The role of endogenous opioids in congestive heart failure: effects of nalmefene on systemic and regional hemodynamics in dogs.

Abstract

We studied the role of endogenous opiates and their interrelationships with the sympathetic nervous system in an experimental preparation of right-sided congestive heart failure (CHF) produced by surgical tricuspid avulsion and progressive pulmonary arterial constriction. Three groups of dogs with CHF and one group of sham-operated dogs were studied. One group of dogs with CHF was given normal saline as pretreatment, while the other two groups were pretreated with either propranolol alone ((3-blockade) or propranolol plus prazosin (a-plus /3-blockade). CHF was characterized by weight gain, ascites, elevated right atrial pressure, tachycardia, and reduced cardiac output. Compared with sham-operated animals, animals with CHF exhibited significantly higher baseline levels of plasma /3-endorphin and cortisol. Furthermore, only the animals with CHF responded to the opiate receptorantagonist nalmefene with significant increases in plasma /3-endorphin, cortisol, and adrenocorticotropic hormone. Administration of nalmefene increased aortic blood pressure, cardiac output, left ventricular dP/dt and dP/dtIP, and blood flow to the myocardium, skeletal muscle, and kidneys in dogs with CHF, but had no appreciable effects in sham-operated dogs. 13-Receptor blockade abolished the increase in cardiac output, left ventricular performance, and blood flow produced by nalmefene, but had no effect on the pressor response to nalmefene. The increase in mean aortic pressure in the ,3-blockade group was accompanied by an increase in skeletal muscle vascular resistance. Addition of prazosin in the a-plus 13-blockade group abolished the increases in mean aortic pressure and skeletal muscle vascular resistance, suggesting that the changes after propranolol probably resulted from unmasking of a-receptor-mediated vasoconstriction. Our present study indicates that the heightened opiate system accompanying CHF limits sympathetic activation, and that the beneficial effects of opiate-receptor inhibition are mediated, at least in part, via stimulation of the sympathetic nervous system.

Decreased adrenergic neuronal uptake activity in experimental right heart failure. A chamber-specific contributor to beta-adrenoceptor downregulation.

“…Similar chamber-specific changes have been reported in patients with right ventricular failure secondary to primary pulmonary hypertension (18). The RHF dogs have been extensively studied; they exhibit an increase in plasma catecholamines, a decrease in myocardial NE stores, a reduced responsiveness to beta-receptor agonists (19), and other neurohormonal and reflex changes (30)(31)(32)(33)(34) that occur in patients with congestive heart failure. Specific 3H uptake activity, defined as the difference in radioactivity between tissue slices incubated in a [3H]NE-containing solution at 370C (total 3H uptake) and those at 40C (nonspecific 3H uptake), was taken to approximate NE uptake activity in the present study.…”

Myocardial and Peripheral Concentrations of .BETA.-Endorphin Before and Following Myocardial Ischemia and Reperfusion During Coronary Angioplasty

“…[2][3][4] There is substantial evidence that cardiac opioid receptors are activated during myocardial ischemia and reperfusion, supporting the hypothesis that EOP are involved in the pathophysiology of ischemic heart disease. 12) We have shown that in patients with acute myocardial infarction, there was an increased plasma concentration of β-endorphin.…”

“…Since the identification of EOP and opioid receptors in the heart, 1) it has become clear that EOP subserve important roles in cardiovascular regulation and are especially involved in various cardiovascular stress situations such as shock, 2) heart failure, 3) and myocardial ischemia. 4) In humans, it has been shown that opioid receptors are present in the heart and that they play an important role in myocardial ischemia.…”

Administration of slow-release nifedipine does not affect lactate threshold, hormone release during exercise, and quality of life in normal subjects

“…The precise role of ~-endorphin is not clear. However, some studies postulate that ~-endorphin may play a role in thermoregulation [37], respiratory regulation [38], hemodynamic regulation [39], and so on. In any case, a 2-week administration of nifedipine-SR had no effect on ~-endorphin.…”