The Vasodilating Effect of Acetazolamide and Dorzolamide Involves Mechanisms Other Than Carbonic Anhydrase Inhibition

Torring, Maria Skytte; Holmgaard, Kim; Hessellund, Anders; Aalkjær, Christian; Bek, Toke

doi:10.1167/iovs.08-2435

Cited by 41 publications

(42 citation statements)

References 24 publications

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“…However, they are also responsible for dilation of the blood vessels in the retina and optic nerve head. 132 Indeed, CA inhibitors are clinically used as antiglaucoma drugs. However, some other compounds being developed as antitumor agents/diagnostic tools for tumors, antiobesity agents, anticonvulsants, and antimicrobials/antifungals agents.…”

Section: Inhibitors Of Carbonic Anhydrasementioning

confidence: 99%

Structure, function and applications of carbonic anhydrase isozymes

Hassan

Shajee

Waheed

et al. 2013

Bioorganic & Medicinal Chemistry

202

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Section: Inhibitors Of Carbonic Anhydrasementioning

confidence: 99%

Structure, function and applications of carbonic anhydrase isozymes

Hassan

Shajee

Waheed

et al. 2013

Bioorganic & Medicinal Chemistry

202

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“…2001; Torring et al. 2009), NMA may have vasodilatory effects on cerebral vessels. While the mechanism for HPV inhibition remains unknown, in the systemic circulation the data point to a likely activation of Ca 2+ -activated potassium (BK) channels (Pickkers et al.…”

Section: Discussionmentioning

confidence: 99%

“…2001), in porcine retinal arterioles (Torring et al. 2009), in rat skeletal muscle cells (Tricarico et al. 2000), hypoxic pulmonary vasoconstriction (HPV) in the dog and human (Hohne et al.…”

Section: Introductionmentioning

confidence: 99%

The noncarbonic anhydrase inhibiting acetazolamide analog N -methylacetazolamide reduces the hypercapnic, but not hypoxic, ventilatory response

Teppema

Swenson

2015

Physiol Rep

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Previous studies have shown that the carbonic anhydrase (CA) inhibitors acetazolamide (AZ) and methazolamide (MZ) have inhibiting actions on breathing. Classically these have been attributed to CA inhibition, but other effects unrelated to CA inhibition have been identified in other tissues. To explore this possibility in the control of ventilation by the central nervous system, we investigated whether an AZ-analog without CA inhibiting properties, by virtue of a single methylation on the sulfonamide moiety, N-methylacetazolamide (NMA), would still display similar actions to acetazolamide and methazolamide. NMA (20 mg kg−1) was given intravenously to anesthetized cats and we measured the responses to steady-state isocapnic hypoxia and stepwise changes in end-tidal pco2 before and after infusion of this AZ analog using the technique of end-tidal forcing. NMA caused a large decrease in the apneic threshold and CO2 sensitivity very similar to those previously observed with AZ and MZ, suggesting that these effects are mediated independently of CA inhibition. In contrast to acetazolamide, but similar to methazolamide, NMA did not affect the steady-state isocapnic hypoxic response. In conclusion, our data reveal complex effects of sulfonamides with very similar structure to AZ that reveal both CA-dependent and CA-independent effects, which need to be considered when using AZ as a probe for the role of CA in the control of ventilation.

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“…Clearly, our results showed that 1) AZ decreased vascular resistance through eNOS activation; and 2) the AZ vasodilator effect is correlated with CA inhibition. In the literature, the mechanism of AZ-induced vasodilatation is controversial because in some cases, it was shown to be independent of eNOS activation (Kiss et al, 1999); in others, AZ increased NO production through eNOS activation (Tuettenberg et al, 2001;An et al, 2013) and others showed that AZ-induced vasodilation is independent of CA inhibition (Hohne et al, 2007;Torring et al, 2009). Recently, Aamand et al have shown that CA II is able to generate vasoactive NO from nitrite at high rates and with no strict requirement for low O 2 (Aamand et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Acetazolamide Protects Steatotic Liver Grafts against Cold Ischemia Reperfusion Injury

Béjaoui

Pantazi

Luca

et al. 2015

J Pharmacol Exp Ther

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Ischemia reperfusion injury (IRI) is a primary concern in liver transplantation, especially when steatosis is present. Acetazolamide (AZ), a specific carbonic anhydrase (CA) inhibitor, has been suggested to protect against hypoxia. Here, we hypothesized that AZ administration could be efficient to protect fatty livers against cold IRI. Obese Zucker rat livers were preserved in Institut Georges Lopez-1 storage solution for 24 hours at 4°C and ex vivo perfused for 2 hours at 37°C. Alternatively, rats were also treated with intravenous injection of AZ (30 mg/kg) before liver recovery. Liver injury, hepatic function, and vascular resistance were determined. CA II protein levels and CA hydratase activity were assessed as well as other parameters involved in IRI (endothelial nitric oxide synthase, mitogen activated protein kinase family, hypoxic inducible factor 1 alpha, and erythropoietin). We demonstrated that AZ administration efficiently protects the steatotic liver against cold IRI. AZ protection was associated with better function, decreased vascular resistance, and activation of endothelial nitric oxide synthase. This was consistent with an effective mitogen activated protein kinase inactivation. Finally, no effect on the hypoxic inductible factor 1 alpha/erythropoietin pathway was observed. The present study demonstrated that AZ administration is a suitable pharmacological strategy for preserving fatty liver grafts against cold IRI.

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The Vasodilating Effect of Acetazolamide and Dorzolamide Involves Mechanisms Other Than Carbonic Anhydrase Inhibition

Abstract: The vasodilating effect of carbonic anhydrase inhibitors on porcine retinal arterioles depends on the perivascular retinal tissue and acidosis, but not on hypercapnia. The effect involves mechanisms other than carbonic anhydrase inhibition.

Cited by 41 publications

References 24 publications

Structure, function and applications of carbonic anhydrase isozymes

Structure, function and applications of carbonic anhydrase isozymes

The noncarbonic anhydrase inhibiting acetazolamide analog N -methylacetazolamide reduces the hypercapnic, but not hypoxic, ventilatory response

Acetazolamide Protects Steatotic Liver Grafts against Cold Ischemia Reperfusion Injury

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