Biomedical subjects

W M Armstead

Publications and source records attributed to W M Armstead.

At least 73 records · Page 4Linked to original sources

PubMed1996

cGMP and cAMP in prostaglandin-induced pial artery dilation and increased CSF opioid concentration.

It has been observed that prostaglandins (PG) PGE2 and PGI2 increased cortical periarachnoid cerebrospinal fluid (CSF) methionine enkephalin (Met-enk) and leucine enkephalin (Leu-enk) concentrations in the newborn pig. It was also observed that PG-induced pial artery dilation was associated with elevated CSF guanosine 3',5'-cyclic monophosphate (cGMP) and adenosine 3',5'-cyclic monophosphate (cAMP) levels in the piglet. However, other studies have not always supported a role for cGMP in PG dilation. The present study used a pharmacological approach to test the hypothesis that both cGMP and cAMP contribute to PG-induced pial dilation and associated elevated CSF opioid concentration. PGE2 produced pial vasodilation that was blunted by the Rp diastereomer of bromoguanosine 3',5'-cyclic monophosphothioate [Rp-8-BrcGMPS (10(-5)M)], a cGMP antagonist (9 +/- 1, 16 +/- 1, and 23 +/- 1 vs. 4 +/- 1, 6 +/- 1, and 9 +/- 1% for 1, 10, and 100 ng/ml PGE2 before and after Rp-8-BrcGMPS, respectively). PGE2 elevated CSF Met-enk concentration, and these biochemical changes were also blunted by Rp-8-BrcGMPS (1,001 +/- 23, 1,424 +/- 54, and 1,973 +/- 56 vs. 804 +/- 41, 988 +/- 52, and 1,222 +/- 21 pg/ml for control, 10, and 100 ng/ml PGE2 in the absence and presence of Rp-8-BrcGMPS, respectively). Similar biochemical and vascular effects of Rp-8-BrcGMPS were observed for PGI2. Additionally, the Rp diastereomer of bromoadenosine 3',5'-cyclic monophosphothioate [Rp-8-BrcAMPS (10(-5)M)], a cAMP antagonist, blunted PGE2 dilation (10 +/- 1, 15 +/- 1, and 24 +/- 1 vs. 5 +/- 1, 8 +/- 1, and 12 +/- 1% for 1, 10, and 100 ng/ml PGE2 before and after Rp-8-BrcAMPS, respectively). PGE2-associated increases in CSF Met-enk and Leu-enk were similarly blunted by Rp-8-BrcAMPS. These data show that both cGMP and cAMP contribute to PG-induced pial dilation and that PG-associated elevated CSF cGMP and cAMP levels result in increased CSF Met-enk and Leu-enk concentration.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1996

Relationship between vasopressin and opioids in hypoxia induced pial artery vasodilation.

