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Biomedical subjects

William M Armstead

Publications and source records attributed to William M Armstead.

At least 19 recordsLinked to original sources
PubMed2006

Neutralizing the neurotoxic effects of exogenous and endogenous tPA.

The clinical use of tissue-type plasminogen activator (tPA) in the treatment of stroke is profoundly constrained by its serious side effects. We report that the deleterious effects of tPA on cerebral edema and intracranial bleeding are separable from its fibrinolytic activity and can be neutralized. A hexapeptide (EEIIMD) corresponding to amino acids 350-355 of plasminogen activator inhibitor type 1 (PAI-1) abolished the tPA-induced increase in infarct size and intracranial bleeding in both mechanical and embolic models of stroke in rats, and reduced brain edema and neuronal loss after traumatic brain injury in pigs. These experiments suggest mechanisms to reduce the neurotoxic effects of tPA without compromising its fibrinolytic activity, through the use of selective antagonists and new tPA formulations.

Amino Acid Sequence↗
PubMed2005

Differential activation of ERK, p38, and JNK MAPK by nociceptin/orphanin FQ in the potentiation of prostaglandin cerebrovasoconstriction after brain injury.

Fluid percussion brain injury elevates the cerebrospinal fluid (CSF) concentration of the opioid nociceptin/orphanin FQ (N/OFQ), which potentiates vasoconstriction to the prostaglandins U 46619, a thromboxane A(2) mimic, and prostaglandin (PG)F(2a). This study investigated the role of the extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK) isoforms of mitogen activated protein kinase (MAPK) in potentiated prostaglandin vasoconstriction after brain injury and the relationship of brain injury induced release of N/OFQ to MAPK. Pial artery diameter was measured with a video microscaler by observation through a glass coverslip cranial window placed in the parietal cortex of newborn pigs. Brain injury potentiated U 46619 induced pial artery vasoconstriction but U 0126 and SB 203580 (10(-6) and 10(-5) M, respectively) (ERK and p38 MAPK inhibitors) blocked the potentiation. In contrast, administration of SP 600125 (10(-6) and 10(-5) M) (JNK MAPK inhibitor) only attenuated brain injury induced U 46619 potentiation and such responses were significantly different than that in the presence of either U 0126 or SB 203580 after FPI. Co-administration of N/OFQ (10(-10) M), the CSF concentration observed after brain injury, with U 46619 or PGF(2a) under non brain injury conditions potentiated prostaglandin vasoconstriction but U 0126 and SB 203580 blocked such potentiation. Administration of SP 600125 modestly attenuated prostaglandin potentiation by N/OFQ. These data show that activation of ERK and p38 primarily contribute to potentiation of prostaglandin constriction after brain injury. These data suggest that N/OFQ differentially activates ERK, p38, and JNK MAPK to contribute to potentiated prostaglandin vasoconstriction after fluid percussion brain injury.

Animals↗
PubMed2005

Nitric oxide contributes to AT2 but not AT1 angiotensin II receptor-mediated vasodilatation of porcine pial arteries and arterioles.

Angiotensin II elicits pial artery dilation by activating angiotensin AT1 and angiotensin AT2 receptors. This study determined if vasodilatation in response to angiotensin AT2 receptor activation is due to stimulated release of nitric oxide (NO) in newborn pigs equipped with a closed cranial window. Angiotensin II (10(-8), 10(-6) M) elicited pial artery dilatation that was unchanged by the NO synthase inhibitor N omega-Nitro-L-Arginine (L-NNA) (10(-6) M) (12+/-3 and 18+/-2 versus 12+/-3 and 21+/-4%). Angiotensin II was not associated with changes in artificial cerebrospinal fluid (CSF) cGMP concentration, an indicator of NO release. Similar data were obtained for the angiotensin AT1 receptor agonist L 162,313. In contrast, the angiotensin AT2 receptor agonist CGP 42112A (10(-8), 10(-6) M) induced vasodilatation that was blocked by L-NNA (9+/-2 and 18+/-3 versus 1+/-1 and 1+/-1%). CGP 42112A dilatation was associated with elevated artificial CSF cGMP concentration (757+/-18, 1590+/-89, and 2101+/-116 fmol/ml) and such stimulated release was blocked by L-NNA. These data indicate that stimulated NO release contributes to angiotensin AT2 but not angiotensin AT1 induced vasodilatation. These data suggest that angiotensin II primarily elicits dilatation via angiotensin AT1 receptor activation.

