Effects Of Pimobendan Research Articles

Effects of pimobendan (P) and UD-CG 212 (U) on coronary flow and interstitial release of prostacyclin (PGI 2) from isolated guinea pig hearts

Effects of pimobendan (P) and UD-CG 212 (U) on coronary flow and interstitial release of prostacyclin (PGI 2) from isolated guinea pig hearts

Effects of pimobendan, a novel inotropic agent, on intracellular calcium and tension in isolated ferret ventricular muscle

1. In this study we have investigated the effects of a novel inotropic agent, pimobendan (UDCG 115-BS), on skinned and intact ventricular muscle from ferrets. 2. Pimobendan (20 or 100 mumol/l) increased tension at a given free [Ca2+] when applied to skinned ventricular muscle, i.e. it increased the Ca2+ sensitivity of the myofibrils. 3. Tension and intracellular free Ca2+ [( Ca2+]i) were measured simultaneously in intact papillary muscles using the aequorin technique. When 25 mumol/l pimobendan was added to the superfusing solution, a slowly developing positive ionotropic effect was produced, which was accompanied by an increase in the size of the systolic rise in [Ca2+]i (Ca2+ transients) with a similar time course. 4. In order to determine whether pimobendan increased the Ca2+ sensitivity of myofibrils in an intact papillary muscle, we compared the increase in Ca2+ transients and tension observed in response to changes in extracellular [Ca2+] with those observed in response to pimobendan. The result of this comparison was that in intact muscle pimobendan caused no apparent increase in myofibrillar Ca2+ sensitivity. 5. Pimobendan caused an abbreviation of the time course of the Ca2+ transients, but the twitch was slightly prolonged. 6. When isoprenaline was added to the superfusing solution, a positive inotropic effect was produced, which was accompanied by a marked increase in the size of the Ca2+ transients. Isoprenaline caused an abbreviation of the time course of both the Ca2+ transients and the twitch. When the Ca2+ sensitivity of the intact myofibrils was determined as described above, isoprenaline caused a desensitization. Pimobendan produced a sensitization when compared with isoprenaline. 7. These results are consistent with the hypothesis that pimobendan produces an inotropic effect in isolated cardiac muscle which is mediated both by an increase in Ca2+ sensitivity and by an increase in adenosine 3':5'-cyclic monophosphate due to its phosphodiesterase-inhibiting activity. Such a combination of activities may be particularly advantageous for an inotropic agent.

Pimobendan increases calcium sensitivity of skinned human papillary muscle fibers.

The calcium sensitizing effects of the cardiotonic agent pimobendan on force production were investigated on chemically skinned human papillary muscle fibres. The papillary muscles were obtained from patients undergoing mitral valve replacement operations. Tension was produced by different free calcium concentrations and 100 mumol/l of pimobendan shifted the pCa-tension relationship significantly to the left. The effects of pimobendan were concentration dependent (10-300 mumol/l) but additionally also correlated with the state of left ventricular performance of the patients. Skinned papillary muscle fibres obtained from patients with reduced ventricular performance were more sensitive to calcium as well as pimobendan compared with fibres from patients with normal left ventricular performance. No differences in response to pimobendan were observed between fibres from NYHA II and NYHA III heart failure patients.

Effects of pimobendan, milrinone and dobutamine on cardiac performance in anaesthetized dogs with experimental heart failure: W. Diederen, C. Linder, A.B.M. Mauz, W. Wienen, J.C.A. van Meel. Department of Biological Research, Dr. Karl Thomae GmbH, D-7950 Biberach, FRG

Effects of pimobendan, milrinone and dobutamine on cardiac performance in anaesthetized dogs with experimental heart failure: W. Diederen, C. Linder, A.B.M. Mauz, W. Wienen, J.C.A. van Meel. Department of Biological Research, Dr. Karl Thomae GmbH, D-7950 Biberach, FRG

Effects of Pimobendan (UD-CG 115 BS) on Left Ventricular Inotropic State in Conscious Dogs and in Patients with Heart Failure

