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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.

Inotropic effects of histamine have been studied extensively in many species, but data on porcine myocardium, often used as a model for human heart, are not available. We investigated inotropic effects of histamine on atrial and ventricular trabeculae obtained from porcine hearts. For comparison, we also evaluated the effects of histamine on human myocardium. Histamine caused concentration-dependent increases in contractile force in porcine and human atrial tissue [at 1 x 10(-3) M: 267 +/- 70 and 317 +/- 81 mg, or 133 +/- 17 and 85 +/- 12% of the response to 1 x 10(-5) M norepinephrine (NE), respectively], as well as in porcine and human ventricular tissue (at 1 x 10(-3) M: 592 +/- 148 and 773 +/- 203 mg, or 68 +/- 13 and 122 +/- 61% of response to 1 x 10(-5) M NE, respectively). Cimetidine, but not mepyramine, antagonized the contractile effects of histamine in porcine and human atrial tissue and in human ventricular tissue. In contrast, the histamine-induced positive inotropic effect in porcine ventricular tissue was antagonized by mepyramine but not by cimetidine. Propranolol failed to block the inotropic effect of histamine in all four tissues. These results indicate that, as with human atrial trabeculae, the positive inotropic effect on porcine atrial trabeculae is mediated by H2 receptors. In contrast to human ventricular trabeculae, however, the positive inotropic effect on porcine ventricular trabeculae appears to be mediated by H1 receptors.

Positive chronotropic as well as inotropic effects of 5-hydroxytryptamine (5-HT) have been observed in pig atrial tissue, but no data are available about the direct effects of 5-HT on ventricular tissue. In the present study we investigated inotropic effects of 5-HT on atrial and ventricular trabeculae obtained from hearts of 3 months old pigs. The baseline isometric contractile force was significantly higher in ventricular (4.14 +/- 1.25 mN) than in atrial tissue (0.47 +/- 0.11 mN). A noradrenaline concentration-response curve (0.01 to 10 mumol/l) was used to check contractile responsiveness of the tissue and all responses were expressed as percentage of the response to 10 mumol/l noradrenaline. Noradrenaline caused a concentration-dependent increase in contractile force in both atrial and ventricular trabeculae. In contrast, though 5-HT (0.01 to 100 mumol/l) did increase force of contraction in atrial tissue (maximum: 72 +/- 20% of the response to noradrenaline 10 mumol/l), the contractility of ventricular trabeculae was not significantly affected (maximum: 12 +/- 6%). The present data show that, in contrast to atrial tissue, contractile force of ventricular tissue could not be significantly affected by 5-HT. To our knowledge, this is the first study to show that an agent which increased force of contraction in the atrium, did not have a corresponding effect on the ventricle. These findings may have important implications for a better understanding of the physiology and pharmacology of cardiac contractility.