Role of aldehyde dehydrogenase in hypoxic vasodilator effects of nitrite in rats and humans

Abstract

Background and PurposeHypoxic conditions favour the reduction of nitrite to nitric oxide (NO) to elicit vasodilatation, but the mechanism(s) responsible for bioconversion remains ill defined. In the present study, we assess the role of aldehyde dehydrogenase 2 (ALDH2) in nitrite bioactivation under normoxia and hypoxia in the rat and human vasculature.Experimental ApproachThe role of ALDH2 in vascular responses to nitrite was studied using rat thoracic aorta and gluteal subcutaneous fat resistance vessels from patients with heart failure (HF; 16 patients) in vitro and by measurement of changes in forearm blood flow (FBF) during intra-arterial nitrite infusion (21 patients) in vivo. Specifically, we investigated the effects of (i) ALDH2 inhibition by cyanamide or propionaldehyde and the (ii) tolerance-independent inactivation of ALDH2 by glyceryl trinitrate (GTN) on the vasodilator activity of nitrite. In each setting, nitrite effects were measured via evaluation of the concentration–response relationship under normoxic and hypoxic conditions in the absence or presence of ALDH2 inhibitors.Key ResultsBoth in rat aorta and human resistance vessels, dilatation to nitrite was diminished following ALDH2 inhibition, in particular under hypoxia. In humans there was a non-significant trend towards attenuation of nitrite-mediated increases in FBF.Conclusions and ImplicationsIn human and rat vascular tissue in vitro, hypoxic nitrite-mediated vasodilatation involves ALDH2. In patients with HF in vivo, the role of this enzyme in nitrite bioactivation is at the most, modest, suggesting the involvement of other more important mechanisms.

Nitrite-mediated renal vasodilatation is increased during ischemic conditions via cGMP-independent signaling

“…Cyanamide, an ALDH inhibitor, only slightly attenuated the nitrite effect. Recently Arif and colleagues reported, both in human resistance vessels and in rat aorta, that nitrite-mediated vasodilatation during hypoxia involved ALDH2 [11]. A possible explanation for the different conclusion in our study may be related to different characteristics of the renal vasculature.…”

“…Administration of inorganic nitrate or nitrite to humans and rodents is linked to enhanced NO-like bioactivity such as vasodilatation, increased blood flow, reduction in blood pressure, and generation of cGMP [2][3][4][5]. A handful of enzymatic and nonenzymatic pathways have been demonstrated to catalyze nitrite reduction to NO in blood and tissues, including deoxyhemoglobin and deoxymyoglobin [6,7], aldehyde oxidase (AO) [8], aldehyde dehydrogenase (ALDH) [9][10][11], xanthine oxidoreductase (XOR) [12,13], and endothelial NO synthase (NOS) [14]. Nitrite has enhanced bioactivity at low oxygen tensions and under acidic conditions [6,15,16], and studies have demonstrated a protective effect of this anion in ischemia-reperfusion injury [17,18].…”

Modulation of the orthostatic blood pressure response by acute nitrate consumption is dependent upon ethnic origin

“…In contrast, for SE Asian subjects, consumption of nitrate had no effect on either DP or HR, suggesting no reduction in cardiac work following nitrate supplementation. What is unclear from our data is whether these observations represent a direct effect of the nitrate or whether the nitrate required biotransformation to an active species in order to demonstrate vascular activity …”

“…Commensal bacteria reduce dietary nitrate to nitrite in the buccal cavity. This nitrite then undergoes further reduction to NO through the actions of aldehyde dehydrogenase 2 (ALDH2) . This mechanism is given further support as ALDH2 transcript was found within the intimal layer of blood vessels close to the site of NO activity.…”

“…Given the potential contribution of ALDH2 for the conversion of nitrite to NO, subjects presenting with mutations in ALDH2 leading to low activity would be less likely to benefit from hypotensive effects of dietary nitrate. SE Asian populations have previously been noted to possess a high incidence of mutations in ALDH2, characterised by poor tolerance of alcohol …”