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Background: Levosimendan improves ventricular function, induces vasodilation and induces myocardial preconditioning. We determined the external efficiency and assessed the effects on arrhythmias., Methods: In isolated, blood-perfused rabbit hearts, levosimendan (0.75 micromol) or placebo was administered, while hemodynamics were recorded. After no-flow ischemia and reperfusion, data were recorded again., Results: Placebo in normoxic hearts did not affect measurements, while levosimendan increased heart rate (+ 18 %) and improved coronary output (+ 52 %), stroke volume (+ 28 %), maximal left ventricular pressure (+ 30 %), maximal rate of pressure increase (+ 36 %), work (+ 68 %), minimal rate of pressure increase (+ 53 %), coronary blood flow (+ 41 %), coronary resistance (- 19 %) and external efficiency (33 %; P < 0.05). During reperfusion, hemodynamics in the levosimendan group were significantly better preserved compared with the placebo group. Early reperfusion arrhythmias were decreased (levosimendan group: 7 +/- 3 % vs. placebo group: 25 +/- 17 %; P < 0.05)., Conclusions: Levosimendan does not impair diastole, dilates coronary vessels, induces pharmacological preconditioning, improves external efficiency and exerts antiarrhythmic properties during reperfusion. As this drug protects the heart from reperfusion injury, it seems well suited for treating dysfunctional hearts after cardiac surgery.

Background: After open-chest cardiac surgery, ventricular function remains depressed (myocardial stunning). Catecholamines (epinephrine) improve ventricular function by increasing the intracellular Ca(2+) concentration. In parallel, the oxygen consumption is increased, so that the hitherto intact myocardium can be jeopardized. In the very insufficient ventricle, epinephrine can even become ineffective. Since Ca(2+) sensitizers provide another therapeutic avenue, the effects of epinephrine and levosimendan on postischemic hemodynamics were investigated., Methods: After hemodynamic steady state, isolated, blood (erythrocyte-enriched Krebs-Henseleit solution)-perfused rabbit hearts were subjected to 25 min normothermic, no-flow ischemia and 20 min reperfusion. Heart rate (HR), cardiac output (CO), left ventricular pressure (LVP), coronary blood flow (CBF), and arterio-venous oxygen difference (AVDO(2)) were recorded during reperfusion and after administration of either epinephrine (n=16; 0.03 micromol), or levosimendan (n=11; 0.75 micromol) or epinephrine plus levosimendan (n=5)., Results: Epinephrine increased HR (19%, p=0.01) and improved hemodynamics in terms of CO (62%, p=0.0006), stroke volume SV (46%, p=0.02), stroke work W (158%, p=0.01), LVP(max) (58%, p=0.0001), maximal pressure increase dP/dt(max)(140%, p=0.0004), minimal pressure increase dP/dt(min) (104%, p=0.0002), LVP(ed) (-26%, p=0.02), and increased coronary resistance CR (31%, p=0.05). Epinephrine impaired hemodynamics in terms of AVDO(2) (+63%, p=0.003), myocardial oxygen consumption MVO(2) (+67%, p=0.0003) and MVO(2)/beat (+36%, p=0.01). External efficiency eta was increased by 92% (p=0.02). Levosimendan in postischemic hearts increased HR (32%, p=0.009) and improved hemodynamics in terms of CO (85%, p=0.01), SV (44%, p=0.03), W (115%, p=0.04), LVP(max) (95%, p=0.04), dP/dt(max) (133%, p=0.009), dP/dt(min) (121%, p=0.007), LVP(ed) (-63%, p=0.0006), and CR (-17%; n.s., p=0.1). It altered hemodynamics in terms of AVDO(2) (+7.0%; n.s., p=0.3) and MVO(2) (+32%, p=0.007) and MVO(2)/beat (+2.3%; n.s., p=0.4). External efficiency was increased by 307% (p=0.04). In five additional extremely dysfunctional rabbit hearts, epinephrine was ineffective. Additional levosimendan increased hemodynamics in terms of HR (56%; n.s., p=0.1), CO (159%, p=0.04), SV (89%, p=0.03), W (588%, p=0.02), LVP(max) (168%, p=0.03), dP/dt(max) (102%, p=0.005), dP/dt(min) (78%, p=0.006), LVP(ed) (-98%, p=0.0006), and CR (-50%, p=0.02). It altered hemodynamics in terms of AVDO(2) (-11%; n.s., p=0.05), MVO(2) (+131%, p=0.04) and MVO(2)/beat (+171%, p=0.03). External efficiency was increased by 212% (p=0.04)., Conclusion: In contrast to epinephrine, levosimendan improves ventricular function without increasing oxygen demand, thereby considerably improving external efficiency. Even during epinephrine resistance in extremely dysfunctional hearts, levosimendan successfully improves ventricular function.

