It has previously been reported that ischemia and reperfusion of the heart cause accumulation of lysophosphatidylcholine (LPC) within the myocardium. While it is known that LPC causes the transient increase of intracellular free Ca2+ concentration ([Ca2+]i) during contraction of cardiac cells, little is known about the mechanism for decreasing [Ca2+]i in cardiomyocytes during LPC accumulation. Since cumulative elevation in [Ca2+]i leads to irreversible injury to cardiomyocytes, elevated [Ca2+]i must be restored to an unstimulated level to maintain cell functions. In the present study, we therefore examined the effect of LPC on Ca2+ efflux from freshly isolated adult rat cardiomyocytes. LPC stimulated the efflux of 45Ca2+ from the cells in a concentration-dependent manner (10(-7)M-10(-5)M). Other lysophospholipids, which are generated from phospholipids of the cell membrane, failed to induce 45Ca2+ efflux from the cells. Dilazep and K-7259, which are known to inhibit the increase in [Ca2+]i caused by LPC, likewise reduced 45Ca2+ efflux caused by LPC addition. Furthermore, the LPC-stimulated 45Ca2+ efflux was not affected by removal of extracellular Ca2+, but was dependent on the presence of extracellular Na+. On the other hand, inhibitors of Na+/Ca2+ exchange, amiloride and 5-(N,N-dimethyl)-amiloride, inhibited LPC induced 45Ca2+ efflux. These results suggest that LPC stimulates extracellular Na(+)-dependent 45Ca2+ efflux from freshly isolated adult rat cardiomyocytes, probably through Na+/Ca2+ exchange on the plasma membrane of the cells.

01 Aug 1997·Journal of Pharmacy and PharmacologyQ3 · MEDICINE

Protective Effects of Dilazep and its Derivative K-7259 on the Haemolysis Induced by Amphiphiles in Rat Erythrocytes

Q3 · MEDICINE

Article

Author: Hashizume, Hiroko ; Abiko, Yasushi ; Hayase, Nobumasa ; Hara, Akiyoshi

AbstractThe effects of dilazep and K-7259, a dilazep derivative, on the haemolysis (as evidenced by release of haemoglobin) induced by palmitoyl-l-carnitine (PAL-CAR) or palmitoyl 1-α-lysophosphatidylcholine (PAL-LPC) have been determined in rat erythrocytes.At concentrations above the critical micelle concentration both PAL-CAR and PAL-LPC induced haemolysis; the concentrations of PAL-CAR and PAL-LPC producing 50% haemolysis were approximately 13 and 14 μm, respectively. The 50% haemolysis induced by PAL-CAR or PAL-LPC was attenuated by dilazep (1, 10 or 100 μm) but not at the highest concentration used (1 mm). K-7259 attenuated the 50% haemolysis induced by PAL-CAR or PAL-LPC at concentrations ranging from 1 μm to 1 mm. Similarly, dilazep (1 to 100 μm) and K-7259 (1 μm to 1 mm) significantly or insignificantly attenuated the 25% and 75% haemolysis induced by PAL-CAR or PAL-LPC. Neither dilazep nor K-7259 affected micelle formation by PAL-CAR or PAL-LPC, nor, at concentrations of 1 and 10 μm, did they attenuate the haemolysis induced by osmotic imbalance (hypotonic haemolysis).These results suggest that both dilazep and K-7259 protect the erythrocyte membrane from the damage induced by PAL-CAR or PAL-LPC. The protective effects of dilazep and K-7259 are mediated by some mechanism other than prevention of micelle formation or protection of the erythrocyte membrane against osmotic imbalance.

01 Jan 1997·The Japanese Journal of Pharmacology

Cardioprotective Effect of K-7259, a Novel Dilazep Derivative, against Ischemia-Reperfusion Damage in Isolated, Working Rat Hearts.

Article

Author: Nina Hoque ; Kazuo Ichihara ; Akiyoshi Hara ; Yasushi Abiko ; A.N. Ehsanul Hoque ; Hiroko Hashizume

Global ischemia (15 min) followed by reperfusion (10, 20 or 30 min) was performed in isolated, working rat hearts. Ischemia depressed mechanical function, which was not restored by reperfusion of 20 min. Preischemic administration of K-7259 (N,N'-bis[4-(3,4,5-trimethoxyphenyl)butyl]homopiperazine dihydrochloride) (1, 5 or 10 microM) decreased the function before ischemia, but it attenuated the ischemia-induced dysfunction during reperfusion (20 min). Postischemic administration of K-7259 (10 microM) or dilazep (20 microM) also attenuated the ischemia-induced dysfunction during reperfusion (30 min). Ischemia-reperfusion (10 min) increased the tissue malondialdehyde level, and postischemic administration of K-7259 (10 microM) or dilazep (20 microM) attenuated the malondialdehyde accumulation. K-7259 has a cardioprotective effect when given either before or after ischemia.

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Indication	Highest Phase	Country/Location	Organization	Date
Myocardial Ischemia	Discovery	Japan	Kowa Co., Ltd.	-
Stroke	Discovery	Japan	Kowa Co., Ltd.	-

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