Pulmonary vasodilation by acetazolamide during hypoxia is unrelated to carbonic anhydrase inhibition

Höhne, Claudia; Pickerodt, Philipp A.; Francis, Roland C. E.; Boemke, Willehad; Swenson, Erik R.

doi:10.1152/ajplung.00205.2006

Cited by 47 publications

(34 citation statements)

References 15 publications

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“…Acetazolamide has been reported to attenuate hypoxic pulmonary vasoconstriction by modulating Ca 21 responses independently of carbonic anhydrase inhibition (33,34). Our data contrast with previous reports in which acetazolamide increased subretinal fluid absorption in rabbits, but these effects may have been due to its systemic effects involving the adrenergic pathway (30).…”

Section: Discussioncontrasting

confidence: 99%

Carbonic Anhydrase II and Alveolar Fluid Reabsorption during Hypercapnia

Chen¹,

Lecuona²,

Briva³

et al. 2008

Am J Respir Cell Mol Biol

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IllinoisCarbonic anhydrase II (CAII) plays an important role in carbon dioxide metabolism and intracellular pH regulation. In this study, we provide evidence that CAII is expressed in both type I (AECI) and type II (AECII) alveolar epithelial cells by RT-PCR and Western blotting in freshly isolated rat cells. These results were further confirmed by double immunostaining with CAII antibodies and AECI-or AECII-specific markers in freshly isolated alveolar epithelial cells and rat lung tissues. Inhibition of CAII by acetazolamide or methazolamide delayed the decrease in the intracellular pH observed during hypercapnia in cultured AECI, AECII, and AECI-like cells. In an isolated-perfused rat lung model, alveolar fluid reabsorption significantly decreased during high CO 2 exposure, which was not prevented by carbonic anhydrase inhibition. Thus, we provide evidence that CAII is expressed in rat alveolar epithelial cells and does not regulate lung alveolar fluid reabsorption during hypercapnia.

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Section: Discussioncontrasting

confidence: 99%

Carbonic Anhydrase II and Alveolar Fluid Reabsorption during Hypercapnia

Chen¹,

Lecuona²,

Briva³

et al. 2008

Am J Respir Cell Mol Biol

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“…For ACTZ, vasodilatation at various locations in the systemic circulation could be demonstrated, in humans already occurring at low doses (31), whereby evidence is strengthened that ACTZ exerts a direct vasodilator effect mediated by vascular K Ca channel activation (22). On the other hand, MTZ was not able to counteract hypoxic pulmonary vasoconstriction, as did ACTZ by inhibiting the rise of intracellular [Ca 2ϩ ] in pulmonary artery smooth muscle cells (11,25). Thus, at least in the pulmonary vascular bed and under hypoxic conditions a vasodilator effect independent of CA inhibition seems to be lacking for MTZ.…”

Section: Discussionmentioning

confidence: 99%

“…ACTZ is also widely used against acute mountain sickness (1,18,29), most likely because it is able to reduce hypoxic pulmonary vasoconstriction and to prevent high-altitude pulmonary edema (2,32). However, there is growing evidence from recent studies in different species that ACTZ may prevent hypoxic pulmonary vasoconstriction entirely independent of carbonic anhydrase inhibition (11) and rather may diminish the hypoxia-induced rise in intracellular Ca 2ϩ in pulmonary arterial smooth muscle cells (25).…”

mentioning

confidence: 99%

Methazolamide does not impair respiratory work performance in anesthetized rabbits