It has been observed that a vasopressin receptor antagonist attenuates hypoxic hyperemia in fetal sheep, whereas methionine enkephalin (Met) and leucine enkephalin (Leu) contribute to hypoxia-induced pial artery dilation in newborn pigs. This study was designed to investigate the relationship between vasopressin and opioids in hypoxia-induced pial artery dilation in the newborn pig by use of the closed cranial window technique. Hypoxia-induced pial artery dilation was attenuated during moderate [arterial Po2 (PaO2) approximately 35 mmHg] and severe hypoxia (PaO2 approximately 25 mmHg) by the vasopressin receptor antagonist, [beta-mercapto-beta beta-cyclopentamethylenepropionyl, 2-O-Me-Tyr2, Arg8]vasopressin (MeAVP, 5 micrograms/kg i.v.; 29 +/- 1 vs. 14 +/- 2 and 37 +/- 2 vs. 18 +/- 2% for moderate and severe hypoxia in absence vs. presence of MeAVP, respectively, n = 7). Hypoxia-induced dilation was accompanied by increased cerebrospinal fluid (CSF) vasopressin concentration (26 +/- 1 vs. 67 +/- 4 and 26 +/- 1 vs. 99 +/- 4 pg/ml for control vs. moderate and control vs. severe hypoxia, n = 5). Vasopressin increased CSF Met (895 +/- 28, 1,147 +/- 63, 1,327 +/- 48, and 1,600 +/- 75 pg/ml for control and 40, 400, and 4,000 pg/ml vasopressin, respectively, n = 7). CSF Leu concentration was similarly increased by vasopressin. Furthermore, MeAVP attenuated the release of Met during moderate hypoxia (910 +/- 38 and 2,682 +/- 49 vs. 911 +/- 38 and 2,110 +/- 84 pg/ml for control and moderate hypoxia in absence and presence of MeAVP, respectively, n = 5). MeAVP had similar effects on hypoxia-induced Leu release. These data show that vasopressin contributes to hypoxia-induced pial artery dilation and that vasopressin increases CSF Met and Leu concentrations. These data also suggest that elevated CSF vasopressin concentrations that occur during hypoxemia result in opioid release, which subsequently contributes to hypoxic pial artery dilation.

Animals↗

PubMed1996

Age dependence of cerebrovascular response mechanisms in domestic pigs.

Hypercapnia-induced cerebral vasodilation in the newborn pig is a prostanoid-associated response. In some adult models, hypercapnic cerebral vasodilation is associated with the generation of nitric oxide (NO). Acetylcholine (ACh) produces a NO-dependent cerebral vasodilation in many adult models, but topical ACh is a prostanoid-associated cerebral vasoconstrictor in the newborn pig. We hypothesized that mediators influencing cerebral response can be age dependent. Juvenile domestic pigs were compared with newborn pigs, and pial arteriolar diameters were measured by use of a closed cranial window during hypercapnia and topical ACh (10(-5) M). Four different conditions were explored: control, topical N omega-nitro-L-arginine (L-NNA, 10(-3) M), indomethacin (5 mg/kg i.v.), and both L-NNA and indomethacin. All animals were anesthetized with alpha-chloralose. As opposed to the complete block in the newborn, indomethacin only partially attenuated the hypercapnic cerebral vasodilation in the juvenile pig.L-NNA, which had no effect on the response of the newborn, produced a partial attenuation of the hypercapnic response of the juvenile. The combination of indomethacin and L-NNA blocked the response in both age groups. Topical ACh in both age groups initially produced cerebral vasoconstriction, but, in the juvenile, this was followed by a sustained cerebral vasodilation. Indomethacin blocked the early vasoconstriction in both age groups. L-NNA, which had no effect in the response of the newborn to ACh, blocked the vasodilation seen in the juvenile. The combination of both inhibitors blocked all response to ACh in the juvenile. These data indicate that although the cerebral vascular responses to ACh and hypercapnia are prostanoid associated and NO independent in the newborn pig, NO assumes an increasing role in dilatory responses with development.

Acetylcholine↗

PubMed1996

Role of endothelin in pial artery vasoconstriction and altered responses to vasopressin after brain injury.

