Characterization of the non-adrenergic/non-cholinergic response to perivascular nerve stimulation in the double-perfused mesenteric bed of the mouse.
OBJECTIVE
Calcitonin gene-related peptide (CGRP), a capsaicin-sensitive neuromodulator of splanchnic vascular tone in several animal species, remains poorly investigated in mouse models. We therefore assessed whether endogenous CGRP is a non-adrenergic/non-cholinergic (NANC) neuromodulator in the mesenteric vascular bed of the mouse.


METHODS
Arterial and venous changes in perfusion pressure in response to perivascular nerve stimulation (PNS) were monitored in the mouse mesenteric bed under basal conditions or precontracted with KCl (artery) or U46619 (vein) in circuits pretreated with guanethidine, atropine, indomethacin and prazosin. Arterial responses to NANC were also characterized with a CGRP1 antagonist, halphaCGRP8-37. Finally, the PNS-induced release of arterial CGRP was measured by enzyme immunoassay.


RESULTS
HalphaCGRP8-37 enhanced PNS-induced arterial increases in perfusion pressure under basal tone. PNS-induced stimulation of NANC triggered an halphaCGRP8-37 or capsaicin- sensitive reduction in perfusion pressure of the pre-contracted arterial bed only. Chemical removal of the endothelium inhibited PNS- and halphaCGRP- induced reduction in perfusion pressure in the arterial mesenteric bed. Responses to NANC nerves were reduced by guanylate and adenylate cyclase inhibitors (1H-[1,2,4]oxadiazole[4,3-a] quinoxalin-1-one (ODQ)) and [9-(tetrahydro-2-furanyl)-9H-purin-6-amine] (SQ 22,536), respectively. A neuronal NOS inhibitor (7-nitroindazole; 7-NI) also enhanced the response to NANC in vessels from wild-type, eNOS KO but not iNOS KO mice. Finally, PNS enhanced the release of immunoreactive CGRP from the perfused arterial mesenteric bed.


CONCLUSIONS
Our study demonstrates a role for CGRP in the NANC-dependent reduction in perfusion pressure of the arterial but not venous mesenteric bed of the mouse.
Legros
E
E
Department of Pharmacology, Medical School, Institut de pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec, Canada.
Tirapelli
C R
CR
Carrier
E
E
Brochu
I
I
Fournier
A
A
D'Orléans-Juste
P
P
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D004558:Electric Stimulation; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005260:Female; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D008642:Mesenteric Veins / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D009924:Organ Culture Techniques; D010069:Oxadiazoles / Q000494:pharmacology; D010477:Perfusion; D010525:Peripheral Nerves / Q000187:drug effects / Q000502:physiology*; D011189:Potassium Chloride / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D013152:Splanchnic Circulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D010069:Oxadiazoles; D011810:Quinoxalines; C017759:9-(tetrahydro-2-furyl)-adenine; D009569:Nitric Oxide; D011189:Potassium Chloride; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D000225:Adenine; D015740:Calcitonin Gene-Related Peptide