Hemodynamic and Biochemical Effects of a New Positive Inotropic Agent

Abstract

The antibiotic ionophores RO 2-2985 (Hoffman-LaRoche; X537A) and A23187 (Lilly) produced an abrupt release of previously bound calcium from isolated sarcoplasmic reticulum. Only RO 2-2985 produced a significant inhibition of sodium, potassium-adenosinetriphosphatase activity. In anesthetized, open-chest dogs, RO 2-2985 caused a marked increase in right and left ventricular contractile force, aortic and coronary flow, and mean central aortic blood pressure with modest changes in heart rate and no change in calculated mean peripheral resistance. A single injection of 1 mg/kg produced a sustained augmentation of mean blood pressure from a control of 45 mm Hg in dogs that were in induced shock to approximately 125 mm Hg for a period up to 7-9 hours. At that time, tyramine produced a release of catecholamines, and norepinephrine and isoproterenol produced a marked increase in force of contraction. Dogs that were treated with reserpine did not respond to the drug. RO 2-2985, but not A23187, produced positive inotropism in isolated rabbit atrial and perfused ventricular preparations. RO 2-2985 still produced an augmentation in blood pressure after β-receptor blockade. It is suggested that RO 2-2985 acts by a mechanism involving a very slow release of humoral substances, by a direct effect on a specific calcium-proton exchange, or by both. It is thought that this agent has potential therapeutic applications.