Angiotensin II↗
PubMed2005

Plasminogen activators contribute to impairment of hypercapnic and hypotensive cerebrovasodilation after cerebral hypoxia/ischemia in the newborn pig.

BACKGROUND AND PURPOSE: Babies are frequently exposed to hypoxia and ischemia during the perinatal period as a result of stroke or problems with delivery or respiratory management post delivery. The only U.S. Food and Drug Administration-approved treatment for acute stroke is the administration of tPA. Nonetheless, basic science studies indicate that tPA exhibits both beneficial and deleterious effects on central nervous system function. Cerebral hypoxia/ischemia (H/I) impairs dilation to hypercapnia and hypotension in the newborn pig. We investigated the role of exogenous and endogenous plasminogen activators (PA) in piglet hypercapnic and hypotensive dilator impairment after H/I. METHODS: Responses to dilator stimuli were measured in chloralose-anesthetized piglets equipped with a closed cranial window before and after hypoxia (Po2 35 mm Hg) and subsequent global cerebral ischemia. Data (n=6) were analyzed by repeated-measures analysis of variance. RESULTS: Hypercapnic (Pco2 75 mm Hg) and hypotensive (mean arterial blood pressure decreased by 45%) pial artery dilation (PAD) was blunted after H/I and reversed to vasoconstriction in animals pretreated with tPA or uPA (10(-7) mol/L; 26+/-2, 11+/-1, and -4+/-1% for hypercapnia before, after H/I, and after H/I with tPA). In animals pretreated with EEIIMD (10(-7) mol/L), a peptide that binds uPA and tPA but does not affect proteolysis or soluble uPA receptor (suPAR, 10(-7) mol/L), which binds but does not affect the proteolytic activity of uPA. PAD induced by hypercapnia and hypotension was attenuated to a lesser extent (25+/-2 and 17+/-1% for hypercapnic PAD before and after H/I in EEIIMD-pretreated animals and 21+/-1 and 18+/-2% in suPAR-pretreated animals). CONCLUSIONS: These data show that exogenous PA administration potentiates the impairment of hypercapnic and hypotensive PAD that occurs after H/I. Inhibition of endogenous PA may ameliorate the impairment of PAD induced by hypercapnia and hypotension PAD that develops after hypoxic central nervous system injury of diverse etiologies.

Analysis of Variance↗
PubMed2005

NOC/oFQ activates ERK and JNK but not p38 MAPK to impair prostaglandin cerebrovasodilation after brain injury.

Fluid percussion brain injury (FPI) elevates the CSF concentration of the opioid nociceptin/orphanin FQ (NOC/oFQ), which contributes to impairment of pial artery dilation to the prostaglandins (PG) PGE2 and PGI2. This study investigated the role of the ERK, p38, and JNK isoforms of mitogen-activated protein kinase (MAPK) in impaired PG cerebrovasodilation after FPI, and the relationship of brain injury induced release of NOC/oFQ to MAPK in such vascular impairment in newborn pigs equipped with a closed cranial window. FPI blunted PGE2 pial artery dilation, but U 0126 and SP 600125 (10(-6) M) (ERK and JNK MAPK inhibitors, respectively) partially prevented such impairment (7 +/- 1, 12 +/- 1, and 17 +/- 1 vs. 2 +/- 1, 3 +/- 1, and 5 +/- 1 vs. 4 +/- 1, 7 +/- 1, and 12 +/- 1% for 1, 10, and 100 ng/ml PGE2 in control, FPI, and FPI + U 0126 pretreated animals, respectively). In contrast, administration of SB 203580 (10(-5) M) (p38 MAPK inhibitor) did not prevent FPI impairment of PGE2 dilation. Co-administration of NOC/oFQ at the dose of 10(-10) M, the cerebrospinal fluid concentration observed after FPI, with PGE2 under non-brain injury conditions blunted PG dilation, but U 0126 or SP 600125 partially prevented such impairment (7 +/- 1, 11 +/- 1, and 16 +/- 2 vs. 0 +/- 1, 1 +/- 1, and 2 +/- 1, vs. 5 +/- 1, 9 +/- 1, and 13 +/- 2 for responses to PGE2 in control, NOC/oFQ, and NOC/oFQ + U 0126 treated animals, respectively). Administration of SB 203580 did not prevent impairment of PG pial artery dilation by NOC/oFQ. These data show that activation of ERK and JNK but not p38 MAPK contributes to impairment of PG cerebrovasodilation after FPI. These data suggest that NOC/oFQ induced ERK and JNK but not p38 MAPK activation contributes to impaired cerebrovasodilation to PG after FPI.

