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

Abstract

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 approximately 1,000-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.

Fig. 1.

Bar graphs showing changes in pulmonary and systemic arterial pressures and cardiac output in response to iv injections of glyceryl trinitrate, sodium nitrite, and sodium nitroprusside before and after administration of 25 mg/kg cyanamide iv. n = No. of experiments. *P < 0.05 when control responses (filled bars) are compared with responses after cyanamide treatment (open bars).

Fig. 2.

Bar graphs showing changes in pulmonary and systemic arterial pressures and cardiac output in response to iv injections of glyceryl trinitrate, sodium nitrite, and sodium nitroprusside before and after administration of 25 mg/kg cyanamide iv in experiments in which pulmonary arterial pressure was increased to ∼30 mmHg by iv infusion of U-46619. n = No. of experiments. *P < 0.05 when comparing control responses with responses after cyanamide treatment.

Fig. 3.

Bar graphs showing changes in pulmonary and systemic arterial pressures and cardiac output in response to iv injections of glyceryl trinitrate, sodium nitrite, and sodium nitroprusside before and after administration of 25 mg/kg cyanamide iv in animals treated with N^G-nitro-l-arginine methyl ester (l-NAME) to inhibit endogenous nitric oxide production when comparing responses in l-NAME-treated animals before (filled bars) and after treatment with cyanamide (open bars). n = No. of experiments. *P < 0.05.

Fig. 4.

Bar graphs showing changes in pulmonary and systemic arterial pressures and cardiac output in response to iv injections of glyceryl trinitrate, sodium nitrite, and sodium nitroprusside before (filled bars) and after administration of the xanthine oxidoreductase (XOR) inhibitor allopurinol at 25 mg/kg iv in U-46619-infused animals (open bars). n = No. of experiments. *P < 0.05.

Fig. 5.

Dose-response curves comparing decreases in pulmonary and systemic arterial pressures in response to iv injections of glyceryl trinitrate and sodium nitrite in U-46619-infused animals when doses are expressed on a μmol/kg iv basis. n = No. of experiments.

Fig. 6.

Pathway by which mitochondrial aldehyde dehydrogenase (ALDH2) is postulated to activate glyceryl trinitrate (GTN). The cellular metabolism of GTN by ALDH2 yields 1,2-glyceryl dinitrate (1,2-GDN) and nitrite anion. The results of the present study using cyanamide and allopurinol and comparing the biological activity of GTN and nitrite are consistent with the hypothesis that vasodilator responses to GTN in the intact-chest rat are mediated by the formation of a molecule that activates soluble guanylate cyclase and that the reduction of nitrite to nitric oxide (NO) is not involved.