Effects Of OPC-18790 Research Articles

Effects of OPC-18790, a new positive inotropic agent, on energetics in the ischaemic canine heart: a 31P-MRS study

Effects of OPC-18790, a novel positive inotropic agent, on cardiohaemodynamics and cardiac energetics were assessed simultaneously in dogs with cardiac ischaemia using phosphorus-31 magnetic resonance spectroscopy (31P-MRS) and compared with those of amrinone, a pure cGMP-inhibited PDE inhibitor. Cardiac ischaemia was produced by partial stenosis of the coronary artery. Dogs with cardiac ischaemia were instrumented for the determination of regional coronary blood flow (non-radioactive coloured microsphere method), regional contractile function (sonomicrometry), and haemodynamics. Myocardial phosphate compounds were measured simultaneously by 31P-MRS. Coronary stenosis produced regional dyskinesis, a slight decrease in cardiac output (CO), intracellular acidosis, an increase in the inorganic phosphate (Pi)/creatine phosphate (PCr) ratio concomitantly with a decrease in regional coronary blood flow (CBF) in the ischaemic region. OPC-18790 dose-dependently produced an increase in contractility (measured by peak LVdP/dt) and CO, with only slight changes in heart rate (HR) and mean blood pressure (mBP). OPC-18790 did not change regional dyskinesis, but improved the Pi/PCr ratio at the high dose compared with ischaemic values (before drug administration). Amrinone produced an increase in CO comparable to that of OPC-18790; however, the increase in peak LVdP/dt was smaller while the increase in HR and decrease in mBP were larger than those seen with OPC-18790. Amrinone worsened the Pi/PCr ratio and intracellular acidosis only at the high dose. These observed differences in energy metabolism between OPC-18790 and amrinone at the high dose may be due to the ability of OPC-18790 to increase CBF in the ischaemic region and which may attributed to its differing effect on overall haemodynamics. Thus, OPC-18790 may be useful in the management of ischaemic heart failure.

P1-200 - Effects of OPC-18790 in combination with drugs for heart failure treatment in anesthetized dogs

P1-200 - Effects of OPC-18790 in combination with drugs for heart failure treatment in anesthetized dogs

Cardiovascular Effects of the Combination of OPC-18790 and Dopamine in Halothane-Anesthetized Dogs

OPC-18790, (±)-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]-2(1H)-quinolinone, is a novel positive inotropic agent, and its mechanism of positive inotropic action involves not only phosphodiesterase inhibition, but also a prolongation of action potential duration in ventricular muscle. Prolongation of action potential duration is also a property of class III antiarrhythmic agents; therefore, we examined the cardiohemodynamic effects and arrhythmogenicity of a combination of OPC-18790 and dopamine in halothane-anesthetized dogs. Dopamine (5 μg/kg/min) alone increased the peak of the first derivative of left ventricular pressure (LVdP/dtmax) and cardiac output (CO) by 43-48% and 16-20%, respectively, while OPC-18790 (10 μg/kg/min) increased these parameters by 56% and 22%, respectively. The combination of OPC-18790 (10 μg/kg/min) and dopamine (5 μg/kg/min) and dopamine alone at an increased dose of 10 μg/kg/min further increased LVdP/dtmax and CO by 104-113% and 29-30%, respectively. Thus, positive inotropic effects were equally observed in both groups, and the effects of OPC-18790 and dopamine seemed to be additive. The other hemodynamic effects were similar among all groups. Arrhythmias such as premature ventricular contraction developed in 5 out of 7 dogs (71.4%) in the 10-μg/kg/min dopamine group, while only one premature ventricular contraction was observed in 1 of 7 dogs (14.3%) in the OPC-18790 (10 μg/kg/min) and dopamine (5 μg/kg/min) combination group. These results suggest that the combination of OPC-18790 and dopamine may provide new therapeutic options for the treatment of heart failure.

Ionic basis for OPC-8212-induced increase in action potential duration in isolated rabbit, guinea pig and human ventricular myocytes

