Role of Mitochondrial Aldehyde Dehydrogenase in Nitroglycerin-Induced Vasodilation of Coronary and Systemic Vessels

Abstract

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.

The Glu504Lys Polymorphism of Aldehyde Dehydrogenase 2 Contributes to Development of Coronary Artery Disease

“…However, after taking sublingual nitroglycerine, the degree of brachial artery dilatation in patients with the ALDH2 *504Lys allele was significantly lower than in those with the wild-type (Xu et al 2011). These results demonstrate that the ALDH2 *504Lys allele exerts a significant effect on non-endothelium-dependent vasodilation and an insignificant effect on endothelium-dependent vasodilation, which is consistent with previous studies (Zhang et al 2004;Mackenzie et al 2005). Previous studies have confirmed that coronary spasm is significantly correlated with damaged endothelium-but not with non-endotheliumdependent vasodilation.…”

“…ALDH2 inhibition can significantly reduce the vasodilatory effects of nitroglycerine (Mackenzie et al 2005;Daiber et al 2009). Another canine study also confirmed that the inhibition of ALDH2 activity can significantly reduce the dilation of canine coronary vessels (Zhang et al 2004). Therefore, regardless of the impact of ALDH2 *504Lys allele on coronary atherosclerosis, the significant activity reduction may decrease the production of vasodilators such as nitric oxide and then induces coronary spasm which triggering ACS occurrence.…”

Effects of Cyanamide, an Aldehyde Dehydrogenase Type 2 Inhibitor, on Glyceryl Trinitrate- and Isosorbide Dinitrate-Induced Vasodilation in Rabbit Excised Aorta and in Anesthetized Whole Animal

“…5 could be around 1). Again, our middle dose GTN (10 µg/kg) is similar to that at which cyanamide inhibited the hypotensive effect of GTN in a canine model, 17) which is considered within the range of high affinity pathway.…”

“…17) Similarly, it is reported that the vasodilatory effects of GTN and NO 2 − on pulmonary and systemic vascular beds of anesthetized rats were attenuated by cyanamide, while the inhibitor had no effect on SNP-induced vasodilation. 18) The doses of GTN used in the above studies correspond to the middle dose (about 10 µg/kg) that used in the present in vivo study.…”

Aldehyde dehydrogenase 2 protects human umbilical vein endothelial cells against oxidative damage and increases endothelial nitric oxide production to reverse nitroglycerin tolerance

“…Earlier reports described the inhibition of ALDH by organic nitrates, but the pharmacological implications were not considered before the discovery of ALDH2-catalyzed GTN bioactivation in 2002 (Chen et al, 2002;Kollau et al, 2005). Zhang et al (2004) reported that reductants are essential for sustained ALDH2-catalyzed GTN metabolism and bioactivation. Furthermore, Baretta et al (2008) found that GTN biotransformation was promoted by addition of ALDH2 expressed and purified in vitro.…”