Effects of capsaicin on nonadrenergic noncholinergic nerves in the guinea pig atria: role of calcitonin gene-related peptide as cardiac neurotransmitter.

Transmural nerve stimulation (TNS) in vitro produced positive chronotropic and inotropic responses in the spontaneously beating right atria and electrically driven left atria of guinea pigs, respectively. Both the positive responses of the atria were mediated not only by adrenergic but also by nonadrenergic noncholinergic (NANC) nerves. Numerous calcitonin gene-related peptide (CGRP)-like immunoreactive nerves were found in the sinus node and the muscle layers of both atria of guinea pigs. Exogenously applied CGRP produced positive chronotropic and inotropic responses in a dose-dependent manner. In both the right and left atria, capsaicin (10(-5) M) induced positive chronotropic and inotropic responses. The second application of capsaicin did not cause any responses in the atria, indicating a rapid development of tachyphylaxis. When the tissues developed tachyphylaxis to capsaicin, the intensity of CGRP-like immunoreactivity greatly decreased in the sinus node and in both atria. In the atria that developed tachyphylaxis to capsaicin, the positive chronotropic and inotropic responses to NANC nerve stimulation diminished markedly, but the responses to exogenous CGRP and those attributed to adrenergic nerves were not affected. These results suggest that CGRP is the neurotransmitter of intracardiac NANC nerves and that capsaicin produces positive chronotropic and inotropic responses through the release of CGRP from NANC nerves in the guinea pig atria. It is also suggested that capsaicin depletes endogenous CGRP, thereby accounting for the rapid development of tachyphylaxis to capsaicin and the marked and selective diminution of TNS-induced NANC responses following application of capsaicin.