CARDIOVASCULAR EFFECTS OF THE CALCIUM SENSITIZER, LEVOSIMENDAN, IN HEART-FAILURE INDUCED BY RAPID PACING IN THE PRESENCE OF AORTIC CONSTRICTION

1 The haemodynamic effects of a novel cardiotonic drug, levosimendan, which has both calcium-sensitizing and phosphodiesterase III (PDE III) inhibitory properties, were studied in conscious dogs in which heart failure had been induced by prolonged cardiac pacing in the presence o f aortic constriction. These effects were compared with those in sham- operated dogs with essentially normal cardiac function. 2 Eighteen mon grel dogs were instrumented for the measurement of left ventricular pr essure (LVSP, LVEDP) and contractile function (dP/dt; dP/dt/P). In twe lve dogs a balloon catheter, positioned in the thoracic aorta, was inf lated producing an approximate 60% reduction in effective aortic diame ter. Twenty min later rapid ventricular pacing (240 beats mean(-1)) wa s commenced and maintained for 48 h by means of a bipolar pacing elect rode introduced into the right ventricle. This electrode served also f or recording changes in the endocardial electrogram in the absence of pacing. Six of these dogs were used to evaluate the haemodynamic chang es of pacing-induced heart failure; a further six of these dogs the ha emodynamic changes elicited by levosimendan under these conditions. Si x sham-operated dogs (group 2) served as controls. 3 In six dogs (grou p 1) the haemodynamic alterations were assessed after the development of heart failure. In the presence of aortic constriction, 48 h continu ous rapid cardiac pacing resulted in a marked deterioration in left ve ntricular function which remained stable for at least 48 h after cessa tion of pacing. Thus, there was a marked reduction in LVSP (15%), +dP/ dt(max) (35%), -dP/dt(max) (36%) and also in dP/dt/P (29%), whereas LV EDP was increased considerably (from 6.4 +/- 1.4 to 20.0 +/- 2.2 mmHg) . A marked elevation occurred in endocardial ST-segment (138%), lastin g for 20 min. 4 Levosimendan was administered intravenously in doses o f 0.005, 0.01 and 0.03 mu mol kg(-1) to 2 groups of conscious dogs. In the sham-operated dogs (group 2), only the higher dose (0.03 mu mol k g(-1)) produced significant increases in LVSP (19%), +dP/dt(max) (37%) , and in dP/dt/P (32%). In dogs with heart failure (group 3) doses of 0.005, 0.01 and 0.03 mu mol kg(-1) levosimendan resulted in an improve ment in +dP/dt(max) (26%, 38% and 49%), -dP/dt(max) (20%, 25% and 38%) and in dP/dt/P (19%, 34% and 50%) and reduction in the elevated LVEDP (from 20 +/- 2.2 mmHg to 16 +/- 1.0, 10 +/- 1.3 and 9 +/- 1.0 mmHg, r espectively). 5 Levosimendan proved to be a potent cardiotonic drug at the doses used, and was approximately three times more effective unde r conditions of impaired left ventricular function than in normal hear ts.