Aim: We compared protective effects of a ss-adrenoceptor blocker (metoprolol; Met) and a If current (Ivabradine; Iva) in a rabbit model of myocardial infarction., Methods: Experiments were performed on 44 adult New-Zealand-White (NZW) rabbits. The effects of either metoprolol or ivabradine were assessed 15 min after experimental occlusion of a coronary artery (CAO), 28 days after CAO (drug gavage), and in vitro hearts (Langendorff apparatus). The results were compared with sham and placebo hearts., Results: Metoprolol (0.25 mg/kg) slightly reduced heart rate and left ventricular systolic function. Ivabradine (0.25 mg/kg) reduced heart rate significantly (P<0.05) (18% vs control). Both drugs provided advantages over placebo: mortality was significantly (P<0.01)smaller (6/13 Pla animals died, 2/10 Met animals, and 3/11 Iva animals), left ventricular function was better preserved after 28 days (external power; Pla; Met; Iva=56%; 76%; 74%), and dilatation (BNP) was reduced (P<0.05). In the Pla group, the ST segment was significantly (P<0.05) elevated by 0.35 mV after CAO and exhibited in 50% of the animals Q waves after 28 days, while after ivabradine or metoprolol, ST displacement and Q waves had disappeared. The uneconomic myosin isoenzyme V3 predominated in Met hearts and Iva hearts (V3/V1: 63/37% and 62/38%), while it was further increased in Pla hearts (78/21%). External efficiency was lowest in Pla hearts (1.00+/-0.50 a.u.; P<0.05) and was significantly higher both in Met hearts (4.0+/-1.8 a.u.) and in Iva hearts (3.3+/-1.6 a.u.)., Conclusions: Met and Iva seem suited for the treatment of chronic myocardial infarction.

Several clinical studies demonstrate the importance of the heart rate for the cardiovascular morbidity and mortality. Over the last 50 years, some thought has been given to those substances that selectively reduce the heart rate. It is now recognized that I(f) ion channels of the sinus node play a major role in the automatism and modulation of the heart rate. Substances that selectively reduce the heart rate should decrease myocardial oxygen consumption and increase oxygen delivery via the prolonged diastolic coronary perfusion. Direct inotropic effects, however, are unlikely. In principle, anti-anginal and anti-ischemic effects of specific bradycardic substances can be expected. The clinical experience with some of the former bradycardic substances has not been sufficiently convincing. The more recent ivabradine (Procoralan presents an exception to this, as it successfully completed a clinical program for the treatment of chronically stable angina pectoris. In this review article, specific bradycardic substances (= I(f) channel inhibitors) are presented together with the corresponding experimental and clinical studies. The studies were selected against the background of the efficacy of I(f) channel inhibitors in the therapy of cardiovascular disease. As only ivabradine has completed a study on 5,000 patients, the discussion on that particular I(f) channel inhibitor is somewhat extensive. In addition, prospective possibilities and limitations of bradycardic substances are presented.

We tested whether decreased Ca2+ sensitivity is a major cause for dysfunctional stunned myocardium. The experiments employed a novel Ca2+ sensitizing agent: the thiadiazinone derivative EMD 60 263. Experiments were done on 14 isolated, blood-perfused rabbit hearts. After control, seven hearts were subjected to 20 min no-flow ischemia, and then allowed to recover during 30 min reperfusion. Thereafter, EMD 60 263 was administered (3, 10 and 30 microm). For comparison, the effect of the same doses was investigated in seven non-ischemic hearts. At the low dose, the agent improved ventricular systolic function in the post-ischemic group significantly (LVPmax: 65+/-13 v 91+/-17 mmHg; dP/dtmax: 845+/-235 v 1300+/-350 mmHg/s), and non-significantly in the non-ischemic group (LVPmax: 115+/-35 v 132+/-39 mmHg; dP/dtmax: 1415+/-545 v 1885+/-720 mmHg/s). Early relaxation (dP/dtmin) was slightly improved in both groups (800+/-225 v 1050+/-220 mmHg/s post-ischemic; 1120+/-315 v 1205+/-285 mmHg/s non-ischemic). Heart rate was increased (151+/-35 v 175+/-45 beats/min) in the post-ischemic group and was unaffected in the non-ischemic group. At the higher dose, systolic ventricular function in the post-ischemic group was further improved (LVPmax: 109+/-17 mmHg, dP/dtmax: 1330+/-180 mmHg/s), but tended to decrease in the non-ischemic group (LVPmax: 121+/-40 mmHg, dP/dtmax: 1605+/-680 mmHg/s). This dose decreased heart rate in both groups (133+/-34 and 134+/-23 beats/min). 30 microm EMD 60 263 had deleterious effects in both groups. The different responses towards Ca2+ sensitization suggest that a decrease in Ca2+ sensitivity might play a role in dysfunctional stunned myocardium. Therefore, Ca2+ sensitizing agents of the thiadiazinone type could be useful to recruit a positive inotropic reserve in stunned myocardium.