Kiwull-Schöne¹,

Li²,

Kiwull³

et al. 2009

American Journal of Physiology-Regulatory, Integrative and Comp

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Kiwull-Schöne HF, Li Y, Kiwull PJ, Teppema LJ. Methazolamide does not impair respiratory work performance in anesthetized rabbits. Am J Physiol Regul Integr Comp Physiol 297: R648-R654, 2009. First published June 24, 2009 doi:10.1152/ajpregu.00134.2009.-In human medicine, the carbonic anhydrase (CA) inhibitor acetazolamide is used to treat irregular breathing disorders. Previously, we demonstrated in the rabbit that this substance stabilized closed-loop gain properties of the respiratory control system, but concomitantly weakened respiratory muscles. Among others, the highly diffusible CA-inhibitor methazolamide differs from acetazolamide in that it fails to activate Ca 2ϩ -dependent potassium channels in skeletal muscles. Therefore, we aimed to find out, whether or not methazolamide may exert attenuating adverse effects on respiratory muscle performance as acetazolamide. In anesthetized spontaneously breathing rabbits (n ϭ 7), we measured simultaneously the CO 2 responses of tidal phrenic nerve activity, tidal transpulmonary pressure changes, and tidal volume before and after intravenous application of methazolamide at two mean (Ϯ SE) cumulative doses of 3.5 Ϯ 0.1 and 20.8 Ϯ 0.4 mg/kg. Similar to acetazolamide, low-and high-dose methazolamide enhanced baseline ventilation by 52 Ϯ 10% and 166 Ϯ 30%, respectively (P Ͻ 0.01) and lowered the base excess in a dose-dependent manner by up to 8.3 Ϯ 0.9 mmol/l (P Ͻ 0.001). The transmission of a CO2-induced rise in phrenic nerve activity into volume and/or pressure and, hence, respiratory work performance was 0.27 Ϯ 0.05 ml ⅐ kg Ϫ1 ⅐ kPa ⅐ unit Ϫ1 under control conditions, but remained unchanged upon low-or high-dose methazolamide, at 0.30 Ϯ 0.06 and 0.28 Ϯ 0.07 ml ⅐ kg Ϫ1 ⅐ kPa ⅐ unit Ϫ1 , respectively. We conclude that methazolamide does not cause respiratory muscle weakening at elevated levels of ventilatory drive. This substance (so far not used for medication of respiratory diseases) may thus exert stabilizing influences on breathing control without adverse effects on respiratory muscle function. control of breathing; metabolic acidosis; acetazolamide; neuromuscular coupling IN CARDIO-RESPIRATORY MEDICINE, the carbonic anhydrase (CA) inhibitor acetazolamide (ACTZ) is known for beneficial effects in patients with central sleep apnea (12,41). Furthermore, it is used to improve blood gases in obstructive lung disease and to restore acid-base values in metabolic alkalosis, reviewed by (30). ACTZ is also widely used against acute mountain sickness (1, 18, 29), most likely because it is able to reduce hypoxic pulmonary vasoconstriction and to prevent high-altitude pulmonary edema (2, 32). However, there is growing evidence from recent studies in different species that ACTZ may prevent hypoxic pulmonary vasoconstriction entirely independent of carbonic anhydrase inhibition (11) and rather may diminish the hypoxia-induced rise in intracellular Ca 2ϩ in pulmonary arterial smooth muscle cells (25).Among possible side effects of ACTZ, skeletal muscle weakness and fatigue are...

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“…Another study observed that acetazolamide could act on pulmonary circulation through a decrease in intracellular calcium in smooth muscle cells during an acute hypoxic challenge [28,29]. However this effect of acetazolamide on hypoxic pulmonary vasoconstriction is still under discusion in humans, as FAORO et al [30] failed to reduce it in 10-days acclimatised (3,700-4,700 m above sea level) sea-level natives acutely treated by acetazolamide, suggesting a possible larger effect of acetazolamide on remodelling as compared with pulmonary vasodilation.…”

Section: Pulmonary Vascular Diseasementioning

confidence: 99%

Acetazolamide and chronic hypoxia: effects on haemorheology and pulmonary haemodynamics

et al. 2012

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We tested the effect of acetazolamide on blood mechanical properties and pulmonary vascular resistance (PVR) during chronic hypoxia.Six groups of rats were either treated or not treated with acetazolamide (curative: treated after 10 days of hypoxic exposure; preventive: treated before hypoxic exposure with 40 mg?kg) and either exposed or not exposed to 3 weeks of hypoxia (at altitude .5,500 m). They were then used to assess the role of acetazolamide on pulmonary artery pressure, cardiac output, blood volume, haematological and haemorheological parameters.Chronic hypoxia increased haematocrit, blood viscosity and PVR, and decreased cardiac output. Acetazolamide treatment in hypoxic rats decreased haematocrit (curative by -10% and preventive by -11%), PVR (curative by -36% and preventive by -49%) and right ventricular hypertrophy (preventive -20%), and increased cardiac output (curative by +60% and preventive by +115%). Blood viscosity was significantly decreased after curative acetazolamide treatment (-16%) and was correlated with PVR (r50.87, p,0.05), suggesting that blood viscosity could influence pulmonary haemodynamics. The fall in pulmonary vascular hindrance (curative by -27% and preventive by -45%) after treatment suggests that acetazolamide could decrease pulmonary vessels remodelling under chronic hypoxia.The effect of acetazolamide is multifactorial by acting on erythropoiesis, pulmonary circulation, haemorheological properties and cardiac output, and could represent a pertinent treatment of chronic mountain sickness.

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Pulmonary vasodilation by acetazolamide during hypoxia is unrelated to carbonic anhydrase inhibition

Cited by 47 publications

References 15 publications

Carbonic Anhydrase II and Alveolar Fluid Reabsorption during Hypercapnia

Carbonic Anhydrase II and Alveolar Fluid Reabsorption during Hypercapnia

Methazolamide does not impair respiratory work performance in anesthetized rabbits

Acetazolamide and chronic hypoxia: effects on haemorheology and pulmonary haemodynamics

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