0
January 15, 1988, Vol 259, No. 3 >
ARTICLE | January 15, 1988

A Reappraisal of Nitrate Therapy FREE

Jonathan Abrams, MD
[+] Author Affiliations

This article is one of a series sponsored by the American Heart Association.

Reprint requests to Department of Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131 (Dr Abrams).


JAMA. 1988;259(3):396-401. doi:10.1001/jama.1988.03720030056035
Text Size: A A A
Published online
Article
References

Nitroglycerin and the long-acting nitrates are beneficial in stable and unstable angina pectoris and acute myocardial infarction and as adjunctive therapy in congestive heart failure. Nitroglycerin compounds relax vascular smooth muscle, producing venous, arterial, and arteriolar dilatation. These actions are modulated by stimulation of intracellular cyclic guanosine monophosphate. Nitrate efficacy in ischemic heart disease is due to peripheral venous and arterial vasodilatation that results in decreased myocardial oxygen consumption. Nitrates also dilate coronary arteries and collaterals, reverse coronary vasoconstriction, and enlarge some coronary atherosclerotic lesions. Nitrates improve exercise performance in stable angina pectoris. Intravenous nitroglycerin should be used in the initial treatment of unstable angina. Nitrates may be beneficial in myocardial infarction for control of ischemic pain, acute hypertension, and left ventricular failure. In subjects with congestive heart failure, nitrates reduce symptoms and improve exercise tolerance. Nitrate tolerance is a problem with continuous nitrate therapy. Tolerance is most likely to occur with frequent dosing or the use of long-acting nitrates, particularly transdermal nitroglycerin disks, and can be prevented or reversed with intermittent-dosing regimens.

(JAMA 1988;259:396-401)

