Pharmacological investigation in a swine model of chronic left ventricular dysfunction

In this thesis we first investigated the cardiovascular actions of several classes of drugs in conscious pigs in which heart failure was induced by occluding a coronary artery 3-4 weeks before the studies were performed and compared the results to those observed in normal conscious animals. Positive inotropic agents and vasodilators are frequently used to treat heart failure as they may improve the depressed myocardial contractility and lower the elevated systemic vascular resistance. In chapter 2 and 3 the effects of the 1.4- dihydropyridine derivative calcium antagonists nisoldipine and elgodipine are studied because of their capability to unload the heart by reducing systemic vascular resistance in normal anesthetized pigs (Duncker et al., 1986 and Sassen et al.. 1990) and by increasing cardiac output in normal conscious pigs (Duncker et aL, 1987). To study the potential advantage of vasodilators with positive inotropic properties to vasodilators alone we also investigated the actions of the phosphodiesterase inhibitor pimobendan with nisoldipine in the porcine model for heart failure (Chapter 4 ). In chapter 5 we describe the effects of a novel class of drugs which causes systemic vasodilation by potassium channel activation. The results of bimakalim are compared to the nicotinamide derivative nicorandil, which in addition to their nitrate-like properties, also possess potassium channel activator properties (Taira, 1989). One of the most prominent drugs in the treatment of ischaemic heart disease is nitroglycerin, despite the frequent occurrence of tolerance. In chapter 6 we first evaluated 5 novel nitrate-esters in normal conscious pigs. In the second part nitroglycerin and one of the novel compounds, CEDO 8956, were selected for further study of distribution of cardiac output in conscious pigs with chronic coronary artery occlusion. Tachycardia is an unwanted situation, especially in patients with coronary artery disease. Selective bradycardic agents, which exert an anti-ischemic effect because of their ability to reduce oxygen demand and improve oxygen supply of the myocardium and especially of the subendocardial layers (Schamhardt et aL, 1981, Krumpl eta!., 1988 and lndolfi et a!., 1989), may thus have some benefit in patients with left ventricular dysfunction, provided that the negative chronotropic properties are not accompanied by negative inotropic properties. We therefore studied the effects of UL-FS 49, a specific bradycardic agent and compared the results to those of the non-selective beta-adrenoceptor antagonist propranolol