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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.

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We have shown previously that right heart failure (RHF) in dogs is associated with activated endogenous opiate systems, and that administration of the opioid receptor antagonist, naloxone, increases arterial pressure, cardiac contractile function and organ blood flows. To study whether the cardiovascular effects of naloxone are mediated via the mu- or delta-opioid receptors, we administered ICI-154,129, a delta-receptor antagonist, and naloxonazine, a mu-receptor antagonist, to 10 conscious dogs with RHF on 2 separate days. Like naloxone, ICI-154,129 increased mean aortic pressure, cardiac output, peak positive first derivative of left ventricular pressure, and blood flows to the myocardium, kidneys, splanchnic beds, and skeletal muscle. These changes were associated with increases in plasma epinephrine and norepinephrine. In contrast, naloxonazine had no effects on systemic hemodynamics, regional blood flow distribution, and plasma catecholamines in RHF. These findings suggest that the increased endogenous opioids during heart failure act on the delta-opioid receptors to decrease myocardial mechanical performance and alter regional blood flow distribution. Opioid receptor-blocking agents may exert beneficial cardiovascular effects in heart failure.

The increase in basal plasma beta-endorphin suggests that the endogenous opiate system is activated in left-sided congestive heart failure. Because naloxone improves the systemic hemodynamics and myocardial contractile function under this condition, the endogenous opioids appear to play an important role in mediating the myocardial depression that occurs in heart failure. However, the endogenous opiate system has no apparent effect on the regulation of baroreflex control in heart failure induced by rapid pacing.