Involvement of calcitonin gene-related peptide in the positive chronotropic and inotropic effects of piperine and development of cross-tachyphylaxis between piperine and capsaicin in the isolated rat atria

Abstract

Piperine as well as capsaicin showed positive chronotropic and inotropic effects in the isolated spontaneously beating right atria and electrically driven left atria of rats, respectively. The responses to piperine were not affected by the presence of the antagonists to norepinephrine, acetylcholine, histamine and serotonin. However, once the tissue was pretreated with piperine or capsaicin, the response to subsequent application of piperine was reduced significantly. Both positive chronotropic and inotropic effects of capsaicin were also attenuated after the tissue was treated with piperine or capsaicin. Thus, not only a tachyphylaxis to either piperine or capsaicin itself but also a cross-tachyphylaxis between piperine and capsaicin developed. Nonadrenergic noncholinergic calcitonin gene-related peptide (CGRP)-like immunoreactive nerves were distributed in the muscle layers of both atria. CGRP-like immunoreactivity was depleted considerably by treatment of the tissue with piperine or capsaicin. When endogenous CGRP was depleted, although the positive chronotropic and inotropic effects of piperine and capsaicin were abolished, the effects of CGRP and isoproterenol were not affected. These results indicate that both piperine and capsaicin cause positive chronotropic and inotropic responses by releasing CGRP from nonadrenergic noncholinergic nerves, and that the development of cross-tachyphylaxis between piperine and capsaicin is due to the depletion of endogenous CGRP.