REFERENCES

1 +
Abrams J:  Vasodilator therapy for congestive heart failure. JAMA 1985;;254:3070-3074.
2 +
Abrams J:  Tolerance to organic nitrates. Circulation 1986;;74:1181-1185.
3 +
Ignarro LJ, Lippton H, Edwards JC, et al:  Mechanism of vascular smooth-muscle relaxation by organic nitrates, nitrites, nitroprusside and nitric oxide: Evidence for the involvement of S-nitrosothiols as active intermediates. J Pharmacol Exp Ther 1981;;281:739-749.
4 +
Kukovetz WR, Holzmann S:  Mechanism of nitrate-induced vasodilatation and tolerance. Z Kardiol 1983;;72( (suppl 3) ):14-19.
5 +
Murad F:  Cyclic guanosine monophosphate as a mediator of vasodilation. J Clin Invest 1987;;78:1-5.
6 +
Kukovetz WR, Holzmann S:  Mechanisms of nitrate-induced vasodilatation and tolerance on a biochemical base. Z Kardiol 1985;;74( (suppl 1) ):39-44.
7 +
Rehr RB, Jackson JA, Winniford MD, et al:  Mechanism of nitroglycerin-induced coronary dilatation: Lack of relation to intracoronary thromboxane concentrations. Am J Cardiol 1984;;54: 971-974.
8 +
Abrams J:  Hemodynamic effects of nitroglycerin and long-acting nitrates. Am Heart J 1985;;110:216-224.
9 +
Loos D, Schneider R, Schorner W:  Changes in regional body blood volume caused by nitroglycerin. Z Kardiol 1983;;72( (suppl 3) ):29-34.
10 +
Fung H-L, Sutton SC, Kamiya A:  Blood vessel uptake and metabolism of organic nitrates in the rat. Pharmacol Exp Ther 1984;;228:334-341.
11 +
Mehta JL, Pepine CJ:  Effect of sublingual nitroglycerin on regional flow in patients with and without coronary disease. Circulation 1978;;58: 803-807.
12 +
Brown G, Bolson E, Petersen RB, et al:  The mechanisms of nitroglycerin action: Stenosis vasodilatation as a major component of drug response. Circulation 1981;;64:1089-1097.
13 +
Gage JE, Hess OM, Murakami T, et al:  Vasoconstriction of stenotic coronary arteries during dynamic exercise in patients with classic angina pectoris: Reversibility by nitroglycerin. Circulation 1986;;73:865-876.
14 +
Abrams J:  The role of nitroglycerin and long-acting nitrates in the treatment of angina , in Weiner DA, Frishman W (eds): Therapy of Angina . New York, Marcel Dekker Inc, 1986;, pp 53-81.
15 +
Parker JO:  Nitrate therapy in stable angina pectoris. N Engl J Med 1987;;316:1635-1641.
16 +
Hoekenga D, Abrams J:  Rational medical therapy for stable angina pectoris. Am J Med 1984;;76: 309-314.
17 +
Curfman GD, Heinsmer JA, Lozner EC, et al:  Intravenous nitroglycerin in the treatment of spontaneous angina pectoris: A prospective randomized trial. Circulation 1983;;67:276-282.
18 +
Distante A, Maseri A, Severi S, et al:  Management of vasospastic angina at rest with continuous infusion of isosorbide dinitrate. Am J Cardiol 1979;;44:533-539.
19 +
Kaplan K, Davison R, Parker M, et al:  Intravenous nitroglycerin for the treatment of angina at rest unresponsive to standard nitrate therapy. Am J Cardiol 1983;;51:694-698.
20 +
Hill JA, Feldman RL, Pepine CJ, et al:  Randomized double-blind comparison of nifedipine and isosorbide dinitrate in patients with coronary arterial spasm. Am J Cardiol 1982;;49:431-438.
21 +
Ginsburg R, Lamb I, Schroeder JS, et al:  Randomized double-blind comparison of nifedipine and isosorbide dinitrate therapy in variant angina pectoris due to coronary arterial spasm. Am Heart J 1982;;103:44-49.
22 +
Schang SJ, Pepine CJ:  Transient asymptomatic ST-segment depression during daily activity. Am J Cardiol 1977;;39:396-402.
23 +
Shell WE:  Mechanisms and therapy of silent myocardial ischemia and the effect of transdermal nitroglycerin. Am J Cardiol 1985;;56:231-271.
24 +
Flaherty JT, Becker LC, Bulkley BH:  A randomized prospective trial of intravenous nitroglycerin in patients with acute myocardial infarction. Circulation 1983;;68:576-584.
25 +
Roberts R:  Intravenous nitroglycerin in acute myocardial infarction. Am J Med 1983;;74( (suppl 6B) ):45-52.
26 +
Chiarello M, Gold HK, Leinbach RC, et al:  Comparison between the effects of nitroprusside and nitroglycerin on ischemic injury during acute myocardial infarction. Circulation 1976;;54:766-773.
27 +
Bussmann WD, Giebeler B:  Beeinflusst eine Dauertherapie mit hochdosierten Nitraten die Prognose bei koronarer Herzkrankheit? Klin Wochenschr 1983;;61:423-428.
28 +
Rapaport E, Remedios P:  The high-risk patient after recovery from myocardial infarction: Recognition and management. J Am Coll Cardiol 1983;;1:391-400.
29 +
Chatterjee K, Parmley WW:  Vasodilator therapy for acute myocardial infarction and chronic congestive heart failure. J Am Coll Cardiol 1983;;1: 133-153.
