Altered [Beta]-adrenergic signal transduction in nonfailing hypertrophied myocytes from Dahl salt-sensitive rats

Nagata, Kohzo, Catherine Communal, Chee C. Lim, Mohit Jain, Thomas M. Suter, Franz R. Eberli, Naoya Satoh, Wilson S. Colucci, Carl S. Apstein, and Ronglih Liao. Altered [Beta]-adrenergic signal transduction in nonfailing hypertrophied myocytes from Dahl salt-sensitive rats. Am J Physiol Heart Circ Physiol 279: H2502-H2508, 2000.--Desensitization of the [Beta]-adrenergic receptor ([Beta]-AR) response is well documented in hypertrophied hearts. We investigated whether [Beta]-AR desensitization is also present at the cellular level in hypertrophied myocardium, as well as the physiological role of inhibitory G ([G.sub.i]) proteins and the L-type [Ca.sup.2+] channel in mediating [Beta]-AR desensitization. Left ventricular (LV) myocytes were isolated from hypertrophied hearts of hypertensive Dahl salt-sensitive (DS) rats and nonhypertrophied hearts of normotensive salt-resistant (DR) rats. Cells were paced at a rate of 300 beats/min at 37 [degrees] C, and myocyte contractility and intracellular [Ca.sup.2+] concentration ([[[Ca.sup.2+]]sub.i]) were simultaneously measured. In response to increasing concentrations of isoproterenol, DR myocytes displayed a dose-dependent augmentation of cell shortening and the [[[Ca.sup.2+]]sub.i] transient amplitude, whereas hypertrophied DS myocytes had a blunted response of both cell shortening and the [[[Ca.sup.2+]]sub.i] transient amplitude. Interestingly, inhibition of [G.sub.i] proteins did not restore [Beta]-AR desensitization in DS myocytes. The responses to increases in extracellular [Ca.sup.2+] and an L-type [Ca.sup.2+] channel agonist were also similar in both DS and DR myocytes. Isoproterenol-stimulated adenylyl cyclase activity, however, was blunted in hypertrophied myocytes. We concluded that compensated ventricular hypertrophy results in a blunted contractile response to [Beta]-AR stimulation, which is present at the cellular level and independent of alterations in inhibitory G proteins and the L-type [Ca.sup.2+] channel. hypertension; hypertrophy; [Beta] -adrenergic desensitization