Cardiovascular effects of AR-L115 BS in conscious dogs with and without chronic congestive heart failure.
AR-L115 BS is a phenyl-imidazo-pyridine derivative that combines positive inotropic and vasodilator properties. To analyze the mechanisms of action of AR-L115 in the presence or absence of heart failure, we administered it intravenously to conscious dogs (seven normals and eight with a volume-overload heart failure). In normals, at a plasma level around 1,000 ng/ml, AR-L115 BS increased left ventricular (LV) peak (+) dP/dt (+48%; p less than 0.02) and heart rate (+29 beats/min; p less than 0.05) without altering significantly cardiac filling pressures or cardiac output. The mean aortic pressure and the systemic vascular resistances (-20%; p less than 0.02) were reduced, but plasma renin activity (PRA) was unchanged. In heart failure, the same plasma level increased peak (+) dP/dt by 36% (p less than 0.01), but heart rate stayed unchanged. Mean aortic pressure, systemic vascular resistances (-20%; p less than 0.01), and LV end-diastolic pressure (-9.1 mm Hg; p less than 0.01) all dropped significantly, while cardiac output increased slightly; PRA did not rise significantly. After beta-blockade, the increases in peak (+) dP/dt and the changes in systemic vascular resistances were markedly reduced. In conclusion, AR-L115 BS has strong positive inotropic and vasodilator effects, both of which are partially dependent on the level of the sympathetic tone in the intact animal. These combined properties improve hemodynamics in heart failure; this improvement is already significant at relatively low plasma levels, at which deleterious changes in heart rate or PRA are absent.
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004285:Dogs; D006321:Heart / Q000033:anatomy & histology / Q000187:drug effects; D006333:Heart Failure / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects; D012083:Renin / Q000097:blood
D000319:Adrenergic beta-Antagonists; D002316:Cardiotonic Agents; D007093:Imidazoles; D012083:Renin; C029758:sulmazole; D002118:Calcium