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 μmol/L ONOO⁻ was added to the bath. In other MCAs, responses to CGRP (1 × 10⁻⁹ −5 × 10⁻⁸) or cromakalim (3 × 10⁻⁸ −8 × 10⁻⁷) were measured before and after the addition of 25 μmol/L ONOO⁻. Inactive ONOO⁻ (n = 6, P = 0.40), pH-adjusted ONOO⁻ (n = 6, P = 0.29), and 10 μmol/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) μmol/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.