Animals↗
PubMed2005

Heat shock protein modulation of KATP and KCa channel cerebrovasodilation after brain injury.

Fluid percussion brain injury (FPI) impairs pial artery dilation to activators of the ATP-sensitive (K(ATP)) and calcium-activated (K(Ca)) K(+) channels. This study investigated the role of heat shock protein (HSP) in the modulation of K(+) channel-induced pial artery dilation after FPI in newborn pigs equipped with a closed cranial window. Under nonbrain injury conditions, topical coadministration of exogenous HSP-27 (1 mug/ml) blunted dilation to cromakalim, CGRP, and NS-1619 (10(-8) and 10(-6) M; cromakalim and CGRP are K(ATP) agonists and NS-1619 is a K(Ca) agonist). In contrast, coadministration of exogenous HSP-70 (1 mug/ml) potentiated dilation to cromakalim, CGRP, and NS-1619. FPI increased the cerebrospinal fluid (CSF) concentration of HSP-27 from 0.051 +/- 0.012 to 0.113 +/- 0.035 ng/ml but decreased the CSF concentration of HSP-70 from 50.42 +/- 8.96 to 30.9 +/- 9.9 ng/ml at 1 h postinsult. Pretreatment with topical exogenous HSP-70 (1 mug/ml) before FPI fully blocked injury-induced impairment of cromakalim and CGRP dilation and partially blocked injury-induced impairment of dilation to NS-1619. These data indicate that HSP-27 and HSP-70 contribute to modulation of K(+) channel-induced pial artery dilation. These data suggest that HSP-70 is an endogenous protectant of which its actions may be unmasked and/or potentiated with exogenous administration before brain injury.

Animals↗
PubMed2005

Plasminogen activators contribute to age-dependent impairment of NMDA cerebrovasodilation after brain injury.

Previous studies have observed that fluid percussion brain injury (FPI) impaired NMDA induced pial artery dilation in an age-dependent manner. This study was designed to investigate the contribution of plasminogen activators to impaired NMDA dilation after FPI in newborn and juvenile pigs equipped with a closed cranial window. In the newborn pig, NMDA (10(-8), 10(-6) M) induced pial artery dilation was reversed to vasoconstriction following FPI, but pretreatment with the plasminogen activator inhibitor PAI-1 derived hexapeptide (EEIIMD) (10(-7) M) prevented post injury vasoconstriction (9 +/- 1 and 16 +/- 1, vs. -6 +/- 2 and-11 +/- 3, vs. 5 +/- 1 and 9 +/- 1% for responses to NMDA 10(-8), 10(-6) M prior to FPI, after FPI, and after FPI in EEIIMD pretreated animals, respectively). In contrast, in the juvenile pig, NMDA dilation was only attenuated following FPI and EEIIMD pretreatment partially prevented such inhibition (9 +/- 1 and 16 +/- 1 vs. 2 +/- 1 and 4 +/- 1 vs. 5 +/- 1 and 7 +/- 1% for responses to NMDA prior to FPI, after FPI, and after FPI in EEIIMD pretreated animals, respectively). Additionally, EEIIMD blunted age-dependent pial artery vasoconstriction following FPI. EEIIMD blocked dilation to the plasminogen activator agonists uPA and tPA while responses to SNP and papaverine were unchanged. Pretreatment with suPAR, which blocked dilation to uPA, elicited effects on pial artery diameter and NMDA vascular activity post FPI similar to that observed with EEIIMD. These data show that EEIIMD and suPAR partially prevented FPI induced alterations in NMDA dilation and reductions in pial artery diameter. EEIIMD and suPAR are efficacious and selective inhibitors of plasminogen activator induced dilation. These data suggest that plasminogen activators contribute to age-dependent impairment of NMDA induced dilation following FPI.

