Studies of myocardial ischaemia followed by reperfusion : New experimental models and their application

Abstract: Studies of Myocardial Ischaemia Followed by Reperfusion New Experimental Models and their Application Yozo Uriuda Despite great efforts to reduce morbidity and mortality in ischaemic heart disease, this is still the most common cause of death in the industrialised countries. To improve the management of such patients, further knowledge is needed of the pathophysiology of ischaemic heart disease. Experimental studies are an important and commonly utilised tool for accomplishing this goal. Three different experimental models are described, two of which were developed for the purpose of these studies. The models were applied to investigate if myocardial injury induced by ischaemia followed by reperfusion could be reduced by the calcium blocker felodipine and by synchronised coronary venous retroperfusion. Furthermore, the effects of a novel selective thrombin inhibitor were studied as regards the prevention of coronary thrombosis and in conjunction with thrombolysis. A new experimental model was developed in which drug was infused retrogradely into the coronary veins of isolated rat hearts subjected to coronary occlusion. This technique resulted in a specific accumulation of the test compound in the ischaemic myocardium. Felodipine was tested in this model and a myocardioprotective effect was documented after 60 min of regional ischaemia followed by 60 min of reperfusion. This experimental model is particularly suited for studies of myocar dioprotection with myocardiodepressive drugs and of those with vasodilatatory effects. In canine hearts subjected to 90 min of regional ischaemia followed by six hours of reperfusion, short-term treatment with synchronised coronary venous retroperfusion before full reperfusion reduced the final extent of myocardial damage. The mechanism behind this beneficial effect was probably a gradual induction of reperfusion. To mimic the clinical situation during thrombolysis in patients with threatening myocardial infarction, a model of coronary thrombosis followed by thrombolysis was established in closed-chest pigs. Induction of a coronary thrombotic occlusion via the insertion of a copper coil and subsequent thrombolysis achieved by tissue plasmin activator caused reproducible myocardial areas at risk and infarct sizes. This model is intended for investigations of pharmacological interventions interfering with the thrombotic and thrombolytic process. Inogatran, a new selective inhibitor of thrombin, was more effective in preventing the formation of a coronary thrombus than heparin and acetylsalicylic acid. The most likely explanation for this is inhibition of clot-bound thrombin and platelet activation induced by thrombin. Thrombotic occlusions formed in the presence of inogatran seemed more susceptible to spontaneous endogenous fibrinolysis than those formed in the absence of this compound. An enhanced local release of endothelin-like immuno-reactivity and a more marked vasoconstrictor response were demonstrated in the ischaemic/reperfused coronary artery in the coronary thrombosis/ thrombolysis model. This effect, which was related to the activation of endothelin-A receptors, may contribute to the development of myocardial injury following ischaemia and reperfusion, for instance, by enhancing the no-reflow phenomenon. Key words: myocardial infarction, myocardial ischaemia, reperfusion injury, animal experiment, rat, pig, dog, coronary venous retroinfusion, synchronised coronary venous retroperfusion, thrombosis, thrombolysis, inogatran, endothelin Slockholm 1997 lssN 91-628-2379-5