Dietary nitrate facilitates an acetazolamide-induced increase in cerebral blood flow during visual stimulation

Abstract

Aamand R, Ho YL, Dalsgaard T, Roepstorff A, Lund TE. Dietary nitrate facilitates an acetazolamide-induced increase in cerebral blood flow during visual stimulation. J Appl Physiol 116: 267-273, 2014. First published December 12, 2013 doi:10.1152/japplphysiol.00797.2013The carbonic anhydrase (CA) inhibitor acetazolamide (AZ) is used routinely to estimate cerebrovascular reserve capacity in patients, as it reliably increases cerebral blood flow (CBF). However, the mechanism by which AZ accomplishes this CBF increase is not entirely understood. We recently discovered that CA can produce nitric oxide (NO) from nitrite, and that AZ enhances this NO production in vitro. In fact, this interaction between AZ and CA accounted for a large part of AZ's vasodilatory action, which fits well with the known vasodilatory potency of NO. The present study aimed to assess whether AZ acts similarly in vivo in the human cerebrovascular system. Hence, we increased or minimized the dietary intake of nitrate in 20 healthy male participants, showed them a full-field flickering dartboard, and measured their CBF response to this visual stimulus with arterial spin labeling. Doing so, we found a significant positive interaction between the dietary intake of nitrate and the CBF modulation afforded by AZ during visual stimulation. In addition, but contrary to studies conducted in elderly participants, we report no effect of nitrate intake on resting CBF in healthy human participants. The present study provides in vivo support for an enhancing effect of AZ on the NO production from nitrite catalyzed by CA in the cerebrovascular system. Furthermore, our results, in combination with the results of other groups, indicate that nitrate may have significant importance to vascular function when the cerebrovascular system is challenged by age or disease.nitrate; cerebral blood flow; nitric oxide; acetazolamide ACETAZOLAMIDE (AZ) IS WELL known to increase cerebral blood flow (CBF) and is used routinely to estimate cerebrovascular reserve capacity (CVRC) in patients (13, 32). However, the mechanism by which AZ accomplishes this CBF increase is not entirely understood (35). AZ is an inhibitor of the ubiquitous enzyme carbonic anhydrase (CA), which normally catalyzes the reversible hydration of CO 2 (CO 2 ϩ H 2 O ↔ H 2 CO 3 ↔ HCO 3 Ϫ ϩ H ϩ ). CA is thus an integral part of the system that rids the body of the CO 2 produced in tissues (26). For the same reason, CA also acts to equilibrate the pH transients occurring, e.g., upon metabolic activity. The effect of AZ is usually assumed to be linked to cerebral acidosis caused by an AZ-induced increase in the cerebral partial pressure of CO 2 (PCO 2 ) (5).We recently discovered that CA is also capable of catalyzing the conversion of the endogenous anion nitrite into nitric oxide (NO) (2), a potent vasodilator. In that study, we also attempted to block CA's catalyzation of the NO production by introducing the CA inhibitor AZ to the reaction. However, to our surprise, AZ markedly increased the production of NO ...

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“…Further, reduced NO bioavailability and signaling has been implicated in disrupted neurovascular coupling in which cerebrovascular blood flow is no longer matched to regional metabolic demand, thereby destabilizing neurons, synapses and neurotransmission [ 53 , 56 ]. Consistent with this idea, evidence of improved coupling of blood flow to visual stimuli with co-administration of nitrate and the carbonic anhydrase inhibitor acetazolamide has been shown in young men [ 57 ]. Lastly, in preclinical studies in mice, we have demonstrated that chronic low-grade inflammation, as indicated by elevated tissue expression of pro-inflammatory cytokines, is a major mechanism contributing to vascular and motor dysfunction with aging [ 58 , 59 ], and that sodium nitrite supplementation reverses age-related increases in vascular and skeletal muscle inflammation in these models [ 55 , 59 ].…”

The effect of sodium nitrite infusion on renal function, brachial and central blood pressure during enzyme inhibition by allopurinol, enalapril or acetazolamide in healthy subjects: a randomized, double-blinded, placebo-controlled, crossover study

“…In vitro studies have shown nitrite reducing effects of CA, and suggest a stimulatory effect of acetazolamide on NO generation, despite the inhibition of CO 2 hydration [ 13 , 14 ]. A recent clinical trial found a positive effect of nitrate intake on the increase in visually stimulated cerebral blood flow when injecting acetazolamide in healthy male subjects [ 15 ].…”

Pharmacology and therapeutic role of inorganic nitrite and nitrate in vasodilatation

“…While the former could theoretically provide a convenient way of exporting nitrite-derived NO from RBCs under hypoxic conditions, recent animal experimental results suggest that the majority of hypoxic vasodilatation is not mediated by Hbmediated nitrite reduction (Umbrello et al, 2014). The nitrite reductase activity of carbonic anhydrase appears to be linked to the coupling of cerebral blood flow and metabolic activity in response to visual stimulation (Aamand et al, 1985(Aamand et al, , 2009.…”