Changes in transmembrane ionic currents induced by OPC-8212 (3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]- 2(1H)-quinoline), a recently introduced positive inotropic agent which lengthens cardiac action potential duration, were examined using whole-cell voltage-clamp techniques in single rabbit, guinea pig and human ventricular myocytes. In rabbit, OPC-8212 (12 μmol/l) significantly increased membrane action potential duration measured at 90% of repolarization by an average of 88 ms (from 462 ± 25 to 550 ± 35 ms, n = 4; P < 0.05). In rabbit this increase in duration was not associated with significant changes in either the inward rectifier or transient outward K + currents. The magnitude of the secondary inward current evoked from a holding potential of −50 mV was significantly increased by 97 ± 8% (n = 6; P < 0.01) while a demonstrable delayed rectifier outward current could not be identified in the rabbit myocytes examined at room temperature. In guinea pig ventricular myocytes, where the delayed rectifier was large, 12 μmol/l OPC-8212 significantly depressed the current by 58 ± 10% (n = 6; P < 0.01). The effects of OPC-8212 in human ventricular myocytes obtained from the explanted heart of a single patient having an idiopathic cardiomyopathy most closely resembled those observed in isolated rabbit ventricular myocytes. Thus, in rabbit and a few human ventricular myocytes examined at room temperature, OPC-8212 appeared to lengthen cardiac membrane action potential duration primarily by increasing the amplitude of the secondary inward current believed to primarily represent current through L-type Ca 2+ channels. In guinea pig preparations, OPC-8212 also decreased the delayed rectifier outward K + current which also would account for an increase in action potential duration. OPC-8212 could not be demonstrated to affect Na + current inactivation in a manner similar to that produced by 1 mg/l veratrine, a recognized Na + channel agonist, which dramatically slowed this process.

P-075 - Different effects of OPC-18790 and cardenolide on the intracellular Na and Ca contents in working heart

P-075 - Different effects of OPC-18790 and cardenolide on the intracellular Na and Ca contents in working heart

慢性心不全患者の運動耐容能に対するＯＰＣ‐８２１２の急性効果 ＡＴを指標とした二重盲検法による検討

慢性心不全患者の運動耐容能に対するＯＰＣ‐８２１２の急性効果 ＡＴを指標とした二重盲検法による検討

Antitachycardiac Effect of OPC-8212, a Novel Cardiotonic Agent, on Tachycardiac Responses of Guinea Pig Isolated Right Atria to Isoproterenol and Histamine

In isolated right atria of guinea pigs, OPC-8212 produced a concentration-dependent decrease in spontaneous beating rate that had previously been elevated by isoproterenol or histamine in the presence of nadolol. OPC-8212 scarcely affected the baseline rate, however, OPC-8212 depressed the maximum increase in right atrial rate induced by isoproterenol or histamine in the presence of nadolol. These effects of OPC-8212 were discernible from the effects of its solvent sulfolane. We propose the term "antitachycardiac" to describe such effects of OPC-8212 to distinguish it from those of bradycardic agents. When the concentration-response curves of isoproterenol or histamine for positive chronotropy were normalized, these curves were shifted in a parallel way to the left with OPC-8212, indicating that OPC-8212 retains activity as a cyclic AMP phosphodiesterase inhibitor. The virtual absence of the chronotropic effect of OPC-8212 on the baseline rate and the antitachycardiac effect are discussed in terms of the opposing effects in increasing the inward calcium current on one hand and in decreasing the outward potassium and the inward current activated by hyperpolarization on the other.

Effects of OPC-8212, a New Positive Inotropic Agent, and Dobutamine on Left Ventricular Global and Ischemic Regional Functions and Coronary Hemodynamics Under Coronary Artery Stenosis

We have investigated the effects of OPC-8212, a new positive inotropic agent, and dobutamine, a known cardioselective inotropic agent, on global left ventricular (LV) and ischemic regional functions in 14 excised canine hearts with a flow-limiting stenosis of the left circumflex coronary artery (LCX) (i.e., 20-25% of control flow). OPC-8212 infusion (n = 7) under LCX stenosis improved cardiac depression [i.e., peak LV dP/dt increased from 1,295 +/- 143 mm Hg/s to 2,669 +/- 266 mm Hg/s (mean +/- SEM) (p less than 0.001)], while myocardial ischemic injury, assessed by myocardial CO2-tension and electrocardiogram (ECG)-ST changes, improved (i.e., delta CO2-tension and ECG-ST deviation decreased from 21.1 +/- 3.6 mm Hg and 3.8 +/- 0.6 mV to 13.3 +/- 2.8 mm Hg (p less than 0.01) and 2.0 +/- 0.7 mV (p less than 0.05), respectively). On the other hand, dobutamine infusion (n = 7) further increased myocardial CO2-tension and ECG-ST deviation [i.e., delta CO2-tension and ECG-ST deviation increased from 14.4 +/- 4.2 mm Hg and 2.5 +/- 1.2 mV to 29.0 +/- 6.0 mm Hg (p less than 0.01) and 4.9 +/- 1.0 mV (p less than 0.01), respectively]. At the same time, peak LV dP/dt clearly improved, but to a lesser degree; from 1,425 +/- 153 mm Hg/s to 2,393 +/- 245 mm Hg/s (p less than 0.001). There was also an increase in percent systolic segment shortening of each corresponding area as with OPC-8212.(ABSTRACT TRUNCATED AT 250 WORDS)

P2H0213) - Effects of OPC-8212 on membrane currents of the single ventricular cell of the guinea-pig heart

P2H0213) - Effects of OPC-8212 on membrane currents of the single ventricular cell of the guinea-pig heart