Author + information
- Received August 9, 1988
- Revision received September 23, 1988
- Accepted October 18, 1988
- Published online March 1, 1989.
- Juliet H. Ashton, PhD,
- Paolo Golino, MD,
- Janice M. McNatt,
- L.M. Buja, MD, FACC and
- James T. Willerson, MD, FACC∗
- ↵∗Address for reprints:James T. Willerson, MD, Cardiology Division, Room L5.134, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235-9047.
The object of this study was to test the hypothesis that administration of both serotonin S2and thromboxane A2-prostaglandin H2(PGH2) receptor antagonists provides significant protection against epinephrine-induced cyclic coronary artery flow variations in open chest, anesthetized dogs with severe proximal coronary artery stenosis and endothelial injury. Three groups of dogs were studied. In Group 1(n = 7) and Group 2 (n = 6), cyclic coronary flow variations were initiated after placement of a concentric constrictor around the left anterior descending coronary artery and were abolished by administration of either a thromboxane A2-prostaglandin H2receptor antagonist, SQ29,548 (SQ) (Group 1), or a serotonin S2receptor antagonist, LY53,857 (LY) (Group 2). Cyclic flow variations were restored with an epinephrine infusion and the second antagonist (LY for Group 1; SQ for Group 2) was administered to abolish epinephrine-induced cyclic flow variations. The rate of epinephrine infusion was increased until cyclic coronary flow variations returned (n = 8) or significant hemodynamic changes occurred. Plasma epinephrine concentrations were determined during a control period of cyclic coronary flow variations, after epinephrine restored cyclic flow variations in the presence of either SQ or LY, and again after epinephrine restored cyclic flow variations in the presence of both SQ and LY.
A third group of dogs (Group 3, n = 9) required both SQ and LY to eliminate the initial cyclic coronary flow variations and infused epinephrine restored cyclic flow variations (n = 8). Plasma epinephrine concentrations were determined during a control period and after cyclic coronary flow variation restoration with epinephrine. Yohimbine, an alpha2-receptor antagonist, eliminated epinephrine-induced cyclic coronary flow variations in the presence of both SQ and LY in most dogs.
Plasma epinephrine at control was 0.03 ± 0.01 ng/ml plasma (n = 22). Plasma epinephrine concentrations of 3.11 ± 0.63 ng/ml (n = 13) were required to restore cyclic coronary flow variations in the presence of either SQ or LY. Restoration of cyclic flow variations in the presence of both SQ and LY required a plasma epinephrine concentration of 13.9 ± 4.8 ng/ml (n = 18). Cyclic flow variations could not be restored in the presence of both SQ and LY in four dogs; plasma epinephrine in these dogs was 64.8 ± 18.3 ng/ml.
Thus, combined serotonin and thromboxane receptor antagonists provide substantial protection against epinephrine-restored cyclic coronary flow variations in this experimental model. In fact, the plasma epinephrine concentrations required to restore cyclic flow variations in the presence of both receptor antagonists were considerably higher than those normally encountered in patients during maximal exercise or with myocardial infarction.
☆ This work was supported in part by the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland (NHLBI Ischemic SCOR HL 17669) and the Moss Heart Fund, Dallas.
☆☆ We express our appreciation to Martin L. Ogletree, PhD (Squibb Institute for Medical Research, Princeton, New Jersey) for generously supplying SQ29, 548 and Marlene Cohen, PhD (Eli Lilly Research Laboratories, Indianapolis, Indiana) for providing LY 53, 857. We also acknowledge the secretarial assistance of Nancy Dickey in preparing this manuscript.
- Received August 9, 1988.
- Revision received September 23, 1988.
- Accepted October 18, 1988.