guanylyl-imidodiphosphate and Hypertrophy--Left-Ventricular

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(i)) proteins and the L-type Ca(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(2+) concentration ([Ca(2+)](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+)](i) transient amplitude, whereas hypertrophied 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 increases in extracellular Ca(2+) and an L-type Ca(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(2+) channel.

Topics: Adenylate Cyclase Toxin; Adenylyl Cyclases; Adrenergic beta-Agonists; Animals; Calcium; Calcium Channel Agonists; Calcium Channels, L-Type; Disease Models, Animal; Dose-Response Relationship, Drug; GTP-Binding Protein alpha Subunits, Gi-Go; Guanylyl Imidodiphosphate; Heart Function Tests; Hypertrophy, Left Ventricular; In Vitro Techniques; Isoproterenol; Male; Manganese; Myocardial Contraction; Myocardium; Rats; Rats, Inbred Dahl; Receptors, Adrenergic, beta; Signal Transduction; Virulence Factors, Bordetella