Carbonic anhydrase inhibitors modify intracellular pH transients and contractions of rat middle cerebral arteries during CO₂/HCO₃^- fluctuations.

ABSTRACT: The CO₂/HCO₃^- buffer minimizes pH changes in response to acid-base loads, HCO₃^- provides substrate for Na⁺,HCO₃^--cotransporters and Cl^-/HCO₃^--exchangers, and H⁺ and HCO₃^- modify vasomotor responses during acid-base disturbances. We show here that rat middle cerebral arteries express cytosolic, mitochondrial, extracellular, and secreted carbonic anhydrase isoforms that catalyze equilibration of the CO₂/HCO₃^- buffer. Switching from CO₂/HCO₃^--free to CO₂/HCO₃^--containing extracellular solution results in initial intracellular acidification due to hydration of CO₂ followed by gradual alkalinization due to cellular HCO₃^- uptake. Carbonic anhydrase inhibition decelerates the initial acidification and attenuates the associated transient vasoconstriction without affecting intracellular pH or artery tone at steady-state. Na⁺,HCO₃^--cotransport and Na⁺/H⁺-exchange activity after NH₄⁺-prepulse-induced intracellular acidification are unaffected by carbonic anhydrase inhibition. Extracellular surface pH transients induced by transmembrane NH₃ flux are evident under CO₂/HCO₃^--free conditions but absent when the buffer capacity and apparent H⁺ mobility increase in the presence of CO₂/HCO₃^- even after the inhibition of carbonic anhydrases. We conclude that (a) intracellular carbonic anhydrase activity accentuates pH transients and vasoconstriction in response to acute elevations of pCO₂, (b) CO₂/HCO₃^- minimizes extracellular surface pH transients without requiring carbonic anhydrase activity, and (c) carbonic anhydrases are not rate limiting for acid–base transport across cell membranes during recovery from intracellular acidification.

SUBMITTER: Rasmussen JK 

PROVIDER: S-EPMC5851140 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature