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Comments
LETTER TO LOBO AND IBANEZ ON THE RESPONSE TO JANSSENS
This letter is in response to Lobo and Ibanez (1) who discuss the unexpected
findings of Janssens (2). In their letter, Lobo and Ibanez list three possible reasons to explain why
inhaled nitric oxide (iNO) plus nitroglycerin was less effective than iNO and nitroglycerin used alone
in limiting infarct size.To the list which includes primary outcome selection, iNO dose and timing
of iNO initiation, I would like to add the possible involvement of superoxide anion production resulting
from the uncoupling of endothelial nitric oxide synthase as part of a mechanism leading to nitroglycerin
tolerance (3)..
Nitroglycerin, in the absence of sufficient substrate for endothelial nitric oxide synthase,
generates superoxide anions (4) which react with with iNO to form peroxynitrite,which is incapable of
activating soluble guanylate cyclase (sGC) and increasing plasma cyclic guanosine monophosphate
(cGMP) levels (5). Hence, those subjects who received iNO plus nitroglycerin may have experienced less
activationof sGC, the molecular target of nitric oxide, with iNO causing accelerated tolerance
development. This would explain the increased cGMP levels and reduced infarct size in nitroglycerine-
naïve patients vs those patients who received iNO plus nitroglycerin (2)..
This problem can be prevented by co-administering nitroglycerin with L-arginine which
suppresses superoxide production and prevents tolerance (4,6,7)). Future STEMI studies with iNO
should consider comparing iNO used alone vs iNO plus IV nitroglycerin co-administered with L-arginine.
Wayne Kaesemeyer M D
Augusta Hypertension P C
108 Tharrington Drive
Chapel Hill, North Carolina 27516
USA
REFERENCES
1] Lobo M1, Ibanez B. Take a deep (nitric oxide) breath and follow the reverse translational research pathway. Eur Heart J. 2018 Jun 25. doi: 10.1093/eurheartj/ehy355. [Epub ahead of print]
2 ] Janssens SP1,2, Bogaert J3, Zalewski J4, Toth A5, Adriaenssens T1,2, Belmans A2, Bennett J1, Claus P2, Desmet W1,2, Dubois C1,2, Goetschalckx K1, Sinnaeve P1,2, Vandenberghe K2, Vermeersch P2, Lux A5, Szelid Z5, Durak M6, Lech P6, Zmudka K6, Pokreisz P2, Vranckx P7, Merkely B5, Bloch KD8, Van de Werf F2; NOMI investigators. Nitric oxide for inhalation in ST-elevation myocardial infarction (NOMI): a multicentre, double-blind,randomized controlled trial. Eur Heart J. 2018 May 24. doi: 10.1093/eurheartj/ehy232. [Epub ahead of print]
3] Knorr M1, Hausding M, Kröller-Schuhmacher S, Steven S, Oelze M, Heeren T, Scholz A, Gori T, Wenzel P, Schulz E, Daiber A, Münzel T. Nitroglycerin-induced endothelial dysfunction and tolerance involve adverse phosphorylation and S-Glutathionylation of endothelial nitric oxide synthase: beneficial effects of therapy with the AT1 receptor blocker telmisartan. Arterioscler Thromb Vasc Biol. 201Oct;31(10):2223-31. doi: 10.1161/ATVBAHA.111.232058. Epub 2011 Jul 14.
\4] Kaesemeyer WH1, Ogonowski AA, Jin L, Caldwell RB, Caldwell RW. Endothelial nitric oxide synthase is a site of superoxide synthesis in endothelial cells treated with glyceryl trinitrate. Br J Pharmacol. 2000 Nov;131(5):1019-23.
5] Beckman JS1, Koppenol WH.. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol. 1996 Nov;271(5 Pt 1):C1424-37.
6] Parker JO1, Parker JD, Caldwell RW, Farrell B, Kaesemeyer WH. The effect of supplemental L-arginine on tolerance development during continuous transdermal nitroglycerin therapy. J Am Coll Cardiol. 2002 Apr 3;39(7):1199-203.
7] Kaesemeyer WH, Abou-Mohamed G, Crute TD, Caldwell RW. Nitrates treated with L-arginine for the reversal and treatment of nitrate tolerance: Two case reports. Applied Cardiopumonary Pathophysiology. 1997;6,255-262.