30 +
Packer M:  New perspectives on therapeutic application of nitrates as vasodilator agents for severe chronic heart failure. Am J Med 1983;; 74( (suppl 6B) ):61-72.
31 +
Leier CV, Huss P, Magorien RD, et al:  Improved exercise capacity and differing arterial and venous tolerance during chronic isosorbide dinitrate therapy for congestive heart failure. Circulation 1983;;67:817-822.
32 +
Franciosa JA, Cohn JN:  Sustained hemodynamic effects without tolerance during long-term isosorbide dinitrate treatment in chronic left ventricular failure. Am J Cardiol 1980;;45:640-654.
33 +
Cohn JN, Archibald DG, Ziesches S, et al:  Effect of vasodilator therapy on mortality in chronic congestive heart failure: Results of a Veterans Administration Cooperative Study. N Engl J Med 1986;;314:1547-1552.
34 +
The Consensus Trial Study Group:  Effects of enalapril on mortality in severe congestive heart failure: Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987;;316:1429-1435.
35 +
Herling IM:  Intravenous nitroglycerin: Clinical pharmacology and therapeutic considerations. Am Heart J 1984;;108:141-149.
36 +
Conn HO:  Vasopressin and nitroglycerin in the treatment of bleeding varices: The bottom line. Hepatology 1986;;6:523-525.
37 +
Curry SH, Kwon H-R, Perrin JH, et al:  Nitroglycerin levels after administration via transdermal therapeutic system or nitroglycerin ointment. Lancet 1984;;1:1297.
38 +
Abrams J:  The brief saga of transdermal nitroglycerin discs: Paradise lost? Am J Cardiol 1984;; 54:220-224.
39 +
Reichek N:  Long-acting nitrates: Relative utility of nitroglycerin patches. Am J Med 1984;;76: 63-66.
40 +
Reichek N, Priest C, Zimrin D, et al:  Antianginal effects of nitroglycerin patches. Am J Cardiol 1984;;54:1-7.
41 +
Parker JO, Fung H-L:  Transdermal nitroglycerin in angina pectoris. Am J Cardiol 1984;; 54:471-476.
42 +
Olivari MT, Carlyle PF, Levine B, et al:  Hemodynamic and hormonal response to transdermal nitroglycerin in normal subjects and in patients with congestive heart failure. J Am Coll Cardiol 1983;;2:872-878.
43 +
Jordan RA, Seth L, Henry DA, et al:  Dose requirements and hemodynamic effects of transdermal nitroglycerin compared to placebo in patients with congestive heart failure. Circulation 1985;;71:900-985.
44 +
Elkayam U, Roth A, Henriquez B, et al:  The hemodynamic and hormonal effects of high-dose transdermal nitroglycerin in patients with chronic congestive heart failure. Am J Cardiol 1985;;56: 555-559.
45 +
Thadani U, Hamilton SF, Olson E, et al:  Transdermal nitroglycerin patches in angina pectoris. Ann Intern Med 1986;;105:485-492.
46 +
Sharpe N, Coxon R, Webster M, et al:  Hemodynamic effects of intermittent transdermal nitroglycerin in chronic congestive heart failure. Am J Cardiol 1987;;59:895-899.
47 +
Parker JO, Van Koughnett KA, Fung H-L:  Transdermal isosorbide dinitrate in angina pectoris: Effect of acute and sustained therapy. Am J Cardiol 1984;;54:8-13.
48 +
Scardi S, Pivotti F, Fonda F, et al:  Effect of a new transdermal therapeutic system containing nitroglycerin on exercise capacity in patients with angina pectoris. Am Heart J 1985;;110:546-551.
49 +
Muiesen G, Agabita IRE, Muiesen L, et al:  A multicenter trial of transdermal nitroglycerin in exercise-induced angina: Individual antianginal response after repeated administration. Am Heart J 1986;;112:233-238.
50 +
Cowan JC, Bourke JP, Reid DS, et al:  Prevention of tolerance to nitroglycerin patches by overnight renewal. Br Med J 1987;;294:544-545.
51 +
Schaer DH, Buff LA, Katz RJ:  Sustained Nitropatch antianginal efficacy utilizing an overnight nitrate-free interval, abstracted. Circulation 1987;;76:IV-127.
52 +
Abrams J:  Nitrate tolerance and dependence. Am Heart J 1980;;99:113-123.
53 +
Silber S:  Clinical relevance of nitrate tolerance , in Cohn JN, Rittinhausen R (eds): Mononitrates . Berlin, Springer-Verlag, 1985;, pp 130-146.
54 +
Cowan JC:  Nitrate tolerance. Int J Cardiol 1986;;12:1-19.
55 +
Abrams J:  Nitrate tolerance in angina pectoris , in Cohn JN, Rittinhausen R (eds): Mononitrates . Berlin, Springer Verlag, 1985;, pp 154-170.
56 +
Lee G, Mason DT, DeMaria A:  Effects of long-term oral administration of isosorbide dinitrate on the antianginal response to nitroglycerin: Absence of cross-tolerance and self-tolerance shown by exercise testing. Am J Cardiol 1978;;41:82-87.
57 +
Parker JO, Farrell B, Lahey KA, et al:  Effect of intervals between doses on the development of tolerance to isosorbide dinitrate. N Engl J Med 1987;;316:1440-1444.

