Synergistic internal carotid vasodilator effects of human alpha-calcitonin gene-related peptide and nimodipine in conscious rats.
1. In a first series of experiments, male Long Evans rats were chronically instrumented for the measurement of internal carotid blood flow and systemic arterial blood pressure; cardiovascular changes were assessed during and after 30 min infusions of human alpha-calcitonin gene-related peptide (CGRP) (0.06 and 0.6 nmol h-1), or nimodipine (60 and 600 nmol h-1) or human alpha-CGRP plus nimodipine. The effects of human alpha-CGRP or nimodipine on internal carotid vasoconstriction induced by endothelin-1 were also measured. 2. Human alpha-CGRP (0.06 nmol h-1) caused a small (+15%), transient increase in internal carotid blood flow and a tachycardia (+33 beats min-1), but no change in mean blood pressure. Nimodipine (60 nmol h-1) caused a brief internal carotid hyperaemia (+16%) but no changes in blood pressure or heart rate. However, concurrent administration of human alpha-CGRP (0.06 nmol h-1) and nimodipine (60 nmol h-1) caused a sustained increase in internal carotid blood flow (+40%) unaccompanied by significant changes in heart rate or blood pressure. 3. Human alpha-CGRP at a dose of 0.6 nmol h-1 or nimodipine at a dose of 600 nmol h-1 caused substantial reductions in internal carotid vascular resistance (-43 and -40%, respectively); concurrent administration of these doses did not have an additive vasodilator effect. 4. Infusion of endothelin-1 (1.2nmolhV1) for 20min caused incremental constriction of the internal carotid vascular bed; human alpha-CGRP infusion (0.6 and 6.0nmolh-1) begun tOmin after the onset of endothelin-1 infusion reversed this effect (dose-dependently); nimodipine (600nmolh-1) also caused a substantial attenuation of the effects of endothelin-1. 5. In a second series of experiments the haemodynamic effects of human alpha-CGRP and/or nimodipine were assessed in rats chronically instrumented for the measurement of renal, superior mesenteric and hindquarters blood flow together with systemic arterial blood pressure. 6. Administration of human alpha-CGRP (0.06 nmol h-') alone or in conjuction with nimodipine (60nmolh-1) had no significant effects on renal or superior mesenteric vascular resistances, although there was a slight hindquarters vasodilatation. Human alpha-CGRP at a dose of 0.6 nmol -1 caused hypotension, tachycardia and reductions in renal and superior mesenteric blood flows, together with a marked (+31% maximum) hindquarters hyperaemia. Nimodipine at a dose of 600 nmol h-1 caused hypotension, tachycardia and a reduction (-34%) in renal blood flow; mesenteric blood flow was unchanged and there was an increase in hindquarters flow (+ 59%). 7. Concurrent administration of human alpha-CGRP (0.6 nmol h 1) and nimodipine (600 nmol h') did not have an additive hypotensive effect or an enhanced hindquarters hyperaemic effect, but was associated with a marked impairment of renal blood flow (-48%). 8. The present results indicate that concurrent administration of low doses of human alpha-CGRP and nimodipine might be particularly helpful in the acute treatment of patients with cerebral vasospasm and impaired renal perfusion, since this intervention improved internal carotid blood flow without compromising blood flow to the kidney.
Gardiner
S M
SM
Department of Physiology & Pharmacology, Medical School, Queen's Medical Centre, Nottingham.
Compton
A M
AM
Bennett
T
T
Kemp
P A
PA
Ney
U
U
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D002339:Carotid Arteries / Q000187:drug effects; D004357:Drug Synergism; D016232:Endothelins; D006439:Hemodynamics / Q000187:drug effects; D006614:Hindlimb / Q000098:blood supply / Q000187:drug effects; D006801:Humans; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D009553:Nimodipine / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D012039:Regional Blood Flow / Q000187:drug effects; D012079:Renal Circulation / Q000187:drug effects; D013152:Splanchnic Circulation / Q000187:drug effects; D014665:Vasodilator Agents
D016232:Endothelins; D010455:Peptides; D014665:Vasodilator Agents; D009553:Nimodipine; D015740:Calcitonin Gene-Related Peptide