Interaction of endothelium with dilation produced by inhibitors of cyclic nucleotide diesterases in mouse brain arterioles in vivo.

Abstract

In vitro evidence gathered from extracerebral conductance vessels suggests interaction between the endothelium-derived relaxing factor for acetylcholine (EDRFACh) and cyclic nucleotide action in vascular smooth muscle. The purpose of this study was to examine this interaction in vivo in pial arterioles. As had been done in vitro, we used phosphodiesterase inhibitors that elevate cyclic nucleotide levels in vascular smooth muscle. Pial vessels of mice were observed with television microscopy. Diameter of the arterioles was monitored with an image-splitting technique. The responses to topically applied phosphodiesterase inhibitors were tested before and after focal endothelial injury or before and during application of N-guanidino-L-monomethyl arginine (L-NMMA). Both treatments are known to eliminate the endothelium-dependent response to acetylcholine in this preparation. Phosphodiesterase inhibitors dilated pial arterioles. This was true for phosphodiesterase inhibitors elevating levels of both adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP) as well as for inhibitors thought to selectively affect either nucleotide. The dilation was inhibited by endothelial injury and by L-NMMA. The data suggest that brain arterioles are dilated by both cAMP and cGMP but that this action is impaired if EDRFACh levels are reduced. Since EDRFACh elevates cGMP levels, these data support the hypothesis that the relaxing actions of cGMP and cAMP depend upon adequate basal levels of cGMP in vascular smooth muscle. This hypothesis, originally introduced in studies of extracerebral conductance arteries in vitro, can now be applied to brain resistance vessels in vivo.