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

British Journal of Pharmacology - Tập 131 Số 3 - Trang 638-644 - 2000
Hao Wang1, Kiyoharu Sakurai1, Masao Endoh1
1Department of Pharmacology, Yamagata University School of Medicine, Yamagata 990-9585, Japan,

Tóm tắt

The role of Na+/H+ exchange in endothelin‐1 (ET‐1)‐induced increases in Ca2+ 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 nM induced an increase in Ca2+ 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 Ca2+ transients was much smaller than that induced by isoprenaline (ISO, 10 nM).

Pretreatment with HOE642 and KB‐R9032 (1 μM) inhibited the increase in cell shortening induced by 0.1 nM ET‐1 by 51 and 65.4%, respectively, without a significant alteration of ET‐1‐induced increase in Ca2+ transients. HOE642 and KB‐R9032 did not affect baseline levels of cell shortening and peak Ca2+ transients, and the effects of ISO (10 nM).

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 Ca2+ sensitivity in rabbit ventricular myocytes.

British Journal of Pharmacology (2000) 131, 638–644; doi:10.1038/sj.bjp.0703608

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British Journal of Pharmacology

Tập 131 Số 3

638-644

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