An Old Drug with a New Purpose: Cardiovascular Actions of Acetaminophen (Paracetamol)

Abstract

For over 50 years, acetaminophen (paracetamol) has been a staple in industrialized and non-industrialized countries for the treatment of pain and fever. Although its precise mechanisms of action are not known, the drug generates dose-dependent reduction in circulating prostaglandins, inhibits myeloperoxidase and the oxidation of lipoproteins, and appears to confer cardioprotection by blocking the effects of hydroxyl radical, peroxynitrite, and hydrogen peroxide. The drug might inhibit cyclooxygenase, although its ultimate target(s) is (are) still unclear. Sadly, since most investigations of acetaminophen have focused on its analgesic/antipyretic properties and hepatotoxicity, the effects of the drug on other mammalian organ systems, including the heart and circulation, have been ignored. Recently, work in our laboratory has shown acetaminophen to have a protective role in the injured mammalian myocardium. The cardioprotection was first observed in isolated, perfused guinea pig hearts subjected to ischemia-reperfusion injury. Hearts pretreated with acetaminophen recovered greater ventricular function and exhibited improved myofibrillar ultrastructure when compared to vehicle-treated hearts. More recent in vitro investigations have suggested protective roles for acetaminophen in barbiturate-induced arrhythmogenesis and myocardial hypoxia-reoxygenation injury. We have also extended our work to the in vivo arena. There, we found that acetaminophen reduced infarct size in dogs exposed to 60 minutes regional myocardial ischemia and 180 minutes reperfusion. We invite and encourage readers of this review to repeat/duplicate our experiments. Such work is needed to either challenge or support our findings. Further, more clinically-relevant work depends on these basic and related translational experiments.

Acetaminophen Attenuates Pulmonary Vascular Resistance and Pulmonary Arterial Pressure and Inhibits Cardiovascular Collapse in a Porcine Model of Endotoxemia

“…However, as TXA 2 is mostly a paracrine or autocrine substance (25) and the current experimental setup did not permit the analysis of TXA 2 levels in tissues at the relevant time points, we can only assume that acetaminophen inhibited thromboxane synthesis in our experimental setting. Acetaminophen has been found to be protective during myocardial infarction in dogs and guinea pigs and to increase the contractility of heart myocytes in vitro (26). However, the mechanism remains unclear, and further studies investigating the local effect of acetaminophen on TXA 2 and other substances in the lungs and other organs are needed.…”

Acetaminophen-mediated cardioprotection via inhibition of the mitochondrial permeability transition pore-induced apoptotic pathway

“…We have previously reported both chronic and acute acetaminophen treatment (0.35 mM) to be cardioprotective following ischemia/reperfusion in the isolated perfused guinea pig myocardium (17,18). Highperformance liquid chromatography analysis shows that treatment with acetaminophen at this molarity yields arterial and venous concentrations of 45-50 g/ml (44). These values fall within the range of therapeutic human plasma concentrations (10 -100 g/ml) and well below those concentrations resulting in hepatotoxicity (Ն300 g/ml; Refs.…”

Clinical evaluation of postoperative analgesia, cardiorespiratory parameters and changes in liver and renal function tests of paracetamol compared to meloxicam and carprofen in dogs undergoing ovariohysterectomy

“…Recently, the antiarrhythmic effects of paracetamol on the myocardium of dogs have also been described, as this drug reduces the activity of myeloperoxidase, which in turn significantly reduces the oxidation of low-density lipoproteins (LDLs) in macrophages. The cardioprotective effects of paracetamol include its reduction of infarct sizes and mortality within 48 hours after this obstructive event, actions that imply a mechanism mediated by catalase/superoxide dismutase in a dog model [21,22]. The anti-inflammatory effects of this drug have also been explored in a placebo-controlled cross-over trial in dogs that underwent surgery of the third metacarpus of the thoracic limb.…”