Biomedical subjects

W M Armstead

Publications and source records attributed to W M Armstead.

At least 19 recordsLinked to original sources

PubMed2004

Endothelins and the role of endothelin antagonists in the management of posttraumatic vasospasm.

Increasing evidence implicates endothelin in the pathophysiological development of cerebral vasospasm. This review summarizes background topics such as the structures and biosynthesis of endothelins, the types of endothelin and their receptors, as well as their biological effects. Basic science and clinical observations supportive of the role of endothelins in the spasm associated with stroke and subarachnoid hemorrhage are presented. Similar basic science and clinical observations are presented regarding the role of endothelins in impaired cerebral hemodynamics following traumatic brain injury, cryogenic cortical lesion injury and fluid percussion brain injury. The role of age in the contribution of endothelin to impaired cerebral hemodynamics following fluid percussion brain injury is discussed. Finally, potential mechanisms for endothelin contributions to vasospasm following fluid percussion brain injury such as impaired K+ channel function are described.

Animals↗

PubMed2001

Vasopressin induced cyclooxygenase dependent superoxide generation contributes to K(+) channel function impairment after brain injury.

This study determined if vasopressin generates superoxide anion (O2(-)) in a cyclooxygenase dependent manner and if such production contributes to impairment of dilation to activators of ATP sensitive K(+) (K(ATP)) and calcium sensitive K(+) (K(ca)) channels following fluid percussion brain injury (FPI) in newborn pigs equipped with closed cranial windows. Superoxide dismutase (SOD) inhibitable nitroblue tetrazolium (NBT) reduction was determined as an index of O2(-) generation. Under non-brain injury conditions, topical vasopressin (40 pg/ml, the concentration present in CSF following FPI) increased SOD inhibitable NBT reduction from 1+/-1 to 25+/-4 pmol/mm(2). Indomethacin, a cyclooxygenase inhibitor, blunted such NBT reduction (1+/-1 to 5+/-1 pmol/mm(2)), while the vasopressin antagonist, l-(beta-mercapto-beta beta-cyclopentamethylene propionic acid) 2-(o-methyl)-Tyr-AVP (MEAVP) blocked NBT reduction. MEAVP and indomethacin also blunted the NBT reduction observed after FPI. Under non-brain injury conditions, vasopressin (40 pg/ml) coadministered with the K(ATP) and K(ca) channel agonists, cromakalim and NS1619 (10(-8), 10(-6) M) diminished dilation to these K(+) channel agonists while indomethacin partially prevented such impairment (13+/-1 and 23+/-1 vs. 4+/-1 and 10+/-2 vs. 8+/-1 and 19+/-1% for cromakalim in untreated, vasopressin, and vasopressin plus indomethacin treated piglets, respectively). Cromakalim and NS1619 induced pial artery dilation was attenuated following FPI, while indomethacin or MEAVP preadministration partially prevented such impairment (13+/-1 and 23+/-1, sham control; 1+/-1 and 4+/-1, FPI; 8+/-1 and 16+/-3%, FPI-indomethacin pretreated for responses to cromakalim 10(-8), 10(-6) M, respectively). These data show that vasopressin increased O2(-) production in a cyclooxygenase dependent manner and contributed to this production after FPI. These data also show that vasopressin blunted K(ATP) and K(ca) channel mediated cerebrovasodilation in a cyclooxygenase dependent manner. These data suggest that vasopressin induced cyclooxygenase dependent O2(-) generation contributes to K(ATP) and K(ca) channel function impairment after FPI.

Animals↗

PubMed2001

Nociceptin/orphanin FQ contributes to hypoxic/ischemic impairment of hypercapnic cerebrovasodilation.

Previous studies in piglets show that hypercapnic pial artery dilation was blunted following cerebral ischemia. Unrelated studies show that the newly described opioid nociceptin orphanin FQ (NOC/oFQ) is released into cerebrospinal fluid and contributes to altered cerebral hemodynamics following hypoxia/ischemia. This study was designed to determine the contribution of NOC/oFQ to hypoxic/ischemic impairment of hypercapnic pial dilation in piglets equipped with a closed cranial window. Global cerebral ischemia was produced via elevated intracranial pressure. Hypoxia decreased P(O2) to 34 +/- 3 mmHg. Topical NOC/oFQ (10(-10) M), the CSF concentration following hypoxia/ischemia, had no effect on pial artery diameter by itself but attenuated hypercapnia P(CO2) of (73 +/- 2 mmHg)-induced pial artery dilation (28 +/- 2 vs. 19 +/- 2%). Hypercapnia pial artery dilation was blunted by hypoxia/ischemia but such dilation was partially protected by pretreatment with the putative NOC/oFQ receptor antagonist, [F/G] NOC/oFQ (1-13) NH(2) (10(-6) M), (25 +/- 1, sham control; 4 +/- 1, hypoxia/ischemia; and 12 +/- 3%, hypoxia/ischemia + [F/G] NOC/oFQ (1-13) NH(2), respectively). These data suggest that NOC/oFQ release contributes to impaired hypercapnia-induced cerebrovasodilation following hypoxia/ischemia.

