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Biomedical subjects

W M Armstead

Publications and source records attributed to W M Armstead.

At least 55 records · Page 3Linked to original sources
PubMed1998

Vasopressin contributes to dynorphin modulation of hypoxic cerebrovasodilation.

Because pial artery dilation during a 20- or 40-min hypoxic exposure was less than that observed during a 5- or 10-min exposure, stimulus duration determines the vascular response to hypoxia. Dynorphin (Dyn) modulates hypoxic pial dilation and contributes to decremented dilation during longer hypoxic exposures. This study was designed to determine whether vasopressin (VP) contributes to Dyn modulation of hypoxic pial dilation in newborn pigs equipped with a closed cranial window. Moderate (M) and severe (S) hypoxia (arterial PO2 approximately 35 and 25 mmHg, respectively) had no effect on cerebrospinal fluid VP during a 5-min exposure but increased its concentration during longer exposure periods. The VP antagonist [beta-mercapto-beta,beta-cyclopentamethylenepropionyl1,O-Me-Tyr2, Arg8]vasopressin (MEAVP) had no influence on pial dilation during the 5-min exposure but potentiated the 20- and 40-min M and S hypoxic exposure dilations: 21 +/- 2 vs. 29 +/- 3% and 23 +/- 2 vs. 33 +/- 2% for 20- and 40-min S hypoxic dilation before and after MEAVP. Topical VP during 5 min of hypoxia elicited dilation that was reversed to vasoconstriction during 20 min of S and 40 min of M and S hypoxia. Similarly, during 5 min of hypoxia, Dyn elicited dilation that was reversed to vasoconstriction during longer hypoxic periods. MEAVP blunted this Dyn-induced vasoconstriction. These data show that VP modulates hypoxic pial dilation in a stimulus duration-dependent manner and that VP contributes to the reversal of Dyn from a dilator to a constrictor during prolonged hypoxia. Finally, these data suggest that VP contributes to Dyn modulation of hypoxic cerebrovasodilation.

Animals↗
PubMed1997

Role of impaired cAMP and calcium-sensitive K+ channel function in altered cerebral hemodynamics following brain injury.

Previous studies have shown that pial arteries constricted and responses to dilator opioids were blunted after fluid percussion injury (FPI) in newborn pigs. Membrane potential of vascular muscle is a major determinant of vascular tone and activity of K+ channels is a major regulator of membrane potential. Recent data show that opioids elicit dilation via the sequential production of cAMP and subsequent activation of calcium-sensitive K+ (K(Ca2+)) channels by this second messenger. The present study was designed to investigate the effect of FPI on cAMP and K(Ca2+) channel function. Chloralose-anesthetized piglets equipped with a closed cranial window were connected to a percussion device consisting of a saline-filled cylindrical reservoir and a metal pendulum. Brain injury of moderate severity (1.9-2.1 atm) was produced by allowing the pendulum to strike a piston on the cylinder. FPI blunted dilation to the cAMP analogs 8-Bromo cAMP and Sp 8-Bromo cAMPs (10(-8), 10(-6) M), (9 +/- 1 and 16 +/- 1 vs. 2 +/- 1 and 3 +/- 1% dilations to 8-Bromo cAMP before and after FPI, respectively, n = 8). Similarly, FPI attenuated dilation to pituitary adenylate cyclase activating peptide (PACAP), an endogenous activator of adenylate cyclase, and NS 1619, a K(Ca2+) channel agonist (9 +/- 1 and 16 +/- 1 vs. 3 +/- 1 and 5 +/- 1% for NS 1619 10(-8), 10(-6) M before and after FPI, respectively, n = 8). Moreover, FPI attenuated PACAP, methionine enkephalin, leucine enkephalin, and dynorphin induced elevations in CSF cAMP concentration (940 +/- 2, 1457 +/- 50, and 2191 +/- 53 vs. 810 +/- 17, 1033 +/- 36, and 1218 +/- 49 fmol/ml for control, PACAP 10(-8), 10(-6) M before and after FPI, respectively, n = 8). These data show that cAMP and K(Ca2+) channel function is impaired after FPI. Further these data suggest that impaired cAMP and K(Ca2+) channel function contribute to altered cerebral hemodynamics following FPI.

Animals↗
PubMed1997

Role of activation of calcium-sensitive K+ channels and cAMP in opioid-induced pial artery dilation.

The present study was designed to investigate the role of activation of Kca+2 channels and cAMP in opioid-induced pial artery dilation in newborn pigs equipped with closed cranial windows. Methionine enkephalin, an endogenous mu agonist, elicited dilation that was modestly attenuated by the Kca+2 channel antagonist, iberiotoxin (10(-7) M) (7 +/- 1, 11 +/- 1 and 16 +/- 1 vs. 4 +/- 1, 7 +/- 1, and 11 +/- 1% for methionine enkephalin 10(-10), 10(-8), 10(-6) M in the absence and presence of iberiotoxin, respectively). Dilator responses to leucine enkephalin and dynorphin, endogenous delta and kappa agonists, as well as the synthetic analogues DAMGO, DPDPE, deltorphin and U50488H all were similarly attenuated by iberiotoxin. Dilation in response to methionine enkephalin was accompanied by increased CSF cAMP concentration (1170 +/- 21, 1358 +/- 22, 1473 +/- 26, and 1575 +/- 24 fmol/ml for control, 10(-10), 10(-8), 10(-6) M methionine enkephalin, respectively). Methionine enkephalin-induced dilation was attenuated by Rp 8-bromo cAMPs (10(-5) M), a cAMP antagonist (7 +/- 1, 11 +/- 1 and 17 +/- 1 vs. 2 +/- 1, 4 +/- 1, and 7 +/- 1% for methionine enkephalin 10(-10), 10(-8), and 10(-6) M in the absence and presence of Rp 8-bromo cAMPs, respectively). Dilation by the other endogenous and synthetic opioid analogues was also accompanied by elevated CSF cAMP and attenuated by Rp 8-bromo cAMPs. Additionally, dilation produced by the cAMP analogue, 8-bromo cAMP, was blunted by iberiotoxin. These data show that both cAMP and activation of Kca+2 channels contribute to opioid-induced pial artery dilation. Further, these data suggest that opioids elicit dilation, at least in part, via the sequential release of cAMP and subsequent activation of Kca+2 channels by this second messenger.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1997

