Miconazole represses CO2-induced pial arteriolar dilation only under selected circumstances

Previous experimental findings have led to the suggestion that guanosine 3' ,5'-cyclic monophosphate (cGMP) plays a permissive role in hypereapnic cere bral vasodilation. However, we recently reported that the technique used to reveal a permissive role for cGMP [cGMP repletion in the presence of nitri c oxide synthase (NOS) inhibition] created a situation where CO2 reactivity was normalized but where different mechanisms (i.e., K+ channels) particip ated in the response. In the present study, we examined whether that nascen t K+-channel dependence is related in any way to an increase in the influen ce of the miconazole-inhibitable cytochrome P-450 epoxygenase pathway. Usin g intravital microscopy and a closed cranial window system in adult rats, w e measured pial arteriolar diameters during normo- and hypercapnia, first i n the absence and then in the presence of a neuronal NOS (nNOS) inhibitor [ 7-nitroindazole (7-NI)]. This was followed by suffusion of a cGMP analog an d then cGMP plus miconazole. Separate groups of rats were used to evaluate whether miconazole either alone or in the presence of 8-bromoguanosine 3',5 '-cyclic monophosphate (8-BrcGMP) or its vehicle (0.1% ethanol) had any eff ect on CO2 reactivity and whether miconazole affected K+-channel opener-ind uced dilations. Hypercapnic (arterial PCO2, congruent to 65 mmHg) pial arte riolar dilations, as expected, were reduced by 70-80% with 7-NI and restore d with cGMP repletion. CO2 reactivity was again attenuated after miconazole introduction. Miconazole, with and without 8-BrcGMP, and its vehicle had n o influence on pial arteriolar CO2 reactivity in the absence of nNOS inhibi tion combined with cGMP repletion. Miconazole alone also did not affect vas odilatory responses to K+-channel openers. Thus present results suggest tha t the nascent K+-channel dependence of the hypercapnic response found in ou r earlier study may be related to increased epoxygenase activity. The speci fic reasons why the pial arteriolar CO2 reactivity gains a K+-channel and e poxygenase dependence only under conditions of nNOS inhibition and cGMP res toration remain to be identified. These findings again call into question t he interpretations applied to data collected in studies evaluating potentia l permissive actions of cGMP or NO.