Animals↗

PubMed2001

Age dependent endothelin contribution to NOC/oFQ induced impairment of NMDA cerebrovasodilation after brain injury.

This study was designed to characterize the role of endothelin-1 (ET-1) in nociceptin/orphanin FQ (NOC/oFQ) induced impairment of NMDA cerebrovasodilation after fluid percussion brain injury (FPI) as a function of age in newborn (1-5 days old) and juvenile (3-4 weeks old) pigs equipped with a closed cranial window. Previous studies have observed that NOC/oFQ is released into CSF and contributes to impaired NMDA induced pial artery dilation following FPI to a greater extent in newborn vs juvenile pigs. Topical ET-1 (10(-10) M), a concentration approximating that observed in CSF following FPI in the newborn, increased CSF NOC/oFQ from 67 +/- 4 to 119 +/- 7 pg/ml under non FPI conditions. CSF NOC/oFQ was elevated within 60 min of FPI (70 +/- 3 to 444 +/- 51 pg/ml) but such release was attenuated by the ET-1 antagonist BQ123 in the newborn (66 +/- 3 to 145 +/- 10 pg/ml). CSF ET-1 and NOC/oFQ were not elevated as greatly in the juvenile following FPI and BQ123 correspondingly did not attenuate CSF NOC/oFQ release as much as in the newborn. Under non injury conditions, ET-1 (10(-10) M) coadministered with NMDA attenuated pial dilation to this excitatory amino acid. Following FPI in the newborn, NMDA (10(-8), 10(-6) M) induced pial artery dilation was reversed to vasoconstriction and both NOC/oFQ and ET-1 receptor antagonists partially prevented such alterations (9 +/- 1 and 16 +/- 1, sham control; -7 +/- 1 and -12 +/- 1, FPI; -2 +/- 1 and -3 +/- 1, FPI-NOC/oFQ antagonist; and 2 +/- 1 and 5 +/- 1 %, FPI-ET-1 antagonist). NMDA induced pial dilation was only attenuated following FPI in the juvenile and modestly restored by NOC/oFQ and ET-1 receptor antagonists. These data show that ET-1, in concentrations present in CSF following FPI, contributes to the release of CSF NOC/oFQ following such an insult. The greater release of such ET-1 following FPI in the newborn contributes to the corresponding greater release of NOC/oFQ in the newborn vs the juvenile. Moreover, ET-1 also contributes to the impairment of NMDA cerebrovasodilation after brain injury to a greater extent in newborns vs juveniles. These data suggest that ET-1 contributes to NOC/oFQ induced impairment of NMDA cerebrovasodilation after brain injury in an age dependent manner.

Age Factors↗

PubMed2001

Endothelin-Induced cyclooxygenase-dependent superoxide generation contributes to K+ channel functional impairment after brain injury.

This study determined if endothelin (ET-1) generates superoxide anion (O2-) in a cyclooxygenase-dependent manner and if such production contributes to impairment of dilation to activators of ATP-sensitive K+ (KATP) and calcium-sensitive K+ (Kca) channels following fluid percussion brain injury (FPI) in newborn pigs equipped with closed cranial windows. Superoxide dismutase (SOD)-inhibitable nitroblue tetrazolium (NBT) reduction was determined as an index of O2- generation. Under non-brain injury conditions, topical ET-1 (10(-10) M, the concentration present in CSF following FPI) increased SOD-inhibitable NBT reduction from 1 +/- 1 to 17 +/- 3 pmol/mm2. Indomethacin, a cyclooxygenase inhibitor, blunted such NBT reduction (1 +/- 1 to 4 +/- 1 pmol/mm2), while the ET-1 antagonist BQ123 blocked NBT reduction. BQ123 and indomethacin also blunted the NBT reduction observed after FPI. Under non-brain injury conditions, ET-1 (10(-10) M) coadministered with the KATP and Kca channel agonists cromakalim and NS1619 (10-8, 10(-6) M) diminished dilation to these K+ channel agonists, while indomethacin partially prevented such impairment (13 +/- 1 and 23 +/- 1 vs. 2 +/- 1 and 6 +/- 1 vs. 6 +/- 1 and 14 +/- 2% for cromakalim in untreated, ET-1, and ET-1 plus indomethacin-treated piglets, respectively). Cromakalim- and NS1619-induced pial artery dilation was attenuated following FPI, while indomethacin or BQ123 preadministration partially prevented such impairment (13 +/- 1 and 23 +/- 1, sham control; 1 +/- 1 and 4 +/- 1, FPI; 8 +/- 1 and 16 +/- 3%, FPI and indomethacin-pretreated for responses to cromakalim 10(-8), 10-6 M, respectively). These data show that ET-1 increased O2- production in a cyclooxygenase-dependent manner and contributed to this production after FPI. These data also show that ET-1 blunted KATP and Kca channel-mediated cerebrovasodilation in a cyclooxygenase dependent manner. These data suggest that ET-1-induced cyclooxygenase-dependent O2- generation contributes to KATP and Kca channel function impairment after FPI.