The purpose of this study was to examine the time course of the changes in left ventricular inotropic state after intravenous pimobendan administration. In conscious dogs, cumulative doses of 1 and 2.5 mg of pimobendan significantly increased heart rate and the isovolumic indices of inotropic state and relaxation. The maximal effect, however, required 2 h to be present. The changes in cardiac index and capillary wedge pressure after the intravenous administration of 5 mg to patients with heart failure confirmed this slightly delayed action of pimobendan. Accordingly, the effects of pimobendan on left ventricular inotropic state in patients with moderate to severe heart failure were determined during cardiac catheterization 130-150 min after injection of 5 (n = 3) or 2.5 (n = 4) mg. After drug administration, heart rate increased slightly (+7 beats/min; NS) while left ventricular end-diastolic and systolic pressure both decreased significantly (from 22.7 to 9.2 mm Hg, p less than 0.007 and from 123 to 90 mm Hg, p less than 0.025, respectively). The isovolumic index of contractility (dP/dt)/DP40 increased by 19.6 +/- 14.7% (p less than 0.02) and the slope of the late systolic stress-volume relationship improved by 48% (p less than 0.05). It is concluded that pimobendan is a positive inotropic agent in the failing human heart as well as a powerful veno- and arteriodilator.

Effects of Pimobendan (UD-CG 115 BS) on Left Ventricular Inotropic State in Conscious Dogs and in Patients with Heart Failure

Effects of Pimobendan (UD-CG 115 BS) on Left Ventricular Inotropic State in Conscious Dogs and in Patients with Heart Failure

Effects of Pimobendan on Hemodynamics and Myocardial Energetics in Patients with Idiopathic Dilated Cardiomyopathy

The influence of pimobendan and nitroprusside on hemodynamics was investigated in nine patients with idiopathic dilated cardiomyopathy (NYHA class II-III). Pimobendan and nitroprusside resulted in a comparable decrease of left ventricular end-diastolic wall stress (preload) by 46% (p less than 0.01) and 52% (p less than 0.01), respectively, and of end-systolic wall stress (afterload) by 36% (p less than 0.01) and 34% (p less than 0.01), respectively. Cardiac index increased from 3.2 +/- 0.4 to 4.2 +/- 0.8 L/min/m2 with pimobendan (p less than 0.01) and did not significantly change with nitroprusside (3.0 +/- 0.6 L/min/m2). Compared to nitroprusside, pimobendan resulted in a significant increase in stroke volume index by 37% (p less than 0.01) and maximum rate of left ventricular pressure rise by 23% (p less than 0.05). Heart rate did not significantly change with either drug. Following the application of pimobendan, there was a decrease in myocardial oxygen consumption from 14.3 +/- 5.1 to 10.6 +/- 3.8 ml/min/100 g (p less than 0.05). The ratio of myocardial oxygen consumption and systolic stress-time integral did not significantly change. Thus, in comparison with nitroprusside, pimobendan exhibits significant inotropic and vasodilating properties. The hemodynamic actions of pimobendan are associated with favorable effects on myocardial energetics.

Effects of Pimobendan on Hemodynamics and Myocardial Energetics in Patients with Idiopathic Dilated Cardiomyopathy

Effects of Pimobendan on Hemodynamics and Myocardial Energetics in Patients with Idiopathic Dilated Cardiomyopathy

Acute and Long-Term Hemodynamic Effects of Pimobendan (UD-CG 115 BS) in Comparison with Captopril

The acute and long-term hemodynamic efficacy of the positive inotropic and vasodilatory drug pimobendan (5 mg b.i.d.) was compared with that of the angiotensin converting enzyme (ACE) inhibitor captopril (25 mg t.i.d.) in a double-blind, randomized study in 20 patients suffering from chronic congestive heart failure (NYHA functional classes II-III). The hemodynamics at rest and under comparable exercise conditions were always obtained on the first and 14th treatment day before and 2 h following drug administration. Under resting conditions, pimobendan reduced the end-diastolic pulmonary arterial pressure measured 2 h after drug administration by 33% (p less than 0.05) and increased the cardiac output by 16% (p less than 0.05). These effects were maintained after a treatment period of 14 days. Following administration of captopril, no significant hemodynamic changes at rest were noted 2 h after the first dose on day 1 and the last dose on day 14. There was, however, a tendency to continuous decline of the end-diastolic pulmonary arterial pressure over the study period. Under comparable work load (median of 25 W), both substances decreased the end-diastolic pulmonary arterial pressure 2 h following the first dose (pimobendan, -38%, p less than 0.01; captopril, -9%, p less than 0.05). The difference in the magnitude of effect between both treatment groups was statistically significant (p less than 0.01). Following a treatment period of 14 days, the end-diastolic pulmonary arterial pressure before drug administration was significantly reduced (-24%, p less than 0.05) only in the pimobendan group, whereas the reduction in the captopril group (-11%) could not be statistically verified.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic Profile of the Cardiotonic Agent Pimobendan

