Systemic and regional myocardial responses to AR-L 115 BS, a positive inotropic imidazo-pyridine, in the absence or in the presence of the bradycardiac action of alinidine

Abstract

SummaryThe effects of the imidazo-pyridine AR-L 115 BS on global and regional myocardial function were investigated in anesthetized pigs in the absence and in the presence of the bradycardiac action of alinidine. AR-L 115 BS (0.1-0.8 mg 9 kg -1 9 rain -1) increased myocardial contractility (up to 75 %) and reduced preload (50 %) and afterload (50 %) in a dose-dependent manner. These changes were accompanied by moderate increases in heart rate (up to 20 %). The increase in cardiac output was only moderate (20 %), due to the reduction in preload. Renal blood flow increased slightly, but coronary blood flow was not significantly affected, due to the marked decrease in coronary vascular resistance (up to 50 %). Regional perfusion was not impaired as the endo/epi flow ratio was not affected and the coronary venous 02-saturation increased slightly but significantly. Myocardial wall thickness tracings (ultrasound principle) showed some pronounced changes. The positive inotropic action of AR-L 115 BS were best reflected by the changes in the velocity of wall thickening (up to 90 %, P < 0.001), and the timing of the occurrence of maximal wall thickness (maxT) with respect to aortic valve closure, as maxT, which occurred 5-10 msee after aortic valve closure during base line, preceded aortic valve closure with 45 msee after AR-L 115 BS (P < 0.001).Since the adverse effects of positive chronotropy on isehemie myocardium are well documented, AR-L 115 BS was also investigated in combination with alinidine, an agent which has predominantly negative chronotropie properties. This study revealed that alinidine did not interfere with the positive inotropic action of AR-L115BS but mainly reduced heart rate. Consequently, combination of the two drugs, which resulted in an improved myocardial function at a lower O2-demand, may offer an attractive addition in the treatment of myocardial pump failure.

Stimulation of Ca++ binding and ATPase activity of dog cardiac myofibrils by AR-L 115BS, a novel cardiotonic agent.

“…Yet AR-L directly activates the myofibrils in a concentration range close to the plasma concentrations of AR-L 115BS associated with positive inotropic effects in intact pigs (Verdouw et al, 1981). Effects of AR-L on cardiac cell membranes have not been studied extensively, but there are data showing that AR-L 115BS enhances the process of Ca ++ -induced Ca ++ release in mechanically skinned heart muscle cells.…”

“…In the intact animal, AR-L has a number of effects depending on the dose. Contractility, heart rate, and preload are increased and afterload is decreased (Diederen and Kadatz, 1981;Verdouw et al, 1981). Thus, whereas direct effects of AR-L on the heart appear to be a likely mode of action of the drug, in the intact animal effects of AR-L on cardiac output most likely are the result of a variety of pharmacological actions.…”

“…(Circ Res 51: 290-294, 1982) AR-L 115BS IS a benzimidazole derivative ( Fig. 1) which, when infused into intact animals, increases contractility and reduces afterload (Diederen and Kodatz, 1981;Verdouw et al, 1981). These effects make this compound interesting as a potentially useful agent in the treatment of heart failure, since it apparently combines two modes of alleviation of the disease.…”

Intracoronary infusion of small doses of nifedipine lowers regional myocardial O2-consumption without altering regional myocardial function

“…The analysis of the echocardiograms was carried out as described elsewhere (5,6). and 150 mg metomidate i.v.…”

“…It has been suggested that the concomitant decrease in myocardial O2-extraction was caused by an increase in 02-supply due to a coronary vasodilatation and a decrease in O2-demand as a consequence of a reduction in afterload and a negative inotropic action (1)(2)(3)(4). Regional myocardial function was described with the aid of myocardial wall thickness tracings obtained from the same myocardial segment (5,6). O2-consumption of the LAD-perfused area was calculated from the LAD-flow and the difference between the O2-content in the LAD and the great cardiac vein.…”