Acetaminophen in the hypoxic and reoxygenated mammalian myocardium: Mechanisms of cardioprotection.

摘要

Acetaminophen has been used in Western medicine for over 100 years for its analgesic and antipyretic properties. Despite its widespread use, little information exists regarding the effects of this drug on the cardiovascular system. In the first part of this study, we investigated the effects of 0.35 mmol/l acetaminophen and its vehicle on isolated, perfused guinea pig hearts (Langendorff) made hypoxic and subsequently reoxygenated. Acetaminophen treated hearts retained a greater fraction of mechanical function during hypoxia and reoxygenation. For example, the average percent change from baseline of left ventricular developed pressure in acetaminophen- and vehicle-treated hearts at 6 minutes reoxygenation was 9 +/- 2% and -8 +/- 5% (P0.05), respectively. In addition, electron micrographs revealed greater preservation of myofibrillar ultrastructure in acetaminophen-treated hearts. Biochemical analyses revealed the potential of coronary effluent from acetaminophen-treated hearts to significantly neutralize peroxynitrite (ONOO-)-dependent chemiluminescence in all recorded time periods.; In the second part of this study, we hypothesized that acetaminophen, an effective antioxidant against ONOO-, would attenuate ONOO --mediated activation of intramyocardial matrix metalloproteinase-2 (MMP-2) and improve cardiac mechanical function. Isolated, perfused guinea pig hearts were treated with either acetaminophen [0.35 mmol/l] or its vehicle and administered a bolus injection of ONOO- (6 muM) after reaching steady state function. Mechanical data revealed that treatment with acetaminophen preserved contractile function (particularly diastolic function) after ONOO- administration. For example, 5 minutes after administration of ONOO- percent baseline -dP/dtmax was 10 +/- 3% and -4 +/- 7% (P0.05) in acetaminophen- and vehicle-treated hearts respectively. Western blotting and gel zymography revealed higher pro-MMP-2 activity in heart homogenates of vehicle- versus acetaminophen-treated hearts. In addition, Western blotting of heart homogenates showed increased degradative products of troponin I (TnI) in vehicle- versus acetaminophen-treated hearts. Our results support the following conclusions: (1) Acetaminophen is protective against hypoxia/reoxygenation by decreasing the oxidant burden, particularly of ONOO-. (2) Attenuation of the reactivity of ONOO - decreases the activity of MMP-2. (3) The decrease in MMP-2 activity results in a decrease in TnI cleavage. (4) Inhibition of TnI cleavage results in improved diastolic function during periods of increased oxidant load.