Biomedical subjects

William M Armstead

Publications and source records attributed to William M Armstead.

31 records · Page 2Linked to original sources

PubMed2003

Cyclooxygenase-2-dependent superoxide generation contributes to age-dependent impairment of G protein-mediated cerebrovasodilation.

BACKGROUND: Previous studies have observed that activation of cyclooxygenase-2 contributes to generation of superoxide anion 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 cyclooxygenase-2-dependent superoxide anion generation in such effects as a function of age. METHODS: Lateral FPI was induced in anesthetized newborn (1-5-day-old) and juvenile (3-4-week-old) pigs equipped with a closed cranial window. RESULTS: Mastoparan (10(-8), 10(-6) M) elicited pial artery dilation that was blunted more 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%, juveniles). Similar results were observed for mastoparan-7 but the inactive analog mastoparan-17 had no effect on pial artery diameter. Indomethacin (a cyclooxygenase-1 and cyclooxygenase-2 inhibitor), NS398 (a cyclooxygenase-2 inhibitor), and polyethylene glycol superoxide dismutase and catalase (free radical scavengers) partially restored impaired mastoparan dilation after FPI in the newborn in a roughly equivalent manner but not in the juvenile (3 +/- 1 and 5 +/- 1 vs. 8 +/- 1 and 13 +/- 1% newborn, 6 +/- 1 and 9 +/- 1 vs. 7 +/- 1 and 10 +/- 1% juvenile for NS398 pretreatment). CONCLUSIONS: These data show that G protein activation elicits cerebrovasodilation that is blunted following FPI in an age-dependent manner, and suggest that cyclooxygenase-2-dependent superoxide anion generation contributes to G protein activation-induced dilator impairment after the insult in an age-dependent manner.

Aging↗

PubMed2003

Selective blockade of AT1 receptor attenuates impairment of hypotensive autoregulation and improves cerebral blood flow after brain injury in the newborn pig.

BACKGROUND: Fluid percussion injury (FPI) in piglets produces vasoconstriction of pial arteries (PAs), decreases in cerebral blood flow (CBF), and impairment of hypotensive autoregulation. Two types of angiotensin II receptors, AT1 and AT2, have been identified in the brain. This study characterized the effect of pretreatment with AT1- and AT2-selective antagonists on CBF and hypotensive autoregulation after FPI. METHODS: Fluid percussion injury was induced in chloralose-anesthetized newborn pigs equipped with closed cranial windows. CBF was determined by the radiolabeled microsphere technique. RESULTS: Moderate and severe hypotension (71 +/- 3, 53 +/- 2, and 40 +/- 1 mmHg for normotension, moderate hypotension, and severe hypotension, respectively) elicited PA dilation without changes in CBF in sham control piglets. The AT1 antagonist ZD 7155 partially restored impaired hypotension-induced PA dilation after FPI (19 +/- 1 and 34 +/- 1 vs. 5 +/- 1 and 7 +/- 1 vs. 12 +/- 1 and 20 +/- 3% for PA dilation during moderate and severe hypotension in sham control, FPI, and FPI + ZD 7155 animals, respectively). ZD 7155 also blunted the reductions in CBF during normotension and hypotension observed in untreated animals (43 +/- 4, 38 +/- 5, and 55 +/- 3 vs. 32 +/- 4, 19 +/- 2, and 27 +/- 5% CBF reductions during normotension, moderate hypotension, and severe hypotension in untreated and pretreated animals, respectively). The AT2 selective antagonist PD 123,319 did not restore hypotension-induced PA dilation and did not prevent decreases in CBF observed during normotension and moderate and severe hypotension after FPI. CONCLUSION: These data indicate that blockade of the AT1 and not the AT2 receptor diminished the reduction in hypotensive PA dilation after FPI. AT1 blockade also blunted the decrease in CBF during normotension as well as the further decrease in CBF observed during hypotension after FPI. These data suggest that AT1 receptor activation by angiotensin II contributes to cerebrovascular dysregulation during hypotension after FPI.

Angiotensin II Type 1 Receptor Blockers↗

PubMed2003

PTK, MAPK, and NOC/oFQ impair hypercapnic cerebrovasodilation after hypoxia/ischemia.

