The possible role of peptides locally released from sensory nerves in the control of cardiac contractility and the coronary vascular tone was investigated in the present study. Immunohistochemical investigations revealed that calcitonin gene-related peptide (CGRP) -like immunoreactivity (-LI) was colocalized in sensory ganglia and in nerve fibres in the heart with substance P (SP) -LI. CGRP-LI was associated with myocardial cells, blood vessels and epicardia and endocardia in the atria while in the ventricles, CGRP-LI was mainly seen close to blood vessels and very few fibres were present in the myocardium. The level of CGRP-LI was three to four times higher in the right atria than in the ventricles. The tissue content of CGRP-LI was markedly reduced by systemic pretreatment with capsaicin, suggesting a sensory origin. Activation of capsaicin-sensitive cardiac C-fibres by K+, nicotine, bradykinin, ouabain and ischaemia was associated with a release of CGRP as indicated by an increased overflow from the isolated perfused guinea-pig heart. In addition, K+ and capsaicin induced the release of neurokinin A. Nicotine and K+ evoked the release of neuropeptide Y, which is present in sympathetic nerves. CGRP induced a prolongation of the action potential plateau phase in atrial myocytes, increased the velocity of relaxation and evoked positive chronotropic and inotropic effects. Capsaicin induced electrophysiological and contractile effects similar to those of CGRP. Furthermore, specific high affinity binding sites for CGRP were demonstrated in the rat heart and in the atrium CGRP stimulated adenylate cyclase activity. The capsaicin effects were abolished after systemic capsaicin pretreatment, which did not influence the stimulatory effects of CGRP or noradrenaline (NA), however. Repeated administration of CGRP to the same atrial preparation induced tachyphylaxis. After CGRP tachyphylaxis the stimulatory effects of capsaicin but not of NA were absent. The stimulatory actions of capsaicin on atrial contractility therefore seem to be evoked by CGRP. The inhibitory effects of capsaicin on ventricular contractility were not dependent on mediators released from capsaicin-sensitive sensory nerves. CGRP, SP and capsaicin induced coronary vasodilatation in the pig in vivo and in vitro. The vasodilatory effect of SP was subject to rapid tachyphylaxis and endothelium-dependent. Neither the CGRP- nor the capsaicin-induced relaxation was influenced by SP tachyphylaxis or removal of the endothelium. It is therefore suggested that CGRP is a more likely candidate than SP as a causative agent in the vasodilatory response seen upon activation of cardiac sensory nerves.(ABSTRACT TRUNCATED AT 400 WORDS)