Beta-adrenergic receptor and cyclic AMP alterations in the canine ventricular septum during long-term norepinephrine infusion: implications for hypertrophic cardiomyopathy.

Abstract

Norepinephrine infusion in dogs has been shown to cause ventricular septal hypertrophy that mimics the syndrome of hypertrophic cardiomyopathy in humans. To characterize the mechanisms involved in septal hypertrophy, the adrenergic system of the right and left ventricles and the septum were analyzed before and after norepinephrine infusion. In the normal unperturbed state, the septum was found to be more sensitive to beta-adrenergic stimulation than either the right or left ventricles. That is, more cyclic AMP could be generated with a smaller dose of beta-agonist (isoproterenol) in septal tissue homogenate than in homogenates of the right or left ventricles. With infusions of norepinephrine (1.4 micrograms/min) to subhypertensive levels over 3 months, beta-receptor number increased twofold to threefold in the ventricles and septum. Adenylate cyclase activity also increased in the ventricles, but not in the septum. The sensitivity of adenylate cyclase to beta-agonist stimulation increased in the septum but remained unchanged in the right and left ventricles. We conclude that the alterations in the myocardial adrenergic system occur in response to the norepinephrine infusion and are not a consequence of hypertrophy. We formulated a hypothesis suggesting that depleted tissue stores of cyclic AMP and/or adenosine triphosphate may be one of the mechanisms involved in the development of hypertrophic cardiomyopathy.