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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