Pharmacological tools for the limitation of myocardial reperfusion injury - Experimental evidence

Prompt re-establishment of coronary flow following coronary occlusion is ma ndatory for the preservation of myocardial tissue. The establishment of rep erfusion 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 earl y initiation of successful reperfusion. Some of this damage has been ascrib ed to what has been labelled as reperfusion injury. Clinical manifestations of reperfusion injury include ventricular arrhythmi a, compromised myocardial contractility and, most important for the subsequ ent prognosis, extension of the final infarct size. Many factors may contri bute to the reperfusion injury. Among them is the release of free oxygen ra dicals with subsequent lipid peroxidation of cellular membranes. Intracellu lar calcium overload may cause excessive myofilament activation and impaire d mitochondrial function, limit metabolic recovery and also activate protea ses. Inflammatory activity and neutrophil activation are other factors of i mportance, as are endothelial dysfunction causing disturbances in nitric ox ide (NO) availability and a compromised microvascular blood flow (the 'no-r eflow' phenomenon). Moreover, there is evidence that activation of the reni n-angiotensin system may cause harm, e.g., by increasing the calcium conten t in the myocytes, by coronary vasoconstriction, and by modulation of the c ardiac and vascular sympathetic activity. Some of these mechanisms may be i nterrelated. 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 i n 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 som e of them, namely beta-blockers, free oxygen radical scavengers, antioxidan ts, calcium channel blockers, inhibitors of the renin-angiotensin system an d the combination of several of these drugs, are reviewed. Apart from beta- blockers, all these compounds have given effective protection from myocardi al 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. (C) 2001 T he European Society of Cardiology.