Effects of Compound Mj‐1988 on Myocardial Contractility, Oxygen Consumption, Coronary Blood Flow and Vascular Resistance

Abstract

Preliminary reports have shown that 6,7-dimethoxy-4-ethylquinazoline, known as MJ-1988, possesses potent cardiac stimulating, bronchodilator and vasodilating properties (Lish, Cox, Dungan & Robbins, 1964). A drug with this combination of pharmacological effects might have important therapeutic possibilities. This study was undertaken to assess the potency of an effective dose of .the compound on the contractility of the working canine left ventricle. The experimental preparation used also allowed the assessment of coronary blood flow, myocardial oxygen consumption and vascular resistance. METHODSExperiments were performed in adult mongrel dogs, weighing 10.5 to 17 kg. The dogs were anaesthetized by an intravenous infusion of a warmed solution of urethane (600 mg/kg) and chloralose (60 mg/kg). The rate and depth of respiration was controlled by a Bird Mark 8 positive pressure respirator. The chest was opened through a median sternotomy and the working left heart model was prepared as follows (Fig. 1). After preliminary dissection, haemostasis, and isolation of a femoral artery, heparin, 3 mg/kg, was administered, followed by 30 mg every hour. The superior and inferior vena cavae were cannulated and the azygos vein divided. The caval return was led to a reservoir (Res. 1) by siphon drainage. From the reservoir the blood drained by gravity to a bubble oxygenator. Oxygenated blood, warmed to 370 C, was returned via a roller pump (P) through a Shipley-Wilson rotameter (RI) to the main pulmonary artery. A ligature placed around the cannulated pulmonary artery thus completely isolated the right heart so that it received only coronary venous drainage. The total coronary flow (less left ventricular Thebesian flow) was led from the cannulated right heart through a rotameter (R2) to the reservoir (Res. 1). This rotameter was calibrated during each experiment by timed volumetric collection of coronary venous blood flow.

Cardiovascular pharmacology of quazodine (MJ‐1988), with particular reference to effects on myocardial blood flow and metabolic heat production

“…This larger dose also had a more pronounced hypotensive effect and actually decreased external cardiac work. Previous authors (Aviado et al, 1967) have demonstrated a degree of cardiac depression with very large doses of quazodine and also noticed the occurrence of (unspecified) cardiac arrhythmias (Aviado et al, 1967;Carr et al, 1967). Only very occasional arrhythmias (mainly nodal) were noticed in our experiments with a total dose of 10 mg/kg.…”

“…6 N CH30 N Perhaps the most striking property of quazodine is its apparent ability to increase myocardial contractility without increasing myocardial oxygen consumption (Carr et al, 1967). It is possible that this 'oxygen sparing effect' is related to a reduction in metabolic waste heat produced by the myocardium which would result from a reduced intramyocardial wall tension.…”

“…Carr and his colleagues concluded that quazodine has direct actions on cardiac and smooth muscle cells, and does not owe its effects to interaction with adrenoceptors, with release of stored catecholamines or with activation of cardiac autonomic reflexes. CH30 6 N CH30 N Perhaps the most striking property of quazodine is its apparent ability to increase myocardial contractility without increasing myocardial oxygen consumption (Carr et al, 1967). It is possible that this 'oxygen sparing effect' is related to a reduction in metabolic waste heat produced by the myocardium which would result from a reduced intramyocardial wall tension.…”

“…The effects on myocardial metabolic heat production were of particular interest, in view of the findings of Carr et al (1967) that quazodine increases myocardial contractility without increasing myocardial oxygen consumption. Drugs (like the catecholamines) which increase contractility, invariably increase the production of heat by cardiac muscle.…”

“…Cardiac performance is improved in the dog heart-lung preparation and augmented myocardial contractility is accompanied by increased coronary blood flow and by pulmonary vasodilatation. Carr, Cooper, Daggett, Lish, Nugent & Powers (1967) showed that quazodine increased left ventricular dP/dt max and decreased both left ventricular end-diastolic pressure and the duration of systole in dogs on right heart bypass. Despite these changes, myocardial oxygen consumption was not increased.…”