Role of nitric oxide, cyclic nucleotides, and the activation of ATP-sensitive K+ channels in the contribution of adenosine to hypoxia-induced pial artery dilation.

Previously, it had been observed that nitric oxide (NO) contributes to hypoxia-induced pial artery dilation in the newborn pig. Additionally, it was also noted that activation of ATP-sensitive K+ channels (KATP) contribute to cGMP-mediated as well as to hypoxia-induced pial dilation. Although somewhat controversial, adenosine is also thought to contribute to hypoxic cerebrovasodilation. The present study was designed to investigate the role of NO, cyclic nucleotides, and activation of KATP channels in the elicitation of adenosine's vascular response and relate these mechanisms to the contribution of adenosine to hypoxia-induced pial artery dilation. The closed cranial window technique was used to measure pial diameter in newborn pigs. Hypoxia-induced artery dilation was attenuated during moderate (PaO2 approximately 35 mm Hg) and severe hypoxia (PaO2 approximately 25 mm Hg) by the adenosine receptor antagonist 8-phenyltheophylline (8-PT) (10(-5) M) (26 +/- 2 vs. 19 +/- 2 and 34 +/- 2 vs. 22 +/- 2% for moderate and severe hypoxia in the absence vs. presence of 8-PT, respectively). This concentration of 8-PT blocked pial dilation in response to adenosine (8 +/- 2, 16 +/- 2, and 23 +/- 2 vs. 2 +/- 2, 4 +/- 2, and 6 +/- 2% for 10(-8), 10(-6), and 10(-4) M adenosine before and after 8-PT, respectively). Similar data were also obtained using adenosine deaminase as a probe for the role of adenosine in hypoxic pial dilation. Adenosine-induced dilation was associated with increased CSF cGMP concentration (390 +/- 11 and 811 +/- 119 fmol/ml for control and 10(-4) M adenosine, respectively). The NO synthase inhibitor, L-NNA, and the cGMP antagonist, Rp 8-bromo cGMPs, blunted adenosine-induced pial dilation (8 +/- 1, 14 +/- 1, and 20 +/- 3 vs. 3 +/- 1, 5 +/- 1, and 8 +/- 3% for 10(-8), 10(-6), and 10(-4) M adenosine before and after L-NNA, respectively). Adenosine dilation was also blunted by glibenclamide, a KATP antagonist (9 +/- 2, 14 +/- 3, 21 +/- 4 vs. 4 +/- 1, 8 +/- 2, and 11 +/- 2% for 10(-8), 10(-6), and 10(-4) M adenosine before and after glibenclamide, respectively). Finally, it was also observed that adenosine-induced dilation was associated with increased CSF cAMP concentration and the cAMP antagonist, Rp 8-bromo cAMPs, blunted adenosine pial dilation. These data show that adenosine contributes to hypoxic pial dilation. These data also show that NO, cGMP, cAMP, and activation of KATP channels all contribute to adenosine induced pial dilation. Finally, these data suggest that adenosine contributes to hypoxia-induced pial artery dilation via cAMP and activation of KATP channels by NO and cGMP.

Adenosine↗
PubMed1997

Role of PACAP in the relationship between cAMP and opioids in hypoxia-induced pial artery vasodilation.

The opioids methionine enkephalin and leucine enkephalin contribute to hypoxic pial artery dilation in the newborn pig, and adenosine 3',5'-cyclic monophosphate (cAMP) analogs have been shown to elevate cerebrospinal fluid (CSF) opioid concentration. The present study was designed to investigate the contribution of cAMP to hypoxic dilation and to determine whether an endogenous activator of adenylate cyclase, pituitary adenylate cyclase-activating peptide (PACAP), could modulate the cAMP-induced release of opioids to contribute to hypoxic pial dilation in piglets equipped with closed cranial windows. An alpha level of P < 0.05 was considered significant in all statistical tests. Moderate and severe hypoxia (PO2 approximately 35 and 25 mmHg, respectively) induced pial artery dilation that was attenuated by the Rp diastereomer of 8-bromoadenosine 3',5'-cyclic monophosphothioate (Rp-8-BrcAMPS), a cAMP antagonist (24 +/- 1 and 36 +/- 2% vs. 21 +/- 1 and 30 +/- 1% for moderate hypoxia and 34 +/- 1 and 46 +/- 2% vs. 24 +/- 1 and 32 +/- 1% for severe hypoxia before and after Rp-8-BrcAMPS, respectively). These responses were associated with an increased CSF cAMP (1,046 +/- 25, 1,366 +/- 28, and 1,735 +/- 47 fmol/ml for control, moderate, and severe hypoxia, respectively). Hypoxic pial dilation was also accompanied by an increase in CSF methionine enkephalin (1,101 +/- 62, 3,283 +/- 119, and 3,835 +/- 129 pg/ml for control, moderate, and severe hypoxia, respectively). Hypoxic dilation additionally increased CSF PACAP (1,727 +/- 86, 2,268 +/- 157, and 7,980 +/- 238 pg/ml for control, moderate, and severe hypoxia, respectively). PACAP (10(-8) and 10(-6) M) elicited pial dilation that was associated with increased CSF cAMP and blunted by Rp-8-BrcAMPS. PACAP-induced dilation was also accompanied by increases in the opioid methionine enkephalin (1,059 +/- 23, 1,483 +/- 34, and 2,108 +/- 77 pg/ml for control and 10(-8) and 10(-6) M PACAP, respectively). These data show that cAMP contributes to hypoxic pial artery dilation. Hypoxia increases CSF PACAP, whereas PACAP elevates CSF opioid concentration. These data, therefore, suggest that PACAP modulates cAMP-induced opioid release, thereby contributing to hypoxic pial dilation.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1997

