Vol. 285, Issue 1, 1-8, April 1998

RSR13, a Synthetic Modifier of Hemoglobin-Oxygen Affinity, Enhances the Recovery of Stunned Myocardium in Anesthetized Dogs¹

Paul S. Pagel, Douglas A. Hettrick, Matthew W. Montgomery, Judy R. Kersten, Robert P. Steffen and David C. Warltier

Departments of Anesthesiology, Pharmacology and Toxicology, and Medicine (Division of Cardiovascular Diseases), the Medical College of Wisconsin and the Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin, the Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin, and Allos Therapeutics, Denver, Colorado

RSR13 (2-[4-[[(3,5-dimethylanilino)carbonyl]methyl]phenoxyl]-2-methylproprionic acid) is a synthetic allosteric modifier of oxygen (O₂)-hemoglobin affinity that increases O₂ release to tissue by allosterically stabilizing deoxyhemoglobin. We tested the hypothesis that RSR13 enhances the functional recovery of stunned myocardium in barbiturate-anesthetized dogs instrumented for measurement of left ventricular (LV) and aortic blood pressure, LV +dP/dt_max and subendocardial segment shortening (%SS) in ischemic [left anterior descending (LAD) coronary artery] and normal (left circumflex coronary artery) zones. The partial pressure of oxygen and the Hill coefficient at 50% saturation (P₅₀ and n₅₀, respectively) were determined in arterial blood samples by multiple point tonometry and nonlinear regression analysis. Coronary collateral blood flow in the LAD zone was quantified with radioactive microspheres. Dogs received intravenous vehicle (0.45% saline) or one of two doses of RSR13 (100 or 150 mg·kg¹ bolus followed by a 0.50 or 0.75 mg·kg¹·min¹ infusion, respectively) in a random manner. All dogs were subjected to five 5-min periods of LAD occlusion separated by 5-min periods of reperfusion and followed by 180 min of final reperfusion during which hemodynamics, %SS, arterial blood gases, P₅₀ and n₅₀ were determined at selected intervals. RSR13 caused no hemodynamic effects and coronary collateral blood flow was equivalent among groups. RSR13 increased P₅₀ (+40 ± 4% for the high dose) and decreased n₅₀ (31 ± 2% for the high dose). LAD occlusion caused regional dyskinesia during each 5-min occlusion. Enhanced recovery of %SS by 180 min after final reperfusion was observed in dogs treated with high-dose RSR13 (47 ± 9% of base line) but not low-dose RSR13 (10 ± 18% of base line) or vehicle alone (2 ± 16% of base line). The results suggest that high-dose RSR13 improves the recovery of stunned myocardium throughout reperfusion in open-chest dogs. These findings may be related to increases in O₂ availability to ischemic myocardium resulting from RSR13-induced stabilization of the deoxy form of hemoglobin.