Pharmacological analysis by HOE642 and KB-R9032 of the role of Na+/H+ exchange in the endotbelin-1-induced Ca2+ signalling in rabbit ventricular myocytes

1 The role of Na+/H+ exchange in endothelin-1(ET-1)-induced increases in Ca + transients and cell shortening was studied in rabbit ventricular myocytes loaded with indo-1/AM. Selective Inhibitors of Na+/H- exchange HOE632 (4-i sopropyl-3-methyl-sulphonylbenzoyl guanidine methanrsulphonate) and KB-R903 2 (N-(4-isopropyl-2,2-dimethyl-3-oxo-3 was studied in rabbit ventricular in hibitors of Na+/H- exchange H [1,4]oxazine-6-carbonyl) guanidine methanesul phonate) were used as pharmacological tools for the analysis. 2 ET-1 at 0.1 nM induced an increase in Ca2+ transients by 45.6%, while it increased cell shortening by 109.6%. For a given increase in cell shortenin g, the ET-1-induced increase in Ca2+ transients was much smaller than that induced by isoprenaline (ISO. 10 nM). 3 Pretreatment with HOE632 and KB-R9032 (1 mu M) inhibited the increase in cell shortening induced by 0.1 nM ET-1 by 51 and 65.4%, respectively, witho ut a significant alteration of ET-1-Induced increase in Ca2+ transients. HO E642 and KB-R9032 did nor affect baseline levels of cell shortening and pea k Ca2+ transients, and the effects of ISO (10 nM). 4 These results indicate that activation of Na+/H+ - exchange by ET-I may p lay an important role In the positive inotropic effect and the ET-1-induced increase in myofilament Ca2+ sensitivity in rabbit ventricular myocytes.