Nitrates: Why and how should they be used today?

Abstract

Nitrates are highly effective both in terminating acute attacks of angina pectoris and in the prophylaxis of symptomatic and asymptomatic myocardial ischemia. Preload reduction by venodilatation is the prevailing mechanism of nitrates in patients with chronic stable angina and is the unique feature distinguishing them from beta and calcium-channel blockers. Nitrates dilate coronary arteries not only in pre- and poststenotic vessels, but also in eccentric lesions. In patients with endothelial dysfunction, nitrates seem to be the physiological substitute for endothelium-derived relaxing factor. During the past decade, however, there has been substantial evidence of a clinically relevant loss of the anti-ischemic effects ("nitrate tolerance"). Many studies with oral dosing of isosorbide dinitrate or isosorbide-5-mononitrate at least three times daily have proven nitrate tolerance in patients with coronary artery disease and/or congestive heart failure. Complete loss of anti-ischemic effects after repetitive, continuous patch attachments has also been found. As we first showed in 1983, intermittent therapy with once-daily ingestion of high-dose sustained-release isosorbide dinitrate was successful in preventing the development of tolerance. Similarly, tolerance to isosorbide-5-mononitrate also does not develop when it is ingested once daily. It is now generally accepted that a daily low-nitrate interval is required to prevent tolerance development. Although the minimal patch-free interval required to prevent tolerance needs further investigation, a 12-h patch-free interval should prevent tolerance in most patients. The prolonged duration of action of once-daily high-dosage administration of sustained-release formulations, the improved patient compliance with a single daily administration, and the increased likelihood of maximal anti-ischemic effects are important reasons for recommending high single daily doses of isosorbide dinitrate or isosorbide-5-mononitrate.

The Safety and Tolerance of Herbal Anti-Angina Drug Compound Danshen Droplet Pill in Healthy Volunteers

“…The major problem with long-term used of nitroglycerin and long-acting nitrates is development of tolerance. Although in some clinical trials intermittent therapy seems to be a hopeful strategy in preventing nitrate tolerance and has proved superior to continuous therapy [19,20], it still has problems, such as possible association with rebound myocardial ischemia during the nitrate-free period and adverse effects on performance on treadmill exercise tests during the period of withdrawal from nitrates [16]. In search of better treatment options, many patients in both east and west have turned to alternative medicines in the hopes of identifying "natural" substances with less toxicity but equal effectiveness.…”

Modulation of Anti-Glomerular Basement Membrane Nephritis in Rats by ONO-1301, a Non-Prostanoid Prostaglandin I2 Mimetic Compound with Inhibitory Activity against Thromboxane A2 Synthase

“…ISDN has a vasodilator effect upon the large coro nary artery, and an attenuating effect on preload by dilating veins (16)(17)(18). Nifedipine (19) and lemakalim (20,21) have a vasodilator effect on large and small coronary arteries and an attenuating effect on afterload by dilating peripheral arteries.…”

Maternal Venous Hemodynamic Dysfunction in Proteinuric Gestational Hypertension: Evidence and Implications

“…Nitroglycerin and other nitrates are well known endothelium dependent venodilating agents [149], with successful application in the management of preeclampsia, eclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), with or without pulmonary edema [150,151]. Improvements of abnormal Doppler flow measurements in uterine and umbilical arteries during nitroglycerin administration have been reported [152,153].…”