The effect of supplemental L-arginine on tolerance development during continuous transdermal nitroglycerin therapy.
OBJECTIVE
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.
Parker
John O
JO
Department of Medicine, Queen's University, Kingston, Ontario, Canada.
Parker
John D
JD
Caldwell
Robert W
RW
Farrell
Bernice
B
Kaesemeyer
Wayne H
WH
D000279:Administration, Cutaneous; D000284:Administration, Oral; D000787:Angina Pectoris / Q000188:drug therapy* / Q000503:physiopathology; D001120:Arginine / Q000008:administration & dosage / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004361:Drug Tolerance; D005080:Exercise Test; D006801:Humans; D019001:Nitric Oxide Synthase / Q000378:metabolism; D005996:Nitroglycerin / Q000008:administration & dosage* / Q000627:therapeutic use; D013997:Time Factors; D014665:Vasodilator Agents / Q000008:administration & dosage* / Q000627:therapeutic use
D014665:Vasodilator Agents; D001120:Arginine; D019001:Nitric Oxide Synthase; D005996:Nitroglycerin