Capsinolol: the first beta-adrenoceptor blocker with an associated calcitonin gene-related peptide releasing activity in the heart.

1. The beta-adrenoceptor blocking and calcitonin gene-related peptide (CGRP)-releasing properties of capsinolol (N-[4-(2-hydroxy-3 (isopropylamino) propoxy)-3-methoxybenzyl]-nonanamide), derived from nonivamide, were investigated under in vivo and in vitro conditions. 2. Capsinolol (0.1, 0.5, 1.0 mg kg-1, i.v.), as well as (+/-)-propranolol, produced a dose-dependent bradycardia response and a temporary pressor action in urethane-anaesthetized normotensive Wistar rats. These cardiovascular effects were different from the vagus reflex and parasympathetic efferent effects shown by capsaicin (0.1 mg kg-1, i.v.) in the rat. 3. Capsinolol (1.0 mg kg-1) inhibited the tachycardia effects induced by (-)-isoprenaline, but had no blocking effect on the arterial pressor responses induced by (-)-phenylephrine. The findings suggest that capsinolol possesses beta-adrenoceptor blocking activity, but it has no alpha-adrenoceptor blocking activity. 4. In guinea-pig isolated tissues, capsinolol (10(-8) to 10(-6) M) antagonized (-)-isoprenaline-induced positive chronotropic and inotropic effects of the atria and tracheal relaxation responses in a concentration-dependent manner. The parallel shift to the right of the concentration-response curve of (-)-isoprenaline suggests capsinolol is a beta-adrenoceptor competitive antagonist. 5. Capsinolol (10(-5) to 10(-4) M) exhibited a positive cardiotonic effect that was not inhibited by (+/-)-propranolol and reserpine, but was inhibited by capsazepine (10(-6) M) and CGRP8-37 (10(-6) M). This effect was independent of intrinsic sympathomimetic effects. 6. An immunoassay of released CGRP from guinea-pig isolated perfused heart indicated that capsinolol increases the release of CGRP and thus produces positive cardiotonic effects. 7. In conclusion, capsinolol is a non-selective beta-adrenoceptor antagonist with capsaicin-like cardiotonic properties unrelated to traditional intrinsic sympathomimetic effects. It is suggested that capsinolol causes CGRP release from cardiac sensory neurones via a non-adrenergic mechanism and then activates CGRP receptors on cardiac muscle.