This study characterized the contributions of protein tyrosine kinase (PTK) and mitogen-activated protein kinase (MAPK) in nociceptin/orphanin FQ (NOC/oFQ)-induced impairment of hypercapnic pial artery dilation (PAD) after hypoxia/ischemia (H/I) in piglets equipped with a closed cranial window. NOC/oFQ (10(-10) M cerebrospinal fluid H/I concentration) impaired hypercapnic PAD (21 +/- 2% vs. 13 +/- 1%). Coadministration of either of the PTK inhibitors genistein or tyrphostin A23 or the MAPK inhibitors U-0126 or PD-98059 with NOC/oFQ (10(-10) M) partially prevented the inhibition of hypercapnic PAD compared with that observed in their absence (21 +/- 2% vs. 17 +/- 1% for genistein). After exposure to H/I, PAD in response to hypercapnia was impaired, but pretreatment with either genistein, tyrphostin A23, U-0126, or PD-98059 partially protected such impairment (17 +/- 1% vs. 4 +/- 1% vs. 9 +/- 1% for sham control, H/I, and H/I + genistein pretreatment, respectively). These data show that PTK and MAPK activation contribute to NOC/oFQ-induced impairment of hypercapnic PAD. These data suggest that activation of PTK and MAPK is also involved in the mechanism by which NOC/oFQ impairs hypercapnic PAD after H/I.

Animals↗

PubMed2003

Differential role of PTK and ERK MAPK in superoxide impairment of K(ATP) and K(Ca) channel cerebrovasodilation.

Previously, superoxide (O2 -) has been observed to impair pial artery dilation (PAD) to activators of the ATP-sensitive (KATP) and calcium-sensitive (KCa) K+ channels. This study tested the hypothesis that activation of protein tyrosine kinase (PTK) and the ERK isoform of MAPK by O2 - contribute to impairment of KATP and KCa channel PAD. Exposure of the cerebral cortex to a xanthine oxidase O2 --generating system (OX) blunted PAD to cromakalim, a KATP agonist, but preadministration of genistein, a PTK antagonist, or U-0126, an ERK MAPK inhibitor, almost completely prevented such impairment (11 +/- 1 and 22 +/- 1 vs. 3 +/- 1 and 7 +/- 1 vs. 10 +/- 1 and 16 +/- 2% for cromakalim with 10-8 and 10-6 M PAD during control, OX, and OX + genistein conditions). In contrast, neither genistein nor U-0126 robustly protected PAD to NS-1619, a KCa agonist, after OX exposure (11 +/- 1 and 18 +/- 2 vs. 1 +/- 1 and 2 +/- 1 vs. 4 +/- 1 and 6 +/- 1% for 10-8 and 10-6 M NS-1619 during control, OX, and OX + genistein conditions). These data show that PTK and ERK MAPK activation contribute to O2 --induced KATP and KCa channel PAD impairment and suggest a differential greater role for PTK and ERK MAPK in KATP vs. KCa channel PAD impairment.

Adenosine Triphosphate↗

PubMed2002

G protein activation elicits cerebrovasodilation through interaction with K(ATP) and K(Ca) channels.

This study was designed to characterize the vascular activity of two activators of a pertussis toxin-sensitive G protein, mastoparan and mastoparan-7, on pial artery diameter and their interaction with the ATP sensitive K (K(ATP)) and calcium sensitive K (K(Ca)) channel in newborn pigs equipped with a closed cranial window. Mastoparan (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) (10+/-1 and 17+/-1 vs. 3+/-1 and 6+/-1 vs. 6+/-1 and 10+/-2% for mastoparan in the absence and presence of glibenclamide or iberiotoxin, respectively). Similar results were observed for mastoparan-7 but the inactive analogue mastoparan-17 had no effect on pial artery diameter. These data show that G protein activation elicits cerebrovasodilation through interaction with K(ATP) and K(Ca) channels.

Adenosine Triphosphate↗

PubMed2002

Age dependent NMDA contribution to impaired hypotensive cerebral hemodynamics following brain injury.

Previous studies have observed that fluid percussion brain injury (FPI) impaired NMDA induced pial artery dilation (PAD) in an age dependent manner. Unrelated studies observed a similar age dependent impairment of hypotensive cerebral autoregulation after FPI. This study was designed to test the hypothesis that NMDA receptor activation contributes to impairment of cerebral autoregulation during hypotension after FPI in an age dependent manner. Therefore, the role of NMDA in impaired hypotensive cerebrovascular regulation after FPI was compared in newborn and juvenile pigs equipped with a closed cranial window. Ten minutes of hypotension (10-15 ml blood/kg) decreased mean arterial blood pressure uniformly in both groups (approximately 44%). In the newborn, hypotensive PAD was blunted within 1 h of FPI but partially protected by pretreatment with the NMDA antagonist MK801 (1 mg/kg i.v.) (34+/-1 vs. 8+/-1 vs. 25+/-2% for sham control, FPI, and FPI-MK801, respectively). Cerebral blood flow (CBF) was reduced during normotension by FPI, further reduced by hypotension, but both were partially protected by MK801 in the newborn (56+/-5, 35+/-2, and 16+/-1 vs. 62+/-6, 45+/-3, and 30+/-2 ml/min 100 g for normotension, normotension-FPI, and hypotension-FPI in the absence and presence of MK801, respectively). In contrast, blunted hypotensive PAD was protected significantly less by MK801 in the juvenile (32+/-2 vs. 7+/-2 vs. 16+/-2% for sham control, FPI, and FPI-MK801, respectively). 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 brain injury in an age dependent manner.

