Acute cardiovascular effects of OPC-18790 in patients with congestive heart failure. Time- and dose-dependence analysis based on pressure-volume relations.

BACKGROUND OPC-18790 is a water-soluble quinolinone derivative that shares the pharmacological properties of vesnarinone and that may be useful for treating heart failure. We studied the contribution and relative dose sensitivities of the inotropic, lusitropic, and vascular effects of OPC-18790 in patients with dilated cardiomyopathy. METHODS AND RESULTS Pressure-volume (PV) analysis was performed in 17 patients who received either 5 micrograms.kg-1.min-1 (low dose, n = 10) or 10 micrograms.kg-1.min-1 (high dose, n = 7) OPC-18790 by 1-hour IV infusion. Right heart pressures and flow and left heart PV relations (conductance catheter) were measured at baseline and every 15 minutes during infusion. Transient inferior vena caval obstruction was used to determine PV relations. Both doses produced venodilation reflected by a 10% decline in left ventricular end-diastolic volume and a 30% fall in atrial and pulmonary artery pressures. Arterial dilation was four times greater at the high dose, with an approximately 40% fall in effective arterial elastance and systemic resistance. Contractility rose by 25% to 100% (depending on PV index) with both doses. Ventricular-arterial coupling (ratio of ventricular end-systolic to arterial elastances) was approximately 0.25 at baseline and doubled (or tripled) at low (or high) dose, correlating with improved efficiency. Isovolumetric relaxation shortened, whereas the diastolic PV relation was generally unchanged. Heart rate was unaltered. CONCLUSIONS OPC-18790 has potent venous and arterial vasodilator effects and moderate inotropic and lusitropic effects without a change in heart rate. These combined actions suggest a unique potential of OPC-18790 for heart failure treatment.

[1]  M. Starling,et al.  Left ventricular-arterial coupling relations in the normal human heart. , 1993, American heart journal.

[2]  J. W. Kennedy,et al.  Left ventricular volume and mass from single-plane cineangiocardiogram. A comparison of anteroposterior and right anterior oblique methods. , 1970, American heart journal.

[3]  Toyoki Mori,et al.  Differential effects of OPC‐18790, amrinone and dobutamine on cardiac function and energy metabolism in the guinea‐pig isolated ischaemic heart , 1995, British journal of pharmacology.

[4]  C. Boucher,et al.  Positive inotropic and lusitropic effects of intravenous flosequinan in patients with heart failure. , 1992, Journal of the American College of Cardiology.

[5]  H. Suga,et al.  Instantaneous Pressure‐Volume Relationships and Their Ratio in the Excised, Supported Canine Left Ventricle , 1974, Circulation research.

[6]  K. Sagawa,et al.  Optimal Arterial Resistance for the Maximal Stroke Work Studied in Isolated Canine Left Ventricle , 1985, Circulation research.

[7]  W C Hunter,et al.  Ventricular stroke work and efficiency both remain nearly optimal despite altered vascular loading. , 1993, The American journal of physiology.

[8]  D. Kass,et al.  Diminished Contractile Response to Increased Heart Rate in Intact Human Left Ventricular Hypertrophy Systolic Versus Diastolic Determinants , 1993, Circulation.

[9]  W. Abraham,et al.  Comparative hemodynamic effects of OPC-18790 and dobutamine in patients with advanced heart failure. , 1994, Journal of cardiac failure.

[10]  D. Kass,et al.  Comparative influence of load versus inotropic states on indexes of ventricular contractility: experimental and theoretical analysis based on pressure-volume relationships. , 1987, Circulation.

[11]  L. Hillis,et al.  Comparison of single and biplane ventriculography for determination of left ventricular volume and ejection fraction. , 1992, The American journal of cardiology.

[12]  2(1H)-quinolinones with cardiac stimulant activity. 3. Synthesis and biological properties of 6-imidazol-1-yl derivatives. , 1989, Journal of medicinal chemistry.

[13]  H. Herrmann,et al.  Inotropic effect of enoximone in patients with severe heart failure: demonstration by left ventricular end-systolic pressure-volume analysis. , 1987, Journal of the American College of Cardiology.

[14]  M. Tominaga,et al.  Novel positive inotropic agents: synthesis and biological activities of 6-(3-amino-2-hydroxypropoxy)-2(1H)-quinolinone derivatives. , 1992, Journal of medicinal chemistry.

[15]  E. Braunwald,et al.  Evaluation of a new bipyridine inotropic agent--milrinone--in patients with severe congestive heart failure. , 1983, The New England journal of medicine.

[16]  W L Maughan,et al.  Determinants of end-systolic pressure-volume relations during acute regional ischemia in situ. , 1989, Circulation.

[17]  D. Kass,et al.  Hemodynamic dependence of myocardial oxygen consumption indexes. , 1990, The American journal of physiology.

