Altered beta-adrenergic signal transduction in nonfailing hypertrophied myocytes from Dahl salt-sensitive rats

Desensitization of the beta -adrenergic receptor (beta -AR) response is wel l documented in hypertrophied hearts. We investigated whether beta -AR dese nsitization is also present at the cellular level in hypertrophied myocardi um, as well as the physiological role of inhibitory G (G(i)) proteins and t he L-type Ca2+ channel in mediating beta -AR desensitization. Left ventricu lar (LV) myocytes were isolated from hypertrophied hearts of hypertensive D ahl salt-sensitive (DS) rats and nonhypertrophied hearts of normotensive sa lt-resistant (DR) rats. Cells were paced at a rate of 300 beats/min at 37 d egreesC, and myocyte contractility and intracellular Ca2+ concentration ([C a2+](i)) were simultaneously measured. In response to increasing concentrat ions of isoproterenol, DR myocytes displayed a dose-dependent augmentation of cell shortening and the [Ca2+](i) transient amplitude, whereas hypertrop hied DS myocytes had a blunted response of both cell shortening and the [Ca 2+](i) transient amplitude. Interestingly, inhibition of G(i) proteins did not restore beta -AR desensitization in DS myocytes. The responses to incre ases in extracellular Ca2+ and an L-type Ca2+ channel agonist were also sim ilar 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 respo nse to beta -AR stimulation, which is present at the cellular level and ind ependent of alterations in inhibitory G proteins and the L-type Ca2+ channe l.