Figures

Tables

Interactive Graphics

Video

Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Abrams J:  Vasodilator therapy for congestive heart failure. JAMA 1985;;254:3070-3074.
2 +
Abrams J:  Tolerance to organic nitrates. Circulation 1986;;74:1181-1185.
3 +
Ignarro LJ, Lippton H, Edwards JC, et al:  Mechanism of vascular smooth-muscle relaxation by organic nitrates, nitrites, nitroprusside and nitric oxide: Evidence for the involvement of S-nitrosothiols as active intermediates. J Pharmacol Exp Ther 1981;;281:739-749.
4 +
Kukovetz WR, Holzmann S:  Mechanism of nitrate-induced vasodilatation and tolerance. Z Kardiol 1983;;72( (suppl 3) ):14-19.
5 +
Murad F:  Cyclic guanosine monophosphate as a mediator of vasodilation. J Clin Invest 1987;;78:1-5.
6 +
Kukovetz WR, Holzmann S:  Mechanisms of nitrate-induced vasodilatation and tolerance on a biochemical base. Z Kardiol 1985;;74( (suppl 1) ):39-44.
7 +
Rehr RB, Jackson JA, Winniford MD, et al:  Mechanism of nitroglycerin-induced coronary dilatation: Lack of relation to intracoronary thromboxane concentrations. Am J Cardiol 1984;;54: 971-974.
8 +
Abrams J:  Hemodynamic effects of nitroglycerin and long-acting nitrates. Am Heart J 1985;;110:216-224.
9 +
Loos D, Schneider R, Schorner W:  Changes in regional body blood volume caused by nitroglycerin. Z Kardiol 1983;;72( (suppl 3) ):29-34.
10 +
Fung H-L, Sutton SC, Kamiya A:  Blood vessel uptake and metabolism of organic nitrates in the rat. Pharmacol Exp Ther 1984;;228:334-341.
11 +
Mehta JL, Pepine CJ:  Effect of sublingual nitroglycerin on regional flow in patients with and without coronary disease. Circulation 1978;;58: 803-807.
12 +
Brown G, Bolson E, Petersen RB, et al:  The mechanisms of nitroglycerin action: Stenosis vasodilatation as a major component of drug response. Circulation 1981;;64:1089-1097.
13 +
Gage JE, Hess OM, Murakami T, et al:  Vasoconstriction of stenotic coronary arteries during dynamic exercise in patients with classic angina pectoris: Reversibility by nitroglycerin. Circulation 1986;;73:865-876.
14 +
Abrams J:  The role of nitroglycerin and long-acting nitrates in the treatment of angina , in Weiner DA, Frishman W (eds): Therapy of Angina . New York, Marcel Dekker Inc, 1986;, pp 53-81.
15 +
Parker JO:  Nitrate therapy in stable angina pectoris. N Engl J Med 1987;;316:1635-1641.
16 +
Hoekenga D, Abrams J:  Rational medical therapy for stable angina pectoris. Am J Med 1984;;76: 309-314.
17 +
Curfman GD, Heinsmer JA, Lozner EC, et al:  Intravenous nitroglycerin in the treatment of spontaneous angina pectoris: A prospective randomized trial. Circulation 1983;;67:276-282.
18 +
Distante A, Maseri A, Severi S, et al:  Management of vasospastic angina at rest with continuous infusion of isosorbide dinitrate. Am J Cardiol 1979;;44:533-539.
19 +
Kaplan K, Davison R, Parker M, et al:  Intravenous nitroglycerin for the treatment of angina at rest unresponsive to standard nitrate therapy. Am J Cardiol 1983;;51:694-698.
20 +
Hill JA, Feldman RL, Pepine CJ, et al:  Randomized double-blind comparison of nifedipine and isosorbide dinitrate in patients with coronary arterial spasm. Am J Cardiol 1982;;49:431-438.
21 +
Ginsburg R, Lamb I, Schroeder JS, et al:  Randomized double-blind comparison of nifedipine and isosorbide dinitrate therapy in variant angina pectoris due to coronary arterial spasm. Am Heart J 1982;;103:44-49.