Aging↗

PubMed2002

Protein tyrosine kinase and mitogen-activated protein kinase activation contribute to K(ATP) and K(ca) channel impairment after brain injury.

Previous studies have observed that pial artery dilation to activators of the ATP sensitive K (K(ATP)) and calcium sensitive K (K(ca)) channel was blunted following fluid percussion brain injury (FPI) in the piglet. In recent studies in the rat, protein tyrosine kinase (PTK) activation was observed to contribute to K(ATP) channel impairment after FPI, but such a role in K(ca) channel impairment was unclear. This study investigated the role of PTK and mitogen activated protein kinase (MAPK) activation in blunted pial dilation to K(ATP) and K(ca) channel agonists following FPI in piglets equipped with a closed cranial window. Cromakalim and NS1619 (10(-8), 10(-6) M) induced pial artery dilation was blunted after FPI, but partially restored by the PTK inhibitors genistein (10(-6) M) and tyrphostin A23 (10(-5) M) (10+/-1 and 19+/-1%, sham control; 2+/-1 and 4+/-1%, FPI; and 7+/-1 and 11+/-1% FPI-genistein pretreated for NS1619 10(-8), 10(-6) M, respectively). Cromakalim- and NS1619-induced pial dilation was also partially restored after FPI by pretreatment with the MAPK inhibitors U0126 (10(-6) M) and PD98059 (10(-5) M) (12+/-1 and 21+/-1%, sham control; 2+/-1 and 4+/-1%, FPI; and 6+/-1 and 10+/-2%, FPI-U0126 pretreated for NS1619 10(-8), 10(-6) M, respectively). These data suggest that PTK and MAPK activation contribute to K(ATP) and K(ca) channel impairment following FPI.

Animals↗

PubMed2002

Relationship between NOC/oFQ, dynorphin, and COX-2 activation in impaired NMDA cerebrovasodilation after brain injury.

Previous studies have observed that the recently described endogenous opioid, nociceptin/orphanin FQ (NOC/oFQ), contributes to impairment of N-methyl-D-aspartate (NMDA)-induced cerebrovasodilation following fluid percussion brain injury (FPI) via a cyclooxygenase (COX)-dependent generation of superoxide anion (O(2)(-)). This study was designed to investigate the relationship between NOC/oFQ, another opioid, dynorphin, and activation of the COX-2 isoform of the enzyme in such impaired dilation to NMDA after FPI in piglets equipped with a closed cranial window. Superoxide dismutase (SOD)-inhibitable nitroblue tetrazolium (NBT) reduction was determined as an index of O(-)(2) generation. Under non-brain injury conditions, NOC/oFQ (10(-10) M), the CSF concentration observed after FPI, increased CSF dynorphin, while the NOC/oFQ antagonist [F/G] NOC/oFQ (1-13) NH(2) attenuated the stimulated release of dynorphin following FPI (34 +/- 3 and 97 +/- 6 vs. 36 +/- 3 and 68 +/- 8 pg/mol for CSF dynorphin before and after FPI in untreated and NOC/oFQ antagonist-pretreated animals). FPI increased SOD-inhibitable NBT reduction, but pretreatment with norbinaltorphimine, a dynorphin antagonist, or NS398, a COX-2 inhibitor, blunted such reduction (1 +/- 1 vs. 19 +/- 3 vs. 4 +/- 1 vs. 4 +/- 1 pmol/mm(2) for control, FPI, FPI-norbinaltorphimine and FPI-NS398, respectively). Under non-brain injury conditions, dynorphin, in a concentration observed in CSF after FPI, also increased SOD-inhibitable NBT reduction, which was blunted by NS398. NMDA-induced pial artery dilation was reversed to vasoconstriction following FPI, but pretreatment with norbinaltorphimine or NS398 partially protected such responses (9 +/- 1 and 16 +/- 1, control; - 8 +/- 1 and - 13 +/- 2, FPI; 6 +/- 1 and 12 +/- 1% FPI-norbinaltorphimine for NMDA 10(-8), 10(-6) M, respectively). These data show that NOC/oFQ modulates the CSF release of dynorphin after FPI. These data also show that dynorphin contributes to O(2)(-) generation after FPI via COX-2 activation. These data additionally indicate that dynorphin and COX-2 activation contribute to impairment of NMDA pial artery dilation after FPI. Finally, these data suggest that NOC/oFQ impairs NMDA dilation postinsult via the sequential release of dynorphin, activation of COX-2, and generation of O(2)(-).

