ENHANCED MYOCARDIAL RELAXATION IN-VIVO IN TRANSGENIC MICE OVEREXPRESSING THE BETA(2)-ADRENERGIC RECEPTOR IS ASSOCIATED WITH REDUCED PHOSPHOLAMBAN PROTEIN

To assess the effect of targeted myocardial beta-adrenergic receptor ( AR) stimulation on relaxation and phospholamban regulation, we studied the physiological and biochemical alterations associated with overexp ression of the human beta(2)-AR gene in transgenic mice. These mice ha ve an similar to 200-fold increase in beta-AR density and a 2-fold inc rease in basal adenylyl cyclase activity relative to negative litterma te controls. Mice were catheterized with a high fidelity micromanomete r and hemodynamic recordings were obtained in vivo, Overexpression of the beta(2)-AR altered parameters of relaxation. At baseline, LV dP/dt (min) and the time constant of LV pressure isovolumic decay (Tau) in t he transgenic mice were significantly shorter compared with controls, indicating markedly enhanced myocardial relaxation. Isoproterenol stim ulation resulted in shortening of relaxation velocity in control mice but not in the transgenic mice, indicating maximal relaxation in these animals, Immunoblotting analysis revealed a selective decrease in the amount of phospholamban protein, without a significant change in the content for either sarcoplasmic reticulum Ca2+ ATPase or calsequestrin , in the transgenic hearts compared with controls. This study indicate s that myocardial relaxation is both markedly enhanced and maximal in these mice and that conditions associated with chronic beta-AR stimula tion can result in a selective reduction of phospholamban protein.