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.


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.
Feldman
M D
MD
Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, Md, USA.
Pak
P H
PH
Wu
C C
CC
Haber
H L
HL
Heesch
C M
CM
Bergin
J D
JD
Powers
E R
ER
Cowart
T D
TD
Johnson
W
W
Feldman
A M
AM
Kass
D A
DA
D001794:Blood Pressure; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy / Q000503:physiopathology*; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D015363:Quinolones / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D013318:Stroke Volume
D002316:Cardiotonic Agents; D015363:Quinolones; C077543:toborinone