Acute effects of toborinone on vascular capacitance and conductance in experimental heart failure.
BACKGROUND
Toborinone (OPC-18790), a phosphodiesterase III inhibitor, enhances cardiac contractility and is an arterial dilator. However, its effects on the venous system have not yet been clearly defined. Because toborinone administration reduces left ventricular (LV) end-diastolic pressure, it is probably also a venodilator. Because of the known arterial effects and the hypothesized venous effects, we compared changes in systemic vascular conductance (the inverse of resistance) with changes in venous capacitance.


RESULTS
In 15 anesthetized, splenectomized dogs (10 treatment, 5 control), pressures were measured in the right atrium, aorta, portal vein, and LV. A cuff constrictor was placed around the portal vein. Cardiac output was measured by thermodilution, and splanchnic vascular capacitance was measured by blood-pool scintigraphic methods. Data were collected at baseline, after induction of heart failure (microsphere embolization into the left coronary artery), and then after toborinone boluses of 0.1, 0.2, 0.4, and 0.8 mg/kg. Heart failure was associated with decreased capacitance and conductance (to 87+/-3% and 64+/-4% of baseline values, respectively, P<0.05). After administration of the lower doses of toborinone, capacitance increased more than conductance; however, the effects were more balanced at the higher doses. Compared with nitroglycerin, hydralazine, and enalaprilat (results of an earlier study) in the same model, toborinone increased capacitance to a degree similar to that with nitroglycerin, at higher doses increased conductance similarly to hydralazine, and increased both capacitance and conductance considerably more than did enalaprilat.


CONCLUSIONS
Toborinone is a potent balanced venous and arterial dilator in experimental acute heart failure. These marked effects suggest that it may prove to be a clinically important alternative to other vasodilators.
Semeniuk
L M
LM
Department of Medicine, The University of Calgary, Alberta, Canada.
Belenkie
I
I
Tyberg
J V
JV
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D004285:Dogs; D015773:Enalaprilat / Q000494:pharmacology; D005260:Female; D006333:Heart Failure / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects*; D006830:Hydralazine / Q000494:pharmacology; D008297:Male; D005996:Nitroglycerin / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D018924:Vascular Capacitance / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D002316:Cardiotonic Agents; D010726:Phosphodiesterase Inhibitors; D015363:Quinolones; D014665:Vasodilator Agents; C077543:toborinone; D006830:Hydralazine; D005996:Nitroglycerin; D015773:Enalaprilat