[18]  S. Sasayama,et al.  Ventricular load optimization by unloading therapy in patients with heart failure. , 1991, Journal of the American College of Cardiology.

[19]  N. Taira,et al.  Membrane current changes responsible for the positive inotropic effect of OPC-8212, a new positive inotropic agent, in single ventricular cells of the guinea pig heart. , 1987, The Journal of pharmacology and experimental therapeutics.

[20]  B Buis,et al.  Continuous measurement of left ventricular volume in animals and humans by conductance catheter. , 1984, Circulation.

[21]  David A. Kass,et al.  Effective Arterial Elastance as Index of Arterial Vascular Load in Humans , 1992, Circulation.

[22]  D. DeMets,et al.  Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. , 1991, The New England journal of medicine.

[23]  R Beyar,et al.  Influence of contractile state on curvilinearity of in situ end-systolic pressure-volume relations. , 1989, Circulation.

[24]  E. Braunwald,et al.  Positive inotropic and vasodilator actions of milrinone in patients with severe congestive heart failure. Dose-response relationships and comparison to nitroprusside. , 1985, The Journal of clinical investigation.

[25]  F. Schoen,et al.  Deficient production of cyclic AMP: pharmacologic evidence of an important cause of contractile dysfunction in patients with end-stage heart failure. , 1987, Circulation.

[26]  T. Awaji,et al.  Effects of OPC-18790, a new positive inotropic agent, on canine ventricular arrhythmias. , 1993, Japanese journal of pharmacology.

[27]  M. Wood,et al.  Long-term oral therapy of congestive heart failure with phosphodiesterase inhibitors. , 1989, The American journal of the medical sciences.

[28]  I. Norota,et al.  Effects of a Novel Cardiotonic Agent (±)-6-[3-(3,4‐Dimethoxybenzylamino)-2‐Hydroxypropoxy]-2(1H)-Quinolinone (OPC‐18790) on Contractile Force, Cyclic AMP Level, and Aequorin Light Transients in Dog Ventricular Myocardium , 1994, Journal of cardiovascular pharmacology.

[29]  W L Maughan,et al.  Left ventricular interaction with arterial load studied in isolated canine ventricle. , 1983, The American journal of physiology.

[30]  R. Walsh,et al.  Effects of a novel inotropic agent (OPC-18790) on systolic and diastolic function in patients with severe heart failure. , 1994, American heart journal.

[31]  M. Yokota,et al.  Relation between ventriculoarterial coupling and myocardial energetics in patients with idiopathic dilated cardiomyopathy. , 1994, Journal of the American College of Cardiology.

[32]  S. Lawless,et al.  Amrinone in cardiac surgical patients with left-ventricular dysfunction. A prospective, randomized placebo-controlled trial. , 1993, Chest.

[33]  M. Yokoyama,et al.  Determination of left ventricular volume using a conductance catheter in the diseased human heart. , 1992, European heart journal.

[34]  R. Bain,et al.  Effects of vesnarinone on morbidity and mortality in patients with heart failure , 1993 .

[35]  J. Weiss,et al.  Usefulness of OPC-8212, a quinolinone derivative, for chronic congestive heart failure in patients with ischemic heart disease or idiopathic dilated cardiomyopathy. , 1991, The American journal of cardiology.

[36]  W L Maughan,et al.  Use of a conductance (volume) catheter and transient inferior vena caval occlusion for rapid determination of pressure-volume relationships in man. , 1988, Catheterization and cardiovascular diagnosis.

[37]  M. Packer,et al.  Hemodynamic changes mimicking a vasodilator drug response in the absence of drug therapy after right heart catheterization in patients with chronic heart failure. , 1985, Circulation.

[38]  D. Kass,et al.  Ventricular systolic assessment in patients with dilated cardiomyopathy by preload-adjusted maximal power. Validation and noninvasive application. , 1994, Circulation.

[39]  G. A. Rooke,et al.  Work as a Correlate of Canine Left Ventricular Oxygen Consumption, and the Problem of Catecholamine Oxygen Wasting , 1982, Circulation research.

[40]  S Sasayama,et al.  Ventriculoarterial coupling in normal and failing heart in humans. , 1989, Circulation research.

[41]  A. Hirayama,et al.  Pharmacokinetics and Pharmacodynamics of Intravenous OPC‐18790 in Humans: A Novel Nonglycosidic Inotropic Agent , 1994, Journal of clinical pharmacology.

[42]  D. Glower,et al.  Linearity of the Frank-Starling relationship in the intact heart: the concept of preload recruitable stroke work. , 1985, Circulation.

[43]  S. Sasayama,et al.  Ventricular-load optimization by inotropic stimulation in patients with heart failure. , 1991, International journal of cardiology.

[44]  R. O'rourke,et al.  Influence of Heart Rate on Left Ventricular Performance in Conscious Dogs , 1987, Circulation research.