Pial artery constriction following fluid-percussion injury to the brain is associated with elevated cerebrospinal fluid (CSF) vasopressin concentration in newborn pigs. It has also been observed that fluid-percussion injury reverses the function of vasopressin from that of a dilator to a constrictor. Endothelin-1 (ET-1), a purported mediator of cerebral vasospasm, can be released by several stimuli, including vasopressin. The present study was designed to investigate the role of ET-1 in pial artery constriction and in the reversal of vasopressin from a dilator to a constrictor, which is observed after fluid-percussion injury. Brain injury of moderate severity (1.9-2.3 atm) was produced in anesthetized newborn pigs that had been equipped with a closed cranial window. Endothelin-1 elicited pial dilation at low concentrations and vasoconstriction at higher concentrations. Fluid-percussion injury reversed the process of dilation to that of constriction at the low ET-1 concentration and potentiated this constriction at high ET-1 concentrations (10% +/- 1%, -8% +/- 1%, and -15% +/- 1% vs. -6% +/- 1%, -17% +/- 1%, and -26% +/- 2% for 10(-12), 10(10),10(-8) M ET-1 before and after fluid-percussion injury, respectively). Vasopressin modestly increased CSF ET-1 concentration before fluid-percussion injury. Fluid-percussion injury markedly increased CSF ET-1 concentration and the ability of vasopressin to release ET-1 (20 +/- 2, 26 +/- 3, and 40 +/- 4 pg/ml vs. 93 +/- 6, 141 +/- 9, and 247 +/- 31 pg/ml for control, 40 pg/ml vasopressin, and 400 pg/ml vasopressin before and after fluid-percussion injury, respectively). An ET-1 antagonist, BQ 123 (10(-6) M) blunted pial artery constriction following fluid-percussion injury (146 +/- 5 microns -127 +/- 6 microns vs.144 +/- 5 microns-136 +/- 4 microns). The BQ 123 also blocked the reversal of vasopressin's function from that of a dilator to a constrictor after fluid-percussion injury (8% +/- 1%, 21% +/- 3%, and -5% +/- 1%, -14% +/- 2% vs. 8% +/- 1%, 21% +/- 2% and 4% +/- 1%, 2% +/- 1% for 40 and 4000 pg/ml vasopressin before and after fluid-percussion injury in the absence and presence of BQ 123, respectively). The BQ 123 blocked the constrictor component to ET-1, whereas it had no effect on the dilator component. These data show that ET-1 contributes to pial constriction after fluid-percussion injury. These data also indicate that vasopressin-induced release of ET-1 contributes to the reversal of vasopressin from a dilator to a constrictor following fluid-percussion injury. Furthermore, these data indicate that elevated CSF vasopressin and ET-1 interact in a positive feedback manner to promote pial artery constriction following fluid-percussion injury.

Animals↗

PubMed1996

Relationship between opioids and prostaglandins in hypoxia-induced vasodilation of pial arteries in the newborn pig.

Previously, it has been observed that methionine enkephalin and leucine enkephalin contribute to hypoxia-induced pial artery dilation in the newborn pig. It has also been observed that the cyclooxygenase inhibitor indomethacin attenuates hypoxic hyperemia in piglets. The present study was designed to determine the relationship between opioids and prostaglandins in hypoxia-induced pial artery dilation. Newborn pigs equipped with closed cranial windows were used to measure pial artery diameter and collect cortical periarachnoid cerebrospinal fluid (CSF) for assay of opioids and prostaglandins. Hypoxia-induced artery vasodilation was mildly attenuated during moderate hypoxia (PaCO2 approximately 35 mm Hg), while this response was blunted during severe hypoxia (PaO2 approximately 25 mm Hg) by indomethacin, 5 mg/kg iv (23% +/- 1 % vs 18% +/- 1% and 33% +/- 2% vs 21% +/- 2% for moderate and severe hypoxia in the absence and presence of indomethacin, respectively). Hypoxic dilation was accompanied by increased CSF prostaglandin E2 (PGE2) concentration (1260 +/- 37 vs 1734 +/- 67 and 1256 +/- 33 vs 2859 +/- 189 pg/ml for moderate and severe hypoxia, respectively). Similar changes in CSF 6 keto PGF1alpha concentration during hypoxia were also observed. Topical PGE2 (10,100 ng/ml) increased CSF methionine enkephalin (874 +/- 35, 1290 +/- 44, and 1791 +/- 143 pg/ml for control, 10 and 100 ng/ml PGE2 respectively). Similar increases in CSF methionine enkephalin concentration were observed for topical PGI2. Additionally, these two prostaglandins also increased CSF leucine enkephalin concentration. Furthermore, while indomethacin had no effect on the release of CSF methionine enkephalin during moderate hypoxia, it attenuated the release of this opioid during severe hypoxia (786 +/- 27 and 2633 +/- 74 vs 781 +/- 51 and 2467 +/- 52; 926 +/- 15 and 3489 +/- 156 vs 898 +/- 11 and 2314 +/- 124 pg/ml for control and moderate/severe hypoxia before and after indomethacin, respectively). Similar effects of indomethacin on hypoxic release of leucine enkephalin were also observed. These data indicate that prostaglandins contribute to hypoxic pial dilation. Additionally, these data show that prostaglandins release the opioids methionine enkephalin and leucine enkephalin. Finally, these data suggest that elevated prostaglandin concentrations during severe hypoxia release opioids which in turn contribute to hypoxic pial dilation.

