Aspects on the treatment of experimentally induced coronary artery disease

In this thesis some therapeutic aspects of experimentally induced coronary artery disease are being highlighted. In chapter 2 the effects of the Ca2 • antagonist diltiazem on the progression of coronary and aortic atherosclerosis in pigs is being studied. So far, studies on the anti-atherosclerotic effects of this drug (Ginsburg et al., 1983; Naito et al., 1984; Sugano et al., 1986; Dicciani et al., 1987; Sugano et al., 1988) have only been performed in the hypercholesterolemic rabbit and in only one study (Ginsburg et al., 1983) also the effect on coronary atherosclerosis was investigated. However, hypercholesterolemic rabbits develop atherosclerosis in the small intramyocardial branches rather than in the large epicardial coronary arteries, as observed in man and in swine. Furthermore, in these studies the doses used were so high that they would never be tolerated by man. Besides a medicamentous regimen, dietary intervention may also present a possible way of dealing with atherosclerosis. In chapter 3 the regression of porcine atherosclerotic lesions and the effects of dietary flsh oil on this process have been investigated. Myocardial ischemia has been mimicked in anesthetized pigs by creating a concentric stenosis by inflating a balloon placed around the vesseL Several therapeutic approaches have been explored (chapters 4, 6, 8 and 10). The effect of a low dose of the Ca2+ antagonist nisoldipine (chapter 4) and L-propionylcarnitine (chapter 6) on ischemic and postischemic blood flow and function have been investigated. Furthermore, an attempt has been made to predict long term outcome of stunned myocardium by means of two markers for long term recovery: the post systolic wall thickening (Takayama et al., 1988) and Ca2+ uptake and phospholamban phosphorylation of the sarcoplasmic reticulum (Schoutsen et al., 1989). The reflex-mediated tachycardia, as observed in conscious (Duncker et al., 1987a), but also in anesthetized animals (Duncker et al., 1986) may, in myocardial ischemia, render a potential detrimental effect of vasodilators such as the Ca 2+ -antagonists. In chapter 5 the cardiovascular profile of the newly developed Ca2+-antagonists elgodipine has been surveyed. In chapter 7 the global and regional cardiovascular effects of nicorandil were investigated while in chapter 8 the drug was tested for its anti-ischemic potential. As indicated, nicorandil is a compound with nitrate-like actions, but it has also been shown that the cardiac effects and possibly in part the vasodilating property, are mediated by K+ channel activation. In chapter 9 we investigated the cardiovascular effects of a selective K+ channel activator for comparison with those of nicorandil. Despite new developments, B-adrenoceptor-antagonists remain important for the treatment of myocardial ischemia. In this respect the cardioselective type of £adrenergic antagonists are of particular interest. One such drug is bisoprolol (Harting et al., 1986), a compound that has been shown to exert pronounced cardiovascular actions at doses considerably lower than required to inhibit the isoproterenol-induced increases in heart rate and contractility (Duncker et al., 1987b ). In chapter 10 its effects on contractile function and myocardial flow in ischemic porcine myocardium are described.