Role of impaired cAMP and calcium-sensitive K+ channel function in altered cerebral hemodynamics following brain injury

Abstract

Previous studies have shown that pial arteries constricted and responses to dilator opioids were blunted after fluid percussion injury (FPI) in newborn pigs. Membrane potential of vascular muscle is a major determinant of vascular tone and activity of K+ channels is a major regulator of membrane potential. Recent data show that opioids elicit dilation via the sequential production of cAMP and subsequent activation of calcium-sensitive K+ (K(Ca2+)) channels by this second messenger. The present study was designed to investigate the effect of FPI on cAMP and K(Ca2+) channel function. Chloralose-anesthetized piglets equipped with a closed cranial window were connected to a percussion device consisting of a saline-filled cylindrical reservoir and a metal pendulum. Brain injury of moderate severity (1.9-2.1 atm) was produced by allowing the pendulum to strike a piston on the cylinder. FPI blunted dilation to the cAMP analogs 8-Bromo cAMP and Sp 8-Bromo cAMPs (10(-8), 10(-6) M), (9 +/- 1 and 16 +/- 1 vs. 2 +/- 1 and 3 +/- 1% dilations to 8-Bromo cAMP before and after FPI, respectively, n = 8). Similarly, FPI attenuated dilation to pituitary adenylate cyclase activating peptide (PACAP), an endogenous activator of adenylate cyclase, and NS 1619, a K(Ca2+) channel agonist (9 +/- 1 and 16 +/- 1 vs. 3 +/- 1 and 5 +/- 1% for NS 1619 10(-8), 10(-6) M before and after FPI, respectively, n = 8). Moreover, FPI attenuated PACAP, methionine enkephalin, leucine enkephalin, and dynorphin induced elevations in CSF cAMP concentration (940 +/- 2, 1457 +/- 50, and 2191 +/- 53 vs. 810 +/- 17, 1033 +/- 36, and 1218 +/- 49 fmol/ml for control, PACAP 10(-8), 10(-6) M before and after FPI, respectively, n = 8). These data show that cAMP and K(Ca2+) channel function is impaired after FPI. Further these data suggest that impaired cAMP and K(Ca2+) channel function contribute to altered cerebral hemodynamics following FPI.