ROLE OF IMPAIRED CAMP AND CALCIUM-SENSITIVE K+ CHANNEL FUNCTION IN ALTERED CEREBRAL HEMODYNAMICS FOLLOWING BRAIN INJURY

Previous studies have shown that pial arteries constricted and respons es to dilator opioids were blunted after fluid percussion injury (FPI) in newborn pigs. Membrane potential of vascular muscle is a major det erminant of vascular tone and activity of K+ channels is a major regul ator of membrane potential. Recent data show that opioids elicit dilat ion via the sequential production of cAMP and subsequent activation of calcium-sensitive Kf (KCa2+) channels by this second messenger. The p resent study was designed to investigate the effect of FPI on cAMP and KCa2+ channel function. Chloralose-anesthetized piglets equipped with a closed cranial window were connected to a percussion device consist ing of a saline-filled cylindrical reservoir and a metal pendulum. Bra in injury of moderate severity (1.9-2.1 atm) was produced by allowing the pendulum to strike st 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-Bro mo cAMP before and after FPI, respectively, n = 8). Similarly, FPI att enuated dilation to pituitary adenylate cyclase activating peptide (PA CAP), an endogenous activator of adenylate cyclase, and NS 1619, a KCa 2+ 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). M oreover, FPI attenuated PACAP, methionine enkephalin, leucine enkephal in, and dynorphin induced elevations in CSF cAMP concentration (940 +/ - 2, 1457 +/- 50, and 2191 +/- 53 vs. 810 +/- 17, 1033 +/- 36, and 121 8 +/- 49 fmol/ml for control, PACAP 10(-8), 10(-6) M before and after FPI, respectively, n = 8). These data show that cAMP and KCa2+ channel function is impaired after FPI. Further these data suggest that impai red cAMP and KCa2+ channel function contribute to altered cerebral hem odynamics following FPI. (C) 1997 Elsevier Science B.V.