Pulmonary vasodilation by acetazolamide during hypoxia: impact of methyl-group substitutions and administration route in conscious, spontaneously breathing dogs

Abstract

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.

Safety of carbonic anhydrase inhibitors

“…Whether this is by inhibition of vascular smooth muscle CA per se or by other actions remains unclear and it may be that both CA and other receptors are involved; with the vasculature of different organs having varying properties in this regard. In the pulmonary vasculature [6,91], it appears that a CA inhibition effect is not responsible for pulmonary artery pressure reduction, particularly against the hypertensive effect of hypoxia, because acetazolamide methylated at the sulfonamide nitrogen to form the substituted inactive n-methyl acetazolamide remains fully active as a hypotensive agent, whereas other equally or more potent CA inhibitors such as benzolamide and ethoxzolamide are ineffective [91][92][93][94]. In the systemic circulation, it would appear that vascular CA inhibition may be a contributor along with other possible mechanisms.…”

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

“…2013; Pickerodt et al. 2014), and rat pulmonary arterial smooth muscle cells (PASMC) (Shimoda et al. 2007).…”

“…2007; Pickerodt et al. 2014) and rat PASMC (Shimoda et al. 2007), AZ inhibits HPV and hypoxia-mediated elevations in cytosolic calcium, respectively, while two other potent CA inhibitors, benzolamide and ethoxzolamide, structurally dissimilar in their heterocyclic ring structures are ineffective.…”

“…2007) as well as inhibiting HPV in the dog (Pickerodt et al. 2014). Thus, NMA, an acetazolamide analog without CA inhibiting properties, was useful in uncovering a yet unknown mechanism by which AZ reduces the hypoxic response of PASMCs and pulmonary vasculature in vivo.…”

High-Altitude Pulmonary Vascular Diseases

“…Counter to the expectation that dexamethasone would enhance alveolar fluid reabsorption, it did not affect any surrogate measures indicative of upregulation of epithelial sodium channels or sodium-potassium ATPase, 2 of the critical alveolar epithelial membrane ion transporters. By a mechanism unrelated to carbonic anhydrase inhibition, acetazolamide has been shown to be a potent inhibitor of HPV in humans and many other mammals, 50 to reduce HAPE in an animal model, 51 and is used off-label by pediatricians in the Colorado Rockies to prevent reentry HAPE. In addition to its known ventilatory stimulation and diuretic effects, its inhibition of HPV makes it an attractive drug to use prophylactically, but formal studies need to be performed.…”