Calcitonin gene-related peptide (CGRP) and capsaicin-induced stimulation of heart contractile rate and force

Abstract

The effects of calcitonin gene-related peptide (CGRP) on guinea-pig heart contractility were investigated in vitro in relation to the responce of capsaicin and noradrenaline (NA). Synthetic rat CGRP (>10⁻⁸ M) caused a long-lasting, positive inotropic and chronotropic effect on the spontaneously beating right atrium. The response to CGRP mimicked the effects of capsaicin and was resistant to betaadrenoceptor blockade using metoprolol. Furthermore, CGRP did not change basal efflux or the release of³H-NA induced by transmural nerve stimulation, suggesting an action independent of sympathetic mechanisms. Mepyramine and cimetidine did not reduce the response to CGRP. After tachyphylaxis to the effects of CGRP (5×10⁻⁷M) which developed within 15–20 min, the positive inotropic and chronotropic atrial response to capsaicin was abolished. The effects of NA, however, were not influenced by CGRP tachyphylaxis. In the isolated perfused whole heart, CGRP had more pronounced stimulatory effects on ventricular contractile rate than on force compared to NA. The CGRP response was resistant to metoprolol and still present in capsaicin-pretreated animals. Capsaicin caused a slight initial inhibition of ventricular contractility, which was followed by a marked stimulatory action. As for CGRP, the cardio-excitatory response to capsaicin was more pronounced on rate than on force. The stimulatory reponses to capsaicin were absent 2 weeks after systemic capsaicin pretreatment. In conclusion, CGRP mimics the non-adrenergic, cardioexcitatory effects of capsaicin, and the capsaicin response is absent after CGRP tachyphylaxis. Therefore, it is suggested that release of CGRP from local sensory nerves within the heart underlies the cardiostimulatory response to capsaicin.