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 carbachol, 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 carbachol were noted.(ABSTRACT TRUNCATED AT 250 WORDS)
Rabkin
S W
SW
Department of Medicine, University Hospital Research Centre, University of British Columbia, Vancouver, Canada.
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002217:Carbachol / Q000494:pharmacology; D006332:Cardiomegaly / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D007190:Indapamide / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*
D000804:Angiotensin II; D005576:Colforsin; D002217:Carbachol; D000242:Cyclic AMP; D007190:Indapamide; D007545:Isoproterenol; D015056:1-Methyl-3-isobutylxanthine