(Circulation. 1999;99:3181-3187.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Evidence for a Causal Role of the Renin-Angiotensin System in Nitrate Tolerance
From the Department of Medicine, Emory University School of Medicine, and Veterans Administration Hospital (S.K., A.B.B., D.G.H.), Atlanta, Ga; and the Cardiology Division, Albert Ludwig University, Freiburg (S.K.); Eppendorf University, Hamburg (U.H., T.M.); and University of Cologne, Division of Cardiology (G.N.), Germany.
Correspondence to Thomas Münzel, MD, Abteilung für Kardiologie, Universitäts-Krankenhaus Eppendorf, Martinistraße 52, D-20246 Hamburg, Germany. E-mail muenzel{at}uke.uni-hamburg.de
Background—We have previously shown that nitroglycerin (NTG) therapy increases vascular expression of endothelin 1 (ET-1) and stimulates vascular superoxide (O2·-) production via activation of NADH/NADPH oxidases. Both phenomena are stimulated by angiotensin II in vitro, and the renin-angiotensin system is activated during early nitrate therapy. We hypothesized that either angiotensin II or ET-1 may increase vascular O2·- production during nitrate therapy.
Methods and Results—In New Zealand White rabbits, 3 days of treatment with NTG patches increased plasma renin activity for the entire treatment period. After 24 hours of NTG treatment, angiotensin II type 1 (AT1) receptor expression and vascular ACE activity were significantly decreased. At this time, constrictions to angiotensin I and II were depressed, but there was no loss of NTG vasodilator potency. Within 3 days of continuous NTG treatment, relaxations to NTG were markedly blunted. This was associated with an increase in AT1 receptor mRNA expression, a return of ACE activity back to baseline, and a marked increase in constrictions to angiotensin I and II despite continuously increased plasma renin activity. Tolerance was associated with a 2-fold increase in vascular O2·-, as estimated by lucigenin-enhanced chemiluminescence. Concomitant treatment with the AT1 receptor antagonist losartan (5 to 25 mg · kg-1 · d-1) dose-dependently normalized vascular O2·- and prevented tolerance to NTG and cross-tolerance to endogenous nitric oxide released by acetylcholine. The nonselective ET-1 receptor blocker bosentan (100 mg · kg-1 · d-1) had similar but less pronounced effects.
Conclusions—The positive effects of AT1 and ET-1 receptor blockade on tolerance and O2·- production imply a pathophysiological role for angiotensin II and to some extent for ET-1 in the development of nitrate tolerance.
Key Words: angiotensin • receptors • losartan • bosentan • chemiluminescence • nitric oxide
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