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Mepacrine, a phospholipase inhibitor. A potential tool for modifying myocardial reperfusion injury
Abstract:
Cardioprotective effects of phospholipase inhibitor, mepacrine, on ischemic reperfused myocardium were investigated in the isolated in situ pig heart preparation, which was subjected to 120 minutes of regional ischemia, with the final 60 minutes having superimposed global cardioplegic arrest followed by 60 minutes of reperfusion. Mepacrine (0.05 mmol/L) was administered before ischemia into the perfusion circuit in 15 of 29 experiments. Significant depletion of myocardial phospholipids occurred in nontreated animals during 60 minutes of reperfusion. Mepacrine prevented the reperfusion-induced phospholipid degradation. Further, the level of high-energy phosphate compounds was higher during ischemia and reperfusion in the mepacrine-treated hearts. Left ventricular developed pressure, maximum rate of rise of left ventricular pressure, and left ventricular end-diastolic pressure were measured under isovolumic conditions to assess cardiac contractility and compliance. During incubation with mepacrine, before ischemia, left ventricular developed pressure and maximum rate of rise of left ventricular pressure decreased to 45% and 51% of baseline values, respectively. This initial decline was improved to 65% and 70% in mepacrine-treated animals during the early period of regional ischemia. In the nontreated control heart, a progressive decline in contractility was observed with ischemia such that no significant difference was apparent in the two groups. Reperfusion resulted in a further deterioration of global cardiac performance in both mepacrine-treated and control animals. Although pretreatment with mepacrine did not improve contractility, myocardial oxygen consumption, coronary flow, and cardiac compliance significantly improved. These results suggest that myocardial injury may develop during reperfusion after temporary ischemia. Mepacrine inhibits such injury by acting as a phospholipase inhibitor, but it also behaves as a negative inotropic agent in ischemic reperfused myocardium.
Insights
Mepacrine, a phospholipase inhibitor, protects ischemic reperfused myocardium by preventing phospholipid degradation and preserving high-energy phosphates. However, it also acts as a negative inotropic agent, impacting cardiac contractility.
Area of Science:
- Cardiology
- Biochemistry
- Pharmacology
Background:
- Myocardial injury during reperfusion after ischemia is a significant clinical concern.
- Phospholipase activity contributes to cellular damage during reperfusion.
- Mepacrine is a known phospholipase inhibitor with potential cardioprotective properties.
Purpose of the Study:
- To investigate the cardioprotective effects of mepacrine on ischemic reperfused myocardium.
- To assess mepacrine's impact on myocardial phospholipids, high-energy phosphates, and cardiac function.
- To determine mepacrine's mechanism of action in the context of ischemia-reperfusion injury.
Main Methods:
- Isolated in situ pig heart preparation subjected to regional ischemia and cardioplegic arrest.
- Administration of mepacrine (0.05 mmol/L) prior to ischemia.
- Measurement of myocardial phospholipids, high-energy phosphate compounds, cardiac contractility (left ventricular developed pressure, dP/dt max), and compliance (LVEDP).
- Assessment of myocardial oxygen consumption and coronary flow.
Main Results:
- Mepacrine prevented the degradation of myocardial phospholipids during reperfusion.
- Mepacrine-treated hearts exhibited higher levels of high-energy phosphate compounds during ischemia and reperfusion.
- While mepacrine did not improve contractility, it significantly improved myocardial oxygen consumption, coronary flow, and cardiac compliance.
- Mepacrine demonstrated a negative inotropic effect, decreasing developed pressure and dP/dt max during initial exposure.
Conclusions:
- Mepacrine exhibits cardioprotective effects against ischemia-reperfusion injury by inhibiting phospholipase activity and preserving energy status.
- Mepacrine's beneficial effects on myocardial oxygen consumption, coronary flow, and compliance are significant.
- Mepacrine acts as a negative inotropic agent, which may limit its therapeutic application in improving cardiac contractility during ischemia-reperfusion.