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(Circulation Research. 2003;93:799.)
© 2003 American Heart Association, Inc.

Editorials

Nitrate Tolerance in Hypertension

New Insight Into a Century-Old Problem

Harm J. Knot

From the Department of Pharmacology and Therapeutics, University of Florida College of Medicine, Gainesville, Fla.

Correspondence to Harm J. Knot, PharmD, PhD, FAHA, University of Florida, Department of Pharmacology and Therapeutics and McKnight Brain Institute, 1600 SW Archer Rd, PO Box 100267, Gainesville, FL 32610-0267. E-mail hknot@college.med.ufl.edu

Key Words: nitrates • Ca²⁺-activated potassium channel • Ca²⁺ sparks

An extract of the first 250 words of the full text is provided, because this article has no abstract.

Nitrate tolerance to a vascular physiologist is the intriguing insensitivity or loss of responsiveness to drugs whose actions mimic the powerful endogenous vasodilator and platelet inhibitor nitric oxide (NO). To the clinician, it is a serious limitation in the use of an otherwise highly promising and widely used therapeutic class of drugs collectively referred to as nitrates. Nitroglycerin (NTG) and organic nitrates are used in the therapy of ischemic heart disease and heart failure. Clinical trials such as the ISIS-4 trial showed a 20% reduction in 24-hour postinfarct mortality with the use of an oral nitrate such as isosorbide mononitrate (ISMN). Sublingual NTG is the drug of choice for chest pain and acute angina attacks, and intravenous NTG is the drug of choice in acute coronary syndromes. Oral long-acting nitrates are effective in the treatment of chronic stable angina.

Brief History of Nitrate Use and Nitrate Tolerance

The promise for nitrates in medicine dates back to the initial observation by Sobrero in Turin in 1847 noting "violent headaches" produced by small quantities of NTG on the tongue. Brunton in Edinburgh recognized the clinical promise for the use of nitrate in angina in 1867.¹ Almost concomitant with his recognition of the strong vasodilatory and other physiological effects of NTG are his poignant observations on its limitations. Brunton noted that if this remedy for relief of angina pain was used for a long time, "...the dose requires to be increased before the effect is produced," perhaps the first reference to what we now refer to as nitrate tolerance.¹ Marsh and . . . [Full Text of this Article]