Animals↗

PubMed2002

Prostaglandins contribute to impaired angiotensin II-induced cerebral vasodilation after brain injury.

This study characterized the effects of fluid percussion brain injury (FPI) on angiotensin II (AII)-induced cerebral vasodilation, determined the role of prostaglandins in such changes and evaluated the contribution of two subtypes of AII receptors (AT(1) and AT(2)) to the effects of AII on cerebrovascular regulation. Topical AII (10(-8), 10(-6), 10(-4) M) elicited vasodilation, which was attenuated by FPI (10 +/- 1; 18 +/- 2; 27 +/- 1% vs. 2 +/- 1; 4 +/- 1; 7 +/- 1%). Such changes in diameter were associated with increases in CSF 6-keto-PGF(1alpha), the stable breakdown product of PGI(2) (1.5 +/- 0.1; 2.1 +/- 0.1; 4.0 +/- 0.3 fold) and TXB(2), the stable breakdown product of TXA(2) (1.2 +/- 0.1; 1.4 +/- 0.1; 1.6 +/- 0.1 fold). However, after FPI, increases in 6-keto PGF(1alpha) were blocked (1.0 +/- 0.1; 1.0 +/- 0.1; 1.1 +/- 0.1 fold) whereas TXB(2) release was enhanced (1.5 +/- 0.1; 1.8 +/- 0.1; 1.9 +/- 0.1 fold). Pretreatment with the cyclooxygenase inhibitor indomethacin (5 mg/kg i.v.) in FPI animals partially protected AII vasodilation (8 +/- 1; 14 +/- 2; 19 +/- 3%). CGP 42112A, a putative AT(2) agonist, elicited vasodilation, which was also blunted by FPI. Such dilation was not associated with CSF prostaglandin changes, and indomethacin did not protect responses altered by FPI. Vasodilatation caused by low concentrations of AII was blunted by an AT(1) antagonist ZD 7155 but unchanged by an AT(2) antagonist PD 123,319. The high AII concentration produced dilation that was blunted by both antagonists. These data show that FPI impairs AII-mediated vasodilation. These data suggest that FPI causes these changes via alteration in an AT(1)-mediated production of prostaglandins. These data additionally suggest that FPI induced impairment of AT(2) mediated vasodilation is independent of an altered production of prostaglandins.

Angiotensin II↗

PubMed2002

Age-dependent NOC/oFQ contribution to impaired hypotensive cerebral hemodynamics after brain injury.

Previous studies have observed that the newly described opioid, nociceptin/orphanin FQ (NOC/oFQ), contributed to age dependent reductions in cerebral blood flow (CBF) and pial artery diameter after fluid percussion brain injury (FPI). Unrelated studies have noted a similar age dependency in impaired hypotensive cerebral autoregulation after FPI. This study was designed to compare the role of NOC/oFQ in impaired hypotensive cerebral autoregulation after FPI in newborn and juvenile pigs equipped with a closed cranial window. Ten minutes of hemorrhagic hypotension (10-15 mL blood/kg) decreased mean arterial blood pressure uniformly in both groups ( approximately 44%). In the newborn, hypotensive pial artery dilation was blunted within 1 h of FPI but partially protected by pretreatment with the NOC/oFQ antagonist, [F/G] NOC/oFQ (1-13) NH(2) (1 mg/kg, i.v.) (34 +/- 1 vs. 8 +/- 1 vs. 20 +/- 2% for sham control, FPI, and FPI-[F/G] NOC/oFQ (1-13) NH(2), respectively). CBF was reduced during normotension by FPI, further reduced by hypotension, but both were partially protected by this antagonist in the newborn (63 +/- 4, 34 +/- 2, and 20 +/- 2 vs. 65 +/- 4, 47 +/- 2, and 29 +/- 2 mL/min.100 g for normotension, normotension-FPI and hypotension-FPI in the absence and presence of [F/G] NOC/oFQ (1-13) NH(2), respectively). In contrast, blunted hypotensive pial artery dilation was protected significantly less by this NOC/oFQ antagonist in the juvenile (32 +/- 2 vs. 7 +/- 2 vs. 13 +/- 2% for sham control, FPI and FPI-NOC/oFQ antagonist, respectively). Similarly, [F/G] NOC/oFQ (1-13) NH(2) had less protective effect on normotensive and hypotensive CBF values post FPI in the juvenile. These data indicate that NOC/oFQ contributes to impaired hypotensive cerebral hemodynamics following brain injury in an age-dependent manner.