Role of activation of calcium-sensitive K+ channels in NO- and hypoxia-induced pial artery vasodilation.

It has been previously observed that nitric oxide (NO) contributes to hypoxic pial artery dilation and that both sodium nitroprusside (SNP), a releaser of NO, and hypoxia elicit dilation via activation of ATP-sensitive K+ channels in the newborn pig. Other studies, however, have shown that NO activates calcium-sensitive K+ (K(Ca)) channels. The present study, therefore, was designed to investigate the role of K(Ca)-channel activation in NO and hypoxic dilation and to relate this mechanism to the previously observed role of NO in hypoxic dilation in newborn pigs equipped with closed cranial windows. SNP (10(-8) and 10(-6) M) elicited pial artery dilation that was unchanged in the presence of the K(Ca)-channel antagonist iberiotoxin (10(-7) M; 10 +/- 1 and 20 +/- 1 vs. 9 +/- 1 and 20 +/- 2% for 10(-8) and 10(-6) M SNP in the absence and presence of iberiotoxin, respectively). Responses to S-nitroso-N-acetylpenicillamine and 8-bromoguanosine 3',5'-cyclic monophosphate were similarly unchanged by iberiotoxin. In contrast, iberiotoxin attenuated the dilation resulting from moderate and severe hypoxia (arterial PO2 approximately 35 and 25 mmHg, respectively; 27 +/- 1 vs. 21 +/- 2 and 34 +/- 1 vs. 16 +/- 2% for moderate and severe hypoxia in the absence and presence of iberiotoxin, respectively). Iberiotoxin blocked responses to the K(Ca)-channel agonist NS-1619, whereas responses to the ATP-sensitive K+ agonist cromakalim were unchanged (8 +/- 1 and 15 +/- 1 vs. 1 +/- 1 and 1 +/- 1% for 10(-8) and 10(-6) M NS-1619 in the absence and presence of iberiotoxin, respectively). These data show that NO and guanosine 3',5'-cyclic monophosphate do not elicit dilation via K(Ca)-channel activation. However, activation of K(Ca) channels does contribute to hypoxic pial dilation. Finally, these data suggest that substances other than NO are involved in the contribution of K(Ca)-channel activation to hypoxic pial artery dilation.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1997

Role of neuronal NO synthase in relationship between NO and opioids in hypoxia-induced pial artery dilation.

Nitric oxide (NO) contributes to hypoxia-induced pial artery dilation, at least in part, via the formation of guanosine 3',5'-cyclic monophosphate (cGMP) and subsequent release of Met-enkephalin and Leu-enkephalin in the newborn pig. In separate studies, these opioids were also observed to elicit NO-dependent pial dilation. The present study was designed to investigate the role of the neuronal isoform of NO synthase (NOS) in hypoxic pial dilation, associated opioid release, and opioid dilation in piglets equipped with a closed cranial window. Tetrodotoxin (10(-6) M) attenuated the dilation resulting from hypoxia (PO2 approximately 35 mmHg; 25 +/- 1 vs. 14 +/- 1%). Similarly, 7-nitroindazole, sodium salt (7-NINA, 10(-6) M), a purported neuronal NOS inhibitor, attenuated hypoxic pial dilation (26 +/- 1 vs. 14 +/- 2%). Hypoxic dilation was accompanied by elevated cerebrospinal (CSF) cGMP, which was blocked by 7-NINA (433 +/- 19 and 983 +/- 36 vs. 432 +/- 19 and 441 +/- 19 fmol/ml for control and hypoxia in absence and presence of 7-NINA, respectively). Additionally, hypoxic dilation was also accompanied by elevated CSF Met-enkephalin, which was attenuated by 7-NINA (1,027 +/- 47 and 2,871 +/- 134 vs. 779 +/- 78 and 1,551 +/- 42 pg/ml for control and hypoxia in absence and presence of 7-NINA, respectively). In contrast, Met-enkephalin (10(-10), 10(-8), and 10(-6) M) induced dilation that was unchanged by 7-NINA (7 +/- 1, 12 +/- 1, and 18 +/- 1 vs. 6 +/- 1, 10 +/- 1, and 17 +/- 1%, respectively). N-methyl-D-aspartate (NMDA, 10(-8) and 10(-6) M), an activator of neuronal NOS, induced pial dilation that was blocked by 7-NINA (10 +/- 1 and 20 +/- 2 vs. 1 +/- 1 and 2 +/- 1%, respectively). However, sodium nitroprusside-induced dilation was unchanged by 7-NINA. These data indicate that neuronal NOS contributes to hypoxic pial artery dilation but not to opioid-induced dilation. Furthermore, these data suggest that neuronally derived NO contributes to hypoxic dilation, at least in part, via formation of cGMP and the subsequent release of opioids.