Pimobendan (UD-CG 115 BS) is a potent positive inotropic agent with vasodilatory properties. This hemodynamic profile was demonstrated in conscious rabbits chronically instrumented with Doppler flow probes. Pimobendan (10, 30, 100, and 300 micrograms/kg i.v.) increased cardiac output, stroke volume, heart rate, and mesenteric, renal, and hindquarter blood flow velocities, and decreased diastolic blood pressure. The positive inotropic effects of pimobendan and its effects on pre- and afterload were also shown in dogs with propranolol-induced depressed myocardial function. Pimobendan exhibited strong effects on stroke volume (up to 59%) and pulmonary capillary wedge pressure (up to -84%). The substance increased left ventricular (LV) dp/dtmax up to 150% and also had favorable effects on renal blood flow. Left ventricular function curves showed the usefulness of pimobendan in this acute heart failure model. Pimobendan is well absorbed and its duration of action is long. Positive inotropic effects of pimobendan were observed for 8-12 h after oral administration of 0.1-1 mg/kg to conscious dogs. It is concluded that pimobendan produces cardiovascular effects that may be useful in the treatment of congestive heart failure.

Correlations Between the Cardiovascular Effects of Pimobendan and Plasma Concentrations of the Parent Compound and of Its Major Active Metabolite, UD-CG 212 CL, in Patients with Congestive Heart Failure

Pimobendan was administered orally (10 mg single dose on day 1, then 5 mg twice daily for 4 weeks) to nine patients with chronic heart failure undergoing hemodynamic monitoring. The time course of changes in plasma concentrations of pimobendan and of its major active metabolite. UD-CG 212 CL, was similar on days 1, 2, and 28. Pimobendan plasma levels peaked 1.5-2.0 h after drug intake: plasma concentrations of UD-CG 212 CL reached a maximum 1 h later; the terminal half-life of pimobendan in plasma varied between 1.44 +/- 0.94 h on day 1 and 1.19 +/- 0.36 h on day 2. Initially, cardiovascular variables changed with increasing plasma drug levels and reached a maximum 4 h after pimobendan intake; later, we found no correlation between plasma concentrations and hemodynamic effects. A steady state of hemodynamic improvement was achieved after 4 weeks of maintenance therapy with pimobendan. Baseline pulmonary capillary wedge pressure dropped from 16 +/- 7 mm Hg on day 1 to 5 +/- 3 mm Hg at noon on day 28 (-69%; p less than 0.001), and baseline cardiac index increased from 2.2 +/- 0.5 L/min/m2 on day 1 to 2.7 +/- 0.9 L/min/m2 on day 28 (+23%; p less than 0.01). Pimobendan is a long-acting drug that effectively improves cardiac performance in patients with chronic congestive heart failure.

Effects of Pimobendan (UD-CG 115 BS), a New Positive Inotropic Agent, on Ventricular Tachycardia and Ischemic Ventricular Fibrillation in a Conscious Canine Model of Recent Myocardial Infarction

Pimobendan (UD-CG 115 BS; 4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl- 3(2H)- pyridazinone) is a newly developed, structurally novel compound with positive inotropic as well as coronary and peripheral vasodilator activities. In vitro, pimobendan has been reported to prolong the duration of the cardiac action potential of ventricular myocardial tissue, suggesting the potential for this agent to increase myocardial refractoriness and possibly exert antiarrhythmic activity in vivo. In the present study, the effects of pimobendan upon cardiac electrophysiologic parameters, the induction of ventricular tachycardia by programmed ventricular stimulation, and upon the development of ischemic ventricular fibrillation were assessed in 16 conscious dogs 3 to 5 days after experimental anterior myocardial infarction. The intravenous administration of 0.3 mg/kg pimobendan to postinfarction dogs significantly reduced the rate-corrected QTc and paced QT intervals, and reduced the relative and effective refractory periods in normal noninjured ventricular myocardium. Electrophysiologic parameters in infarcted ventricular myocardium were not altered by pimobendan. Ventricular tachycardia remained inducible early after anterior myocardial infarction in eight of eight pimobendan-treated postinfarction dogs tested. Six of the eight pimobendan-treated animals that had nonsustained tachyarrhythmias elicited as initial responses to baseline programmed stimulation testing had sustained tachycardias induced at postdrug testing, with a reduction in the number of programmed extrastimuli required to induce the postpimobendan tachyarrhythmias occurring in three animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Pimobendan (UD-CG 115) on the Contractile Function of the Normal and “Postischemic” Canine Myocardium

