Pulmonary vasodilation by acetazolamide during hypoxia is unrelated to carbonic anhydrase inhibition.
Acute hypoxic pulmonary vasoconstriction can be inhibited by high doses of the carbonic anhydrase inhibitor acetazolamide. This study aimed to determine whether acetazolamide is effective at dosing relevant to human use at high altitude and to investigate whether its efficacy against hypoxic pulmonary vasoconstriction is dependent on carbonic anhydrase inhibition by testing other potent heterocyclic sulfonamide carbonic anhydrase inhibitors. Six conscious dogs were studied in five protocols: 1) controls, 2) low-dose intravenous acetazolamide (2 mg.kg(-1).h(-1)), 3) oral acetazolamide (5 mg/kg), 4) benzolamide, a membrane-impermeant inhibitor, and 5) ethoxzolamide, a membrane-permeant inhibitor. In all protocols, unanesthetized dogs breathed spontaneously during the first hour (normoxia) and then breathed 9-10% O(2) for the next 2 h. Arterial oxygen tension ranged between 35 and 39 mmHg during hypoxia in all protocols. In controls, mean pulmonary artery pressure increased by 8 mmHg and pulmonary vascular resistance by 200 dyn.s.cm(-5) (P <0.05). With intravenous acetazolamide, mean pulmonary artery pressure and pulmonary vascular resistance remained unchanged during hypoxia. With oral acetazolamide, mean pulmonary artery pressure increased by 5 mmHg (P < 0.05), but pulmonary vascular resistance did not change during hypoxia. With benzolamide and ethoxzolamide, mean pulmonary artery pressure increased by 6-7 mmHg and pulmonary vascular resistance by 150-200 dyn.s.cm(-5) during hypoxia (P < 0.05). Low-dose acetazolamide is effective against acute hypoxic pulmonary vasoconstriction in vivo. The lack of effect with two other potent carbonic anhydrase inhibitors suggests that carbonic anhydrase is not involved in the mediation of hypoxic pulmonary vasoconstriction and that acetazolamide acts on a different receptor or channel.
Höhne
Claudia
C
Klinik für Anaesthesiologie und operative Intensivmedizin, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum und Campus Mitte, Augustenburger Platz 1, D-13353 Berlin, Germany. claudia.hoehne@charite.de
Pickerodt
Philipp A
PA
Francis
Roland C
RC
Boemke
Willehad
W
Swenson
Erik R
ER
D000086:Acetazolamide / Q000008:administration & dosage / Q000494:pharmacology*; D000136:Acid-Base Equilibrium / Q000187:drug effects; D000532:Altitude Sickness / Q000188:drug therapy / Q000503:physiopathology; D000818:Animals; D001574:Benzolamide / Q000494:pharmacology; D002257:Carbonic Anhydrase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004285:Dogs; D005016:Ethoxzolamide / Q000494:pharmacology; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000188:drug therapy* / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects; D008168:Lung / Q000098:blood supply* / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology
D002257:Carbonic Anhydrase Inhibitors; D014665:Vasodilator Agents; D001574:Benzolamide; D000086:Acetazolamide; D005016:Ethoxzolamide