Chronic α-adrenergic receptor stimulation modulates the contractile phenotype of cardiac myocytes in vitro

Abstract

Background - Heart failure is characterized by contractile dysfunction of the myocardium and elevated sympathetic activity. We tested the hypothesis that chronic α-adrenergic (α-ADR) stimulation modifies the molecular and contractile phenotype of cardiac myocytes. Methods and Results - Adult rat ventricular myocytes in culture were exposed to α-ADR stimulation (ngrepinephrine propranolol) for 48 hours. α-ADR stimulation decreased the mRNAs fof sarcoplasmic reticulum Ca2+-ATPaSe and Ca2+ release channel by 56% and 52%, respectively, and increased mRNA and protein for the Na+-Ca2+ exchanger by 70% and 39%, respectively. After washout of the α-ADR agonist, simultaneous measurement of [Ca2+](i) transients with fura 2 and myocyte shortening by video edge-detection showed that [Ca2+](i) amplitude and myocyte shortening were decreased in α-ADR-treated myocytes, and the time to peak and time from peak to 80% decline of both [Ca2+](i) and myocyte shortening were increased. The concentration-response curve for myocyte shortening by the Na+ channel activcator veratridine was shifted leftward in α-ADR-stimulated myocytes (EC50, 21.6±4.6 versus 105.8±10.5 nmol/L, P<0.001). Conclusions - Chronic α-ADR stimulation of cardiac myocytes causes decreases in the expression of sarcoplasmic reticulum Ca2+-ATPase and the Ca2+ release channel that are associated with decreases in [Ca2+](i) and contractility. α-ADR stimulation simultaneously increases Na+-Ca2+ exchanger expression, thereby increasing sensitivity to intracellular Na+.