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Calcitonin gene-related peptide (CGRP) and nitric oxide (NO) are potent dilators in a variety of vascular beds. Recent evidence suggests that NO may serve as an intermediary messenger for CGRP and/or CGRP may serve as an intermediary messenger for NO in the expression of vasodilation. The present study was designed to provide an initial characterization of the responses to NO and CGRP in parenchymal microvessels and to determine whether NO and/or CGRP act as intermediaries for one another. Microvessels in the parenchyma of in vitro hippocampal slices from rat brain were examined using computer-assisted videomicroscopy. The resting diameter of the microvessels ranged from 9 to 26 microm. Treatment with the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine (L-NNA; 100 microM) constricted vessels to 64.2% +/- 3.0% of resting luminal diameter. Sodium nitroprusside (SNP; 1 microM), a donor of NO, reversed the L-NNA-induced vasoconstriction by 77.0% +/- 15.0%. CGRP alone (10 nM) elicited a small but significant vasodilatory effect on resting vascular tone (2.3% +/- 0.6%). In the presence of L-NNA, CGRP elicited a significant dose-dependent vasodilatory response, and 10 nM CGRP elicited a sizeable response, reversing the L-NNA-induced constriction by 84.3% +/- 15.5%. This CGRP-induced dilation was inhibited by pretreatment with the CGRP receptor antagonist, CGRP fragment (8-37) (1 microM). In contrast, pretreatment with 1 microM CGRP fragment (8-37) did not attenuate the SNP-induced dilation in the presence of L-NNA. Taken together, these findings demonstrate that CGRP and NO are potent dilators of parenchymal microvessels, and that NO provides a substantial relaxant effect on resting tone. In addition, the results indicate that CGRP is not a necessary intermediary in NO-induced dilation, and that NO is not a necessary intermediary in CGRP-induced dilation in parenchymal microvessels.

The regulatory role of endothelins in cerebral microvessels was investigated in a recently developed model system which allows the study of small cerebral vessels in their normal microenvironment. Using brain slices of the rat neocortex, it was shown that the isopeptide endothelin-3 (ET-3) had no effect on cerebral microvessels, while the isopeptide endothelin-1 (ET-1) produced a potent, dose-dependent vasoconstriction. When a recently developed antagonist of ETA receptors (cyclo-[D-Asp-L-Pro-D-Val-L-Leu-D-Trp]; ETant) was administered prior to treatment with ET-1, the vasoconstrictor response to ET-1 was inhibited in a dose-dependent manner. When ETant was administered after the establishment of a constriction by ET-1, the constrictor response to ET-1 was partially reversed, and this effect was weaker than that seen in the pre-treatment paradigm. These findings indicate that constrictor responses to ET-1 in cerebral microvessels are mediated by ETA receptors. Inasmuch as endothelins have been implicated in pathological forms of vasoconstriction in the CNS, the present findings also suggest that endothelin antagonists may be useful in the treatment of cerebral ischemia.