Age Factors↗
PubMed2005

Age and cerebral circulation.

Cerebral blood flow, and its control, vary as a function of age. This review focuses on the perinatal period and compares/contrasts this age period to that of the juvenile/adult. Additionally, this review describes mechanisms important in the control of the cerebral circulation as a function of age during physiologic and pathologic conditions. Two topics of pathophysiology are considered: cerebral hypoxia ischemia, often seen in perinates due to problems with delivery or respiratory management post delivery, and traumatic brain injury, described as the shaken impact syndrome, an example of child abuse. Clinically, it is important to understand the pathophysiology of the cerebral circulation in order to optimize mechanistically appropriate therapeutic modalities.

Journal Article↗
PubMed2004

NMDA dilates pial arteries by KATP and Kca channel activation.

This study was designed to characterize the role of ATP sensitive (K(ATP)) and calcium sensitive (K(ca)) K(+) channel activation in N-methyl-d-aspartate (NMDA)-induced pial artery dilation in newborn pigs equipped with a closed cranial window. NMDA (10(-8), 10(-6)M) elicited pial artery dilation that was blunted by the K(ATP) channel antagonist glibenclamide (10(-6)M) and attenuated by the K(ca) channel antagonist iberiotoxin (10(-7)M) (8 +/- 1% and 14 +/- 1% versus 2 +/- 1% and 4 +/- 1% versus 5 +/- 1% and 9 +/- 2% for NMDA in the absence and presence of glibenclamide or iberiotoxin, respectively). Combined administration of glibenclamide and iberiotoxin essentially eliminated the response. Similar results were observed for glutamate. These data show that NMDA elicits cerebrovasodilation through activation of K(ATP) and K(ca) channels in newborn pigs.

Animals↗
PubMed2004

NMDA and age dependent cerebral hemodynamics after traumatic brain injury.

Activation of N-methyl-D-aspartate (NMDA) glutamatergic receptors elicits cerebrovascular dilation, may couple local cerebral metabolism to blood flow but contribute to excitotoxic neuronal cell death. While cerebral hemodynamics following traumatic brain injury may correlate with neurologic status, the role of NMDA vascular activity is uncertain in the sequelae of brain injury. NMDA dilation was impaired following fluid percussion brain injury (FPI) in an age dependent manner in the pig and the newly described opioid nociceptin/orphanin FQ (NOC/ oFQ) contributes to such impairment via the cyclooxygenase dependent generation of superoxide. Further, hypotensive pial artery dilation (PAD) was blunted after FPI but partially protected by pretreatment with the NMDA antagonist MK801. Cerebral blood flow (CBF) was reduced during normotension by FPI, further reduced by hypotension, but both were partially protected by MK801 in the newborn. In contrast, blunted hypotensive PAD was protected significantly less by MK801 in the juvenile pig. Similarly, MK801 had less protective effect on normotensive and hypotensive CBF values post FPI in the juvenile. These data indicate that NMDA receptor activation contributes to impaired hypotensive cerebral hemodynamics following FPI in an age dependent manner. Further, these data suggest that NMDA receptor activation, NOC/oFQ, and prostaglandins dynamically interact to impair cerebral hemodynamics following FPI.

Age Factors↗
PubMed2004

Nociceptin/orphanin FQ alters prostaglandin cerebrovascular action following brain injury.

