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


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.
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Jian
J
Zhang
Zhiqiang
Z
Chen
Frederick R
FR
Cobb
Jonathan S
JS
Stamler
D000241:Adenosine / Q000494:pharmacology; D000444:Aldehyde Dehydrogenase / Q000502:physiology*; D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects*; D003484:Cyanamide / Q000494:pharmacology; D006152:Cyclic GMP / Q000096:biosynthesis; D003971:Diastole; D004285:Dogs; D008928:Mitochondria / Q000201:enzymology*; D009573:Nitrites / Q000378:metabolism; D005996:Nitroglycerin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*; D009599:Nitroprusside / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D009573:Nitrites; D009599:Nitroprusside; C014509:dinitroglycerol; D003484:Cyanamide; D000444:Aldehyde Dehydrogenase; D005996:Nitroglycerin; D006152:Cyclic GMP; D000241:Adenosine