Pimobendan (UD-CG 115) is a long-acting positive inotropic drug with arterio- and venodilator properties. To determine to what extent this new agent is able to affect contractile function in previously ischemic areas of the left ventricle (LV), the effects of pimobendan on global and regional LV function were studied in eight conscious dogs, 2 days after a 2-h coronary occlusion followed by reperfusion. Before pimobendan, percentage of systolic shortening and mean velocity of shortening were lower in reperfused segments than in control areas (0.41 +/- 0.17 vs. 0.93 +/- 0.07 s-1 and 7 +/- 3 vs. 15 +/- 1%, respectively; both p less than 0.05). Infusion of 1 mg of pimobendan significantly improved peak + dP/dt (3202 +/- 372 to 3848 +/- 498 mm Hg/s; p less than 0.05) and ejection time (166 +/- 13 to 156 +/- 15 ms; p less than 0.05). Cumulative infusion up to 2.5 mg further improved these indexes to 5199 +/- 934 mm Hg/s and to 125 +/- 11 ms, (respectively; both p less than 0.05) without affecting mean arterial pressure (91 +/- 14 to 93 +/- 22 mm Hg; NS). Mean velocity of shortening rose to 1.18 +/- 0.09 s-1 (p less than 0.05) in control segments and to 0.62 +/- 0.18 s-1 (p less than 0.05) in reperfused segments. The ratio between end-systolic pressure and length increased by 26 +/- 9% (p less than 0.05) in the reperfused segments and by 20 +/- 8% (p less than 0.05) in control areas.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac and coronary vasodilator profile of pimobendan, a new cardiotonic drug, revealed by use of isolated, blood-perfused dog heart preparations

Cardiac and coronary vasodilator effects of pimobendan (UD-CG 115 BS) were assessed in isolated, blood-perfused papillary muscle, sinoatrial (SA) node, and atrioventricular (AV) node preparations of dogs. Pimobendan was administered intra-arterially. In paced papillary muscle preparations, the drug increased the force of contraction in a dose-dependent manner. In SA node preparations, the drug produced an increase in sinus rate. When the drug was injected into the artery supplying the AV node, the drug produced a decrease in AV conduction time by accelerating AV nodal conduction in AV node preparations. In spontaneously beating papillary muscle preparations, the drug increased the rate of ventricular automaticity. No ventricular arrhythmias were produced by the drug. In all preparations, the drug increased (coronary) blood flow. The order of effectiveness of pimobendan on the above cardiovascular variables was as follows: ventricular muscle contraction much greater than coronary blood flow greater than SA nodal automaticity greater than AV nodal conduction greater than ventricular automaticity. The results indicate that pimobendan is relatively specific for force and its cardiovascular profile is very similar to those of phosphodiesterase inhibitors. Therefore, it is likely that this cardiovascular profile would be determined by its inhibitory action on phosphodiesterase.

Haemodynamic effects of Pimobendan (UDCG-113), a Phosphodiesterase Inhibitor

Haemodynamic effects of Pimobendan (UDCG-113), a Phosphodiesterase Inhibitor

Calcium antagonism: Effects of calmodulin antagonists and calcium entry blockers on histamin release from mast cells

Pimobendan, a new oral cardiotonic and vasodilator agent, increases myocardial contractile force through specific inhibition of phosphodiesterase type Ill and increased calcium sensitivity of the myocardial contractile elements. The effects of pimobendan on left ventricular performance and maximal exercise capacity were studied in a multicenter, randomized, double-blind, placebo-controlled trial involving 52 patients with severe congestive heart failure despite diuretics, digoxin, and angiotensin-converting enzyme inhibitors. The acute hemodynamic evaluation included three single doses of 2.5, 5.0, and 10.0 mg of oral pimobendan, which was subsequently administered at a daily dose of 5 or 10 mg for 4 weeks. Acute administration of pimobendan significantly increased the resting cardiac index and lowered pulmonary capillary wedge pressure in a dose-dependent manner, whereas heart rate and systemic arterial pressure were not substantially altered. Patients receiving pimobendan, 5 and 10 mg daily, had a significantly greater increase in maximal exercise duration than those receiving placebo, that is, 144 ± 30 and 124 ± 33 seconds versus 58 ± 25 seconds (p = 0.05). Peak oxygen uptake increased by 1.7 ± 0.8 and 2.2 ± 1.3 ml/kg/min in patients receiving pimobendan at a daily dose of 5 and 10 mg, respectively, whereas it decreased by 0.1 ± 0.6 ml/kg/min in patients receiving placebo (p = 0.06). Thus pimobendan acutely improves resting left ventricular performance and chronically increases exercise duration and peak oxygen uptake in patients with severe congestive heart failure concomitantly treated with digoxin, diuretics, and angiotensin-converting enzyme inhibitors.