Animals↗
PubMed1997

Endothelin impairs ATP-sensitive K+ channel function after brain injury.

In piglets, pial arteries constrict, ATP-sensitive K+ (KATP) channel function is impaired, and cerebrospinal fluid endothelin-1 (ET-1) increases to 10(-10) M after brain injury [fluid percussion injury (FPI)]. Nitric oxide (NO) elicits dilation via guanosine 3',5'-cyclic monophosphate (cGMP) and KATP channel activation. This study was designed to characterize the relationship between ET-1 and impaired function of KATP channels after FPI. Injury was produced via the lateral FPI technique in piglets equipped with a closed cranial window. Cromakalim, a KATP agonist, produced dilation that was attenuated by FPI and partially restored by BQ-123, an ET-1 antagonist (11 +/- 1 and 23 +/- 2 vs. 2 +/- 1 and 4 +/- 1 vs. 8 +/- 1 and 17 +/- 2% for responses to 10(-8) and 10(-6) M cromakalim before FPI, after FPI, and after FPI with BQ-123, respectively). Because ET-1 constriction may antagonize dilation, separate experiments were conducted under conditions of equivalent baseline diameter in the absence and presence of ET-1 (10(-10) M). Cromakalim dilation was attenuated by ET-1 and partially restored by the protein kinase C (PKC) inhibitor staurosporine (12 +/- 1 and 28 +/- 1 vs. 2 +/- 1 and 21 +/- 3 vs. 9 +/- 1 and 29 +/- 2% for 10(-8) and 10(-6) M cromakalim, cromakalim with ET-1, and cromakalim with ET-1 + staurosporine, respectively). Similar interactions were observed with calcitonin gene-related peptide, 8-bromoguanosine 3',5'-cyclic monophosphate, and the NO releasers sodium nitroprusside and S-nitroso-N-acetylpenicillamine. These data show that ET-1 blunts KATP channel-, NO-, and cGMP-mediated dilation. These data suggest that ET-1 contributes to altered cerebral hemodynamics after FPI through impairment of KATP channel function via PKC activation.

Animals↗
PubMed1997

Endothelin production links superoxide generation to altered opioid-induced pial artery vasodilation after brain injury in pigs.

BACKGROUND AND PURPOSE: Traumatic brain injury conveys significant morbidity and mortality to infants and children. In the newborn pig, opioids contribute to pial artery vasconstriction after fluid percussion injury (FPI). FPI attenuates vasodilation and cGMP production by methionine enkephalin (Met) and leucine enkephalin (Leu) and reverse dynorphin (Dyn) from a dilator to a constrictor. Superoxide anion (O2-) production contributes to altered cerebral hemodynamics after FPI, and O2- scavengers partially restore decreased dilator responses after FPI. Endothelin-1 (ET-1), a purported mediator of cerebral vasospasm, has been suggested to alter nitric oxide function and cGMP concentration. The present study was designed to determine the contribution of ET-1 to altered opioid-induced dilation after FPI and the role of O2- in such altered responses. METHODS: Injury of moderate severity (1.9 to 2.3 atm) was produced by the lateral FPI technique in anesthetized newborn pigs equipped with a closed cranial window. Superoxide dismutase (SOD)-inhibitable nitroblue tetrazolium (NBT) reduction was determined as an index of O2- generation. RESULTS: FPI increased cerebrospinal fluid ET-1 from 20 +/- 2 to 93 +/- 6 pg/mL (approximately 10(-10) mol/L). Topical ET-1 (10(-10) mol/L) increased SOD-inhibitable NBT reduction from 1 +/- 1 to 16 +/- 3 pmol/mm2, similar to previously reported NBT reduction after FPI (14 +/- 2 pmol/mm2). BQ123 (10(-6) mol/L), an ET-1 antagonist, blunted the NBT reduction observed after FPI (4 +/- 1 pmol/mm2). Met produced pial vasodilation that was attenuated by FPI and partially restored by BQ123 pretreatment (7 +/- 1%, 11 +/- 1%, and 17 +/- 1% versus 3 +/- 1%, 6 +/- 1%, and 9 +/- 2% versus 5 +/- 1%, 9 +/- 1%, and 14 +/- 2% for 10(-10), 10(-8), and 10(-6) mol/L Met during control conditions, after FPI, and after FPI pretreated with BQ123, respectively). Met-induced dilation was associated with increased cerebrospinal fluid cGMP, and these biochemical changes were likewise blunted by FPI and partially restored by BQ123 (357 +/- 12, 455 +/- 15, 500 +/- 19, and 632 +/- 11 versus 264 +/- 4, 267 +/- 4, 295 +/- 12, and 305 +/- 15 versus 309 +/- 19, 432 +/- 11, 529 +/- 10, and 593 +/- 4 pg/mL for resting conditions, 10(-10), 10(-8), and 10(-6) mol/L Met during control conditions, after FPI, and after FPI pretreated with BQ123, respectively). Similar partial restoration of vascular and biochemical parameters was observed for Leu and Dyn. CONCLUSIONS: These data show that ET-1, in concentrations similar to that present in cerebrospinal fluid after FPI, increases O2- production. These data also indicate the opioid-induced vasodilation and cGMP production are partially restored after FPI by ET-1 receptor blockade. These data suggest that ET-1 contributes to altered cerebral hemodynamics after FPI, at least in part, through elevated O2- production.

