Neurally-mediated vasodilatation in normal and portal hypertensive rats: role of nitric oxide and calcitonin gene-related peptide.
OBJECTIVE
Portal hypertension is associated with systemic vasodilatation and vascular hyporeactivity, and is reversed by inhibiting nitric oxide biosynthesis. Nitric oxide and calcitonin gene-related peptide are neurotransmitters of non-adrenergic non-cholinergic nerves. The role of nitric oxide and calcitonin gene-related peptide in nerve-stimulated vasodilatation in portal hypertension is unknown.


METHODS
We tested (i) if in vitro perfused superior mesenteric arterial vascular beds of portal hypertensive rats (induced by partial portal vein ligation) showed an increased vasodilatation to periarterial nerve stimulation compared to normal controls, and (ii) if this vasodilatation was modulated by nitric oxide and calcitonin gene-related peptide antagonism.


RESULTS
Vasodilatatory responses to periarterial nerve stimulation (10 V, 1 ms) with increasing frequencies (Hertz, 2-12) in preconstricted vessels (methoxamine and guanethidine) were significantly smaller in vessel preparations of control (n=8) compared to portal hypertensive (n=7) rats, values with 8 Hertz being 32.3+/-3.6% and 44.9+/-3.6%, respectively (p<0.05). This difference was reversed by inhibiting nitric oxide and calcitonin gene-related peptide action with the nitric oxide-biosynthesis inhibitor N(omega)-Nitro-L-arginine, values for 8 Hertz being 28.7+/-4.8% (controls) and 37.8+/-3.3% (portal hypertensive, ns) or with the calcitonin gene-related peptide antagonist CGRP8-37, values being 25.2+/-2.8% (controls) and 27.8+/-4.2% (portal hypertensive, ns), respectively (n=4-6 per group). Vasodilatation to the beta-agonist isoproterenol was not significantly different between groups with and without calcitonin gene-related peptide and nitric oxide antagonism.


CONCLUSIONS
Portal hypertensive rats display a significantly enhanced vasodilatation to periarterial nerve stimulation, which is reversed by inhibiting the non-adrenergic non-cholinergic neurotransmitters nitric oxide and especially calcitonin gene-related peptide.
Department of Research, University Hospital, Basle, Switzerland.
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Moll-Kaufmann
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Sumanovski
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Sieber
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology / Q000502:physiology*; D004558:Electric Stimulation; D006975:Hypertension, Portal / Q000503:physiopathology*; D008297:Male; D017538:Mesenteric Artery, Superior / Q000294:innervation* / Q000502:physiology* / Q000503:physiopathology; D009131:Muscle, Smooth, Vascular / Q000294:innervation* / Q000502:physiology* / Q000503:physiopathology; D009569:Nitric Oxide / Q000502:physiology*; D019335:Nitroarginine / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D013564:Sympathetic Nervous System / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D010446:Peptide Fragments; C058636:calcitonin gene-related peptide (8-37); D019335:Nitroarginine; D009569:Nitric Oxide; D015740:Calcitonin Gene-Related Peptide