6-Ketoprostaglandin F1 alpha↗

PubMed1995

Relationship between opioids and activation of phospholipase C and protein kinase C in brain injury induced pial artery vasoconstriction.

Previously, it has been observed that newborn pig pial artery constriction after fluid percussion brain injury was associated with elevated CSF dynorphin and beta endorphin concentration. Additionally, brain injury reversed dynorphin-induced pial artery vasodilation to vasoconstriction. The present study was designed to characterize the relationship between opioids and activation of phospholipase C (PLC) and protein kinase C (PKC) in brain injury-induced pial vasoconstriction. Anesthetized newborn pigs equipped with a closed cranial window were connected to a percussion device consisting of a saline-filled cylindrical reservoir with a metal pendulum. Brain injury of moderate severity (1.9-2.3 atm) was produced by allowing the pendulum to strike a piston on the cylinder. Brain injury decreased pial arteriolar diameter within 10 min of injury and continued to fall progressively for 3 h (130 +/- 5, 108 +/- 4 and 102 +/- 5 microns for 0, 10 and 180 min postinjury). In contrast, the PLC inhibitor, neomycin (10(-4) M), blunted brain injury-induced pial vasoconstriction (133 +/- 4, 129 +/- 4 and 135 +/- 5 microns for 0, 10 and 180 min postinjury, respectively). Similarly, staurosporine (10(-7) M), a PKC inhibitor, also blunted brain injury-induced vasoconstriction. beta endorphin (10(-8), 10(-6) M)-induced pial artery vasoconstriction was blunted by neomycin (12 +/- 1, 19 +/- 1 vs. 2 +/- 1, 4 +/- 2% constriction before and after neomycin, respectively). Staurosporine similarly blunted beta endorphin pial constriction (10 +/- 1, 15 +/- 1 vs. 1 +/- 1, 1 +/- 1% constriction before and after staurosporine, respectively). The constrictor potential for dynorphin was also inhibited by neomycin and staurosporine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

The role of nitric oxide in opioid-induced pial artery vasodilation.

The present study was designed to investigate the role of nitric oxide (NO) and the production of cGMP in the vasodilator response to opioid agonists in newborn pigs equipped with a closed cranial window. Methionine-enkephalin (10(-8), 10(-6) M), an endogenous mu opioid agonist, produced pial artery dilation that was attenuated by L-nitroarginine (LNA, 10(-6) M), an NO synthase inhibitor (10 +/- 1 vs. 4 +/- 1 and 16 +/- 1 vs. 7 +/- 1% for 10(-8), 10(-6) M methionine-enkephalin, respectively). Methionine-enkephalin-induced vasodilation was associated with increased cortical periarachnoid CSF cGMP and these changes in CSF cGMP were attenuated by LNA (354 +/- 11 and 596 +/- 32 vs. 278 +/- 13 and 266 +/- 19 fmol/ml for control and methionine-enkephalin 10(-6) M before and after LNA, respectively). Leucine enkephalin, an endogenous delta agonist, elicited similar changes in pial diameter and CSF cGMP while dynorphin, an endogenous k agonist, produced dilation associated with large increases in CSF cGMP (374 +/- 18 vs. 1054 +/- 45 fmol/ml for control and dynorphin 10(-6) M, respectively). Vascular and biochemical changes for these two opioids were similarly attenuated by LNA. The synthetic selective opioid receptor agonists, DAMGO, DPDPE, deltorphin, and U50,488H (10(-8), 10(-6) M) mu, delta 1, delta 2, and kappa agonists, respectively, also elicited increases in pial artery diameter and CSF cGMP that were similarly attenuated by LNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

