Chronic opiate-receptor inhibition in experimental congestive heart failure in dogs.
Acute administration of opiate-receptor antagonists has previously been shown to improve cardiac output aortic blood pressure, systolic ventricular performance, and the baroreflex function in conscious dogs with right-sided congestive heart failure (RHF). However, whether similar changes occur after chronic opiate-receptor inhibition in congestive heart failure is not known. To determine the chronic effects of opiate-receptor antagonism on RHF, we administered naltrexone (200 mg/day), a long-acting, orally active opiate-receptor blocking agent, to RHF and sham-operated animals for 6 wk. Naltrexone had no effects on resting heart rate, right atrial pressure, aortic pressure, or cardiac output in RHF dogs but increased the first derivative of right and left ventricular pressure with respect to time (dP/dt) at rest and improved the dP/dt response to isoproterenol. The inotropic responses to isoproterenol and forskolin in isolated right ventricular trabeculate muscle also were improved by chronic naltrexone in RHF. Myocardial beta-receptor density was reduced in the failing right ventricle compared with the control (58 +/- 3 vs. 108 +/- 6 fmol/mg protein, P < 0.01) but was unaffected by addition of naltrexone. Finally, naltrexone prevented the decline in baroreflex sensitivity that occurred in RHF (-0.2 +/- 0.5 vs. -6.0 +/- 0.5 ms/mmHg, P < 0.01). These effects of naltrexone did not occur in the shamoperated animals. Chronic opiate-receptor blockade with naltrexone attenuates the development of reduced adrenergic inotropic responsiveness and baroreflex subsensitivity that occur in RHF. Because there was a similar improvement in the forskolin response in the absence of significant alterations in myocardial beta-adrenoceptor density after naltrexone treatment, the improvement in adrenergically mediated inotropic effects probably is mediated via a postreceptor mechanism.
Yatani
A
A
Department of Medicine, University of Rochester Medical Center, New York 14642, USA.
Imai
N
N
Himura
Y
Y
Suematsu
M
M
Liang
C S
CS
D000818:Animals; D017704:Baroreflex / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology; D004285:Dogs; D006321:Heart / Q000187:drug effects; D006333:Heart Failure / Q000378:metabolism*; D006439:Hemodynamics / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D013997:Time Factors; D016278:Ventricular Function, Right
D002316:Cardiotonic Agents; D009292:Narcotic Antagonists; D011943:Receptors, Adrenergic, beta; D009271:Naltrexone; D007545:Isoproterenol