Carbonic anhydrase inhibitors modify intracellular pH transients and contractions of rat middle cerebral arteries during CO2/HCO3-fluctuations.
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 CO2followed 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 NH3flux 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.
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Jacob K
JK
Rasmussen
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Ebbe
E
Boedtkjer
D000137:Acid-Base Imbalance / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D002245:Carbon Dioxide / Q000378:metabolism*; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D008297:Male; D020768:Middle Cerebral Artery / Q000187:drug effects*; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D014661:Vasoconstriction
D001639:Bicarbonates; D002257:Carbonic Anhydrase Inhibitors; D002245:Carbon Dioxide; D002256:Carbonic Anhydrases; C477051:carbonic anhydrase VI
Basic science; experimental; pH; physiology; smooth muscle; vascular biology