Beside wall tension and contractility, heart rate is a major determinant of myocardial oxygen consumption. Therefore, a decrease in heart rate could prevent ischemia or reduce its consequences. We examined the effect of a new bradycardic agent of the benzazepinone-type (DK-AH 269) on eight isolated, saline-perfused rabbit hearts, bradycardia resulted from a specific blockade of i(f)-channels in sinus node cells. After control measurements (C), the substance was added in three increasing concentrations (D1: 10(-8) M, D2: 10(-7) M, D3: 10(-6) M). We observed a dose-dependent reduction in heart rate (C: 206 +/- 25, D1: 195 +/- 30, D2: 77 +/- 41, D3: 154 +/- 48/min). In the highest dosage, the duration of diastole was increased by 100%. To characterize systolic function, we measured stroke volume (SV), peak left ventricular pressure (LVPmax) and its first derivative (dP/dtmax). Aortic flow was slightly decreased whereas SV increased to 108% of control after initial reduction at the two lower dosages. LVPmax remained unchanged, and dP/dtmax was dose-dependently reduced to 91, 81, and 70% of control (C: 1885 +/- 376, D1: 1721 +/- 525, D2: 1526 +/- 504, D3: 1327 +/- 337 mm Hg/s); dP/dtmin as a measure of early relaxation was also reduced. The coronary flow per beat did not change compared with control in the presence of the two lower doses of DK-AH 269, but was significantly increased with the highest dose (C: 0.29 +/- 0.06, D1: 0.28 +/- 0.07, D2: 0.29 +/- 0.09, D3: 0.34 +/- 0.11 ml). The myocardial oxygen demand was dose-dependently decreased (C: 10.4 +/- 2.5, D1: 9.6 +/- 2.5, D2: 8.8 +/- 2.6, D3: 7.9 +/- 2.4 ml/min/100 g). The relation between subendocardial and subepicardial flow, assessed with colored microspheres, exhibited no changes in the presence of the highest dose of DK-AH 269 (C: 1.28 +/- 0.09, D3: 1.27 +/- 0.08). DK-AH 269 reduced heart rate in isolated rabbit hearts and increased the duration of diastole. Whereas systolic function was primarily left unchanged, coronary flow per beat and oxygen consumption were decreased. According to our results, this new bradycardic agent could be useful in treating coronary heart disease.

Inotropic agents are used widely for pharmacological bridging of the failing heart either until recovery after surgical intervention or until transplantation. EMD 57033 is a novel specific Ca++ sensitizing agent with purportedly minor phosphodiesterase (PDE) III-inhibiting properties. It acts as an inotropic agent without raising intracellular Ca++ levels. In turn, the PDE III-inhibitor enoximone has been used for several years to treat low cardiac output syndrome. However, little is known about its effects on postischemic reperfused (stunned) myocardium. We investigated the effects of EMD 57033 (EMD; 30 microM) and enoximone (E20 micrograms/ml) on stunned myocardium. The experiments were performed on 16 isolated rabbit hearts perfused with an erythrocyte suspension (hematocrit = 30%; [Ca++] = 2.5 mM). Hearts were reperfused after a 20 min no-flow ischemia. Measurements were performed at control, 30 min after the onset of reperfusion, and after administration of one of the drugs. Both agents significantly improved the depressed systolic function [left ventricular pressure (LVP)max from 61 +/- 12 to 93 +/- 18 mmHg, and its derived pressure (dP/dt)max from 860 +/- 220 to 1340 +/- 300 mmHg/s and LVPmax from 78 +/- 9 to 83 +/- 15 mmHg, and its derivative dP/dtmax from 1040 +/- 230 to 1385 +/- 300 mmHg/s, respectively] and early relaxation (dP/dtmin from 810 +/- 250 to 1260 +/- 345 mmHg/s and from 1000 +/- 200 to 1135 +/- 295 mmHg/s, respectively) that occurred during postischemic reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

A possible cause for the decreased function in postischemic reperfused (= stunned) myocardium could be a decrease in Ca++ sensitivity. To test this hypothesis, we used an agent with reportedly Ca++ sensitizing properties (EMD 57033) and performed experiments on a total of 17 isolated rabbit hearts that were perfused with an erythrocyte-containing medium in a modified Langendorff setting (hct = 30%; Ca++ = 2.0 meq/l). The hearts were divided into two groups. In one group (n = 9), the Ca++ sensitizer (30 microM) was administered to nonischemic myocardium, and in a second group (n = 8), the Ca++ sensitizer was administered after 30 min of reperfusion that followed a period of 20 min normothermic, no-flow ischemia. In the nonischemic group, addition of the agent, improved left ventricular (LV) function significantly. In the ischemic group, LV-function was depressed at 30 min reperfusion compared to control. Again, the agent improved LV-function significantly. The increase in systolic and diastolic function was comparable in both groups as well as the oxygen consumption that was significantly increased after administration of the agent. In both groups, the agent neither exhibited significant, positive chronotropic nor arrhythmogenic effects. We summarize that the novel Ca++ sensitizer acts as a potent positive inotropic agent in the isolated blood-perfused rabbit heart. Because of the agent's properties to ameliorate postischemic contractile dysfunction, this general strategy may be useful for treating poorly functioning reperfused myocardium.