Role of mitochondrial aldehyde dehydrogenase in nitroglycerin-induced vasodilation of coronary and systemic vessels: an intact canine model.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Zhang, J; Chen, Z; Cobb, FR; Stamler, JS

Published Date

  • August 10, 2004

Published In

Volume / Issue

  • 110 / 6

Start / End Page

  • 750 - 755

PubMed ID

  • 15289380

Pubmed Central ID

  • 15289380

Electronic International Standard Serial Number (EISSN)

  • 1524-4539

Digital Object Identifier (DOI)

  • 10.1161/01.CIR.0000138105.17864.6B

Language

  • eng

Conference Location

  • United States