and evokes a venoconstriction.
Claing
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Department of Pharmacology, Medical School, University of Sherbrooke, Québec, Canada.
Télémaque
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Cadieux
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Fournier
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Regoli
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D'Orléans-Juste
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D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D004558:Electric Stimulation; D008297:Male; D008638:Mesenteric Arteries / Q000294:innervation* / Q000502:physiology; D008642:Mesenteric Veins / Q000294:innervation* / Q000502:physiology; D008784:Methysergide / Q000494:pharmacology; D051381:Rats; D018003:Receptors, Calcitonin; D011956:Receptors, Cell Surface / Q000187:drug effects*; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D013152:Splanchnic Circulation / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects*
D001713:Biphenyl Compounds; D018003:Receptors, Calcitonin; D011956:Receptors, Cell Surface; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter; D001285:Atropine; D015740:Calcitonin Gene-Related Peptide; C066892:CP 96345; D008784:Methysergide