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CLINICAL STUDY: MYOCARDIAL ISCHEMIA

The effect of supplemental L-arginine on tolerance development during continuous transdermal nitroglycerin therapy

John O. Parker, MD, FACC^*,*, John D. Parker, MD, FACC, Robert W. Caldwell, PhD, Bernice Farrell, RN^* and Wayne H. Kaesemeyer, MD

^* Department of Medicine, Queen’s University, Kingston, Ontario, Canada
Department of Medicine, University of Toronto, Toronto, Ontario, Canada
Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GeorgiaUSA

Manuscript received August 20, 2001; revised manuscript received December 27, 2001, accepted January 10, 2002.

^* Reprint requests and correspondence: Dr. John O. Parker, Etherington Hall, Room 1040, Queens University, 76 Stuart Street, Kingston, Ontario, K7L 3N6, Canada

OBJECTIVES: This study was designed to assess the effect of oral L-arginine on the development of tolerance during continuous transdermal nitroglycerin (TD-GTN) therapy.

BACKGROUND: Continuous TD-GTN therapy leads to complete tolerance within 24 to 48 h. The mechanism(s) responsible for nitrate tolerance are unclear, but there is increasing evidence that nitroglycerin (GTN) leads to superoxide anion production. The trigger for this is unknown, but there is evidence that GTN alters nitric oxide synthase (NOS) function and also leads to reduced L-arginine availability at its site of action with NOS.

METHODS: Fourteen patients with stable angina pectoris and reproducible treadmill walking time (TWT) until the onset of moderate angina were studied in a placebo-controlled, crossover study. Transdermal GTN (0.4 mg/h) was applied daily for two periods of 5 to 10 days with the patch left in place for 24 h each day. Capsules containing L-arginine (700 mg) or placebo were administered four times daily during a period of TD-GTN therapy. Treadmill walking time was determined before and 4 h after study capsules on day 1 before TD-GTN to assess the effect of L-arginine on exercise performance. On the last day, TWT was determined at 0 h (24 h after TD-GTN and 9 h after study capsule) and 4 h after TD-GTN reapplication and study capsule. After a 5 to 10 day washout period, the study was repeated with the opposite study capsule.

RESULTS: Treadmill walking time until the onset of moderate angina was not influenced by the short-term administration of L-arginine. During continuous TD-GTN, the administration of L-arginine increased TWT 4 h and 24 h after patch application. This was significantly greater than TWT during administration of placebo capsules (p < 0.05).

CONCLUSIONS: The administration of L-arginine modified or prevented the development of nitrate tolerance during continuous TD-GTN therapy.

Abbreviations and Acronyms   BP   blood pressure   GTN   nitroglycerin   NO   nitric oxide   NOS   nitric oxide synthase   TD-GTN   transdermal nitroglycerin   TWT   treadmill walking time

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