QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.108.138784v1 327/1/97    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tsou, P.-S. Articles by Fung, H.-L. Search for Related Content PubMed PubMed Citation Articles by Tsou, P.-S. Articles by Fung, H.-L.

CARDIOVASCULAR

Dissociation between Superoxide Accumulation and Nitroglycerin-Induced Tolerance

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York

We hypothesize that superoxide () accumulation is not a crucial causative factor in inducing nitroglycerin (NTG) tolerance. In LLC-PK1 cells, pre-exposure to NTG resulted in increased accumulation and reduced cGMP response to NTG versus vehicle control. stimulated by NTG was reduced by oxypurinol (100 µM), a xanthine oxidase inhibitor. Exposure to angiotensin II (Ang II) increased but did not reduce cGMP response. The scavenger tiron reduced Ang II-induced production but did not increase NTG-stimulated cGMP production. Using p47^phox–/– and gp91^phox–/– mice versus their respective wild-type controls (WT), we showed that aorta from mice null of these critical NADPH oxidase subunits exhibited similar vascular tolerance after NTG dosing (20 mg/kg s.c., t.i.d. for 3 days), as indicated by their ex vivo pEC₅₀ and cGMP accumulation upon NTG challenge. In vitro aorta production was enhanced by NTG incubation in both p47^phox null and WT mice. Pre-exposure of isolated mice aorta to 100 µM NTG for 1 h resulted in vascular tolerance toward NTG and increased accumulation. Oxypurinol (1 mM) reduced but did not attenuate vascular tolerance. These results suggest that does not initiate either in vitro and in vivo NTG tolerance, and that the p47^phox and gp91^phox subunits of NADPH oxidase are not critically required. Increased accumulation may be an effect, rather than an initiating cause, of NTG tolerance.

Address correspondence to: Dr. Ho-Leung Fung, Hochstetter 547, Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY 14260-1200. E-mail: hlfung{at}buffalo.edu

This article has been cited by other articles:

				P.-S. Tsou, V. Addanki, J. A. Haas, N. A. Page, and H.-L. Fung Role of Glutaredoxin-Mediated Protein S-Glutathionylation in Cellular Nitroglycerin Tolerance J. Pharmacol. Exp. Ther., May 1, 2009; 329(2): 649 - 656. [Abstract] [Full Text] [PDF]