ABSTRACT
The organ selectivity and the effect on myocardial ischemia-reperfusion injury of (R)-acetoxyhexamide ((R)-ACX), a novel sulfonylurea, were examined. (R)-ACX, as well as glibenclamide, concentration-dependently stimulated insulin release from INS-1 cell, a cell line derived from pancreatic beta-cells. The potency of (R)-ACX was about 1/10 of that of glibenclamide. In isolated guinea pig ventricular myocardial tissue, glibenclamide concentration-dependently inhibited the action potential shortening by NIP-121, an ATP-sensitive potassium channel opener, but (R)-ACX showed only slight inhibition. In isolated rat aortic rings contracted with norepinephrine, glibenclamide concentration-dependently inhibited the relaxation by NIP-121, while (R)-ACX showed only slight inhibition. In coronary-perfused guinea pig ventricular preparations, glibenclamide reduced the recovery of contractile force after ischemia-reperfusion, while (R)-ACX did not. In conclusion, (R)-ACX is a beta-cell selective sulfonylurea which, unlike glibenclamide, does not aggravate cardiac ischemia-reperfusion damage.
Subject(s)
Insulin-Secreting Cells/drug effects , Myocardial Reperfusion Injury/physiopathology , Sulfonylurea Compounds/pharmacology , Action Potentials/drug effects , Animals , Benzopyrans/pharmacology , Cells, Cultured , Female , Glyburide/pharmacology , Glyburide/toxicity , Guinea Pigs , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/toxicity , In Vitro Techniques , Male , Muscle Relaxation/drug effects , Muscle, Smooth, Vascular/drug effects , Myocardial Contraction/drug effects , Papillary Muscles/drug effects , RatsABSTRACT
The effects of 2-[4-[(2,5-difluorophenyl) methoxy]phenoxy]-5-ethoxyaniline (SEA0400), a newly synthesized Na(+)-Ca(2+) exchanger (NCX) inhibitor, on the NCX current and other membrane currents were examined in isolated guinea-pig ventricular myocytes and compared with those of 2-[2-[4-(4-nitrobenzyloxy) phenyl]ethyl]isothiourea (KB-R7943). SEA0400 concentration-dependently inhibited the NCX current with a 10 fold higher potency than that of KB-R7943; 1 microM SEA0400 and 10 microM KB-R7943 inhibited the NCX current by more than 80%. KB-R7943, at 10 microM, inhibited the sodium current, L-type calcium current, delayed rectifier potassium current and inwardly rectifying potassium current by more than 50%, but SEA0400 (1 microM) had no significant effect on these currents. These results indicate that SEA0400 is a potent and highly selective inhibitor of NCX, and would be a powerful tool for further studies on the role of NCX in the heart and the therapeutic potential of its inhibition.
Subject(s)
Aniline Compounds/pharmacology , Calcium/metabolism , Heart Ventricles/drug effects , Phenyl Ethers/pharmacology , Sodium-Calcium Exchanger/antagonists & inhibitors , Sodium/metabolism , Thiourea/analogs & derivatives , Animals , Dose-Response Relationship, Drug , Guinea Pigs , Heart Ventricles/cytology , Heart Ventricles/metabolism , In Vitro Techniques , Ion Channels/metabolism , Ion Transport/drug effects , Male , Thiourea/pharmacologyABSTRACT
Effects of Mn2+ on isolated guinea pig ventricular myocardia were examined. In isolated papillary muscles, Mn2+ produced a transient decrease in contractile force followed by a late sustained augmentation. Mn2+ markedly increased the amplitude of post-rest contractions; the time course of potentiation was almost the same as that of the late augmentation of contractile force after Mn2+ application. Mn2+ also increased the amplitude of rapid-cooling contractures. The negative inotropic effect of diltiazem and nicardipine was not affected by the presence of Mn2+. Mn2+ shortened the action potential duration under normal condition whereas it prolonged the duration under Ca2+ free conditions. Mn2+, when applied to fura-2-loaded ventricular myocytes, markedly quenched the cytoplasmic fluorescence excited at 360 nm wavelength. We concluded that Mn2+ not only causes a decrease in contractile force by blocking the L-type Ca2+ channel, but also enters the cytoplasm through the channel and produces late augmentation of the contractile force through enhancement of sarcoplasmic reticulum function.