Age Factors↗

PubMed2002

Role of Nociceptin/Orphanin FQ in the physiologic and pathologic control of the cerebral circulation.

Nociceptin/orphanin FQ is a newly described member of the opioid family. Previous minireviews in this series have described the contribution of important factors, including opioids, in the regulation of the cerebral circulation during physiologic and pathologic conditions. The present review extends these initial comments to an opioid whose vascular actions have only very recently been appreciated. In particular, this review discusses the contribution of nociceptin/orphanin FQ to impaired cerebral hemodynamics after cerebral hypoxia/ischemia and traumatic brain injury.

Animals↗

PubMed2002

NOC/oFQ and NMDA contribute to piglet hypoxic ischemic hypotensive cerebrovasodilation impairment.

Previous studies have observed that hypotensive pial artery dilation was blunted after hypoxia-ischemia. In unrelated studies, the opioid nociceptin/orphanin FQ (NOC/oFQ) was observed to contribute to hypoxic ischemic impairment of N-methyl-D-aspartate (NMDA)-induced pial dilation. This study determined the contribution of NOC/oFQ and NMDA to hypoxic ischemic hypotensive cerebrovasodilation impairment in newborn pigs equipped with a closed cranial window. Global cerebral ischemia was produced via elevated intracranial pressure. Hypoxia decreased PO(2) to 33 +/- 3 mm Hg. Topical NOC/oFQ (10(-10) M), the cerebrospinal fluid concentration after hypoxia-ischemia, had no effect on pial artery diameter by itself but attenuated hypotension (mean arterial blood pressure decrease of 44 +/- 2%) -induced pial artery dilation (35 +/- 2% versus 22 +/- 3%). Hypotensive 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; 29 +/- 2%, sham control; 7 +/- 2%, hypoxia-ischemia; and 13 +/- 2%, hypoxia-ischemia and [F/G] NOC/oFQ (1-13) NH(2)). Coadministration of the NMDA antagonist MK801 (10(-5) M) with NOC/oFQ(10(-10) M) partially prevented hypotensive pial dilation impairment. Similarly, pretreatment with MK801 partially protected hypoxic ischemia impairment of hypotensive pial dilation (35 +/- 2%, sham control; 7 +/- 1%, hypoxia-ischemia; 22 +/- 2%, hypoxia-ischemia + MK801). These data show that NOC/oFQ and NMDA contribute to hypoxic ischemic hypotensive cerebrovasodilation impairment. These data suggest that NOC/oFQ modulation of NMDA vascular activity also contributes to such hypotensive impairment.

Animals↗

PubMedDate not supplied

Endothelin-1 concentrations in clone calves, their surrogate dams, and fetal fluids at birth: association with oxygen treatment.

Increased endothelin-1 (ET-1) plasma concentration in human infants is associated with persistent pulmonary hypertension of the newborn, a problem also identified in calves derived from somatic cell clone technology. Increased ET-1 also is present in the amnionic fluid and plasma of the infant and mother in preeclampsia, a condition associated with abnormal placentation. Abnormalities in placentation are identified in clone calves. We measured ET-1 in fetal fluid, calf plasma, and surrogate dam plasma in 40 clone calves at the time of term delivery. Calves were subsequently identified as being either oxygen treated (O2) or non-oxygen treated based on their postpartum clinical course. Fetal fluid ET-1 concentration greater than 1.4 ng/mL carried a 3-fold increase in odds of the calf being treated with oxygen. Maternal plasma ET-1 concentration was greater in the O2 group (13 pg/ mL: [8-23 pg/mL] versus 25 pg/mL [12-40 pg/mL]; median, 25-75 percentile). Plasma ET-1 concentration in calves was not significantly different between groups. Fetal fluid ET-1 may serve as a marker for neonatal disorders of oxygenation in clone calves and the source of ET-1 may be the placenta.

Amniotic Fluid↗