22 +
Schang SJ, Pepine CJ:  Transient asymptomatic ST-segment depression during daily activity. Am J Cardiol 1977;;39:396-402.
23 +
Shell WE:  Mechanisms and therapy of silent myocardial ischemia and the effect of transdermal nitroglycerin. Am J Cardiol 1985;;56:231-271.
24 +
Flaherty JT, Becker LC, Bulkley BH:  A randomized prospective trial of intravenous nitroglycerin in patients with acute myocardial infarction. Circulation 1983;;68:576-584.
25 +
Roberts R:  Intravenous nitroglycerin in acute myocardial infarction. Am J Med 1983;;74( (suppl 6B) ):45-52.
26 +
Chiarello M, Gold HK, Leinbach RC, et al:  Comparison between the effects of nitroprusside and nitroglycerin on ischemic injury during acute myocardial infarction. Circulation 1976;;54:766-773.
27 +
Bussmann WD, Giebeler B:  Beeinflusst eine Dauertherapie mit hochdosierten Nitraten die Prognose bei koronarer Herzkrankheit? Klin Wochenschr 1983;;61:423-428.
28 +
Rapaport E, Remedios P:  The high-risk patient after recovery from myocardial infarction: Recognition and management. J Am Coll Cardiol 1983;;1:391-400.
29 +
Chatterjee K, Parmley WW:  Vasodilator therapy for acute myocardial infarction and chronic congestive heart failure. J Am Coll Cardiol 1983;;1: 133-153.
30 +
Packer M:  New perspectives on therapeutic application of nitrates as vasodilator agents for severe chronic heart failure. Am J Med 1983;; 74( (suppl 6B) ):61-72.
31 +
Leier CV, Huss P, Magorien RD, et al:  Improved exercise capacity and differing arterial and venous tolerance during chronic isosorbide dinitrate therapy for congestive heart failure. Circulation 1983;;67:817-822.
32 +
Franciosa JA, Cohn JN:  Sustained hemodynamic effects without tolerance during long-term isosorbide dinitrate treatment in chronic left ventricular failure. Am J Cardiol 1980;;45:640-654.
33 +
Cohn JN, Archibald DG, Ziesches S, et al:  Effect of vasodilator therapy on mortality in chronic congestive heart failure: Results of a Veterans Administration Cooperative Study. N Engl J Med 1986;;314:1547-1552.
34 +
The Consensus Trial Study Group:  Effects of enalapril on mortality in severe congestive heart failure: Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987;;316:1429-1435.
35 +
Herling IM:  Intravenous nitroglycerin: Clinical pharmacology and therapeutic considerations. Am Heart J 1984;;108:141-149.
36 +
Conn HO:  Vasopressin and nitroglycerin in the treatment of bleeding varices: The bottom line. Hepatology 1986;;6:523-525.
37 +
Curry SH, Kwon H-R, Perrin JH, et al:  Nitroglycerin levels after administration via transdermal therapeutic system or nitroglycerin ointment. Lancet 1984;;1:1297.
38 +
Abrams J:  The brief saga of transdermal nitroglycerin discs: Paradise lost? Am J Cardiol 1984;; 54:220-224.
39 +
Reichek N:  Long-acting nitrates: Relative utility of nitroglycerin patches. Am J Med 1984;;76: 63-66.
40 +
Reichek N, Priest C, Zimrin D, et al:  Antianginal effects of nitroglycerin patches. Am J Cardiol 1984;;54:1-7.
41 +
Parker JO, Fung H-L:  Transdermal nitroglycerin in angina pectoris. Am J Cardiol 1984;; 54:471-476.
42 +
Olivari MT, Carlyle PF, Levine B, et al:  Hemodynamic and hormonal response to transdermal nitroglycerin in normal subjects and in patients with congestive heart failure. J Am Coll Cardiol 1983;;2:872-878.
