OPIATE RECEPTOR INHIBITION IN CONGESTIVE HEART FAILURE

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Endogenous opioid peptides, which have a variety of cardiovascular effects, have been shown to be elevated and play an important role in the pathophysiology of acute circulatory failure. Increased plasma levels of opioid peptides also occur during physical exercise. We propose to study whether the endogenous opiods play a similar role during chronic congestive heart failure (CHF) with and without added exercise stress. We speculate that the endogenous opioids are increased in CHF at rest and significantly more during exercise. Administration of opiate antagonists would be expected to improve cardiac performance and increase organ blood flow under these conditions. This is supported by our preliminary studies that show resting plasma levels of beta-endorphin, ACTH and cortisol were elvated in the CHF dogs and that opiate antagonists (naloxone and nalmefene) increased left ventricular dP/dt, cardiac output, arterial blood pressure and blood flow to the skeletal muscle, myocardium and kidneys. In the proposed study, CHF will be produced by tricuspid valve avulsion and progressive pulmonary artery constriction in conscious dogs. Plasma levels of beta-endorphin, ACTH, cortisol (all by radioimmunoassay) and catecholamines (using a high performance liquid chromatographic method) will be measured in the CHF and sham-operated dogs both at rest and during exercise. In addition, heart rate, aortic blood pressure, cardiac output (using an idocyanine green dilution technique), left ventricular dP/dt and dP/dt/P, and regional blood flow (using radioactive microspheres) will be measured before and after intravenous naloxone administration. Furthermore, to determine whether the effects of naloxone are mediated via the beta-adrenergic receptors, naloxone will be administered to dogs pretreated with propranolol. The effects of naloxone also will be compared to those of naloxone methylbromide which does not penetrate the brain blood barrier to determine if the nervous system. Finally, specific opiate receptor blocking agents will be administered intravenously to determine whether naloxone exerts its cardiovascular effects via either mu or delta receptors. Results of the study will further our understanding of neurohumoral control of the circulation in CHF and yield useful information regarding the potential use of opiate antagonists in the clinical management of CHF.