The contribution of delta 1- and delta 2-opioid receptors to hypoxia-induced pial artery dilation in the newborn pig.

Previously, it has been observed that mu-opioid receptors contribute to while kappa-opioid receptors oppose pial artery dilation in response to hypoxia. The present study was designed to investigate the contribution of delta 1- and delta 2-opioid receptor activation to hypoxia-induced pial vasodilation. Newborn pigs equipped with a closed cranial window were used to measure pial artery diameter and collect cortical periarachnoid CSF for assay of opioids. Hypoxia increased CSF leucine enkephalin (a delta -agonist) from 36 +/- 6 to 113 +/- 17 pg/ml (n = 5). Hypoxia-induced pial artery vasodilation was attenuated during moderate hypoxia (PaO2 approximately 35 mm Hg), while this response was blunted during severe hypoxia (PaO2 approximately 25 mm Hg), by the delta 1-opioid receptor antagonist 7-benzylidenenaltrexone (BNTX; 10(-8) M) (23 +/- 2 vs. 13 +/- 2 and 34 +/- 6 vs. 10 +/- 3% for moderate and severe hypoxia in the absence and presence of BNTX, respectively; n = 5). In contrast, the delta 2-opioid receptor antagonist naltrindole (10(-9) M) blunted pial vasodilation during moderate hypoxia, but only attenuated the vasodilator response during severe hypoxia (22 +/- 2 vs. 8 +/- 2 and 33 +/- 4 vs. 23 +/- 4% for moderate and severe hypoxia in the absence and presence of naltrindole, respectively; n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Opioids and nitric oxide contribute to hypoxia-induced pial arterial vasodilation in newborn pigs.

The present study was designed to investigate the contribution of opioids and nitric oxide (NO) to hypoxia-induced pial vasodilation. Newborn pigs equipped with a closed cranial window were used to measure pial arteriolar diameter and to collect cortical periarachnoid cerebrospinal fluid (CSF) for assay of opioids and guanosine 3',5'-cyclic monophosphate (cGMP). Hypoxia-induced pial dilation was potentiated by norbinaltorphimine, 10(-6) M, a kappa-opioid antagonist (25 +/- 2 vs. 33 +/- 3%, n = 5), but was blunted by beta-funaltrexamine, 10(-8) M, a mu-opioid antagonist (28 +/- 2 vs. 19 +/- 1%, n = 5). Hypoxia-induced vasodilation was associated with increased CSF methionine enkephalin, a mu-opioid agonist (884 +/- 29 vs. 2,638 +/- 387 pg/ml, n = 5). N omega-nitro-L-arginine (L-NNA), an NO synthase inhibitor (10(-6) M), also blunted hypoxia-induced vasodilation that was further diminished by coadministration of L-NNA and beta-funaltrexamine (26 +/- 2, 14 +/- 1, and 9 +/- 1%, respectively, n = 5). Reversal of the above order of antagonist administration resulted in similar inhibition of hypoxia-induced pial dilation. Hypoxia-induced vasodilation was also associated with an increase in CSF cGMP that was attenuated by L-NNA (2.1 +/- 0.1- vs. 1.1 +/- 0.2-fold change in CSF cGMP, n = 5). Sodium nitroprusside (10(-6) M) increased CSF cGMP and methionine enkephalin concentration similar to hypoxia. These data suggest that hypoxia-induced pial arterial vasodilation, in part, is due to NO and/or cGMP-induced methionine enkephalin release as well as the direct action of NO.

