Carbonic anhydrase I inhibition by nitric oxide: Implications for mediation of the hypercapnia-induced vasodilator response

1. At present, CO2 is considered to be the most important factor in regulat ing cerebral blood flow by modification of the interstitial fluid and extra cellular pH, but the mechanism by which hypercapnia produces vasodilation i s still controversial. In the present paper we investigated the effect of h ypercapnia on carbonic anhydrase (CA) activity. We also studied the combine d effects of CO2 with either indomethacin or an L-arginine analogue on CA a ctivity. 2. Nine groups of 12 rabbits each were established. Groups 1-4 were ventila ted with a mixture of 10% CO2, 21% O-2 and 69% N-2 for 20, 60, 120 and 180 min. Group 5 rabbits received 15 mg/kg bodyweight, i.v., indomethacin and, after 1 h, were ventilated with a mixture of 10% CO2, 21% O-2 and 69% N-2 f or 2 h. Group 6 animals were ventilated with a mixture of 10% CO2, 21% O-2 and 69% N-2 for 2 h and then received indomethacin. Group 7 rabbits receive d 100 mg/kg bodyweight, i.v., N-G-monomethyl-L-arginine (L-NMMA) and, after 1 h, were ventilated with a mixture of 10% CO2, 21% O-2 and 69% N-2 for 2 h. Group 8 rabbits were ventilated for 2 h with a mixture of 10% CO2, 21% O -2 and 69% N-2 and were then administered L-NMMA. Group 9 rabbits received L-NMMA treatment concomitant with ventilation for 2 h with a mixture of 10% CO2, 21% O-2 and 69% N-2. In all groups, the erythrocyte CA activity was m easured, as well as PaCO2 before and after ventilation or treatment. 3. The present study shows that CO2 reduces CA I activity down to complete inhibition and antagonizes the activating effects of indomethacin and L-NMM A on this isozyme. Our data prove that nitric oxide- and prostaglandin-indu ced CA I inhibition is involved in the vasodilation produced by hyper-capni a. These results suggest that, due to subsequent pH changes, CA I is direct ly implicated in the modulation of vascular processes in the organism.