Role of cAMP and K+ channel-dependent mechanisms in piglet hypoxic/ischemic impaired nociceptin/orphanin FQ-induced cerebrovasodilation

This study was designed to determine the role of altered cAMP and K+ channel-dependent mechanisms in impaired pial artery dilation to the newly described opioid, nociceptin/orphanin FQ (NOC/oFQ) following hypoxia/ischemia in newborn pigs equipped with a closed cranial window. Recent studies have observed that NOC/oFQ elicits pial dilation via release of cAMP which, in turn, activates the calcium sensitive (K-ca) and the ATP-dependent K+ (K-ATP) channel. Global cerebral ischemia (20 min) was induced via elevation of intracranial pressure, while hypoxia (10 min) decreased pO(2) to 35 +/- 3 mmHg with unchanged pCO(2). Topical NOC/oFQ (10(-8), 10(-6) M) induced vasodilation was attenuated by ischemia/reperfusion (I + R) and reversed to vasoconstriction by hypoxia/ischemia/reperfusion (H + I + R) at 1 h of reperfusion (control, 9 +/- 1 and 16 +/- 1%; I + R, 3 +/- 1 and 6 +/- 1%; H + I + R, -7 +/- 1 and -12 +/- 1%). Such altered dilation returned to control values within 4 h in I + R animals and within 12 h in H + I + R animals. NOC/oFQ dilation was associated with elevated CSF cAMP in control animals but such biochemical changes were attenuated in ISR animals and reversed to decreases in cAMP concentration in H + I + R animals (control, 1037 +/- 58 and 1919 +/- 209 fmol/ml; I + R, 1068 +/- 33 and 1289 +/- 30 fmol/ml; H + I + R, 976 +/- 36 and 772 +/- 27 fmol/ml for absence and presence of NOC/oFQ 10-6 M, respectively). Topical 8-Bromo cAMP (10(-8), 10-6 M) pial dilation was unchanged by ISR but blunted by H + I + R (control, 10 +/- 1 and 20 +/- 1%; I + R, 11 +/- 1 and 20 +/- 2%; H + I + R , Oil and 0 +/- 2%). Pituitary adenylate cyclase activating polypeptide and cromakalim, adenylate cyclase and K-ATP channel activators, respectively, elicited dilation that was blunted by both I + R and H + I + R while NS1619, a K-ca channel activator, elicited dilation that was unchanged by I + R but blunted by H + I + R. These data indicate that impaired NOC/oFQ dilation following I + R results form altered adenylate cyclase and K-ATP channel-dependent mechanisms. These data further indicate that impaired NOC/oFQ dilation following H + I + R results not only from altered adenylate cyclase and K-ATP channel but also from altered cAMP and K-ca channel-dependent mechanisms. (C) 2000 Elsevier Science BN. All rights reserved.