Previous studies have observed that fluid percussion brain injury (FPI) elevated the CSF concentration of the opioid nociceptin/orphanin FQ (NOC/oFQ). In separate studies, FPI impaired pial artery dilation to the prostaglandins PGI2 and PGE2. This study was designed to investigate the following: (1) role of NOC/oFQ in impaired dilation to PGI2 and PGE2, (2) the effects of FPI on vasoconstriction to the TXA2 mimic U46619 and PGF2alpha, and (3) the role of NOC/oFQ in such FPI induced effects on U46619 and PGF(2alpha). Lateral FPI was induced in newborn pigs equipped with a closed cranial window. PGI2 (1, 10, 100 ng/ml) vasodilation was blunted by FPI and fully restored by the NOC/oFQ antagonist, [F/G] NOC/oFQ (1-13) NH2 (10(-6)M) (9 +/- 1, 13 +/- 1, and 19 +/- 1 vs. 2 +/- 1, 4 +/- 1, and 5 + 1 vs 7 +/- 1, 12 +/- 2, and 17 +/- 3% for control, FPI, and FPI + [F/G] NOC/oFQ (1-13) NH2, respectively). Similar effects were observed for PGE2. In contrast, U46619 (1, 10 ng/ml) induced vasoconstriction was potentiated by FPI but returned to the response observed prior to FPI by [F/G] NOC/oFQ (1-13) NH2 ( -8 +/- 1 and -14 +/- 1 vs. -15 +/- 1 and -25 +/- 1 vs. -7 +/- 1 and -12 +/- 2% for control, FPI, and FPI + [F/G] NOC/oFQ (1-13) NH2, respectively). Similar effects were observed for PGF(2alpha). Coadministration of NOC/oFQ (10(-10)M), the CSF concentration observed after FPI, with agonists under nonbrain injury conditions blunted PGI2 and PGE2 vasodilation, but potentiated U46619 and PGF2alpha vasoconstriction similarly to that observed after FPI. These data show that FPI blunted PGI2 and PGE2 vasodilation but potentiated U46619 and PGF2alpha vasoconstriction. Additionally, these data show that administration of a NOC/oFQ receptor antagonist prevented such FPI associated events. NOC/oFQ administrated in a concentration observed after FPI produced blunted dilator prostaglandin and potentiated vasoconstriction prostaglandin vascular responses under nonbrain injury conditions. Finally, these data suggest that NOC/oFQ alters prostaglandin cerebrovascular action following brain injury.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2004

Altered NO function contributes to impairment of uPA and tPA cerebrovasodilation after brain injury.

Urokinase (uPA) and tissue plasminogen activator (tPA) are serine proteases implicated in fibrinolysis, but their role in the regulation of the cerebrovascular response to brain trauma has not been investigated. This study was designed to (1) characterize the cerebrovascular activity of uPA and tPA, (2) investigate the role of nitric oxide (NO) in uPA and tPA vascular activity, and (3) characterize the effect of fluid percussion brain injury (FPI) on vascular responses to uPA and tPA. The closed cranial window technique in chloralose anesthetized newborn pigs was used to measure pial artery diameter and collect CSF for radioimmunoassay (RIA) of cGMP concentration. Topical uPA (10(-9), 10(-7) M) elicited pial artery dilation that was blunted by the NO synthase inhibitor, L-NNA (10(-6) M) (8 +/- 1% and 13 +/- 1 vs. 3 +/- 1% and 7 +/- 2%, respectively). Vasodilation in response to uPA was associated with an increase in CSF cGMP concentration (645 +/- 20, 865 +/- 39 and 1088 +/- 33 fmol/mL cGMP for control, uPA 10(-9), 10(-7) M, respectively). Similar data were obtained for tPA. Pial artery dilation to uPA was blunted following FPI (7 +/- 1% and 12 +/- 1% vs. 3 +/- 1% and 6 +/- 1%, respectively), while uPA-associated release of cGMP was blocked (677 +/- 45, 909 +/- 53, and 1110 +/- 55 vs. 283 +/- 10, 316 +/- 18, and 333 +/- 26 fmol/mL for control, uPA 10(-9), 10(-7) M before and after FPI, respectively). Similar data were obtained for tPA. These data show that uPA and tPA produce pial artery dilation in an NO-dependent manner. FPI blunted uPA and tPA induced pial artery dilation as well as the associated release of cGMP. These data suggest therefore that altered NO function contributes to the impairment of uPA and tPA cerebrovasodilation after brain injury.