ATP-Binding Cassette Transporters↗

PubMed2001

Age-Dependent vasopressinergic modulation of Noc/oFQ-induced impairment of NMDA cerebrovasodilation after brain injury.

This study was designed to characterize the role of vasopressin in nociceptin/orphanin FQ (NOC/oFQ)-induced impairment of NMDA cerebrovasodilation after fluid percussion brain injury (FPI) as a function of age in newborn (1-5 days old) and juvenile (3-4 weeks old) pigs equipped with a closed cranial window. Previous studies have observed that NOC/oFQ is released into CSF and contributes to impaired NMDA induced pial artery dilation following FPI to a greater extent in newborn versus juvenile pigs. Topical vasopressin (40 pg/mL), a concentration approximating that observed in CSF following FPI in the newborn, increased CSF NOC/oFQ from 69 +/- 3 to 102 +/- 8 pg/mol under non-FPI conditions. CSF NOC/oFQ was elevated within 60 min of FPI (70 +/- 3 to 444 +/- 51 pg/mL), but release was attenuated by MEAVP, a vasopressin antagonist, in the newborn (71 +/- 3 to 146 +/- 11 pg/mL). CSF vasopressin and NOC/oFQ were not elevated as greatly in the juvenile following FPI and MEAVP correspondingly did not attenuate CSF NOC/oFQ release as much as in the newborn. Under noninjury conditions, vasopressin (40 pg/mL) coadministered with NMDA (10(-8), 10(-6) M) attenuated pial dilation to this excitatory amino acid (9 +/- 1% and 16 +/- 1% vs. 3 +/- 1% and 5 +/- 2%). Following FPI in the newborn, NMDA-induced pial artery dilation was reversed to vasoconstriction, and both NOC/oFQ and vasopressin receptor antagonists partially prevented these alterations (9 +/- 1%) and 16 +/- 1%, sham control; -7 +/- 1% and -12 +/- 1%, FPI; -2 +/- 1% and -3 +/- 1%, FPI-NOC/oFQ antagonist; and 1 +/- 1% and 4 +/- 1%, FPI-vasopressin antagonist). NMDA-induced pial dilation was only attenuated following FPI in the juvenile and modestly restored by NOC/oFQ and vasopressin receptor antagonists. These data show that vasopressin, in concentrations present in CSF following FPI, contributes to the release of CSF NOC/oFQ following such an insult. The greater release of vasopressin following FPI in the newborn contributes to the corresponding greater release of NOC/oFQ in the newborn versus the juvenile. Moreover, vasopressin also contributes to the impairment of NMDA cerebrovasodilation after brain injury to a greater extent in newborn versus juveniles. These data suggest that vasopressin modulates NOC/oFQ-induced impairment of NMDA cerebrovasodilation after brain injury in an age-dependent manner.

Aging↗

PubMed2001

Vasopressin-induced protein kinase C-dependent superoxide generation contributes to atp-sensitive potassium channel but not calcium-sensitive potassium channel function impairment after brain injury.

