Pharmacological Aspects of Cardiac Hypertrophy

Catecholamines have been implicated in the regulation of cardiac hypertrophy. The serial injection of a catecholamine (epinephrine, norepinephrine or isoproterenol) will increase cardiac muscle mass. In a canine model of left ventricular hypertrophy secondary to aortic coarctation, the endogenous catecholamine which increased in circula­ ting blood in parallel with increased myocardial mass was epinephrine. The adrenal medulla is the major source of plasma epinephrine. The medullary release of catecholamines into the inferior vena cava occurs following stress-induced sympathetic stimulation. The stress of coarc­ tation imposed by inflating a balloon implanted intraluminally in the descending aorta resulted in epinephrine plasma levels 3.5-fold above basal levels, concurrent with increased left ventricular wet weight to body weight ratios of 1207= above control. This response was blocked by propranolol, a nonselective beta-adrenergic receptor antagonist, thereby implicating beta-adrenoceptors in the regulation of cardiac hypertrophy. In order to further assess the involvement of epinephrine in the myocardial growth process, bilateral adrenal medullary denervation was performed on dogs. After denervation, plasma levels of epinephrine were essentially zero. Without epinephrine, left ventricular hyper­ trophy was not demonstrable after aortic constriction. In fact, there was a decreased myocardial wet and dry weight ratio, suggesting epi­ nephrine might provide basal sympathetic tone to the heart. Since vii viii epinephrine has beta-1 and beta-2 agonistic properties, and antagonism by propranolol is nonspecific, we wanted to determine the precise pharmacological nature of the receptor(s) involved. The heart contains both beta-1 and beta-2 receptors with a predominance of the former 4:1. It has been suggested that these subtypes subserve similar physiologi­ cal responses; however, the precise role of the cardiac beta-2 receptor is unknown. The nature of the cardiac beta receptor coupled to the trophic response was evaluated in a mouse model during embryogenesis. Mice were used because of the high cost of dogs and the necessity to use large numbers of animals to determine receptor specificity. Previous studies suggested the generality of beta-receptor coupling in heart to increased ornithine decarboxylase activity and increased tissue mass. At 18 days of development, the fetal murine heart responded to epinephrine or isoproterenol with a 200-300% increase in ornithine decarboxylase activity. These increases were not inhibited by: (1) prazosin, an alpha-1 receptor antagonist, (2) yohimbine, an alpha-2 receptor antagonist, or (3) metoprolol, a beta-1 receptor antagonist. The stimulation of ornithine decarboxylase was blocked by propranolol. Thus, it appeared a beta-2 inhibitor was required to prevent stimula­ tion by nonselective alphaor beta-adrenergic agonists. To further evaluate the specific nature of the receptor coupled to the trophic response, terbutaline, a specific beta-2 agonist, was injected directly into each fetus alone or with either propranolol or metoprolol. Terbu­ taline resulted in a 3-fold stimulation of ornithine decarboxylase ix activity either as a single agent or with metoprolol. The stimulation of ornithine decarboxylase activity was blocked by simultaneous pro­ pranolol administration. The pharmacological results in the fetal mouse heart suggested that beta-2 adrenergic stimulation was coupled to increased ornithine decarboxylase activity, a marker of cellular hypertrophy. In order to concurrently measure heart weights and plasma catecholamine levels after serial beta-2 stimulation, the use of a large animal model was necessary. Therefore, the dog model of myocardial hypertrophy after aortic constriction was utilized. Dogs subjected to aortic coarctation and treated with metoprolol, a beta-1 receptor antagonist, developed significant ventricular hypertrophy and markedly elevated plasma epinephrine levels. In noncoarcted dogs treated with terbutaline, a specific beta-2 agonist, ventricular weight increased to 150% above control and circulating epinephrine was elevated 4-fold. These data support the concept that hypertrophic growth occurs selectively in response to beta-2 adrenergic receptor stimulation in the heart.