Analysis of Variance↗
PubMed1997

Brain injury impairs ATP-sensitive K+ channel function in piglet cerebral arteries.

BACKGROUND AND PURPOSE: Traumatic injury is the leading cause of death for infants and children, and mortality is increased with head injury. Previous studies have shown that pial arteries constricted and that responses to several nitric oxide (NO)-dependent dilator stimuli were blunted after fluid percussion injury (FPI) in newborn pigs. Membrane potential of vascular muscle is a major determinant of vascular tone, and activity of K+ channels is a major regulator of membrane potential. Recent data show that the NO releasers sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP) and 8-bromo-cGMP elicit dilation via ATP-sensitive K+ channel (KATP) activation. The present study was designed to investigate the effect of FPI on KATP channel function. METHODS: Chloralose-anesthetized newborn pigs equipped with a closed cranial window were connected to a percussion device that consisted of a saline-filled cylindrical reservoir and a metal pendulum. Brain injury of moderate severity (1.9 to 2.1 atm) was produced by allowing the pendulum to strike a piston on the cylinder. Pial artery diameter was measured with a video microscaler. Data were analyzed by repeated measures ANOVA. An alpha level of P < .05 was considered significant. RESULTS: FPI blunted dilation to cromakalim (10(-8), 10(-6) mol/L), a KATP agonist (10 +/- 1% and 27 +/- 2% versus 3 +/- 1% and 7 +/- 2% before and after FPI, respectively, n = 8). Similarly, FPI blunted dilation to calcitonin gene-related peptide, an endogenous KATP activator. FPI also blunted dilator responses to SNP, S-nitroso-N-acetylpenicillamine, and 8-bromo-cGMP (10(-6) to 10(-8) mol/L) (10 +/- 1% and 20 +/- 1% versus 2 +/- 1% and 8 +/- 2% for SNP before and after FPI; 9 +/- 1% and 16 +/- 1% versus 2 +/- 1% and 4 +/- 1% for 8-bromo-cGMP before and after FPI, respectively, n = 8). In contrast, responses to papaverine and brain natriuretic peptide were unchanged after FPI. CONCLUSIONS: These data show that KATP channel function is impaired after FPI. Furthermore, these data suggest that impaired function of mechanisms distal to NO synthase contribute to altered cerebral hemodynamics after FPI.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1997

Role of cyclic nucleotides in vasopressin-induced piglet pial artery dilation and opioid release.

It has previously been observed that the opioids methionine enkephalin and leucine enkephalin contribute to hypoxia-induced pial artery dilation in the piglet. It has also been demonstrated that vasopressin elicits pial artery dilation and contributes to hypoxia-induced pial dilation both directly and indirectly through the release of the above opioids. The present study was designed to investigate the role of cyclic nucleotides in this vasopressin-induced pial artery dilation and opioid release in newborn piglets equipped with a closed cranial window. Pial artery diameter and cortical periarachnoid cerebrospinal fluid (CSF) opioid and cyclic nucleotides were measured after topical application of vasopressin (40, 400, and 4000 pg/mL). Opioid levels and pial diameter were examined in the absence and presence of (Rp)-8-bromo-(Br)-cAMPs and (Rp)-8-Br-cGMPs, purported cAMP and cGMP antagonists, respectively. Periarachnoid cortical CSF cAMP concentration increased in response to topical vasopressin (1048 +/- 22, 1199 +/- 51, 1334 +/- 61 and 1453 +/- 59 fmol/mL for control, 40, 400, and 4000 pg/mL vasopressin, respectively, n = 9). Vasopressin elicited pial artery dilation, which was attenuated by (Rp)-8-Br-cAMPs (14 +/- 1, 22 +/- 1, and 29 +/- 2 versus 8 +/- 1, 12 +/- 2, and 18 +/- 2% dilation for 40, 400, 4000 pg/mL vasopressin, before and after (Rp)-8-Br-cAMPs, respectively, n = 7). Similarly, vasopressin-induced pial artery dilation was accompanied by elevated CSF cGMP and this dilation was attenuated in the presence of (Rp)-8-Br-cGMPs (13 +/- 1, 21 +/- 1, and 29 +/- 2 versus 5 +/- 1, 9 +/- 1, and 12 +/- 1% dilation for 40, 400, and 4000 pg/mL vasopressin before and after (Rp)-8-Br-cGMPs, respectively, n = 7). CSF opioid concentrations increased with topical vasopressin and these increases were attenuated by (Rp)-8-Br-cAMPs. CSF methionine enkephalin concentrations were 1193 +/- 60, 1530 +/- 63, 1937 +/- 89, and 2422 +/- 104 versus 1032 +/- 25, 1185 +/- 261, 1337 +/- 31, and 1519 +/- 44 pg/mL for control, 40, 400 and 4000 pg/mL vasopressin before and after (Rp)-8-Br-cAMPs. Similarly, vasopressin-induced CSF methionine enkephalin and leucine enkephalin release was attenuated in the presence of (Rp)-8-Br-cGMPs. These data show that both cAMP and cGMP contribute to vasopressin-induced pial artery dilation and the release of the opioids methionine enkephalin and leucine enkephalin.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1996

Influence of cAMP on cerebrospinal fluid opioid concentration: role in cAMP-induced pial artery dilation.

