Mitochondrial aldehyde dehydrogenase mediates vasodilator responses of glyceryl trinitrate and sodium nitrite in the pulmonary vascular bed of the rat

Abstract

PJ. Mitochondrial aldehyde dehydrogenase mediates vasodilator responses of glyceryl trinitrate and sodium nitrite in the pulmonary vascular bed of the rat. Am J Physiol Heart Circ Physiol 299: H819 -H826, 2010. First published June 11, 2010; doi:10.1152/ajpheart.00959.2009.-It has been reported that mitochondrial aldehyde dehydrogenase (ALDH2) catalyzes the formation of glyceryl dinitrate and inorganic nitrite from glyceryl trinitrate (GTN), leading to an increase in cGMP and vasodilation in the coronary and systemic vascular beds. However, the role of nitric oxide (NO) formed from nitrite in mediating the response to GTN in the pulmonary vascular bed is uncertain. The purpose of the present study was to determine if nitrite plays a role in mediating vasodilator responses to GTN. In this study, intravenous injections of GTN and sodium nitrite decreased pulmonary and systemic arterial pressures and increased cardiac output. The decreases in pulmonary arterial pressure under baseline and elevated tone conditions and decreases in systemic arterial pressure in response to GTN and sodium nitrite were attenuated by cyanamide, an ALDH2 inhibitor, whereas responses to the NO donor, sodium nitroprusside (SNP), were not altered. The decreases in pulmonary and systemic arterial pressure in response to GTN and SNP were not altered by allopurinol, an inhibitor of xanthine oxidoreductase, whereas responses to sodium nitrite were attenuated. GTN was ϳ1,000-fold more potent than sodium nitrite in decreasing pulmonary and systemic arterial pressures. These results suggest that ALDH2 plays an important role in the bioactivation of GTN and nitrite in the pulmonary and systemic vascular beds and that the reduction of nitrite to vasoactive NO does not play an important role in mediating vasodilator responses to GTN in the intact chest rat. mitochondrial aldehyde dehydrogenase; xanthine oxidoreductase; nitric oxide; glyceryl trinitrate; sodium nitrite; sodium nitroprusside; allopurinol; cyanamide; U-46619; N G -nitro-L-arginine methyl ester GLYCERYL TRINITRATE (GTN) and, to a lesser extent, amyl nitrite have been used in the treatment of angina and heart failure for more than a century (4, 5, 38). However, the molecular mechanism by which GTN relaxes vascular smooth muscle is still the subject of current investigation and remains unknown. Although it is well established that nitric oxide (NO) activates soluble guanylyl cyclase, increases cGMP formation, and relaxes vascular smooth muscle, the role of NO release in mediating the vasorelaxant response to GTN is uncertain (11,17,21,26,30,37,39). Although studies in the literature provide evidence that NO is released from GTN, other studies show that NO is not released and suggest that the activation of guanylyl cyclase is mediated by a closely related but not currently identified chemical species with NO-guanylyl cyclase stimulating properties (2, 11, 16, 23, 25, 29 -31, 36, 39). There is substantial evidence in the literature that mitochondrial aldehyde dehydrogenase (ALDH2) plays an i...

Advances in Blood Pressure Genomics

“…76 In contrast, antihypertensive molecules, such as Amyl Nitrite, are known to be ALDH2 agonists with vasodilator effects. 77 Twenty-seven of the 72 genes we identified have no prior support in hypertension and can, therefore, be considered as novel hypertension candidates. Six of these novel candidate genes are potentially druggable, determined using the Chembl database; https://www.ebi.ac.uk/chembl/.…”

Short-term hypoxic vasodilationin vivois mediated by bioactive nitric oxide metabolites, rather than free nitric oxide derived from haemoglobin-mediated nitrite reduction

“…ii) systemic vasoconstriction, using an intravenous infusion of norepinephrine at a rate of 1.5 µg/kg/min iii) NOS inhibition, where animals received a 1.5 mg/kg/min infusion of the potent, nonselective NOS inhibitor S-ethyl-isothiourea (SEITU) (Southan et al, 1995); iv) nitrite (NO 2 -) administration, where animals received a 250 µg/kg/min infusion of sodium nitrite, NaNO 2 (Badejo et al, 2010); v) a combination of NOS inhibition with SEITU, and NaNO 2 administration (doses as above); vi) non-haem NO scavenging, using an infusion of the scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (C-PTIO) (Yoshida et al, 1994) running at 0.17 mg/kg/min;…”

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

“…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. However, no direct comparison between GTN and ISDN in vivo with an ALDH2 inhibitor has been reported previously, although cyanamide has been used clinically for many years.…”