BACKGROUND AND PURPOSE: Pial artery dilation in response to activators of the ATP-sensitive K(+) (K(ATP)) and calcium-sensitive K(+) (K(Ca)) channels is impaired after fluid percussion brain injury (FPI). Vasopressin, when coadministered with the K(ATP) and K(Ca) channel agonists cromakalim and NS1619 in a concentration approximating that observed in cerebrospinal fluid (CSF) after FPI, blunted K(ATP) and K(Ca) channel-mediated vasodilation. Vasopressin also contributes to impaired K(ATP) and K(Ca) channel vasodilation after FPI. In addition, protein kinase C (PKC) activation generates superoxide anion (O(2)(-)), which in turn contributes to K(ATP) channel impairment after FPI. We tested whether vasopressin generates O(2)(-) in a protein kinase C (PKC)-dependent manner, which could link vasopressin release to impaired K(ATP) and K(Ca) channel-induced pial artery dilation after FPI. METHODS: Injury of moderate severity (1.9 to 2.1 atm) was produced with the lateral FPI technique in anesthetized newborn pigs equipped with a closed cranial window. Superoxide dismutase-inhibitable nitroblue tetrazolium (NBT) reduction was determined as an index of O(2)(-) generation. RESULTS: Under sham injury conditions, topical vasopressin (40 pg/mL, the concentration present in CSF after FPI) increased superoxide dismutase-inhibitable NBT reduction from 1+/-1 to 23+/-4 pmol/mm(2). Chelerythrine (10(-7) mol/L, a PKC inhibitor) blunted such NBT reduction (1+/-1 to 9+/-2 pmol/mm(2)), whereas the vasopressin antagonist l-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid)2-(o-methyl)-Tyr-arginine vasopressin (MEAVP) blocked NBT reduction. Chelerythrine and MEAVP also blunted the NBT reduction observed after FPI (1+/-1 to 15+/-1, 1+/-1 to 4+/-1, and 1+/-1 to 5+/-1 pmol/mm(2) for sham-, chelerythrine-, and MEAVP-treated animals, respectively). Under sham injury conditions, vasopressin (40 pg/mL) coadministered with cromakalim or NS1619 blunted dilation in response to these K(+) channel agonists, whereas chelerythrine partially restored such impaired vasodilation for cromakalim but not NS1619. Cromakalim- and NS1619-induced pial artery dilation also was blunted after FPI. MEAVP partially protected dilation to both K(+) channel agonists after FPI, whereas chelerythrine did so for only cromakalim responses (for cromakalim at 10(-8) and 10(-6) mol/L, 13+/-1% and 23+/-1%, 2+/-1% and 5+/-1%, 9+/-1% and 15+/-2%, and 9+/-1% and 16+/-2% for sham-, FPI-, FPI-MEAVP-, and FPI-chelerythrine-pretreated animals, respectively). CONCLUSIONS: These data show that vasopressin, in concentrations present in CSF after FPI, increased O(2)(-) production in a PKC-dependent manner and contributes to such production after FPI. These data show that vasopressin contributes to K(ATP) but not K(Ca) channel function impairment in a PKC-dependent manner after FPI and suggest that vasopressin contributes to K(Ca) channel function impairment after FPI via a mechanism independent of PKC activation.

Adenosine Triphosphate↗

PubMed2000

Vasopressin impairs K(ATP) and K(ca) channel function after brain injury.

This study was designed to characterize the role of vasopressin in impaired pial artery dilation to activators of the ATP sensitive K (K(ATP)) and calcium sensitive K (K(ca)) channel following fluid percussion brain injury (FPI) in newborn pigs equipped with a closed cranial window. Topical vasopressin was coadministered with the K(ATP) and K(ca) channel agonists cromakalim and NS1619 in a concentration approximating that observed in CSF following FPI. Vasopressin so administered attenuated pial artery dilation to these K(+) channel activators under conditions of equivalent baseline diameter during non injury conditions (13+/-1 and 23+/-1 vs. 4+/-1 and 10+/-2% for cromakalim 10(-8), 10(-6) M before and after vasopressin, respectively). Attenuated responses were fully restored when these agonists were coadministered with vasopressin and the vasopressin antagonist [l-(beta-mercapto-beta, beta-cyclopentamethylene propionic acid) 2-(o-methyl)-Tyr-AVP] (MEAVP). Cromakalim and NS1619 induced pial artery dilation was attenuated following FPI and MEAVP preadministration partially prevented such impairment (13+/-1 and 23+/-1, sham control; 2+/-1 and 5+/-1, FPI; and 9+/-1 and 15+/-2%, FPI-MEAVP pretreated for responses to cromakalim 10(-8), 10(-6) M, respectively). These data show that vasopressin blunts K(ATP) and K(ca) channel mediated cerebrovasodilation. These data suggest that vasopressin contributes to impaired K(ATP) and K(ca) channel function after brain injury.

Animals↗

PubMed2000

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 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.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed2000

Role of NOC/oFQ in impaired opioid-induced pial artery dilation following brain injury.