Animals↗
PubMed2003

PTK, ERK and p38 MAPK contribute to impaired NMDA-induced vasodilation after brain injury.

N-Methyl-D-aspartate (NMDA)-induced pial artery dilation is reversed to vasoconstriction following fluid percussion brain injury (FPI). This study investigated the contribution of activation of protein tyrosine kinase (PTK) and the extracellular signal-regulated kinase (ERK) and p38 isoforms of mitogen-activated protein kinase (MAPK) in impaired vasodilation to NMDA after fluid percussion brain injury in pigs equipped with a closed cranial window. NMDA (10(-8), 10(-6) M)-induced vasodilation was reversed to vasoconstriction following fluid percussion brain injury, but such responses were partially restored by genistein (4',5,7-trihydroxy isoflavone), U0126 [1,4-diamino-2,3-dicyano-1,4-bis (0-aminophenylmercapto)butadiene] and SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole], PTK, ERK and p38 MAPK inhibitors (9+/-1% and 16+/-1%, sham control; -6+/-2% and -11+/-3%, fluid percussion brain injury; and 3+/-1% and 6+/-1%, fluid percussion brain injury-genistein, respectively). However, the robustness of the protection to NMDA dilation was significantly greater for U0126 vs. SB203580 (4+/-1% and 7+/-1% vs. 1+/-1% and 1+/-2%). Similar results were observed for glutamate. These data show that PTK, ERK and p38 MAPK activation contribute to impaired NMDA cerebrovasodilation after fluid percussion brain injury. These data suggest that activation of the ERK isoform of MAPK contributes to such impairment more than the p38 MAPK isoform.

Animals↗
PubMed2003

Differential role of PTK, ERK and p38 MAPK in superoxide impairment of NMDA cerebrovasodilation.

Previous studies in piglets have shown that the generation of oxygen free radicals (O(-)(2)) following traumatic brain injury and hypoxia/ischemia contribute to the reversal of N-methyl-D-aspartate (NMDA)-induced pial artery dilation to vasoconstriction. This study determined the contribution of protein tyrosine kinase (PTK) and mitogen-activated protein (MAPK) activation to impairment of NMDA cerebrovasodilation by O(-)(2) in piglets equipped with a closed window. Exposure of the cerebral cortex to a xanthine oxidase O(-)(2) generating system (OX) reversed NMDA (10(-8), 10(-6) M) dilation to vasoconstriction but such impairment was partially prevented by the PTK inhibitor, genistein, the MAPK (ERK isoform) inhibitor, U0126, and the MAPK (p38 isoform) inhibitor, SB203580 (9+/-1 and 15+/-1 vs. -1+/-1 and -1+/-1 vs. 5+/-1 and 9+/-1% for sham control, OX and OX in the presence of genistein, respectively). However, the p38 MAPK inhibitor, SB203580, prevented NMDA dilator impairment significantly less than the ERK MAPK inhibitor, U0126. Similar results were obtained for glutamate. These data show that PTK and MAPK activation by the presence of O(-)(2) contributes to the impairment of NMDA dilation. Furthermore, these data indicate a differential role for ERK and p38 MAPK activation in impairment of NMDA dilation by O(-)(2) in the brain.

Animals↗
PubMed2003

Protein kinase C activation generates superoxide and contributes to impairment of cerebrovasodilation induced by G protein activation after brain injury.

