Calcium-dependent and ATP-sensitive potassium channels and the 'permissive' function of cyclic GMP in hypercapnia-induced pial arteriolar relaxation.

The conclusion that cyclic 3'-5 guanosine monophosphate (cGMP) functions in a 'permissive' manner in promoting cerebrovasodilation during hypercapnia was based on findings showing that the nitric oxide synthase (NOS) inhibitor-induced repression of the CO2 response could be reversed upon addition of exogenous cGMP. We hypothesized that the action of cGMP revealed in those studies does not define its normal role in hypercapnic cerebral vasodilation, but rather is a unique function of the artificial situation of NOS inhibition coupled with cGMP repletion. Thus, although CO2 reactivity may be the same in normal versus cGMP-repleted animals, the factors contributing to that response may differ. To test that possibility, the effects of calcium-dependent (KCa) or ATP-sensitive (KATP) potassium channel blockers on pial arteriolar CO2 reactivity, in vivo, were evaluated in the presence and absence of NOS inhibition plus administration of a cGMP analogue. Pial arteriolar diameter changes in hypercapnia were measured in three principal groups of anesthetized rats: (I) KCa channel-inhibited (via iberiotoxin); (II) KATP channel-inhibited (via glibenclamide); and (III) controls. Group I and II rats were further divided into: (a) those treated with the neuronal NOS (nNOS) inhibitor, 7-nitroindazole (7-NI), followed by successive suffusions of the cGMP analogue, 8-bromo-cGMP (8Br-cGMP) and 8Br-cGMP+K-channel blocker; and (b) rats where 7-NI and 8Br-cGMP applications were omitted. Group III rats were divided into time and 8Br-cGMP controls. Hypercapnia (PCO2 congruent with60 mmHg, 3 min)-induced dilations were reduced by 70-80% following 7-NI and restored by 8Br-cGMP. That restoration was reversed by both K-channel blockers. In the absence of 7-NI and exogenous cGMP, CO2 reactivity was unaffected by K-channel inhibition. These findings confirmed that nNOS-derived NO is critically important to the hypercapnic reactivity of cerebral arterioles, and that cGMP repletion, following NOS inhibition, could restore CO2 reactivity. The observation that KCa and KATP channel blockade did not alter CO2 reactivity under baseline conditions, but attenuated CO2 reactivity only in the presence nNOS inhibition (and cGMP repletion), suggests that multiple, redundant, and interactive mechanisms participate in CO2-induced vasodilation. These results also imply that current strategies for revealing permissive actions of cGMP (or NO) may need to be re-evaluated.