EFFECT OF INDAPAMIDE ON CYCLIC ADENOSINE-3',5'-MONOPHOSPHATE SIGNAL-TRANSDUCTION SYSTEM IN ISOLATED ADULT-RAT CARDIOMYOCYTES FROM NORMAL MYOCARDIUM AND CARDIAC-HYPERTROPHY

The objective of this study was to examine the effect of indapamide on cAMP generation in cardiomyocytes. Viable ventricular myocytes were isolated from adult rat hearts which included normal hearts from Wistar rats and hypertrophic hearts from Dahl S rats. cAMP content was measured by competitive binding assay. In normal heart, indapamide did not alter cAMP concentration; however, indapamide pretreatment markedly accentuated forskolin-stimulated cAMP production. In contrast to the response with forskolin, indapamide did not alter isoproterenol-stimulated cAMP generation, suggesting an interaction of indapamide with adenyl cyclase rather than through the guanine stimulatory pathway affected by beta-adrenergic stimulation by isoproterenol. Male inbred Dahl SS/Jr fed a diet supplemented with an additional 6% NaCl from the age of 3 weeks were randomly allocated to receive either indapamide 2 mg/kg s.c. per day or the diluent (ethanol/sterile water) in the same volume. Indapamide or diluent injections were begun 1 week after commencing the high-salt diet. Cardiac hypertrophy is known to be associated with reductions in cellular cAMP. Indapamide-treated animals had significantly greater myocardial cAMP concentrations than control animals. Hypertrophic Dahl S myocytes from untreated animals were less responsive to forskolin compared to myocytes from animals that had been treated with indapamide. Angiotensin II (Ang)-receptor stimulation with Ang II and muscarinic-receptor stimulation with carbacol, accentuate cAMP stimulation in cardiac hypertrophy, whereas the reverse or inhibition was noted in normal myocardium. In cardiomyocytes from rats that had been treated with indapamide, the usual inhibitory effects of Ang II and carbacol were noted. In contrast, Ang II significantly increased cAMP accumulation in hypertrophic Dahl S myocytes stimulated with isoproterenol. Carbacol increased cAMP accumulation in hypertrophic Dahl S myocytes as compared to the effect of isoproterenol alone, and this response was not altered by indapamide treatment. Thus, these data indicate that indapamide treatment ameliorated the reduction in cAMP with the development of cardiac hypertrophy and the reduction in the response to forskolin. In conjunction with the data that indapamide pretreatment increases forskolin-stimulated cAMP in cardiomyocytes from normal hearts, the data suggest a potential cellular mechanism to explain the pathogenesis of cardiac hypertrophy and the potential of indapamide to prevent development of cardiac hypertrophy.