Peroxynitrite reduces vasodilatory responses to reduced intravascular pressure, calcitonin gene-related peptide, and cromakalim in isolated middle cerebral arteries.

Abstract

Vasodilatory responses to progressive reductions in intravascular pressure or to calcitonin gene-related peptide (CGRP) or cromakalim were determined in rodent middle cerebral arteries (MCAs) before and after treatment with peroxynitrite (ONOO-). Middle cerebral artery diameters in isolated, pressurized MCAs were measured as intravascular pressure was reduced from 100 to 20 mm Hg in 20-mm Hg increments before and after inactive ONOO-, pH-adjusted ONOO-, or 10, 20, or 40 micromol/L ONOO- was added to the bath. In other MCAs, responses to CGRP (1 x 10-9 - 5 x 10-8) or cromakalim (3 x 10-8 - 8 x 10-7) were measured before and after the addition of 25 micromol/L ONOO-. Inactive ONOO- (n = 6, P = 0.40), pH-adjusted ONOO- (n = 6, P = 0.29), and 10 micromol/L ONOO- (n = 6, P = 0.88) did not reduce vasodilatory responses to reduced intravascular pressure. Middle cerebral arteries treated with 20 (n = 6, P < 0.0001) and 40 (n = 6, P > 0.0001) micromol/L ONOO- constricted significantly when intravascular pressure was reduced. Vasodilatory responses to CGRP or cromakalim were reduced by ONOO- (P > 0.02, n = 6 and P > 0.01, n = 7, respectively). ONOO- had no effect on vasoconstriction in response to serotonin or vasodilation in response to KCl. These studies demonstrate that ONOO- reduces multiple cerebral vasodilatory responses.