Effects of nisoldipine on endothelin-1- and angiotensin II-induced immediate/early gene expression and protein synthesis in adult rat ventricular cardiomyocytes.
The cellular mechanisms by which dihydropyridine-type calcium antagonists lead to regression of hypertension-related cardiac hypertrophy have not been clarified. We previously showed that angiotensin II (AII) and endothelin-1 (ET-1) induce protein synthesis in isolated adult rat cardiomyocytes, probably through protein kinase C (PKC) as second messenger and the gene product of the early growth response gene-1 (Egr-1) as third messenger. We now show that the dihydropyridine derivative nisoldipine inhibits AII- and ET-1-induced protein synthesis at low concentrations (IC50 7.5 nM for 0.1 microM ET). Induction of c-fos and Egr-1 mRNA by AII and ET was completely blocked by nisoldipine. Therefore, nisoldipine may influence the signal transduction pathway, i.e., through PKC. These results provide a potential pressure-independent mechanism by which nisoldipine may influence development of cardiac hypertrophy.
Grohé
C
C
Medical Policlinic, University of Bonn, Germany.
Nouskas
J
J
Vetter
H
H
Neyses
L
L
D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D017781:Genes, Immediate-Early / Q000187:drug effects*; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D015737:Nisoldipine / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000187:drug effects; D051381:Rats; D011921:Rats, Inbred WKY
D016232:Endothelins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D000804:Angiotensin II; D015737:Nisoldipine