Amino Acid Oxidoreductases↗

PubMed1995

Role of nitric oxide and cAMP in beta-adrenoceptor-induced pial artery vasodilation.

The present study was designed to investigate the role of nitric oxide (NO), guanosine 3',5'-cyclic monophosphate (cGMP), and adenosine 3',5'-cyclic monophosphate (cAMP) in the vasodilator response to beta-adrenoceptor agonists in newborn pigs equipped with a closed cranial window. Dobutamine (10(-8) and 10(-6) M), a beta 1-agonist, produced pial artery dilation that was blunted by NG-nitro-L-arginine (L-NNA; 10(-6) M), a NO synthase inhibitor (12 +/- 1 vs. 0 +/- 2% and 24 +/- 3 vs. 4 +/- 1% for 10(-8) and 10(-6) M dobutamine, respectively). Dobutamine-induced vasodilation was associated with increased cortical periarachnoid cerebrospinal fluid (CSF) cGMP, and these changes in CSF cGMP were blocked by L-NNA (391 +/- 10 and 675 +/- 36 fmol/ml vs. 307 +/- 3 and 346 +/- 37 fmol/ml for control and 10(-6) M dobutamine before and after L-NNA, respectively). In contrast, dobutamine-associated changes in CSF cAMP were unchanged by L-NNA (1,108 +/- 56 and 2,623 +/- 139 fmol/ml vs. 1,059 +/- 24 and 2,500 +/- 61 fmol/ml for control and 10(-6) M dobutamine before and after L-NNA, respectively). Salbutamol, a beta 2-agonist, and isoproterenol, a nonselective beta-agonist, elicited similar changes in pial diameter and cyclic nucleotides; vasodilation and changes in CSF cGMP also were similarly inhibited by L-NNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Albuterol↗

PubMed1995

Role of nitric oxide and cAMP in prostaglandin-induced pial arterial vasodilation.

The present study was designed to investigate the role of nitric oxide (NO), guanosine 3',5'-cyclic monophosphate (cGMP), and adenosine 3',5'-cyclic monophosphate (cAMP) in the vasodilator response to prostaglandin (PG)I2 and PGE2 in newborn pigs equipped with a closed cranial window. PGI2 (1-100 ng/ml) produced pial arterial dilation that was blunted by nitro-L-arginine (L-NNA, 10(-6) M), an NO synthase inhibitor (9 +/- 1 vs. 2 +/- 1%, 21 +/- 1 vs. 5 +/- 3% for 1 and 100 ng/ml PGI2 respectively, n = 6; means +/- SE). PGI2-induced vasodilation was associated with increased cortical periarachnoid cerebrospinal fluid (CSF) cGMP, and these changes in cGMP were blocked by L-NNA (386 +/- 8 and 1,054 +/- 30 fmol/ml vs. 266 +/- 6 and 274 +/- 4 fmol/ml for control and PGI2 100 ng/ml before and after L-NNA respectively, n = 6). In contrast, PGI2-associated changes in CSF cAMP were unchanged by L-NNA (1,021 +/- 25 and 2,703 +/- 129 fmol/ml vs. 980 +/- 23 and 2,636 +/- 193 fmol/ml for control, PGI2 100 ng/ml before and after L-NNA, respectively, n = 6). PGE2 elicited similar changes in pial artery diameter and cyclic nucleotides; vasodilation and changes in CSF cGMP also being similarly inhibited by L-NNA. After L-NNA, topical administration of the NO donor sodium nitroprusside (SNP, 10(-9) M) increased pial artery diameter up to the resting level before L-NNA and partially restored the vasodilation elicited by PGI2 and PGE2.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Opioids contribute to hypoxia-induced pial artery dilation through activation of ATP-sensitive K+ channels.