Previously, it has been observed that cGMP analogs and agents that elevate cGMP levels markedly increase the concentration of the opioids [Met5]enkephalin and [Leu5]enkephalin in cortical periarachnoid cerebrospinal fluid (CSF) of the newborn pig. However, such agents had no effect on CSF dynorphin-(1-13) concentration. The present study was designed to: (1) investigate the influence of cAMP on the CSF concentration of the opioids [Met5]enkephalin, [Leu5]enkephalin and dynorphin-(1-13); and (2) determine the role of these opioids in cAMP-induced pial artery vasodilation. Piglets equipped with closed cranial windows were used to measure pial artery diameter and collect cortical periarachnoid CSF for assay of opioids. The cAMP analog, 8-Bromoadenosine-3',5'-cyclic monophosphate (8-Bromo cAMP) elicited pial dilation that was blunted by a cAMP antagonist, Rp 8-Bromoadenosine-3',5'-cyclic monosphorothioate (10(-5) M) (11 +/- 1 and 19 +/- 1 vs. 1 +/- 1 and 1 +/- 1 for 10(-8) M, 10(-6) M 8-Bromo cAMP before and after Rp 8-Bromoadenosine-3',5'-cyclic monosphorothioate, respectively). The dilation produced by 8-Bromo cAMP was accompanied by modest increases in CSF [Met5]enkephalin and co-administration of Rp 8-Bromoadenosine-3',5'-cyclic monosphorothioate with 8-Bromo cAMP blocked these increases in CSF opioid concentration (1179 +/- 48, 1593 +/- 92 and 2079 +/- 88 vs. 1054 +/- 32, 1038 +/- 15 and 1071 +/- 17 pg/ml for control, 10(-8) M and 10(-6) M 8-Bromo cAMP before and after Rp 8-Bromoadenosine-3',5'-cyclic monosphorothioate, respectively). The release of CSF [Leu5]enkephalin by 8-Bromo cAMP was also blocked by Rp 8-Bromoadenosine-3',5'-cyclic monosphorothioate. In contrast 8-Bromo cAMP produced marked increases in CSF dynorphin-(1-13) (38 +/- 3, 61 +/- 3 and 88 +/- 6 vs. 27 +/- 3, 28 +/- 3 and 30 +/- 4 pg/ml for control, 10(-8) M and 10(-6) M 8-Bromo cAMP before and after Rp 8-Bromoadenosine-3',5'-cyclic monosphorothioate, respectively). Similar blunted vascular and biochemical responses were observed with the co-administration of Sp 8-Bromoadenosine-3',5'-cyclic monophosphorothioate, another analog of cAMP, with Rp 8-Bromoadenosine-3',5'-cyclic monosphorothioate. The opioid receptor antagonist naloxone (1 mg/kg i.v.) attenuated 8-Bromo cAMP-induced dilation (9 +/- 1 and 17 +/- 1 vs. 5 +/- 1 and 8 +/- 1 for 10(-8) M, 10(-6) M 8-Bromo cAMP before and after naloxone). These data show that cAMP contributes to the release of the CSF opioids [Met5]enkephalin, [Leu5]enkephalin and dynorphin-(1-13), and suggest that, while cGMP is more important relative to cAMP in elevating CSF [Met5]enkephalin and [Leu5]enkephalin concentration, the converse is true for dynorphin-(1-13). Further, these data indicate that opioids contribute to cAMP-induced pial artery vasodilation.

Animals↗
PubMed1996

Role of vasopressin in altered pial artery responses to dynorphin and beta-endorphin following brain injury.

Pial artery constriction following fluid percussion brain injury (FPI) is associated with elevated CSF dynorphin and beta-endorphin concentration in newborn pigs. Additionally, dynorphin is a dilator under control conditions and a vasoconstrictor under decreased cerebrovascular tone conditions. Vasopressin contributes to beta-endorphin-induced pial constriction and the constrictor potential for dynorphin. Recently, it has been observed that FPI reverses vasopressin from a dilator to a constrictor. The present study was designed to characterize the effect of FPI on beta-endorphin-induced constriction and the role of vasopressin in that constriction as well as in the reversal of dynorphin's vascular response following FPI. Brain injury of moderate severity (1.9 - 2.3 atm) was produced in anesthetized newborn pigs equipped with a closed cranial window. Dynorphin in physiologic and pharmacologic concentrations (10(-10), 10(-8), 10(-6) M) was reversed from a dilator to a constrictor following FPI (7 +/- 1, 11 +/- 1, and 16 +/- 1 vs -4 +/- 1, -7 +/- 1, and -11 +/- 1% before and after FPI, respectively). Dynorphin-induced vascular changes were accompanied by increased cortical periarachnoid CSF vasopressin and these biochemical changes were potentiated following FPI (24 +/- 4 vs 134 +/- 7 and 53 +/- 7 vs 222 +/- 14 pg/mliter for control and dynorphin (10(-6) M) before and after FPI, respectively). In contrast, in animals pretreated with the vasopressin receptor antagonist [1-(beta-mercapto-beta beta-cyclopentamethylene propionic acid) 2-(O-methyl)-Tyr-AVP] (MEAVP, 5 micrograms/kg iv), dynorphin-induced constriction following FPI was attenuated (6 +/- 1, 12 +/- 1, and 16 +/- 1, vs -2 +/- 1, -4 +/- 1, and -7 +/- 1% before and after FPI, respectively). Additionally, beta-endorphin-induced pial constriction was potentiated following FPI (-7 +/- 1, -10 +/- 1, -15 +/- 1 vs -10 +/- 1 -15 +/- 2, and -21 +/- 2% for beta-endorphin (10(-10), 10(-8), 10(-6) M) before and after FPI, respectively). beta-endorphin-induced CSF vasopressin release was similarly potentiated following FPI. Further, MEAVP blunted the augmented constrictor responses to beta-endorphin observed following FPI (-5 +/- 1, -9 +/- 1, -14 +/- 1 vs -2 +/- 1, -5 +/- 1, and -8 +/- 1% before and after FPI, respectively). These data indicate that FPI potentiates beta-endorphin-induced pial construction and reverses dynorphin from a dilator to a constrictor. Additionally, these data show that vasopressin contributes to augmented beta-endorphin pial constriction and the reversal of dynorphin's vascular effects following FPI. Further, since CSF dynorphin and beta-endorphin concentrations are increased following FPI, these data suggest that these two opioids contribute to pial artery constriction observed following FPI, at least, in part, via the release of vasopressin.

