1 The haemodynamic effects of a novel cardiotonic drug, levosimendan, which has both calciumsensitizing 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 of aortic constriction. These effects were compared with those in sham-operated dogs with essentially normal cardiac function. 2 Eighteen mongrel dogs were instrumented for the measurement of left ventricular pressure (LVSP, LVEDP) and contractile function (dP/dt; dP/dt/P). In twelve dogs a balloon catheter, positioned in the thoracic aorta, was inflated producing an approximate 60% reduction in effective aortic diameter. Twenty min later rapid ventricular pacing (240 beats mean-1) was commenced and maintained for 48 h by means of a bipolar pacing electrode introduced into the right ventricle. This electrode served also for recording changes in the endocardial electrogram in the absence of pacing. Six of these dogs were used to evaluate the haemodynamic changes of pacing-induced heart failure; a further six of these dogs the haemodynamic changes elicited by levosimendan under these conditions. Six sham-operated dogs (group 2) served as controls. 3 In six dogs (group 1) the haemodynamic alterations were assessed after the development of heart failure. In the presence of aortic constriction, 48 h continuous rapid cardiac pacing resulted in a marked deterioration in left ventricular function which remained stable for at least 48 h after cessation of pacing.Thus, there was a marked reduction in LVSP (15%), +dP/atma,, (35%), -dP/dtaax (36%) and also in dP/dt/P (29%), whereas LVEDP was increased considerably (from 6.4 ± 1.4 to 20.0 ± 2.2 mmHg). A marked elevation occurred in endocardial ST-segment (138%), lasting for 20 min. 4 Levosimendan was administered intravenously in doses of 0.005, 0.01 and 0.03 gmol kg-' to 2 groups of conscious dogs. In the sham-operated dogs (group 2), only the higher dose (0.03 ILmol kg-') produced significant increases in LVSP (19%), + dP/dtmax (37%), and in dP/dt/P (32%). In dogs with heart failure (group 3) doses of 0.005, 0.01 and 0.03 pmol kg-' levosimendan resulted in an improvement in +dP/dtmax (26%, 38% and 49%), -dP/dtmax (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, respectively). 5 Levosimendan proved to be a potent cardiotonic drug at the doses used, and was approximately three times more effective under conditions of impaired left ventricular function than in normal hearts.

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The results suggest that brief periods of rapid pacing induce both short term and long term cardioprotection, as shown by reduced electrophysiological and haemodynamic consequences of subsequent pacing periods. Endogenous prostanoids might play a role in the short term cardioprotection.

1The effect ofdiltiazem was studied in a new model ofmyocardial ischaemia in which in addition to a critical constriction of the left circumflex branch (LCX), the left anterior descending coronary artery (LAD) was suddenly occluded. This model is probably more relevant to the clinical situation in which multivessel coronary artery disease is common. 2 In this model diltiazem exerted a beneficial effect, manifested by an increase in myocardial blood flow (MBF) within the stenosed area of the LCX; by a marked reduction of the enhanced preload (LVEDP); by a diminution of the inhomogeneity of electrical activation and by a decrease in STsegment elevation. Diltiazem also caused a significant reduction both in the number of extrasystoles and in the incidence of ventricular fibrillation. 3 Increased MBF within the stenosed area was associated with enhanced blood flow to the ischaemic myocardium, i.e. diltiazem directed flow to the ischaemic zone by improvement of the collateral circulation. 4 The beneficial electrophysiological changes caused by diltiazem are probably at least partly due to the drug-induced improvement of myocardial blood supply to the ischaemic area.

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This work was initiated by the discrepancy existing between the traditional experimental infarction model with occlusion of one single major coronary artery in the otherwise healthy myocardium and the clinical situation in which two or more major coronary arteries are stenosed at the same time. A model mimicking this latter clinical situation was elaborated as follows: In anaesthetized, open-chest dogs the haemodynamic, electrophysiological and blood flow changes due to 5 min occlusion of the left anterior descending coronary artery (LAD) were studied in the absence and presence of a critical constriction of the left circumflex coronary artery (LCX). Control LAD occlusion resulted in enhanced ST-segment elevation and inhomogeneity of electrical activation, depressed left ventricular contractility (LVdP/dt) and local myocardial contractility, as well as in a decline of myocardial blood flow (MBF) in the ischaemic area supplied by LAD. These changes were accompanied by no or slight extrasystolic activity. In the presence of critical stenosis of LCX, occlusion of the LAD aggravated myocardial ischaemia, i.e. ST-segment elevation and diminution of MBF were more marked, mainly in the subepicardium of the ischaemic area. The incidence and severity of arrhythmias significantly increased. Even ventricular fibrillation occurred in one third of the animals, both during LAD occlusion and after its release. Thus, acute LAD occlusion in the presence of a stenosed LCX produced a more severe myocardial ischaemia associated with more severe arrhythmias than occlusion of LAD alone. This model is more relevant to the clinical situation in which multivessel coronary artery disease is common.

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1 The effects of verapamil (0.15/kg) and fendiline (3 mg/kg) were studied in anaesthetized, thoracotomised dogs with a critical constriction of the left anterior descending coronary artery, paced in excess of the initial rate by 60-70 beats/min. Epicardial ST-segment elevation and changes in lactate uptake were used to assess the severity of myocardial ischaemia. 2 Both drugs prevented the ST-segment elevation and the reduced lactate uptake that resulted from atrial pacing. 3 The anti-ischaemic effect of fendiline is mainly due to its negative chronotropic action, whereas that of verapamil is due in part to bradycardia and in part to the reduced preload and afterload. In addition, both agents increase coronary flow to the ischaemic area and thus improve the myocardial oxygen supply/oxygen requirement ratio.