It has been previously observed that hypoxia increases cerebrospinal fluid (CSF) methionine enkephalin and leucine enkephalin levels, and these opioids contribute to hypoxia-induced pial artery vasodilation. The present study was designed to investigate whether the activation of ATP-sensitive K+ channels (KATP) mediates the contribution of opioids to the hypoxia-induced pial artery dilation. The closed-cranial window technique was used to measure pial diameter in newborn pigs. Glibenclamide (10(-6) M), a KATP inhibitor, attenuated the dilation resulting from moderate and severe hypoxia [23 +/- 1 and 33 +/- 2% vs. 7 +/- 1 and 18 +/- 2%, respectively, for moderate and severe hypoxia (arterial PO2 approximately 35 and 25 mmHg, respectively) in the absence vs. presence of glibenclamide]. In addition, glibenclamide attenuated the dilation produced by methionine enkephalin (10(-8) and 10(-6) M) (13 +/- 1 vs. 4 +/- 2% and 21 +/- 2 vs. 7 +/- 3%, respectively, for methionine enkephalin in the absence and presence of glibenclamide). Leucine enkephalin-induced dilation was similarly attenuated by glibenclamide. Cromakalim (10(-8) and 10(-6) M), a KATP agonist, produced dilation that was blocked by glibenclamide (12 +/- 1 and 25 +/- 1 vs. 3 +/- 1 and 5 +/- 1% before and after glibenclamide, respectively). These data show that activation of KATP contributes to methionine enkephalin- and leucine enkephalin-induced dilation. Furthermore, these observations suggest that opioids contribute to hypoxia-induced pial artery dilation via KATP activation.

Adenosine Triphosphate↗

PubMed1995

Influence of brain injury on opioid-induced pial artery vasodilation.

This study was designed to investigate the effect of fluid percussion brain injury on opioid-induced pial artery vasodilation in the newborn pig. Previous observations have shown that brain injury produces pial artery vasoconstriction associated with elevated cerebral spinal fluid (CSF) opioid levels in the piglet. Additionally, opioids produce pial vasodilation that is attenuated by the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine (L-NNA). Anesthetized newborn pigs equipped with a closed cranial window were connected to a percussion device consisting of a saline-filled cylindrical reservoir with a metal pendulum. Brain injury of moderate severity (1.9-2.3 atm) was produced by allowing the pendulum to strike a piston on the cylinder. Methionine enkephalin (Met), an endogenous mu-opioid agonist in physiological and pharmacological concentrations (10(-10), 10(-8), 10(-6) M), produced vasodilation that was attenuated following brain injury (7 +/- 1 vs. 3 +/- 1%, 11 +/- 1 vs. 5 +/- 1% and 16 +/- 1 vs. 8 +/- 1% for 10(-10), 10(-8), 10(-6) M Met before and after injury, respectively, n = 5). Met-induced dilation was associated with increased cortical periarachnoid CSF guanosine 3',5'-cyclic monophosphate (cGMP), and these biochemical changes were blunted by brain injury (342 +/- 12 and 640 +/- 13 fmol/ml vs. 267 +/- 6 and 321 +/- 17 fmol/ml for control and Met 10(-6) M before and after injury, respectively, n = 5). Leucine enkephalin, an endogenous delta-agonist, induced pial dilation and associated changes in CSF cGMP, which were similarly altered by brain injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

The role of opioids in newborn pig fluid percussion brain injury.

