A Study on Dilazep: I. Mechanism of Anti-ischemic Action of Dilazep Is Not Coronary Vasodilation but Decreased Cardiac Mechanical Function in the Isolated, Working Rat Heart

Abstract

ABSTRACT-In the isolated, perfused working rat heart, ischemia (15 min) decreased the mechanical function and the tissue levels of adenosine triphosphate and creatine phosphate and increased the levels of lactate and free fatty acids. Reperfusion (20 min) did not restore the mechanical function, but restored incompletely the levels of metabolites, with the exception of free fatty acids, which increased further during reperfusion. Dilazep was given 5 min before starting ischemia until the end of ischemia. Dilazep at 5 or 10 pM decreased the cardiac mechanical function, but did not affect coronary flow in the pre-ischemic heart. Dilazep at 5 or 10 pM accelerated the recovery of mechanical function and coronary flow during reperfusion, and it attenuated metabolic changes induced by ischemia and reperfusion. Dilazep at 1 pM neither decreased the pre-ischemic mechanical function nor restored the mechanical function during reperfusion, although it attenuated the accumulation of free fatty acids during reperfusion. These results suggest that dilazep attenuates both ischemia-and reperfusion-induced myocardial damage and that the anti-ischemic action of dilazep is not due to coronary vasodilation but probably due to an energy-sparing effect and other effects that remain to be studied.

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

“…In fact, we have shown that dilazep (5 and 10 pM) decreased mechanical function before ische mia and enhanced the recovery of mechanical function after ischemia (2). The results of the present study also demonstrated that K-7259 (5 and 10 tiM) decreased mechanical function before ischemia and enhanced the recovery of mechanical function after ischemia (pre ischemic administration experiments).…”

“…In the previous study, however, we have demonstrated that a preischemic administration of dilazep (10 pM) increases the recovery of mechanical function after ischemia (2). Therefore, the preischemic administration of dilazep is considered more effective in attenuating the mechanical dysfunction induced by ischemia-reperfusion.…”

“…ABSTRACT-Global ischemia (15 min) followed by reperfusion (10,20 Dilazep has been demonstrated to attenuate myocardial ischemic damage (1,2). The cardioprotective action of dilazep has been considered to be due to potentiation of the cardiovascular effects of adenosine, such as vasodilat ing and negative chronotropic effects, through inhibition of adenosine uptake into cardiac and endothelial cells (3).…”

Beneficial Effects of Dilazep on the Palmitoyl-L-carnitine-Induced Derangements in Isolated, Perfused Rat Heart: Comparison with Tetrodotoxin.

“…Hoque et al (27) reported that dilazep (1 pM) attenu ates myocardial derangements induced by ischemia and reperfusion in the isolated, working rat heart. The anti ischemic action of dilazep has been considered to be due to potentiation of the cardiovascular effects of adenosine (11,12).…”

Endothelin-1 Gene Expression in Endothelial Cells Is Potently Inhibited by a Vasodilator, Dilazep

“…The ET-1 inhibiting effect by lower concentrations of DZ may be anticipated in vivo or in real clinical situations. In some ischemia-reperfusion models, lower concentrations of DZ (5-10 µmol/l) have been reported to be effective in suppressing the ischemia-reperfusion injury (20,34,35). In actual clinical practice, a typical pharmacological dose regime of DZ has been shown to exhibit signs of a cardioprotective effect in patients with renal failure under hemodialysis (36).…”