We have recently shown that plasma beta-endorphin and adrenocorticotropic hormone (ACTH) are increased in experimental right heart failure, and that acute administration of opiate receptor antagonists increases cardiac output, aortic pressure, left ventricular dP/dt and dP/dt/P, and blood flow to the skeletal muscle, myocardium, and kidneys. We have further shown that the acute salutary hemodynamic effects are mediated via delta-receptor mediated sympathetic stimulation. These results indicate that endogenous opioid peptides may play an important role in the regulation of circulations in chronic heart failure and that their actions depend on the functional integrity of the beta-adrenoceptor-coupled adenylate cyclase activity. We propose to study the effects of chronic opiate receptor inhibition in heart failure. We speculate that since excessive sympathetic stimulation in heart failure reduces myocardial beta-receptor number and adenylate cyclase activity (probably secondary to alterations in guanine nucleotide-binding proteins) the adrenergically-mediated stimulatory effects associated with the initial administrations of opiate receptor blockers may be lost with time during chronic opiate receptor inhibition, and a worsening of myocardial function ensues. We will administer naltrexone, an orally active long-acting opiate receptor blocking agent, or placebo, for 6 weeks either during the development of heart failure or after stable heart failure has developed, to determine whether chronic opiate receptor inhibition enhances the onset or the degree of beta- adrenoceptor down-regulation, beta-adrenergic sensitivity, guanine nucleotide-binding proteins, and myocardial failure. We will measure the resting and exercise hemodynamics, plasma beta-endorphin, ACTH and catecholamines, baroreflex sensitivity, and inotropic left ventricular responses to adrenergic agents at the start and end of treatment. WE will measure myocardial norepinephrine, beta-adrenoceptor density, adenylate cyclase activity, levels of guanine nucleotide-binding proteins, and right ventricular contractile function using an isolated trabeculate muscle preparation. Results of the study will further our understanding of the role of endogenous opioids in the circulation of heart failure, and may potentially lead to new treatments for heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL035194-04A1
Application #
3348859
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1985-09-30
Project End
1993-07-31
Budget Start
1990-08-01
Budget End
1991-07-31
Support Year
4
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Rochester
Department
Type
Schools of Dentistry
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627
Liang, Chang-seng; Yatani, Akito; Himura, Yoshihiro et al. (2003) Desipramine attenuates loss of cardiac sympathetic neurotransmitters produced by congestive heart failure and NE infusion. Am J Physiol Heart Circ Physiol 284:H1729-36
Lai, L P; Suematsu, M; Elam, H et al. (1996) Differential changes of myocardial beta-adrenoceptor subtypes and G-proteins in dogs with right-sided congestive heart failure. Eur J Pharmacol 309:201-8
Kim, C H; Fan, T H; Kelly, P F et al. (1994) Isoform-specific regulation of myocardial Na,K-ATPase alpha-subunit in congestive heart failure. Role of norepinephrine. Circulation 89:313-20
Himura, Y; Liang, C S; Delehanty, J M et al. (1994) Nitroprusside infusion improves arterial baroreflex control of heart rate in dogs with chronic congestive heart failure. J Cardiovasc Pharmacol 24:702-6
Delehanty, J M; Himura, Y; Elam, H et al. (1994) Beta-adrenoceptor downregulation in pacing-induced heart failure is associated with increased interstitial NE content. Am J Physiol 266:H930-5
Imai, N; Kashiki, M; Woolf, P D et al. (1994) Comparison of cardiovascular effects of mu- and delta-opioid receptor antagonists in dogs with congestive heart failure. Am J Physiol 267:H912-7
Fan, T H; Frantz, R P; Elam, H et al. (1993) Reductions of myocardial Na-K-ATPase activity and ouabain binding sites in heart failure: prevention by nadolol. Am J Physiol 265:H2086-93
Himura, Y; Felten, S Y; Kashiki, M et al. (1993) Cardiac noradrenergic nerve terminal abnormalities in dogs with experimental congestive heart failure. Circulation 88:1299-309
Sharma, A; Plessinger, M A; Sherer, D M et al. (1992) Pregnancy enhances cardiotoxicity of cocaine: role of progesterone. Toxicol Appl Pharmacol 113:30-5
Sakamoto, S; Kashiki, M; Imai, N et al. (1991) Effects of short-term, diet-induced hypercholesterolemia on systemic hemodynamics, myocardial blood flow, and infarct size in awake dogs with acute myocardial infarction. Circulation 84:378-86

Showing the most recent 10 out of 22 publications