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

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.