Activation of protein kinase C by angiotensin II decreases beta 1-adrenergic receptor responsiveness in the rat heart.
Cardiac beta-adrenergic receptors are the primary driving force for the enhancement of contractility in response to sympathetic stimulation. Angiotensin II influences cardiac function by modulating sympathetic activity and by activating cardiac angiotensin II receptors. The aim of this study was to determine whether activation of cardiac angiotensin II receptors modulates the responsiveness of the heart to beta-adrenergic receptor activation. Male Sprague-Dawley rats were anesthetized and the hearts isolated and perfused with oxygenated Krebs-Henseleit buffer (KHB). Coronary artery perfusion pressure, left ventricular pressure (LVP), left ventricular dP/dtmax, and heart rate (HR) were measured. Bolus administration of the beta-adrenergic receptor agonists, isoproterenol, dobutamine, and salbutamol, produced dose-related increases in LVP, LV dP/dt(max), and HR. Addition of angiotensin-II (10-100 nM) to the KHB slightly increased coronary perfusion pressure but did not alter baseline LVP, LV dP/dt(max), or HR. Angiotensin II reduced the increase in LVP, LV dP/dt(max), and HR elicited by isoproterenol and dobutamine but did not affect responses to salbutamol. The inhibitory effect of angiotensin II was blocked by the AT1-receptor antagonist, losartan, and the protein kinase C inhibitor, calphostin C (50 nM). Activation of protein kinase C with phorbol-12, 13-dibutyrate (PDBu; 10 nM) reduced cardiac responses to all three agonists, although the effects were less on responses elicited by salbutamol. These data suggest that activation of protein kinase C by angiotensin II decreases the responsiveness of the rat heart to beta 1-adrenergic stimulation and that angiotensin II-mediated protein kinase C activation may differ from that activated by phorbol esters.
Schwartz
D D
DD
Department of Physiology and Pharmacology, Auburn University, AL 36849, USA.
Naff
B P
BP
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology; D011493:Protein Kinase C / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018342:Receptors, Adrenergic, beta-1 / Q000502:physiology*
D009281:Naphthalenes; D018342:Receptors, Adrenergic, beta-1; D000804:Angiotensin II; D011493:Protein Kinase C; C058819:calphostin C