Carotid blood flow distribution, haemodynamics and inotropic responses following calcitonin gene-related peptide in the pig.
The sensory neuropeptide, calcitonin gene-related peptide (alpha-CGRP), has been implicated in the pathogenesis of migraine headache. The present study aimed to evaluate the effects of intracarotid infusions of human alpha-CGRP (10, 30 and 100 pmol/kg.min; n = 8), as compared to that of saline (4 times; n = 8) on haemodynamics and blood flow distribution within the carotid circulation of the anaesthetized pig, using the radioactive microsphere method. Furthermore, the effects of antimigraine drugs, dihydroergotamine (100 micrograms/kg i.v.; n = 4) or sumatriptan (300 micrograms/kg i.v.; n = 4), on these parameters were studied in the presence of the infusion of the highest concentration of human alpha-CGRP. Additionally, putative positive inotropic responses to human alpha-CGRP (10(-9)-10(-7) M) were investigated in porcine isolated atrial and ventricular trabeculae. Human alpha-CGRP increased carotid artery blood flow and conductance dose-dependently, together with an enhancement in vascular pulsations. These effects were associated with a fall in systemic blood pressure with concomitant increases in heart rate and cardiac output. The increase in carotid blood flow was reflected by an increase in total capillary blood flow, predominantly to extracerebral tissues including the dura, whereas blood flow through arteriovenous anastomoses remained stable. Both dihydroergotamine and sumatriptan reduced carotid blood flow and its capillary fraction without affecting systemic vascular conductance. In tissues, these drugs reversed blood flow increases due to human alpha-CGRP in most extracerebral tissues, but failed to reduce dural blood flow. In porcine isolated atrial and ventricular trabeculae, noradrenaline (10(-8)-10(-5) M) increased force of contraction in a concentration-dependent manner. In contrast, human alpha-CGRP (10(-9)-10(-7) M) failed to increase force of contraction in atrial trabeculae (n = 6) and exerted only a moderate concentration-dependent positive inotropic effect in ventricular trabeculae (approximately 25% of the response to 10(-5) M noradrenaline, n = 10). These data indicate that human alpha-CGRP caused arteriolar dilatation together with a fall in blood pressure in the pig. The tachycardia may be reflex-mediated, but the peptide also exerts a moderate positive inotropic action on ventricular trabeculae. The fall in systemic arterial blood pressure and the marked increase in capillary blood flow most likely prevented the opening of arteriovenous anastomoses. Furthermore, the antimigraine drugs, dihydroergotamine and sumatriptan, were able to reverse blood flow changes induced by human alpha-CGRP in the porcine carotid circulation.
Department of Pharmacology, Faculty of Medicine and Health Sciences, Erasmus University Rotterdam, Netherlands.
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Van Gelderen
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Du
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Schoemaker
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Saxena
D000818:Animals; D001163:Arteriovenous Anastomosis / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D017536:Carotid Artery, Common / Q000187:drug effects*; D004087:Dihydroergotamine / Q000494:pharmacology; D006325:Heart Atria / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D008863:Microspheres; D009200:Myocardial Contraction / Q000187:drug effects*; D018170:Sumatriptan / Q000494:pharmacology; D013552:Swine; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D014662:Vasoconstrictor Agents; D004087:Dihydroergotamine; D018170:Sumatriptan; D015740:Calcitonin Gene-Related Peptide