Pharmacological analysis by HOE642 and KB‐R9032 of the role of Na + /H + exchange in the endothelin‐1‐induced Ca 2+ signalling in rabbit ventricular myocytes

The role of Na + /H + exchange in endothelin‐1 (ET‐1)‐induced increases in Ca 2+ transients and cell shortening was studied in rabbit ventricular myocytes loaded with indo‐1/AM. Selective inhibitors of Na + /H + exchange HOE642 (4‐isopropyl‐3‐methyl‐sulphonylbenzoyl guanidine methanesulphonate) and KB‐R9032 (N‐(4‐isopropyl‐2,2‐dimethyl‐3‐oxo‐3,4‐dihydro‐2H‐benzo‐[1,4]oxazine‐6‐carbonyl) guanidine methanesulphonate) were used as pharmacological tools for the analysis. ET‐1 at 0.1 n M induced an increase in Ca 2+ transients by 45.6%, while it increased cell shortening by 109.6%. For a given increase in cell shortening, the ET‐1‐induced increase in Ca 2+ transients was much smaller than that induced by isoprenaline (ISO, 10 n M ). Pretreatment with HOE642 and KB‐R9032 (1 μ M ) inhibited the increase in cell shortening induced by 0.1 n M ET‐1 by 51 and 65.4%, respectively, without a significant alteration of ET‐1‐induced increase in Ca 2+ transients. HOE642 and KB‐R9032 did not affect baseline levels of cell shortening and peak Ca 2+ transients, and the effects of ISO (10 n M ). These results indicate that activation of Na + /H + exchange by ET‐1 may play an important role in the positive inotropic effect and the ET‐1‐induced increase in myofilament Ca 2+ sensitivity in rabbit ventricular myocytes.British Journal of Pharmacology (2000) 131 , 638–644; doi: 10.1038/sj.bjp.0703608