THERAPY AND PREVENTION PIHARMACOLOGY The effects of organic nitrates on prostacyclin biosynthesis and platelet function in humans

The results of prior studies indicate that nitroglycerin stimulates prostacyclin release by cultured endothelium and by the coronary vasculature in vivo. However, the accuracy of these findings in coronary vasculature relies on plasma samples obtained from the circulation via cardiac catheters, a procedure we have shown to stimulate prostacyclin release, thereby confounding'interpretation of drug action. We studied the effects of short-acting (nitroglycerin) and long-acting (isosorbide dinitrate) nitrates on a noninvasive index of prostacyclin synthesis, excretion of urinary 2,3-dinor-6-keto-PGF,,. Nitroglycerin was infused into six subjects to either a maximum of 480 gg/min or until mean arterial pressure fell by 20 mm Hg. Urine was collected for negative ion chemical ionization gas chromatographic, mass spectrometric analysis before and during the nitroglycerin infusion and for two 2 hr periods after nitroglycerin. The peak nitroglycerin infusion rate was 387 + 67 gg/min, which caused a fall in supine blood pressure (systolic/diastolic) of 11 5/14 ± 4 mm Hg and a 12 ± 3 beats/min increase in heart rate. Excretion of 2,3-dinor-6-keto-PGF,, (pg/mg creatinine) was unchanged from control infusion values (106 ± 19.5) either during (123 ± 21) or after (134 14.6; 139 + 36) nitroglycerin infusion. Platelet aggregation to arachidonic acid (0.33 to 1.33 paM) and epinephrine (1 to 10 gaM) ex vivo was inhibited in only one subject in whom excretion of 2,3-dinor-6-keto-PGF,I was unaltered. Serum thromboxane B2 was not changed by nitroglycerin infusion.' Similarly, oral administration of isosorbide dinitrate (10 and 40 mg four times per day) failed to alter 2,3-dinor-6-keto-PGF,¢a excretion from placebo values in patients with angina pectoris. Noninvasive measurements indicate that nitrates failed to stimulate prostacyclin release in vivo; platelet inhibition during infusion of nitroglycerin was unrelated to altered prostacyclin synthesis in human beings. Circulation 70, No. 2, 297-302, 1984. NITROGLYCERIN is a potent vasodilator that is widely used in 'the treatment of angina pectoris. ' Despite its availability for over 100 years, the basis of its effect on vascular smooth muscle is poorly understood. Nitroglycerin also inhibits platelet function in vitro2 3 and has been reported to prolong the bleeding time in human beings.4 5 In view of these biological properties, it has been postulated that nitroglycerin mediates these effects by enhancing generation of the arachidonic acid metabolite prostacyclin in vivo. Formed From the Divisions of Clinical Pharmacology and Cardiology, Vanderbilt University, Nashville. Supported in part by grants HL 30400 and GM 15431 from the U.S. Public Health Service and a Grant-in-Aid from the American Heart Association, with funds contributed in part by the Tennessee Affiliate. Address for correspondence: G. A. FitzGerald, M.D., Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN 37232. Received March 12, 1984; revision accepted May 10, 1984. Dr. D. J. Fitzgerald is a Merck, Sharpe and Dohme International Fellow in Clinical Pharmacology; Dr. Roy was supported by a fellowship from the Quebec Heart Foundation and a grant from the Tennessee Affiliate of the American Heart Association; Dr. Robertson is an Established Investigator of the American Heart Association; Dr. G. A. FitzGerald is the recipient of a Faculty Development Award from the Pharmaceutical Manufacturers' Association Foundation. Vol. 70, No. 2, August 1984 predominantly by the cyclooxygenase enzyme of vascular endothelium, prostacyclin is a potent vasodilator and inhibitor of platelet function.6 Previous investigations have demonstrated that nitroglycerin enhances prostacyclin release (as measured by' its stable degradation product, 6-keto-PGF,,) from cultured endothelial cells,7 isolated bovine coronary artery,8 human saphenous vein,9 and rat aorta.'0 The present studies were designed to test the hypothesis that the hemodynamic and' platelet inhibitory effects of organic nitrates are associated with an increase in excretion of a major urinary metabolite of prostacyclin, 2,3-dinor-6-keto-PGFia. We selected this approach because previous attempts to address this question have generally relied on pharmacologic inhibition of the cyclooxygenase enzyme to identify the relevance of prostacyclin formation to the action of nitroglycerin. However, these studies have generally yielded conflicting results"1-17 and have been unaccompanied by reliable biochemical indexes of endogenous biosynthesis of prostacyclin. 297 by gest on A ril 6, 2017 http://ciajournals.org/ D ow nladed from