Pulmonary vasodilation by acetazolamide during hypoxia: impact of methyl-group substitutions and administration route in conscious, spontaneously breathing dogs.
Acetazolamide (ACZ) prevents hypoxic pulmonary vasoconstriction (HPV) in isolated lungs, animals, and humans, but not by carbonic anhydrase (CA) inhibition. We studied administration routes in, and certain structural aspects of, ACZ critical to HPV inhibition. Analogs of ACZ during acute hypoxia were tested in unanesthetized dogs. Dogs breathed normoxic gas for 1 h (inspired O2 fraction = 0.21), followed by 10% O2 for 2 h (hypoxia) in these protocols: 1) controls; 2) ACZ intravenously (2 mg · kg(-1) · h(-1)); 3) ACZ orally (5 mg/kg, 12 and 1 h before the experiment); 4) inhaled ACZ (750 mg); 5) methazolamide (MTZ) intravenously (3 mg · kg(-1) · h(-1)); and 6) N-methyl-acetazolamide (NMA) intravenously (10 mg · kg(-1) · h(-1)). In controls, mean pulmonary arterial pressure (MPAP) increased 7 mmHg, and pulmonary vascular resistance (PVR) 224 dyn · s · cm(-5) with hypoxia (P < 0.05). With intravenous and inhaled ACZ, MPAP and PVR did not change during hypoxia. With oral ACZ, HPV was only slightly suppressed; MPAP increased 5 mmHg and PVR by 178 dyn · s · cm(-5) during hypoxia. With MTZ and NMA, the MPAP rise (4 ± 2 mmHg) was reduced, and PVR did not increase during hypoxia compared with normoxia (MTZ intravenous: 81 ± 77 and 68 ± 82 dyn · s · cm(-5) with NMA intravenous). Inhaled ACZ prevents HPV, but not without causing systemic CA inhibition. NMA, a compound lacking CA inhibiting effects by methylation at the sulfonamide moiety, and MTZ, a CA-inhibiting analog methylated at the thiadiazole ring, are only slightly less effective than ACZ in reducing HPV.
Department of Anesthesiology and Intensive Care Medicine, Campus Charité Mitte and Campus Virchow-Klinikum, Charité-University Medicine, Berlin, Germany;
Philipp A
PA
Pickerodt
Roland C
RC
Francis
Claudia
C
Höhne
Friederike
F
Neubert
Stella
S
Telalbasic
Willehad
W
Boemke
Erik R
ER
Swenson
D000086:Acetazolamide / Q000008:administration & dosage* / Q000737:chemistry; D000280:Administration, Inhalation; D000284:Administration, Oral; D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects; D002257:Carbonic Anhydrase Inhibitors / Q000008:administration & dosage / Q000737:chemistry; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D000860:Hypoxia / Q000201:enzymology / Q000503:physiopathology*; D007262:Infusions, Intravenous; D008745:Methylation; D011651:Pulmonary Artery / Q000187:drug effects* / Q000503:physiopathology; D012119:Respiration; D013329:Structure-Activity Relationship; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000008:administration & dosage* / Q000737:chemistry
D002257:Carbonic Anhydrase Inhibitors; D014665:Vasodilator Agents; D000086:Acetazolamide
N-methyl-acetazolamide; acetazolamide; hypoxic pulmonary vasoconstriction; pulmonary arterial pressure; pulmonary vascular resistance