COMPARISON OF THE EFFECTS OF N(G)-NITRO-L-ARGININE AND INDOMETHACIN ON THE HYPERCAPNIC CEREBRAL BLOOD-FLOW INCREASE IN RATS

The effects of N(G)-nitro-L-arginine (NOLAG), an inhibitor of nitric o xide synthase (NOS), and of indomethacin, an inhibitor of cyclooxygena se, on the rise in cerebral blood flow (CBF) accompanying increasing l evels of hypercapnia (paCO2 = 40-135 mmHg) were studied in anesthetize d rats. CBF was measured by intracarotid injection of Xe-133. Progress ive increases in paCO2 of 10 mmHg, at intervals of about 8-10 minutes, were associated with gradual increases in CBF until a paCO2 level of 115 mmHg was reached. No further CBF changes (from the maximum value o f 446 +/- 70 ml 100 g-1 min-1) were seen with additional step increase in paCO2. Intracarotid infusion of 7.5 mg/kg NOLAG significantly atte nuated the CO2-elicited CBF increase by about 45-65% at paCO2 values b elow 115 mmHg. Beyond this level, there was a lesser inhibition of abo ut 27-35%. 30 mg/kg NOLAG had essentially the same effect as 7.5 mg/kg NOLAG. 50 mg/kg NOLAG, given intraperitoneally (i.p.) twice daily for 4 days, also caused an attenuated CBF response to CO2, but the inhibi tory effect was significantly less than with acute NOLAG administratio n in the paCO2 range of 61-90 mmHg. Infusion Of L-arginine, 1 g/kg/h, prevented the effect of 7.5 mg/kg NOLAG. Indomethacin, 10 mg/kg, i.v. produced a more dramatic attenuation of the response, to the extent th at the steady rising curve of CBF as a function of paCO2 was almost co mpletely abolished. With indomethacin, a moderate increase (50%) in CB F was seen at the lowest level of hypercapnia, but raising paCO2 above this level did not result in further increases in CBF. This effect co uld not be prevented by L-arginine. When combining 7.5 mg/kg NOLAG wit h 10 mg/kg indomethacin, the response to hypercapnia was totally block ed. The results suggest that NOLAG and indomethacin act through differ ent mechanisms on the hypercapnic CBF response, and that indomethacin is the more powerful inhibitor.