TREATMENT IN HYPERTENSIVE CARDIAC-HYPERTROPHY .2. POSTRECEPTOR EVENTS

We investigated the effect of pharmacological treatment with captopril, nitrendipine, and captopril plus nitrendipine on myocardial heterologous adenylyl cyclase desensitization and the underlying postreceptor defects in spontaneously hypertensive rats (SHR). In myocardial membranes from SHR, stimulation of adenylyl cyclase with guanylylimido-diphosphate (P<.001) and forskolin (P<.05) was significantly reduced, whereas no difference with forskolin was obtained in the presence of manganese chloride. Reconstitution of G(s alpha) into G(s alpha)-deficient S49 cyc(-) mouse lymphoma cells revealed no difference between SHR and control rats. In contrast, pertussis toxin labeling of G(i alpha) was significantly increased in SHR. The reduction of adenylyl cyclase in SHR was abolished after pertussis toxin treatment of membranes. Treatment with captopril, nitrendipine, or both reduced G(i alpha) and increased guanylylimido-diphosphate-stimulated adenylyl cyclase activity in SHR. In summary, heterologous adenylyl cyclase desensitization due to an increase of G(i alpha) but in the presence of an unchanged activity of G(s alpha) or the catalyst occurs in SHR. This alteration, which could contribute to the progression of contractile dysfunction by producing adrenergic subsensitivity, is sensitive to pharmacological treatment most likely because of a reduction of sympathetic activity.