[Effects of the new cardiotonic agent loprinone hydrochloride (E-1020) on left ventricular diameter in normal and experimental heart failure dogs and its action potential characteristics in isolated guinea pig cardiac muscles and sinus nodes].
In anesthetized dogs, loprinone hydrochloride (LP, 10 approximately 100 micrograms/kg, i.v.) dose-relatedly increased cardiac contractility (LV dP/dt max), enhanced cardiac index and decreased systemic vascular resistance with relatively small reduction in mean aortic pressure (MAP) and a mild increase in heart rate (HR). LP also decreased left ventricular internal diameter (ID), increased fractional shortening (LVFS) and caused a leftward shift and an increase in the slope of the LV end-systolic pressure-ID relation. In the heart failure models induced by propranolol, LP rapidly reversed the cardiac depression and the enlargement in cardiac size. The extent of changes in MAP and HR by LP was smaller than those observed with several other cardiotonic agents. In guinea pig cardiac muscles, LP (10(-6)-10(-4) M) produced a concentration-related increase in contractile force and the maximum rate of rise of Ca(2+)-action potential. In the sinus nodes, LP induced a concentration-related decrease in action potential duration and increase in the slope of slow diastolic depolarization, resulting in an increase in beating rate. These influences of LP on sinus nodes were smaller than those of milrinone. These results indicate that LP increases LVFS, reduces cardiac size and improves the heart failure due to its cardiotonic and vasodilating properties. Moreover, electrophysiological studies suggest that at least a part of the lower chronotropic effects of LP may be due to the mildness of its direct stimulating effects on sinus nodes.
Ohhara
H
H
Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
Sawada
K
K
Ogawa
T
T
Takeda
M
M
Igarashi
T
T
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001283:Atrioventricular Node / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006333:Heart Failure / Q000188:drug therapy*; D006352:Heart Ventricles / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D011728:Pyridones / Q000494:pharmacology* / Q000627:therapeutic use
D002316:Cardiotonic Agents; D007093:Imidazoles; D011728:Pyridones; C059498:olprinone