ORGANIC NITRATES: RELATIONSHIP BETWEEN BIOTRANSFORMATION AND RATIONAL ANGINA PECTORIS THERAPY

¹ Washington University School of Medicine, Departments of Pharmacology and Physiology, St. Louis, Missouri

Unchanged organic nitrates have a very transient lifetime in blood after jugular vein administration. The nitrate metabolites circulate for hours after the transient vascular response and are eventually cleared into the urine by the kidney. High doses of various organic nitrates are quite potent when administered via the jugular vein but are inactive as vasodepressors when injected into the portal vein. After portal injection of radio active organic nitrates, little or none of the intact molecule reaches the circulation but rapid liver denitration is indicated by the appearance of high blood levels of metabolites which are incapable of producing a vasodepression. Similarly, when organic nitrates are administered orally and hence go via the portal vein directly to the liver, they are de graded rapidly and little if any of the parent compound is available in the circulation to relax vascular smooth muscle. The biotransformations in rats are catalyzed rapidly by the liver enzyme glutathione-organic nitrate reductase. Human liven biopsy samples have the same enzyme capacity for denitration as the rat liver. These results lead to the conclusion that there is no rational basis for the use of "long-acting" nitrates (administered orally) in the prophylactic therapy of angina pectonis.

This article has been cited by other articles:

				J. D. Artz, B. Schmidt, J. L. McCracken, and M. A. Marletta Effects of Nitroglycerin on Soluble Guanylate Cyclase. IMPLICATIONS FOR NITRATE TOLERANCE J. Biol. Chem., May 17, 2002; 277(21): 18253 - 18256. [Abstract] [Full Text] [PDF]

				J. D. Parker and J. O. Parker Nitrate Therapy for Stable Angina Pectoris N. Engl. J. Med., February 19, 1998; 338(8): 520 - 531. [Full Text] [PDF]

				U. THADANI, S. F. HAMILTON, E. OLSON, J. ANDERSON, W. VOYLES, R. PRASAD, and S. M. TEAGUE Transdermal Nitroglycerin Patches in Angina Pectoris: Dose Titration, Duration of Effect, and Rapid Tolerance Ann Intern Med, October 1, 1986; 105(4): 485 - 492. [Abstract] [PDF]

				S. Corwin and J. A. Reiffel Nitrate Therapy for Angina Pectoris: Current Concepts About Mechanism of Action and Evaluation of Currently Available Preparations Arch Intern Med, March 1, 1985; 145(3): 538 - 543. [Abstract] [PDF]

				R. H. Thompson The Clinical Use of Transdermal Delivery Devices with Nitroglycerin Angiology, January 1, 1983; 34(1): 23 - 31. [Abstract] [PDF]

				N. REICHEK and ST. J. S. MARTIN Long-Acting Nitroglycerin for Angina, 1982: Old Dog, New Tricks Ann Intern Med, November 1, 1982; 97(5): 774 - 776. [Abstract] [PDF]

				T. Kennedy, W. R. Summer, J. Sylvester, and D. Robertson Airway Response to Sublingual Nitroglycerin in Acute Asthma JAMA, July 10, 1981; 246(2): 145 - 147. [Abstract] [PDF]

				J. A. Franciosa Current Clinical Status of Nitroglycerin and Other Nitrates Arch Intern Med, April 1, 1978; 138(4): 525 - 526. [Abstract] [PDF]

				G. S. Francis and A.D. Hagan Nitroglycerin Ointment: a Review Angiology, December 1, 1977; 28(12): 873 - 878. [PDF]

				M. E. Davidov and W. J. Oczek Effect of Sustained Release Nitroglycerin Capsules On Anginal Frequency and Exercise Capacity: a Double-Blind Evaluation Angiology, March 1, 1977; 28(3): 181 - 189. [PDF]

				N. Reichek Long-Acting Nitrates in the Treatment of Angina Pectoris JAMA, September 20, 1976; 236(12): 1399 - 1402. [Abstract] [PDF]

				M. E. Davidov and W. J. Oczek The Effect of Nitroglycerin Ointment on the Exercise Capacity in Patients with Angina Pectoris Angiology, April 1, 1976; 27(4): 205 - 211. [PDF]

				R. PLAWNER Vasodilators in Heart Failure Ann Intern Med, June 1, 1975; 82(6): 857 - 857. [Abstract] [PDF]

				T. WINSOR Oral Nitrates: Efficacious? Ann Intern Med, March 1, 1973; 78(3): 457 - 458. [Abstract] [PDF]