Animals↗
PubMed1996

Influence of polyethylene glycol superoxide dismutase/catalase on altered opioid-induced pial artery dilation after brain injury.

BACKGROUND: The current study was designed to investigate the influence of pretreatment with the oxygen radical scavengers polyethylene glycol superoxide dismutase and catalase (SODCAT) on altered opioid-induced pial artery dilation after fluid percussion brain injury (FPI) in the newborn pig. It has been observed previously that brain injury produces pial artery vasoconstriction in the piglet associated with elevated cerebrospinal fluid opioid levels. Furthermore, opioid-induced vasodilation and cyclic guanosine monophosphate production are attenuated following brain injury. Finally, oxygen free radicals have been implicated in the pathogenesis of brain injury. METHODS: Anesthetized piglets equipped with a closed cranial window were connected to a percussion device consisting of a saline-filled cylindrical reservoir with a metal pendulum. Fluid percussion brain injury of moderate severity (1.9-2.3 atm) was produced by allowing the pendulum to strike a piston on the cylinder. Superoxide dismutase-inhibited nitroblue tetrazolium reduction was determined as an index of superoxide generation. RESULTS: Superoxide dismutase- inhibited tetrazolium was increased markedly after FPI and these increases were blunted by SODCAT (1,000 U/kg and 10,000 U/kg, respectively) treatment 30 min before FPI (1 +/- 1 vs. 14 +/- 2 vs. 1 +/- 1 pmol/mm(2) for control, FPI, and FPI pretreated with SODCAT, respectively). Methionine enkephalin, an endogenous mu opioid agonist, produced vasodilation that was attenuated by FPI and partially restored by SODCAT pretreatment (17 +/- 1, 8 +/- 1, and 14 +/- 1% for methionine enkephalin 10(-6)m during control conditions, after FPI and after FPI pretreated with SODCAT, respectively). Methionine enkephalin-induced dilation was associated with increased cerebrospinal fluid cycle guanosine monophosphate and these biochemical changes were likewise blunted by FPI and partially restored by SODCAT (342 +/- 12 and 640 +/- 13 vs. 267 +/- 6 and 321 +/- 17 vs. 301 +/- 9 and 504 +/- 43 fmol/ml for resting conditions and 10 (-6)M methionine enkephalin during control, after FPI, and after FPI pretreated with SODCAT, respectively). Leucine enkephalin, an endogenous delta agonist, induced pial dilation and associated changes incerebrospinal fluid cyclic guanosine monophosphate, which were similarly altered by FPI and partially restored by SODCAT. Dynorphin, an endogenous kappa agonist, which has been shown to revert from a dilator to a constrictor after FPI, was restored to a vasodilator by SODCAT (18 +/- 1, -11 +/- 4, and 17 +/-5% for dynorphin 10(-6)m during control conditions, after FPI, and after FPI pretreated with SODCAT, respectively). Dynorphin-induced vasodilation was associated with a large increase in cerebrospinal fluid cyclic guanosine monophosphate, which was blunted by FPI and partially restored by SODCAT. CONCLUSIONS: These data show that superoxide anion is produced after brain injury and that opioid-induced vasodilation and cyclic guanosine monophosphate production are partially restored after brain injury in the presence of SODCAT. (Key words: Brain injury: newborn. Circulation: cerebral. Free radicals: oxygen. Gases: nitric oxide. Nucleotides cyclic.

Animals↗
PubMed1996

Role of ATP-sensitive K+ channels in cGMP-mediated pial artery vasodilation.

The present study was designed to investigate the role of ATP-sensitive K+ channels in guanosine 3',5'-cyclic monophosphate (cGMP)-mediated pial artery vasodilation in newborn pigs equipped with a closed cranial window. Sodium nitroprusside (SNP) (10(-8), 10(-6) M), a nitrovasodilator, elicited pial artery dilation that was attenuated by the ATP-sensitive K+ channel antagonist glibenclamide (10(-6) M). On a percentage basis, these responses were 25 +/- 1% for the presence of SNP (10(-6) M) alone, whereas 15 +/- 1% dilation was observed for SNP (10(-6) M) in the presence of glibenclamide (n = 5 pigs). Dilation produced by the cGMP analogue, 8-BrcGMP (10(-8), 10(-6) M), was similarly attenuated by glibenclamide. SNP-induced pial dilation was accompanied by increased cortical periarachnoid cerebrospinal fluid (CSF) cGMP levels, and these biochemical changes were blocked by the soluble guanylate cyclase inhibitor, LY-83583 (10(-5) M). SNP (10(-6) M) alone increased CSF cGMP concentration from 407 +/- 14 to 956 +/- 41 fmol/ml, whereas SNP in the presence of LY-83583 yielded a CSF cGMP concentration of 340 +/- 13, which was no different from the control value of 335 +/- 23 fmol/ml (n = 5 pigs). SNP-induced pial dilation was blunted by LY-83583, whereas 8-BrcGMP-induced dilation was unchanged. Cromakalim (10(-8), 10(-6) M), an ATP-sensitive K+ channel agonist, produced dilation that was blocked by glibenclamide (24 +/- 1 vs. 5 +/- 1% for cromakalim 10(-6) M, in the absence and presence of glibenclamide, respectively, n = 5). These data indicate that activation of ATP-sensitive K+ channels contribute to cGMP-mediated pial artery dilation.

