THERAPY AND PREVENTION PHARMACOLOGY Potentiation of nitroglycerin-induced coronary dilatation by N-acetylcysteine

Previous studies have suggested that (1) nitroglycerin causes vasodilatation by interacting with sulfhydryl groups in vascular smooth muscle, thereby activating guanylate cyclase and increasing the intracellular concentration of cyclic GMP, and (2) N-acetylcysteine, a source of sulfhydryl groups, potentiates the peripheral vasodilatory effect of nitroglycerin. This study was performed to explore the influence of N-acetylcysteine on nitroglycerin-induced coronary dilatation. In 18 patients (13 men and five women, 30 to 76 years old), coronary sinus blood flow (by thermodilution) was measured before and during intracoronary administration of nitroglycerin, 25 ,g, both before and 5 min after a 15 min intravenous infusion of (1) 5% dextrose in water (n = 8, control) or (2) 100 mg/kg N-acetylcysteine (n = 10). Nitroglycerin caused no change in heart rate or systemic arterial pressure. In the control patients, coronary sinus blood flow behaved similarly during the two injections: it was 134 36 ml/min (mean ± SD) before and 183 + 50 ml/min during injection No. 1 (average increase, 49 25 ml/min; average percent increase, 38 + 21%); and it was 131 ± 34 ml/min before and 178 + 45 ml/min during injection No. 2 (average increase, 47 + 23 ml/min; average percent increase, 37 + 20%) (NS compared with injection 1). In the patients who received N-acetylcysteine, coronary sinus blood flow was 149 + 48 ml/min before and 191 + 54 ml/min during injection 1 (average increase, 42 + 15 ml/min; average percent increase, 30 + 12%) (NS compared with eight control values). AfterNacetylcysteine, coronary sinus blood flow was similar before nitroglycerin (145 ± 44 ml/min), but it rose markedly with nitroglycerin (218 + 68 ml/min) (average increase, 73 + 35 ml/min; average percent increase, 50 20%) (p < .01 compared with the values obtained in the same patients during injection 1). Thus, N-acetylcysteine, a source of sulfhydryl groups, potentiates the coronary vasodilative effect of nitroglycerin. Circulation 73, No. 1, 138-142, 1986. SEVERAL STUDIES have suggested that nitroglycerin causes vasodilatation by interacting with sulfhydryl groups in vascular smooth muscle, thereby activating guanylate cyclase and increasing the intracellular concentration of cyclic GMP. 1-3 According to this hypothesis, any agent that reduces sulfhydryl group availability may diminish the vasodilatory effect of nitroglycerin; in turn, any maneuver that increases sulfhydryl group availability may augment the magnitude of nitroglycerin-induced vasodilatation. In support of this, Needleman et al.' have shown that ethaFrom the Department of Internal Medicine (Cardiovascular Division), the University of Texas Health Science Center, Dallas. Supported in part by Ischemic SCOR grant HL-17669 from the National Institutes of Health, Bethesda, and by a grant from the Texas affiliate of the American Heart Association. Address for correspondence: Dr. L. David Hillis, Room L5.134, University of Texas Health Science Center, 5323 Harry Hines Blvd., Dallas, TX 75235. Received Aug. 6, 1985; revision accepted Sept. 26, 1985. Dr. Hillis is an Established Investigator of the American Heart Association, Dallas. 138 crynic acid (which alkylates sulfhydryl groups) inhibits nitrate-induced relaxation of rabbit aortic strips, and Horowitz et al.4 have demonstrated that Nacetylcysteine, a sulfhydryl group "donor," potentiates the peripheral hemodynamic responses to intravenous nitroglycerin. However, no previously published report has evaluated the influence of modulators of sulfhydryl group availability on the coronary vascular response to nitroglycerin. Therefore, the present study was performed to explore the effect of N-acetylcysteine on the vasodilative response to small amounts of intracoronary nitroglycerin. Materials and methods Patient population. The studies were performed in 18 patients (13 men and five women, 30 to 76 year old) undergoing cardiac catheterization at Parkland Memorial Hospital for the evaluation of chest pain. The protocol was approved by the Human Subjects Review Committee of the University of Texas Health Science Center, and all patients gave written informed consent. Antianginal medications (/3-adrenergic-blocking CIRCULATION by gest on M ay 1, 2017 http://ciajournals.org/ D ow nladed from THERAPY AND PREVENTION-PHARMACOLOGY agents, calcium antagonists, and long-acting nitrates) were discontinued more than 24 hr, and sublingual niroglycerin was not given for more than 4 hr before study. The experimental protocol was performed in subjects in the fasting state after premedication with 10 mg oral diazepam. All measurements were obtained before the introduction of iodinated contrast material. Experimental protocol. A No. 8F femoral arterial sheath was inserted percutaneously, through which a No. 7F Judkins catheter was advanced to the ostium of the left coronary artery. Its position was confirmed by the occurrence of transient T wave alterations during the injection of saline. Systemic arterial pressure was measured through the sheath's side-port extension, and heart rate was determined by electrocardiographic monitoring. A thermodilution catheter (model CCS-7U-90B, Wilton Webster Laboratories, Altadena, CA) was advanced to the coronary sinus from a basilic vein, and its position was verified fluoroscopically and oximetrically. Subsequent determinations of coronary sinus blood flow were performed by the thermodilution technique.5 After catheter placement, mean systemic arterial pressure, heart rate, and coronary sinus blood flow were recorded before, during, and for 30 sec after the intracoronary administration of 25 gg nitroglycerin (in 5 ml of solution). Then, each patient was assigned to receive an intravenous infusion of (1) 200 ml 5% dextrose in water or (2) 100 mg/kg N-acetylcysteine (kindly provided by Mead-Johnson Pharmaceuticals, Evansville, IN) in 200 ml 5% dextrose in water, given over 15 min. Five minutes after the infusion was completed, values for all variables again were recorded before, during, and for 30 sec after intracoronary 25 gg nitroglycerin in an identical manner to that followed 20 min previously. Thus, in each patient, the response of mean systemic arterial pressure, heart rate, and coronary sinus blood flow to intracoronary nitroglycerin was assessed before and after (1) 5% dextrose in water (n = 8, control) or (2) 100 mg/kg N-acetylcysteine (n = 10). Statistical analysis. All results are reported as mean + 1 SD. In each patient, the value for coronary sinus blood flow before nitroglycerin was subtracted from the value during nitroglycerin administration, yielding the net increase in coronary sinus blood flow (in ml/min). In turn, the net increase was divided by the value for coronary sinus blood flow before nitroglycerin to yield the percent increase. Changes occurring from before to after 5% dextrose in water or N-acetylcysteine within each group were evaluated with a paired t test.6 The two groups were compared with Student's t test.7 For all analyses, a p value < .05 was considered significant.