Pathway-specific effects of calcitonin gene-related peptide on irideal arterioles of the rat

1. Arteriolar diameter and membrane voltage have been measured to investigate the actions of calcitonin gene-related peptide (CGRP) in rat irideal arterioles. 2. Activation of sensory nerves inhibited sympathetic vasoconstriction, reduced the accompanying 40-50 mV depolarization by 90 % and caused a 4 mV hyperpolarization. 3. The inhibition of vasoconstriction was prevented by either preincubation in L-NAME (10 mu M), to inhibit nitric oxide production, by preincubation in the cell-permeant adenylate cyclase inhibitor dideoxyadenosine (1 mM) or by preincubation in the ATP-sensitive potassium channel blocker glibenclamide (10 mu M). The subsequent addition of a nitric oxide donor to the glibenclamide solution inhibited nerve-mediated vasoconstriction, suggesting that the potassium channel involvement preceded the production of nitric oxide. The small hyperpolarization was not affected by L-NAME. 4. Nerve-mediated vasodilatation persisted in the presence of L-NAME (10 mu M) but was abolished with the CGRP, receptor antagonist CGRP(8-37). 5. In arterioles preconstricted with the alpha(2)-adrenoceptor agonist UK-14304 (100 nM), exogenous CGRP caused a hyperpolarization and a dose-dependent vasodilatation, neither of which was affected by L-NAME (10 mu M). 6. In arterioles preconstricted with 30 mM KCl, CGRP (10 nM) caused vasodilatation but not hyperpolarization, suggesting that the hyperpolarization was not causal to the vasodilatation. 7. Forskolin (30 nM), in the presence of L-NAME to prevent effects due to nitric oxide, caused vasodilatation. 8. These results suggest that CGRP inhibits sympathetic nerve-mediated vasoconstriction through sequential increases in cyclic AMP and nitric oxide, while vasodilatation results from increases in cyclic AMP alone. The production of nitric oxide, but not its mechanism of action, appears to be dependent on the activation of ATP-sensitive potassium channels. The Possible sites of action of these two pathways are discussed.