Mechanism of myocardial protective action of dilazep during ischaemia and reperfusion

Cargnoni, Anna; Condorelli, E.; Ceconi, Claudio; Curello, Salvatore; Albertini, Alberto; Ferrari, Roberto

doi:10.1016/0031-6989(87)90071-3

Cited by 5 publications

(4 citation statements)

References 17 publications

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“…6). Therefore, the anti-ischemic effect of dilazep on the ischemic heart can be interpreted as an energy-sparing effect (14). Recovery of coronary flow during reperfusion induced by dilazep at 5 pM or 101iM is probably due to recovery of mechanical function as mentioned before.…”

Section: High-energy Phosphatesmentioning

confidence: 72%

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

Hoque

Hashizume

et al. 1995

Japanese Journal of Pharmacology

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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.

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Section: High-energy Phosphatesmentioning

confidence: 72%

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

Hoque

Hashizume

et al. 1995

Japanese Journal of Pharmacology

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“…9 In the present study, we observed both alternans and afterdepolarizations during regional ischemia. Therefore, we speculate that Ca 2+ overload develops not only upon reperfusion, 10,11 but also during the early stage of regional ischemia and may cause ventricular arrhythmias including VF. …”

Section: Temporal Relationship Between Map Changes and Occurrence Of mentioning

confidence: 97%

Ventricular Fibrillation and Shortening, Alternans and Afterdepolarizations of Epicardial Monophasic Action Potentials During Coronary Occlusion and Reperfusion

et al. 1999

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entricular fibrillation (VF) occurs frequently in a setting of acute coronary occlusion and reperfusion, and constitutes a major cause of sudden cardiac death. The mechanisms of the induction of VF by coronary occlusion have been investigated in animal models by recording unipolar electrograms, 1 bipolar electrograms, 2 composite electrograms, 3 and by a mapping technique. 4 According to Kaplinsky et al, there are 2 peaks in the occurrence of ventricular arrhythmias early after acute coronary occlusion: the first peak occurs within 10 min (immediate ventricular arrhythmias) and the second peak occurs between 15 and 20 min (delayed ventricular arrhythmias). 3 The former is attributed to reentry based on a marked conduction delay in the subepicardial layer of the ischemic myocardium. However, ventricular arrhythmias can occur immediately after acute coronary occlusion even without a marked increase in activation time. 4 In such cases, reentry based on repolarization abnormalities, such as shortening or increased dispersion of repolarization, or other mechanisms, including triggered activity and abnormal automaticity, may be involved in the arrhythJapanese Circulation Journal Vol.63, March 1999 mogenesis. However, these possibilities remain to be confirmed, because repolarization abnormalities in ischemic myocardium cannot be examined by the techniques used in the previous studies. [1][2][3][4] Therefore, in the present study we examined the temporal relationship between the ischemia-and reperfusioninduced changes in monophasic action potential (MAP) configurations recorded from the epicardial ischemic zone and the occurrence of VF. We also examined the effects of the repetition of ischemia on MAP changes and the incidence of VF. MethodsThis study was performed in 32 mongrel dogs weighing 12-25 kg. The dogs were anesthetized with pentobarbital (30 mg/kg, iv), and additional doses were given when necessary to maintain anesthesia. The animals were intubated and ventilated with room air by a constant volumecycled respirator (Bird Corporation Mark7). The heart was exposed through a left thoracotomy and pericardotomy. The epicardial surface temperature was kept at 37-38°C with an overhead heat lamp. A cannula in the femoral vein was used to infuse normal saline at a rate of 100-200 ml/h to replace spontaneous fluid loss. A fluid-filled cannula was placed in the right femoral artery and connected to a transducer (Nihon Kohden model TP-400T) to monitor arterial blood pressure.The left anterior descending coronary artery (LAD) was The relationship between the occurrence of ventricular fibrillation (VF) and repolarization abnormalities of the ischemic and reperfused myocardium is poorly understood. The present study examined the temporal relationship between ischemia-and reperfusion-induced changes in monophasic action potential (MAP) configurations and the occurrence of VF, and assessed the effects of repetition of ischemia. The left anterior descending coronary artery of 32 anesthetized dogs was occluded twice for 5 mi...

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“…1,4-Bis[3-(3,4,5-trimethoxybenzoyloxy)propyl]perhydro-1,4-diazepine dihydrochloride monohydrate (dilazep, DZ) has been used clinically in Europe and Japan as a vasodilator (19), antianginal agent (20), antiplatelet agent (21) and proteinuria-reducing agent (22,23). Based on reports that DZ relieves proteinuria (22,23), and that endothelial (1,(14)(15)(16)(17)24) and mesangial cells (24,25) are important sites of ET-1 production, we hypothesized that DZ could inhibit ET-1 gene expression.…”

Section: Introductionmentioning

confidence: 99%

“…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).…”

mentioning

confidence: 99%

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

et al. 2004

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Mechanism of myocardial protective action of dilazep during ischaemia and reperfusion

Cited by 5 publications

References 17 publications

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

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

Ventricular Fibrillation and Shortening, Alternans and Afterdepolarizations of Epicardial Monophasic Action Potentials During Coronary Occlusion and Reperfusion

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

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