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

Altered b -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 b -adrenergic receptor ( b -AR) response is well documented in hypertrophied hearts. We investigated whether b -AR desensitization is also present at the cellular level in hypertrophied myocardium, as well as the physiological role of inhibitory G (G i ) proteins and the L-type Ca 2 1 channel in mediating b -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°C, and myocyte contractility and intracellular Ca 2 1 concentration ([Ca 2 1 ] i ) were simultaneously measured. In response to increasing concentrations of isoproterenol, DR myocytes displayed a dose-dependent augmentation of cell shortening and the [Ca 2 1 ] i transient amplitude, whereas hypertrophied DS myocytes had a blunted response of both cell shortening and the [Ca 2 1 ] i transient amplitude. Interestingly, inhibition of G i proteins did not restore b -AR desensitization in DS myo- cytes. The responses to increases in extracellular Ca 2 1 and an L-type Ca 2 1 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 b -AR stimulation, which is present at the cellular level and independent of alterations in inhibitory G proteins and the L-type Ca 2 1 channel. The contractile response to isoproterenol studied sequentially dose compared two- or three-factor ANOVA with repeated measures appropri-ate, using standard statistical means 6 A P , considered statistically significant.

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