43 +
Jordan RA, Seth L, Henry DA, et al:  Dose requirements and hemodynamic effects of transdermal nitroglycerin compared to placebo in patients with congestive heart failure. Circulation 1985;;71:900-985.
44 +
Elkayam U, Roth A, Henriquez B, et al:  The hemodynamic and hormonal effects of high-dose transdermal nitroglycerin in patients with chronic congestive heart failure. Am J Cardiol 1985;;56: 555-559.
45 +
Thadani U, Hamilton SF, Olson E, et al:  Transdermal nitroglycerin patches in angina pectoris. Ann Intern Med 1986;;105:485-492.
46 +
Sharpe N, Coxon R, Webster M, et al:  Hemodynamic effects of intermittent transdermal nitroglycerin in chronic congestive heart failure. Am J Cardiol 1987;;59:895-899.
47 +
Parker JO, Van Koughnett KA, Fung H-L:  Transdermal isosorbide dinitrate in angina pectoris: Effect of acute and sustained therapy. Am J Cardiol 1984;;54:8-13.
48 +
Scardi S, Pivotti F, Fonda F, et al:  Effect of a new transdermal therapeutic system containing nitroglycerin on exercise capacity in patients with angina pectoris. Am Heart J 1985;;110:546-551.
49 +
Muiesen G, Agabita IRE, Muiesen L, et al:  A multicenter trial of transdermal nitroglycerin in exercise-induced angina: Individual antianginal response after repeated administration. Am Heart J 1986;;112:233-238.
50 +
Cowan JC, Bourke JP, Reid DS, et al:  Prevention of tolerance to nitroglycerin patches by overnight renewal. Br Med J 1987;;294:544-545.
51 +
Schaer DH, Buff LA, Katz RJ:  Sustained Nitropatch antianginal efficacy utilizing an overnight nitrate-free interval, abstracted. Circulation 1987;;76:IV-127.
52 +
Abrams J:  Nitrate tolerance and dependence. Am Heart J 1980;;99:113-123.
53 +
Silber S:  Clinical relevance of nitrate tolerance , in Cohn JN, Rittinhausen R (eds): Mononitrates . Berlin, Springer-Verlag, 1985;, pp 130-146.
54 +
Cowan JC:  Nitrate tolerance. Int J Cardiol 1986;;12:1-19.
55 +
Abrams J:  Nitrate tolerance in angina pectoris , in Cohn JN, Rittinhausen R (eds): Mononitrates . Berlin, Springer Verlag, 1985;, pp 154-170.
56 +
Lee G, Mason DT, DeMaria A:  Effects of long-term oral administration of isosorbide dinitrate on the antianginal response to nitroglycerin: Absence of cross-tolerance and self-tolerance shown by exercise testing. Am J Cardiol 1978;;41:82-87.
57 +
Parker JO, Farrell B, Lahey KA, et al:  Effect of intervals between doses on the development of tolerance to isosorbide dinitrate. N Engl J Med 1987;;316:1440-1444.

Letters

Submit a Letter
CME Course for:


You need to register in order to view this quiz.


To understand the clinical management of acute heart failure syndromes.
Accreditation Information The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
To view and print your certificate and access a summary of your CME courses go to My CME.
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s “Cited By” API will populate this tab (http://www.crossref.org/citedby.html).
Compression-Only CPR: Pushing the Science Forward
Cone
AAM 2010;304:1493-1495.
All you need to read in the other general journals
BMJ 2010;341:c5893-c1494.
Submit a Response

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

© 2012 American Medical Association. All Rights Reserved.
Powered bySilverchair Information Systems