CLINICAL STUDY
Evidence supporting abnormalities in nitric oxide synthase function induced by nitroglycerin in humans
Tommaso Gori, MD*  ,
Susanna S. Mak, MD*,
Susan Kelly, RN* and
John D. Parker, MD, FACC*
* Division of Cardiology, Department of Medicine, Mount Sinai Hospital, Toronto, Canada
Cardiovascular Collaborative Program, University of Toronto, Toronto, Canada
Manuscript received January 10, 2001;
revised manuscript received April 23, 2001,
accepted June 26, 2001.
Reprint requests and correspondence: Dr. John D. Parker, Division of Cardiology, Department of Medicine, Mount Sinai Hospital, Suite 1609, 600 University Avenue, Toronto, Ontario, Canada M5G 1X5
jdp{at}inforamp.net
OBJECTIVES
We studied the effects of nitroglycerin (GTN) therapy on the response to endothelium-dependent and independent vasoactive agents in the forearm circulation of healthy subjects.
BACKGROUND
Recent evidence suggests that therapy with GTN may induce specific changes in endothelial cell function, including increased superoxide anion production and sensitivity to vasoconstrictors. Additionally, continuous GTN therapy worsens endothelial function in the coronary circulation of patients with ischemic heart disease.
METHODS
Forearm blood flow was measured with venous occlusion, mercury-in-silastic strain gauge plethysmography.
RESULTS
Sixteen male volunteers (26 ± 6 years) were randomized to no therapy (control) or GTN, 0.6 mg/h/24 h, for six days in an investigator-blind, parallel-design study. The flow responses to brachial artery infusions of acetylcholine ([Ach] 7.5, 15.0, 30.0 µg/min), N-monomethyl-L-arginine (L-NMMA) (1, 2, 4 µmol/min) and sodium nitroprusside (SNP) (0.8, 1.6, 3.2 µg/min) were recorded. The vasodilator responses to Ach were blunted in the GTN group as compared with the control group (p < 0.05). The vasoconstrictor responses to L-NMMA were also blunted in the GTN group (p < 0.001). In the GTN group, paradoxical vasodilation was observed in response to the lowest infused concentration of L-NMMA. The vasodilator responses to SNP did not differ between groups.
CONCLUSIONS
The response to Ach confirms the hypothesis that continuous GTN causes endothelial dysfunction. The responses to L-NMMA suggest that GTN therapy causes abnormalities in nitric oxide synthase (NOS) function; the vasodilation observed at the lowest infused concentration of L-NMMA in the GTN group also suggests that continuous GTN therapy is associated with a NOS-mediated production of a vasoconstrictor.
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Abbreviations and Acronyms
| | Ach | = acetylcholine | | ANOVA | = analysis of variance | | FBF | = forearm blood flow | | GTN | = nitroglycerin | | I/N | = ratio of forearm blood flow, infused to noninfused arm | | L-NMMA | = N-monomethyl-L-arginine | | NO | = nitric oxide | | NOS | = nitric oxide synthase | | SNP | = sodium nitroprusside |
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