Pharmacological tools for the limitation of myocardial reperfusion injury Experimental evidence

Abstract

Prompt re-establishment of coronary flow following coronary occlusion is mandatory for the preservation of myocardial tissue. The establishment of reperfusion treatment, originally by thrombolysis and subsequently by coronary interventions, was a major improvement in the management of patients with myocardial infarction. Myocardial damage is still seen even after very early initiation of successful reperfusion. Some of this damage has been ascribed to what has been labelled as reperfusion injury. Clinical manifestations of reperfusion injury include ventricular arrhythmia, compromised myocardial contractility and, most important for the subsequent prognosis, extension of the final infarct size. Many factors may contribute to the reperfusion injury. Among them is the release of free oxygen radicals with subsequent lipid peroxidation of cellular membranes. Intracellular calcium overload may cause excessive myofilament activation and impaired mitochondrial function, limit metabolic recovery and also activate proteases. Inflammatory activity and neutrophil activation are other factors of importance, as are endothelial dysfunction causing disturbances in nitric oxide (NO) availability and a compromised microvascular blood flow (the ‘noreflow’ phenomenon). Moreover, there is evidence that activation of the renin-angiotensin system may cause harm, e.g., by increasing the calcium content in the myocytes, by coronary vasoconstriction, and by modulation of the cardiac and vascular sympathetic activity. Some of these mechanisms may be interrelated. From considerations of their nature, an attractive hypothesis has been that some or several of these harmful effects may be counteracted by pharmacological interventions. This hypothesis has mainly been studied in the experimental setting. On the basis of the multiplicity of mechanisms that seem to be involved in the creation of reperfusion injury, a number of pharmacological agents have been investigated for their protective effect. Results from studies of some of them, namely beta-blockers, free oxygen radical scavengers, anti-oxidants, calcium channel blockers, inhibitors of the renin-angiotensin system and the combination of several of these drugs, are reviewed. Apart from beta-blockers, all these compounds have given effective protection from myocardial reperfusion damage. By studying them in different experimental settings and protocols, insight has been gained about important factors for possible future clinical applications of some or several of these drugs.