Carotid blood flow distribution, haemodynamics and inotropic responses following calcitonin gene-related peptide in the pig

Abstract

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.

Effects of the Calcitonin Gene‐Related Peptide (CGRP) Receptor Antagonist BIBN4096BS on α‐CGRP‐Induced Regional Haemodynamic Changes in Anaesthetised Rats

“…It is worthy of note that CGRP is a potent inotropic agent in rabbits, pigs as well as humans (Van Gelderen et al 1995; Bell & McDermott 1996), but not in rats (Ishikawa et al 1987; Bratveit et al 1991). This may explain the lack of effect of α‐CGRP on cardiac output in our study (fig.…”

Effects of the CGRP receptor antagonist BIBN4096BS on capsaicin‐induced carotid haemodynamic changes in anaesthetised pigs

“…Among these neuropeptides, CGRP is considered as a biological marker in migraine pathogenesis ( Van Rossum et al , 1997 ; Goadsby et al , 2002 ; Hagner et al , 2002 ). Moreover, stimulation of trigeminal sensory neurones with electrical procedures or chemical substances, like capsaicin, releases endogenously stored CGRP ( Buzzi et al , 1995 ; Eltorp et al , 2000 ) that, in turn, dilates cranial vessels (Williamson & Hargreaves, 2001), including carotid arteriovenous anastomoses ( Van Gelderen et al , 1995 ). In addition, CGRP may also facilitate sensory nerve transmission between the first‐ and second‐order afferent input from these vessels during migraine headache ( Gulbenkian et al , 2001 ; Goadsby et al , 2002 ; Smith et al , 2002 ).…”

Migraine and beyond: cardiovascular therapeutic potential for CGRP modulators

“…In vitro studies have shown that CGRP causes a positive inotropic effect in the atria of guinea-pig, rat and man [35] and ventricular trabeculae of pig [36] and man [37].…”