Published Online
on August 2, 2004

A more recent version of this article appeared on August 10, 2004

This Article Full Text (PDF) All Versions of this Article: 110/6/750    most recent 01.CIR.0000138105.17864.6Bv1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhang, J. Articles by Stamler, J. S. Search for Related Content PubMed PubMed Citation Articles by Zhang, J. Articles by Stamler, J. S. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Hazardous Substances DB CALCIUM CYANAMIDE CYANAMIDE NITROGLYCERIN Related Collections Animal models of human disease Other Treatment Acute coronary syndromes Endothelium/vascular type/nitric oxide

Submitted on January 20, 2004
Revised on March 18, 2004
Accepted on March 22, 2004

Role of Mitochondrial Aldehyde Dehydrogenase in Nitroglycerin-Induced Vasodilation of Coronary and Systemic Vessels. An Intact Canine Model

Jian Zhang MD, Zhiqiang Chen PhD, Frederick R. Cobb MD, and Jonathan S. Stamler MD^*

From the Department of Medicine, Division of Cardiology (J.Z., F.R.C., J.S.S.) and Howard Hughes Medical Institute (Z.C., J.S.S.), Duke University Medical Center, Durham, NC.

^* To whom correspondence should be addressed. E-mail: staml001{at}mc.duke.edu.

Background--It has recently been shown that mitochondrial aldehyde dehydrogenase 2 (mtALDH) catalyzes the formation of 1,2-glyceryl dinitrate and nitrite from nitroglycerin (glyceryl trinitrate [GTN]) within mitochondria, leading to production of cGMP and vasorelaxation. However, whether this mechanism operates in the systemic and coronary beds that subserve the antianginal action of GTN is not known. In this study, we address this question in an intact canine model.

Methods and Results--Fourteen healthy mongrel dogs (weight, 20 to 25 kg) were studied. Coronary blood flow and hemodynamics were continuously monitored by a pulse Doppler flow probe implanted around the left circumflex coronary artery and with catheters in left ventricle and aorta, respectively. Each dog was given a 1-mL bolus injection of GTN, sodium nitroprusside (SNP), or adenosine through a catheter in the left atrium before and 30 minutes after infusion of cyanamide (17 mg/kg), an inhibitor of mtALDH. Cyanamide significantly inhibited both the classic dehydrogenase and GTN reductase activities of mtALDH in situ and attenuated the coronary blood flow increase and declines in blood pressure and left ventricular end-diastolic pressure produced by GTN in vivo. In contrast, mtALDH inhibition had no effect on the coronary and systemic effects of SNP and adenosine.

Conclusions--Our data suggest that mtALDH contributes to GTN biotransformation in vivo and thus at least partly underlies the antianginal mechanism of drug action. Our findings also highlight the differences in biometabolism of clinically relevant nitrosovasodilators.

Key words: nitroglycerin • nitric oxide • angina • blood flow

This article has been cited by other articles:

				J. S. Stamler Nitroglycerin-Mediated S-Nitrosylation of Proteins: A Field Comes Full Cycle Circ. Res., September 12, 2008; 103(6): 557 - 559. [Full Text] [PDF]

				M. W. Huellner, S. Schrepfer, M. Weyand, H. Weiner, I. Wimplinger, T. Eschenhagen, and T. Rau Inhibition of aldehyde dehydrogenase type 2 attenuates vasodilatory action of nitroglycerin in human veins FASEB J, July 1, 2008; 22(7): 2561 - 2568. [Abstract] [Full Text] [PDF]

				M. Beretta, K. Gruber, A. Kollau, M. Russwurm, D. Koesling, W. Goessler, W. M. Keung, K. Schmidt, and B. Mayer Bioactivation of Nitroglycerin by Purified Mitochondrial and Cytosolic Aldehyde Dehydrogenases J. Biol. Chem., June 27, 2008; 283(26): 17873 - 17880. [Abstract] [Full Text] [PDF]

				U. Hink, A. Daiber, N. Kayhan, J. Trischler, C. Kraatz, M. Oelze, H. Mollnau, P. Wenzel, C. F. Vahl, K. K. Ho, et al. Oxidative Inhibition of the Mitochondrial Aldehyde Dehydrogenase Promotes Nitroglycerin Tolerance in Human Blood Vessels J. Am. Coll. Cardiol., December 4, 2007; 50(23): 2226 - 2232. [Abstract] [Full Text] [PDF]

				J.-P. Bin, A. Doctor, J. Lindner, E. M. Hendersen, D. E. Le, H. Leong-Poi, N. G. Fisher, J. Christiansen, and S. Kaul Effects of Nitroglycerin on Erythrocyte Rheology and Oxygen Unloading: Novel Role of S-Nitrosohemoglobin in Relieving Myocardial Ischemia Circulation, May 30, 2006; 113(21): 2502 - 2508. [Abstract] [Full Text] [PDF]

				T. Munzel, A. Daiber, and A. Mulsch Explaining the Phenomenon of Nitrate Tolerance Circ. Res., September 30, 2005; 97(7): 618 - 628. [Abstract] [Full Text] [PDF]

				A. Daiber, M. Oelze, S. Sulyok, M. Coldewey, E. Schulz, N. Treiber, U. Hink, A. Mulsch, K. Scharffetter-Kochanek, and T. Munzel Heterozygous Deficiency of Manganese Superoxide Dismutase in Mice (Mn-SOD+/-): A Novel Approach to Assess the Role of Oxidative Stress for the Development of Nitrate Tolerance Mol. Pharmacol., September 1, 2005; 68(3): 579 - 588. [Abstract] [Full Text] [PDF]

				I. S. Mackenzie, K. M. Maki-Petaja, C. M. McEniery, Y. P. Bao, S. M. Wallace, J. Cheriyan, S. Monteith, M. J. Brown, and I. B. Wilkinson Aldehyde Dehydrogenase 2 Plays a Role in the Bioactivation of Nitroglycerin in Humans Arterioscler Thromb Vasc Biol, September 1, 2005; 25(9): 1891 - 1895. [Abstract] [Full Text] [PDF]

				Z. Chen, M. W. Foster, J. Zhang, L. Mao, H. A. Rockman, T. Kawamoto, K. Kitagawa, K. I. Nakayama, D. T. Hess, and J. S. Stamler An essential role for mitochondrial aldehyde dehydrogenase in nitroglycerin bioactivation PNAS, August 23, 2005; 102(34): 12159 - 12164. [Abstract] [Full Text] [PDF]