Previous studies in piglets show that opioid-induced pial artery dilation was impaired following fluid percussion brain injury (FPI). This study was designed to determine the role of the newly described opioid nociceptin orphanin FQ (NOC/oFQ) in such impaired dilation to other opioids after FPI. CSF NOC/oFQ concentration was elevated from 70+/-6 to 444+/-56 pg/ml ( approximately 10(-10) M) within 1 h of FPI. Coadministration of NOC/oFQ (10(-10) M) with methionine enkephalin (10(-10), 10(-8), 10(-6) M) attenuated pial dilation induced by this opioid (7+/-1, 13+/-2, and 19+/-2 vs. 2+/-1, 6+/-1, and 7+/-2%) under non-brain injury conditions. Similar inhibition by NOC/oFQ was observed for leucine enkephalin and dynorphin. Methionine enkephalin (10(-10), 10(-8), 10(-6) M)-induced pial artery dilation was also inhibited within 1 h of FPI, but such responses were partially restored in animals pretreated with the NOC/oFQ receptor antagonist [F/G] NOC/oFQ (1-13) NH(2) (10(-6) M) (8+/-1, 14+/-1, and 21+/-1 vs. 1+/-1, 3+/-1, and 4+/-1 vs. 7+/-1, 11+/-1, and 17+/-1% for sham control, FPI and FPI pretreated with the NOC/oFQ receptor antagonist). Leucine enkephalin and dynorphin-induced pial artery dilation were similarly altered by FPI and partially restored by [F/G] NOC/oFQ (1-13) NH(2). These data indicate that the NOC/oFQ released by FPI contributes to impaired dilation to other opioids observed following this insult.

Animals↗

PubMed2000

NOC/oFQ contributes to hypoxic-ischemic impairment of N-methyl-D-aspartate-induced cerebral vasodilation.

Previous studies in piglets show that either hypoxia, ischemia-reperfusion (I+R) or combined hypoxia-ischemia-reperfusion (H+I+R) attenuated N-methyl-D-aspartate (NMDA)-induced pial artery dilation. This study was designed to determine the contribution of the newly described opioid nociceptin orphanin FQ (NOC/oFQ) to hypoxic-ischemic impairment of NMDA induced cerebral vasodilation in piglets equipped with a closed cranial window. Global cerebral ischemia was produced via elevated intracranial pressure. Hypoxia decreased P(O(2)) to 35+/-3 mmHg with unchanged P(CO(2)). I+R elevated CSF NOC/oFQ from 67+/-4 to 266+/-29 pg/ml ( approximately 10(-10) M) while H+I+R elevated CSF NOC/oFQ to 483+/-67 pg/ml within 1 h of reperfusion. Such elevated NOC/oFQ levels returned to control within 4 h in I+R animals and within 12 h in H+I+R animals. Topical NOC/oFQ (10(-10) M) had no effect on pial artery diameter by itself but attenuated NMDA (10(-8), 10(-6) M) induced pial dilation (control, 9+/-1 and 16+/-1; coadministered NOC/oFQ, 5+/-1 and 10+/-1%). NMDA induced pial artery dilation was attenuated by I+R or H+I+R; but such dilation was partially restored by pretreatment with the putative NOC/oFQ antagonist [F/G] NOC/oFQ (1-13) NH(2) (10(-6) M) (control, 9+/-1 and 16+/-1; I+R, 3+/-1 and 5+/-1; I+R+NOC/oFQ antagonist, 6+/-1 and 11+/-1%) Similar results were obtained for glutamate. These data suggest that NOC/oFQ release contributes to impaired NMDA and glutamate-induced cerebrovasodilation following I+R or H+I+R.

Animals↗

PubMed2000

Altered release of prostaglandins contributes to hypoxic/ischemic impairment of NOC/oFQ cerebrovasodilation.

This study was designed to determine if altered release of prostaglandins contributes to 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. Global cerebral ischemia (20 min) was induced via elevation of intracranial pressure, while hypoxia (10 min) decreased P(O(2)) to 35+/-3 mmHg with unchanged P(CO(2)). NOC/oFQ (10(-8) and 10(-6) M) modestly increased cerebrospinal fluid (CSF) 6-Keto PGF(1alpha) and TXB(2), the stable breakdown products of PGI(2) and TXA(2), in sham animals (1199+/-39 to 1704+/-104 and 299+/-9 to 409+/-12 pg/ml for control and 10(-6) M NOC/oFQ 6-Keto PGF(1alpha) and TXB(2), respectively). In 1 h post ischemia/reperfusion (I+R) animals, basal levels of 6-Keto PGF(1alpha) and TXB(2) were elevated. NOC/oFQ-stimulated release of 6-Keto PGF(1alpha) was blocked while such release of TXB(2) was enhanced (526+/-15 to 822+/-36 pg/ml for control and 10(-6) M NOC/oFQ CSF TXB(2)). Similar, though more pronounced, changes were observed in hypoxia/ischemia/reperfusion (H+I+R) animals. Pretreatment with indomethacin (5 mg/kg i.v.) or SQ 29,548 (10(-4) M), cyclooxygenase and PGH(2)/TXA(2) receptor antagonists, partially restored attenuated NOC/oFQ pial artery dilation 1 h after I+R (9+/-1 and 18+/-1 vs. 3+/-1 and 6+/-1 vs. 8+/-1 and 13+/-1% for 10(-8) and 10(-6) M NOC/oFQ in sham, I+R, and I+R - SQ 29,548 pretreated animals). In contrast, NOC/oFQ-induced vasodilation was reversed to vasoconstriction in H+I+R animals and indomethacin or SQ 29,548 similarly partially restored such pial vasodilation. These data indicate that altered stimulated prostaglandin release contributes to hypoxic/ischemic impairment of NOC/oFQ-mediated pial artery dilation.