Adenosine Triphosphate↗
PubMed1996

Relationship between nitric oxide and opioids in hypoxia-induced pial artery vasodilation.

It has previously been observed that nitric oxide (NO) and the opioids Met- and Leu-enkephalin contribute to hypoxia-induced pial artery dilation in the newborn pig. The present study was designed to investigate the relationship between NO and opioids in hypoxic pial dilation. Piglets equipped with closed cranial windows were used to measure pial artery diameter and collect cortical periarachnoid cerebrospinal fluid (CSF) for assay of opioids. Sodium nitroprusside (SNP; 10(-8) and 10(-6) M) elicited pial dilation that was blunted by the soluble guanylate cyclase inhibitor LY-83583 (10(-5) M; 10 +/- 1 and 23 +/- 1 vs. 3 +/- 1 and 7 +/- 1% for 10(-8) and 10(-6) M SNP before and after LY-83583, respectively). SNP-induced dilation was accompanied by increased CSF Met-enkephalin, and coadministration of LY-83583 with SNP blocked these increases in CSF opioid concentration (1,144 +/- 59, 2,215 +/- 165, and 3,413 +/- 168 vs. 1,023 +/- 16, 1,040 +/- 18, and 1,059 +/- 29 pg/ml for control and 10(-8) and 10(-6) M SNP before and after LY-83583, respectively). SNP-induced release of CSF Leuenkephalin was also blocked by LY-83583. Similar blunted vascular and biochemical effects of SNP were observed with coadministration of the purported guanosine 3', 5'-cyclic monophosphate (cGMP) antagonist, the phosphorothioate analogue of 8-bromo-cGMP (BrcGMP) [(R)-p-BrcGMP[S]; 10(-5) M]. The cGMP analogue, BrcGMP, elicited dilation that was also accompanied by increased CSF Met- and Leu-enkephalin. Vascular and biochemical effects of BrcGMP were blunted by (R)-p-cGMP[S] and unchanged by LY-83583. Hypoxia-induced pial artery dilation was attenuated by N omega-nitro-L-arginine (L-NNA; 10(-6) M), an NO synthase inhibitor (25 +/- 2 vs. 14 +/- 1%). Hypoxic pial dilation was accompanied by increased CSF Met-enkephalin, and these increases were attenuated by L-NNA (1,137 +/- 60 and 3,491 +/- 133 vs. 927 +/- 25 and 2,052 +/- 160 pg/ml for control and hypoxia before and after L-NNA, respectively). Hypoxia also increased CSF Leuenkephalin, and these CSF changes were similarly attenuated by L-NNA. These data show that cGMP increases CSF Met- and Leu-enkephalin. Furthermore, these data suggest that NO contributes to hypoxic dilation, at least in part, via formation of cGMP and the subsequent release of opioids.

Aminoquinolines↗
PubMed1996

Influence of brain injury on vasopressin-induced pial artery vasodilation: role of superoxide anion.

The present study was designed to investigate the effect of fluid percussion brain injury (FPI) on vasopressin-induced pial artery vasodilation and the role of superoxide anion generation in those observed effects. In the piglet, it was observed previously the FPI produces pial artery constriction associated with free radical generation. Anesthetized piglets equipped with a closed cranial window were connected to a percussion device consisting of a saline-filled cylindrical reservoir with a metal pendulum. FPI of moderate severity (1.9-2.3 atm) was produced by allowing the pendulum to strike a piston on the cylinder. Vasopressin in physiological and pharmacological concentrations (10 and 1,000 microU/ml) produced vasodilation that was reversed to constriction after FPI (15 +/- 1 vs. -8 +/- 1 and 25 +/- 1 vs. 13 +/- 1% for 10 and 1,000 microU/ml before and after injury, respectively). Vasopressin-induced dilation was associated with increased cerebrospinal fluid guanosine 3', 5'-cyclic monophosphate, and these biochemical changes were blunted by FPI (407 +/- 12 and 720 +/- 28 vs. 4 and 272 +/- 5 fmol/ml for control and 10 microU/ml before and after injury, respectively). In contrast, polyethylene glycol superoxide dismutase (PEG-SOD) and catalase pretreatment 30 min before FPI partially restored vasopressin-induced pial artery dilation (14 +/- 1 vs. 3 +/- 1 and 22 +/- 1 vs. 2 +/- 4% for 10 and 1,000 microU/ml before and after FPI, respectively). Similarly, biochemical changes associated with vasopressin dilation were also partially restored by PEG-SOD and catalase after FPI. These data show that vasopressin is reversed from a dilator to a vasoconstrictor after FPI and suggests the superoxide anion generation contributes to the alteration of vasopressin cerebrovascular effects after injury and that such altered vasopressin cerebrovascular effects contribute to pial vasoconstriction after FPI.

Animals↗