Possible obligatory functions of cyclic nucleotides in hypercapnia-inducedcerebral vasodilation in adult rats

Current evidence suggests that nitric oxide (NO) and vasodilating prostanoi ds, possibly via the actions of cGMP and cAMP, play permissive roles in hyp ercapnic cerebral vasodilation. The present study examined whether cGMP and cAMP have obligatory functions in hypercapnia. Using a closed cranial wind ow in adult rats, we measured pial arteriolar diameters and periarachnoid c erebrospinal fluid (pCSF) cyclic nucleotide levels during normo- and hyperc apnia and in the presence or absence of inhibitors of neuronal NO synthase (nNOS) or cyclooxygenase (COX). Also, we measured cGMP and cAMP contents in primary neuronal and astrocyte cultures, at different levels of CO2. Hyper capnia (arterial PCO2 65 mmHg)-induced pial arteriolar dilation was accompa nied by 70-80% elevations in pCSF cGMP and cAMP. Inhibition of nNOS with 7- nitroindazole (7-NI) significantly reduced both the CO2-induced arteriolar dilation (by 77%) and the pCSF cGMP and cAMP increases (by 60-70%). inhibit ion of COX with indomethacin reduced arteriolar CO2 reactivity (by 83%) and pCSF cyclic nucleotide increases (by 80-100%). In neuronal cultures a tran sient NO-dependent increase in cGMP, but not cAMP, was seen when the CO2 le vel was raised from 5 to 14%. No changes were seen in astrocytes. The 7-NI and indomethacin-inhibitable increases in pial arteriolar diameter and cycl ic nucleotide production during hypercapnia suggest a link between these tw o responses. One possible, although not exclusive, interpretation of these findings is that the cyclic nucleotides have an obligatory function in the CO2 response. The large overlap in the abilities of nNOS and COX inhibitors to elicit those effects further implies interactions ("cross talk") betwee n the cGMP and cAMP vasodilating pathways. The in vitro data suggest that h ypercapnia stimulates NO production in neurons.