Animals↗

PubMed2000

Stimulus duration-dependent contribution of k(ca) channel activation and cAMP to hypoxic cerebrovasodilation.

Activation of calcium sensitive (K(ca)) K channels and cAMP contribute to pial artery dilation observed during a 10-min exposure to hypoxia. Recent studies show that pial dilation during a 20- or 40-min hypoxic exposure was less than that observed during a 5- or 10-min exposure indicating that stimulus duration determines the nature of the vascular response to hypoxia. The present study was designed to determine if the stimulus duration modulates the contribution of K(ca) channel activation and cAMP-dependent mechanisms to hypoxic pial artery dilation in piglets equipped with a closed cranial window. The K(ca) channel antagonist iberiotoxin had no influence on pial dilation during 5 min of hypoxia (pO(2) approximately 25 mmHg), decremented the dilation during 10- and 20-min exposure, but had no effect on the dilation during a 40-min exposure (33+/-1% vs. 32+/-3%, 33+/-1% vs. 25+/-1%, 23+/-1% vs. 19+/-1%, and 21+/-2% vs. 17+/-2% for 5-, 10-, 20-, and 40-min hypoxic dilations before and after iberiotoxin). NS1619, a K(ca) channel agonist, induced pial dilation during hypoxia that was attenuated by 20- and 40-min but not by 5- and 10-min exposure durations. Similarly, the cAMP antagonist Rp 8-Bromo cAMPs had no influence on pial dilation during 5 min of hypoxia, decremented the dilation during a 10-min exposure, but had no effect on the dilation during a 20- or 40-min exposure (36+/-1% vs. 34+/-2%, 34+/-1% vs. 22+/-1%, 24+/-2% vs. 21+/-2%, and 21+/-2% vs. 19+/-2% for 5-, 10-, 20-, and 40-min hypoxic dilations before and after Rp 8-Bromo cAMPs). Additionally, CSF cAMP was unchanged during 5 min, elevated during 10 min, but such elevations were attenuated during 20- and 40-min hypoxic exposure. Pial vasodilation to a cAMP analogue during hypoxia was attenuated by 20- and 40-min but not by 5- and 10-min hypoxic exposure durations. These data show that K(ca) channel activation and cAMP contribute to hypoxic pial artery dilation in a stimulus duration-dependent manner. These data suggest that diminished pial artery dilation during longer hypoxic exposure results from attenuated K(ca) channel and cAMP-dependent mechanisms.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed2000

Role of altered cyclooxygenase metabolism in impaired cerebrovasodilation to nociceptin/orphanin FQ following brain injury.

This study was designed to determine the role of altered cyclooxygenase metabolism in impaired pial artery dilation to the newly described opioid, nociceptin orphanin FQ (NOC/oFQ), following fluid percussion brain injury (FPI) in newborn pigs equipped with a closed cranial window. Recent studies show that NOC/oFQ contributes to oxygen free radical generation observed post FPI in a cyclooxygenase dependent manner. FPI was produced by using a pendulum to strike a piston on a saline filled cylinder that was fluid coupled to the brain via a hollow screw inserted through the cranium. NOC/oFQ (10(-8), 10(-6) M) modestly increased cerebrospinal fluid (CSF) 6-keto-PGF(1alpha), and thromboxane B(2) (TXB(2)), the stable breakdown products of PGI(2) and TXA(2), in sham animals (1148 +/- 83 to 1681 +/- 114 and 308 +/- 16 to 424 +/- 21 pg/ml for control and 10(-6) M NOC/oFQ 6-keto-PGF(1alpha), and TXB(2), respectively). In 1-h post FPI animals, basal levels of 6-keto-PGF(1alpha), and TXB(2) were elevated. NOC/oFQ stimulated release of 6-keto-PGF(1alpha), was blocked while such release of TXB(2) was enhanced (720 +/- 63 to 1446 +/- 117 pg/ml for control and 10(-6) M NOC/oFQ CSF TXB(2)). NOC/oFQ (10(-8), 10(-6) M) induced pial artery dilation that was reversed to vasoconstriction by FPI while the cyclooxygenase inhibitor indomethacin (5 mg/kg, intravenous) partially restored such vascular responses (8 +/- 1 and 15 +/- 1 vs. -7 +/- 1 and -12 +/- 1 vs. 7 +/- 1 and 12 +/- 1% for 10(-8), 10(-6) M NOC/oFQ in sham, FPI and FPI-Indo pretreated animals). Similar observations were made in FPI animals pretreated with the thromboxane receptor antagonist SQ 29,548 or the free radical scavenger polyethylene glycol superoxide dismutase and catalase. These data indicate that altered NOC/oFQ induced cyclooxygenase metabolism contributes to impairment of dilation to this opioid following FPI.

