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