Previous studies have observed that activation of protein kinase C (PKC) contributes to generation of superoxide anion (O(-)(2)) after fluid percussion brain injury (FPI). This study was designed to characterize the effects of FPI on the vascular activity of two activators of a pertussis toxin sensitive G protein, mastoparan and mastoparan-7, and the role of PKC dependent O(-)(2) generation in such effects in newborn pigs equipped with a closed cranial window. Mastoparan (10(-8), 10(-6) M) elicited pial artery dilation that was blunted by FPI and partially restored by the PKC inhibitor chelerythrine (10(-7) M) or the O(-)(2) free radical scavengers polyethylene glycol superoxide dismutase and catalase (SODCAT) (9+/-1 and 16+/-1, sham control; 3+/-1 and 5+/-1, FPI; and 7+/-1 and 11+/-1%, FPI SODCAT pretreated). Similar results were observed for mastoparan-7 but the inactive analogue mastoparan-17 had no effect on pial artery diameter. Exposure of the cerebral cortex to a xanthine oxidase O(-)(2) generating system blunted mastoparan induced pial artery dilation similar to FPI (10+/-1 and 17+/-1 vs. 2+/-1 and 3+/-1%). Pertussis toxin (1 microg/ml) exposure blocked mastoparan and mastoparan-7 vasodilation. These data show that pertussis toxin sensitive G protein activation elicits cerebrovasodilation that is blunted following FPI in a PKC dependent manner. These data also show that O(-)(2) generation similarly blunts G protein mediated cerebrovasodilation. These data suggest that PKC dependent O(-)(2) generation contributes to impaired G protein mediated cerebrovasodilation after FPI.

Alkaloids↗
PubMed2003

Newborn pig nociceptin/orphanin FQ activates protein tyrosine kinase and mitogen activated protein kinase to impair NMDA cerebrovasodilation after ischemia.

This study characterized the contributions of protein tyrosine kinase and mitogen-activated protein kinase in nociceptin/orphanin FQ induced impairment of NMDA dilation after cerebral hypoxia/ischemia in anesthetized newborn pigs equipped with a closed cranial window. Topical nociceptin/orphanin FQ, in a concentration observed after hypoxia/ischemia, impaired NMDA pial artery vasodilation. Co-administration either of the protein tyrosine kinase inhibitor genistein or the mitogen activated protein kinase inhibitor U0126 with nociceptin/orphanin FQ partially prevented the inhibition of NMDA dilation compared to that observed in their absence. After exposure to hypoxia/ischemia, pial artery dilation in response to NMDA was reversed to vasoconstriction but pretreatment with either genistein or U0126 partially protected such impairment. These data show that protein tyrosine kinase and mitogen activated protein kinase activation contribute to nociceptin/orphanin FQ induced impairment of NMDA dilation. These data suggest that protein tyrosine and mitogen activated protein kinase are involved in the mechanism by which nociceptin/orphanin FQ impairs NMDA dilation following hypoxia/ischemia.

Animals↗
PubMed2003

ET-1 contributes to age-dependent G protein impairment after brain injury.

Previous studies have observed that endothelin-1 (ET-1) concentration is elevated in CSF and contributes to impaired cerebral hemodynamics following fluid percussion brain injury (FPI) in an age-dependent manner. This study was designed to characterize the effects of FPI on the vascular activity of two activators of a pertussin toxin-sensitive G protein, mastoparan and mastoparan-7, as a function of age and the role of ET-1 in such effects in newborn (1-5 days old) and juvenile (3-4 weeks old) pigs equipped with a closed cranial window. Mastoparan (10(-8), 10(-6) M) elicited pial artery dilation that was blunted more by FPI in newborn versus juvenile pigs (9 +/- 1 and 16 +/- 1 vs. 3 +/- 1 and 5 +/- 1%, newborn; 9 +/- 1 and 15 +/- 1 vs. 6 +/- 1 and 9 +/- 1%, juvenile). Similar results were observed for mastoparan-7, but the inactive analogue mastoparan-17 had no effect on pial diameter. BQ123 (10(-6) M), an ET-1 antagonist, partially restored impaired mastoparan dilation after FPI in the newborn but not in the juvenile (3 +/- 1 and 5 +/- 1 vs. 7 +/- 1 and 11 +/- 1%, newborn; 6 +/- 1 and 9 +/- 1 vs. 6 +/- 1 and 10 +/- 1%, juvenile). These data show that G protein activation elicits cerebrovasodilation that is blunted following FPI in an age-dependent manner. These data suggest that ET-1 contributes to the impairment of G protein-mediated vasodilation in an age-dependent manner after FPI.

Age Factors↗