Animals↗

PubMed2000

Role of nociceptin/orphanin FQ in age-dependent cerebral hemodynamic effects of brain injury.

This study was designed to compare the role of the newly described endogenous opioid nociceptin/orphanin FQ (NOC/oFQ) in the reductions of cerebral blood flow (CBF) and pial artery diameter observed following fluid percussion brain injury (FPI) in chloralose anesthetized newborn and juvenile pigs as a function of time postinsult. FPI elevated CSF NOC/oFQ concentration from 70 +/- 3 to 444 +/- 51 within 1 h and to 1,931 +/- 112 pg/mL (n = 7) within 8 h, whereas concentrations returned to control value within 168 h in the newborn. In contrast, FPI elevated CSF NOC/oFQ from 77 +/- 4 to 202 +/- 16 pg/mL (n = 7) within 1 h, while values returned to control value within 8 h in the juvenile. Topical NOC/oFQ (10(-8), 10(-6) M) induced vasodilation was reversed to vasoconstriction by FPI in the newborn while such responses were only attenuated in the juvenile at 1 h post insult (control, 9 +/- 1 and 16 +/- 1%; FPI newborn, -8 +/- 1 and -14 +/- 1%; FPI juvenile, 2 +/- 1 and 5 +/- 1%, n = 7). Such altered dilation returned to control value within 168 h in newborns and 8 h in juveniles. Blood flow in the cerebrum was reduced from 57 +/- 4 to 23 +/- 3 mL x min(-1) x 100 g(-1) (n = 7) within 1 h and returned to control value with 168 h post FPI in newborns. In animals pretreated with [F/G] NOC/oFQ (1-13) NH2 (1 mg/kg, i.v.), a NOC/oFQ antagonist, however, CBF only fell to 39 +/- 4 mL x min(-1) x 100 g(-1) (n = 7) at 1 h post insult in newborns. In contrast, CBF was only reduced from 57 +/- 6 to 32 +/- 2 in untreated and to 39 +/- 3 mL/min(-1) x 100 g(-1) (n = 7) in treated juveniles within 1 h post FPI. Similar observations for reductions in pial artery diameter were made in untreated and treated newborns and juveniles. These data suggest that an elevated CSF NOC/oFQ concentration and altered vascular responsiveness to this opioid contribute to reductions in CBF and pial artery diameter observed following FPI. Because such NOC/oFQ changes were greater in newborns versus juveniles, these data further suggest that NOC/oFQ contributes to age-related cerebral hemodynamic differences in the effects of FPI.

Age Factors↗

PubMed2000

Relationship between nociceptin/orphanin FQ and cerebral hemodynamics after hypoxia-ischemia in piglets.

This study was designed to characterize the role of the newly described endogenous opioid nociceptin/orphanin FQ (NOC/oFQ) in reduced cerebral blood flow (CBF) observed after ischemia-reperfusion (I/R) and combined hypoxia and ischemia-reperfusion (H-I/R), as a function of time after onset of reperfusion in newborn pigs equipped with a closed cranial window. Global cerebral ischemia (20 min) was induced via elevation of intracranial pressure, whereas hypoxia (10 min) decreased PO(2) to 35 +/- 3 mmHg with unchanged PCO(2). I/R elevated cerebrospinal fluid (CSF) NOC/oFQ from 67 +/- 4 to 266 +/- 29 pg/ml within 1 h, whereas values returned to control level within 4 h of reperfusion. H-I/R elevated CSF NOC/oFQ to 483 +/- 67 pg/ml within 1 h, and such values returned slowly to control level within 12 h of reperfusion. Topical NOC/oFQ (10(-8) M, 10(-6) M)-induced vasodilation was attenuated by I/R and reversed to vasoconstriction by H-I/R at 1 h of reperfusion (control, 9 +/- 1 and 16 +/- 1%; I/R, 3 +/- 1 and 6 +/- 1%; H-I/R, -6 +/- 1 and -11 +/- 1%). Such altered dilation returned to control values within 4 h in I/R animals and within 12 h in H-I/R animals. Blood flow in the cerebrum was reduced from 58 +/- 4 to 33 +/- 2 ml x min(-1) x 100 g(-1) within 1 h and returned to control value within 4 h in I/R animals. In animals pretreated with [F/G]NOC/oFQ(1-13)-NH(2) (1 mg/kg iv), an NOC/oFQ antagonist, however, CBF only fell to 43 +/- 3 ml x min(-1) x 100 g(-1) at 1 h of reperfusion. Similar observations were made in H-I/R animals. These data suggest that an elevated CSF NOC/oFQ concentration and altered vascular responsiveness to this opioid contribute to reductions in CBF observed after either I/R or H-I/R.

