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 nM 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 nM). Pretreatment with HOE642 and KB-R9032 (1 microM) 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 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 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 Ca(2+) sensitivity in rabbit ventricular myocytes.
Wang
H
H
Department of Pharmacology, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
Sakurai
K
K
Endoh
M
M
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D020013:Calcium Signaling; D002316:Cardiotonic Agents / Q000494:pharmacology; D019332:Endothelin-1 / Q000378:metabolism*; D006146:Guanidines / Q000494:pharmacology; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010078:Oxazines / Q000494:pharmacology; D011817:Rabbits; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000502:physiology*; D013450:Sulfones / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D002316:Cardiotonic Agents; D019332:Endothelin-1; D006146:Guanidines; D007211:Indoles; C419877:N-(4-isopropyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo(1,4)oxazine-6-carbonyl)guanidine; D010078:Oxazines; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C059587:Indo-1 pentaacetoxymethyl ester; C093373:cariporide; D007545:Isoproterenol