title: 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.
authors.affiliation: Department of Anesthesia, The University of Pennsylvania and The Children's Hospital of Philadelphia, 19104, USA.
authors.forename: W M
authors.initials: WM
authors.lastname: Armstead
mesh_terms: D000818:Animals; D001921:Brain / Q000502:physiology*; D001930:Brain Injuries / Q000503:physiopathology*; D002118:Calcium / Q000502:physiology*; D000242:Cyclic AMP / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D006439:Hemodynamics / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D009294:Narcotics / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology*; D013552:Swine; D014665:Vasodilator Agents / Q000494:pharmacology; D014949:Wounds, Nonpenetrating
chemical_list: D009294:Narcotics; D015221:Potassium Channels; D014665:Vasodilator Agents; D000242:Cyclic AMP; D005905:Glyburide; D002118:Calcium