Importance of sympathetic innervation in the positive inotropic effects of bradykinin and ramiprilat.
Isolated rat left atria or right ventricular strips were electrically stimulated at a constant frequency. The amplitude of twitch contractions, thus elicited, rose as a function of stimulation intensity because of increases in the evoked release of sympathetic catecholamines. Bradykinin had no effect on contractile force in preparations paced at a minimal intensity (threshold). By contrast, bradykinin (1 nmol/L to 1 mumol/L) markedly increased twitch contractile force when the preparations were paced at a high intensity (two to three times threshold). The EC50 for the positive inotropic action of bradykinin averaged 42 nmol/L. Ramiprilat (1 mumol/L), an angiotensin I-converting enzyme/kinase II inhibitor, shifted the EC50 for bradykinin to approximately 2 nmol/L. Ramiprilat (1 mumol/L) per se also produced a modest positive inotropic effect. The effects of bradykinin and/or ramiprilate were inhibited by HOE 140 (300 nmol/L), a bradykinin B2-receptor antagonist. Propranolol (1 mumol/L), a beta-adrenoceptor blocker, abolished the effects of bradykinin. After the destruction of sympathetic nerve endings by use of 6-hydroxydopamine, bradykinin no longer exerted a positive inotropic action. Cocaine (10 micrograms/mL), an inhibitor of catecholamine reuptake, potentiated the effect of bradykinin. Bradykinin did not affect the positive inotropic response to tyramine (10 mumol/L), whereas cocaine blocked it. Furthermore, bradykinin did not modify the dose-response curves for added norepinephrine. omega-Conotoxin (100 nmol/L) inhibited the positive inotropic effect of intensified stimulation and bradykinin potentiation. Bradykinin is suggested to facilitate the evoked release of sympathetic catecholamines and thereby cause a positive inotropic effect.
Minshall
R D
RD
Department of Anesthesiology, University of Illinois College of Medicine, Chicago 60612.
Yelamanchi
V P
VP
Djokovic
A
A
Miletich
D J
DJ
Erdös
E G
EG
Rabito
S F
SF
Vogel
S M
SM
D000818:Animals; D001920:Bradykinin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology; D004357:Drug Synergism; D004558:Electric Stimulation; D006321:Heart / Q000187:drug effects*; D006325:Heart Atria; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects; D009411:Nerve Endings / Q000187:drug effects; D016627:Oxidopamine / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D017257:Ramipril / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013564:Sympathetic Nervous System / Q000502:physiology*; D014439:Tyramine / Q000378:metabolism; D020960:omega-Conotoxins
D002316:Cardiotonic Agents; D010455:Peptides; D020960:omega-Conotoxins; C053423:Conus magus toxin; C052549:ramiprilat; D016627:Oxidopamine; D003042:Cocaine; D017257:Ramipril; D001920:Bradykinin; D014439:Tyramine