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.
Chen
I J
IJ
Department of Pharmacology, Kaohsiung Medical College, Taiwan, Republic of China.
Yeh
J L
JL
Lo
Y C
YC
Sheu
S H
SH
Lin
Y T
YT
D058671:Adrenergic beta-1 Receptor Antagonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001919:Bradycardia / Q000139:chemically induced; D015740:Calcitonin Gene-Related Peptide / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009206:Myocardium / Q000276:immunology / Q000378:metabolism*; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013610:Tachycardia / Q000139:chemically induced; D014132:Trachea / Q000187:drug effects
D058671:Adrenergic beta-1 Receptor Antagonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D002316:Cardiotonic Agents; C104667:capsinolol; D011433:Propranolol; D015740:Calcitonin Gene-Related Peptide; D007545:Isoproterenol; D002211:Capsaicin