Animals↗

PubMed2000

NOC/oFQ contributes to age-dependent impairment of NMDA-induced cerebrovasodilation after brain injury.

This study characterized the effects of fluid percussion brain injury (FPI) on N-methyl-D-aspartate (NMDA)-induced vasodilation and determined the role of nociceptin/orphanin FQ (NOC/oFQ) in such changes as a function of age and time postinsult. FPI elevated cerebrospinal fluid (CSF) NOC/oFQ from 70 +/- 3 to 444 +/- 56 pg/ml ( approximately 10(-10) M) within 1 h and to 1,931 +/- 112 pg/ml within 8 h, whereas values returned to control levels within 168 h in the newborn pig. In contrast, FPI elevated CSF NOC/oFQ from 77 +/- 4 to 202 +/- 16 pg/ml within 1 h and values returned to control levels within 8 h in the juvenile pig. Topical NOC/oFQ (10(-10) M) had no effect on pial artery diameter but attenuated NMDA (10(-8), 10(-6) M)-induced dilation (9 +/- 1 and 16 +/- 1 vs. 5 +/- 1 and 10 +/- 1%) in both age groups. In the newborn, NMDA-induced pial artery dilation was reversed to vasoconstriction within 1 h post-FPI and responses remained impaired for 72 h, but such vasoconstriction was attenuated by pretreatment with [F/G]NOC/oFQ(1-13)-NH(2) (10(-6) M, 1 mg/kg iv), an NOC/oFQ antagonist (9 +/- 1 and 16 +/- 1 vs. -7 +/- 1 and -12 +/- 1 vs -2 +/- 1 and -3 +/- 1% for control, FPI, and FPI pretreated with the NOC/oFQ antagonist). In contrast, in the juvenile, NMDA-induced vasodilation was only attenuated within 1 h post-FPI and returned to control within 8 h. Such dilation was also partially restored by the NOC/oFQ antagonist. These data indicate that NOC/oFQ contributes to impaired NMDA pial artery dilation after FPI. These data suggest that the greater NOC/oFQ release in the newborn versus the juvenile may contribute to age-related differences in FPI effects on excitatory amino acid-induced pial dilation.

Aging↗

PubMed2000

NOC/oFQ PKC-dependent superoxide generation contributes to hypoxic-ischemic impairment of NMDA cerebrovasodilation.

This study determined whether nociceptin/orphanin FQ (NOC/oFQ) generates superoxide anion (O(2)(-)) in a protein kinase C (PKC)-dependent manner and whether such production contributes to hypoxic-ischemic (H-I) impairment of N-methyl-D-aspartate (NMDA)-induced pial artery dilation in newborn pigs equipped with closed cranial windows. Superoxide dismutase (SOD)-inhibitable nitroblue tetrazolium (NBT) reduction was an index of O(2)(-) generation. Under non-H-I conditions, topical NOC/oFQ (10(-10) M, concentration present in cerebrospinal fluid after I or H-I) increased SOD-inhibitable NBT reduction from 1 +/- 1 to 20 +/- 3 pmol/mm(2). PKC inhibitors staurosporine and chelerythrine (10(-7) M) blunted NBT reduction (1 +/- 1 to 7 +/- 2 pmol/mm(2) for chelerythrine), whereas the NOC/oFQ receptor antagonist [F/G]NOC/oFQ (1-13)-NH(2) (10(-6) M) blocked NBT reduction. [F/G]NOC/oFQ(1-13)-NH(2) and staurosporine also blunted the NBT reduction observed after I or H-I. NMDA (10(-8), 10(-6) M)-induced pial artery dilation was reversed to vasoconstriction after H-I. The NOC/oFQ antagonist staurosporine and free radical scavengers partially prevented this impaired dilation (sham: 9 +/- 1 and 16 +/- 1; H-I: -5 and -10 +/- 1; H-I staurosporine pretreated: 3 +/- 1 and 6 +/- 1%). These data show that NOC/oFQ increased O(2)(-) production in a PKC-dependent manner and contributed to this production after insult and that NOC/oFQ contributed to impaired NMDA-induced pial artery dilation after H-I, suggesting, therefore, that PKC-dependent O(2)(-) generation by NOC/oFQ links NOC/oFQ release to impaired NMDA dilation after H-I.

Alkaloids↗