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

Abstract

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 mm Hg 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 I+R 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 I+R but blunted by H+I+R (control, 10+/-1 and 20+/-1%; I+R, 11+/-1 and 20+/-2%; H+I+R, 0+/-1 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.

• Authors: G Ben-Haim, W M Armstead
• Journal: Brain research (Brain Res) Vol. 884 Issue 1--2 Pg. 51-8 (Nov 24 2000) ISSN: 0006-8993 [Print] Netherlands
• PMID: 11082486 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• ADCYAP1 protein, human
• Neuropeptides
• Neuroprotective Agents
• Opioid Peptides
• Pituitary Adenylate Cyclase-Activating Polypeptide
• Potassium Channels
• Vasodilator Agents
• Cromakalim
• 8-Bromo Cyclic Adenosine Monophosphate
• nociceptin
• Cyclic AMP

Topics

• 8-Bromo Cyclic Adenosine Monophosphate (pharmacology)
• Age Factors
• Animals
• Animals, Newborn (metabolism)
• Asphyxia Neonatorum (drug therapy, metabolism, physiopathology)
• Cerebral Arteries (drug effects, metabolism, physiopathology)
• Cerebrovascular Circulation (drug effects, physiology)
• Cromakalim (pharmacology)
• Cyclic AMP (cerebrospinal fluid)
• Humans
• Hypoxia-Ischemia, Brain (drug therapy, metabolism, physiopathology)
• Infant, Newborn
• Neuropeptides (pharmacology)
• Neuroprotective Agents (pharmacology)
• Opioid Peptides (pharmacology)
• Pituitary Adenylate Cyclase-Activating Polypeptide
• Potassium Channels (drug effects, metabolism)
• Reperfusion Injury (drug therapy, metabolism, physiopathology)
• Swine
• Vasodilation (drug effects, physiology)
• Vasodilator Agents (pharmacology)