The present study was designed to characterize the relationship between cerebral opioid concentration, cerebral hemodynamics, and cerebral oxygenation following percussion brain injury in neonatal pigs. Previous research found that opioids represent a significant vasoactive component in the regulation of the neonatal piglet cerebral circulation. Anesthetized newborn (1-5 days old) pigs equipped with a closed cranial window were connected to a percussion device consisting of a saline-filled cylindrical reservoir with a metal pendulum. Brain injury of moderate severity (1.9-2.3 atm.) was produced by allowing the pendulum to strike a piston on the cylinder. Fluid percussion brain injury decreased pial arteriolar diameter (132 +/- 5 to 110 +/- 5 microns within 10 min). Cerebral blood flow also fell within 10 min of injury and continued to fall progressively for 3 h, resulting in a 46 +/- 4% decrease. Within 30 s of brain injury, there was a transient increase in cerebral hemoglobin-O2 saturation that was reversed to a progressive profound decrease in cerebral hemoglobin-O2 saturation for the next 3 h, as measured by near infrared spectroscopy. CSF opioid concentrations were increased 10 min after brain injury; dynorphin showed the largest proportional increase (5.8 +/- 0.9 fold). The CSF concentration for other opioids continued to increase over 180 min while the dynorphin concentration progressively decreased with time. In naloxone (1 mg/kg i.v.) pretreated piglets, the brain injury induced decrease in arteriolar diameter was attenuated (129 +/- 5 to 121 +/- 5 microns within 10 min). Similarly, the decrease in regional cerebral blood flow and cerebral hemoglobin-O2 saturation observed following brain injury were also blunted by naloxone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Actinomycin D blocks interleukin-1 alpha-induced pial arteriolar dilation and increased prostanoid production in newborn pigs.

Effects of protein synthesis and cyclooxygenase inhibitors on interleukin-1 alpha (IL-1 alpha)- and histamine-induced pial arteriolar dilation and cerebrospinal fluid (CSF) prostanoid increases were examined in anesthetized piglets using closed cranial windows. Topical IL-1 alpha (10.8 micrograms) increased pial arteriolar diameter from 15 to 30 min after its infusion, and enhanced CSF prostanoids. Topical protein synthesis inhibitor, actinomycin D, at a concentration of 10(-8) M attenuated and 10(-6) M completely blocked both IL-1 alpha-induced vasodilation and CSF prostanoid increase. Inhibition of prostaglandin H synthases with indomethacin blocked both vasodilation and CSF prostanoid increase by IL-1 alpha. Topical histamine (10(-6) M) also increased pial arteriolar diameter and CSF prostanoids but without the delay seen between IL-1 alpha infusion and responses. These histamine effects were not modified by coinfusion of actinomycin D but blocked by indomethacin. These results suggest that, although IL-1 alpha and histamine do share the same mechanism insofar as activation of prostaglandin synthesis is concerned, an additional step appears to be involved for IL-1 alpha, likely involving de novo protein synthesis.

Animals↗

PubMed1994

Different pial arteriolar responses to acetylcholine in the newborn and juvenile pig.

Using the closed cranial window technique, the present study was designed to test the hypothesis that the pial arteriolar response to acetylcholine is age dependent. In newborn pigs (1-5 days old) pretreated with the phosphodiesterase inhibitor isobutyl methyl xanthine (IBMX), acetylcholine (10(-5) M) produced pial arteriolar constriction with no change in CSF cyclic GMP (cGMP) that was blocked by indomethacin (5 mg/kg i.v.). In contrast, in indomethacin- and IBMX-treated juvenile pigs (3-4 weeks old), acetylcholine (10(-) M) increased the pial arteriolar diameter by 17 +/- 1% and increased CSF cGMP by 2.1 +/- 0.3-fold. Similar vascular and biochemical changes for acetylcholine were observed in juvenile pigs pretreated with only IBMX. In the absence of IBMX, acetylcholine produced modest pial constriction in juvenile pigs. In the IBMX-pretreated juvenile pigs, L-nitroarginine (LNA; 10(-6) M) decreased pial arteriolar diameter by 15 +/- 2% and blocked acetylcholine-induced dilation and associated changes in CSF cGMP. A23187, a calcium ionophore, and sodium nitroprusside (SNP) elicited similar dilation and changes in CSF cGMP in both age groups. LNA blocked A23187 dilation, but SNP dilation was unchanged. L-Arginine (10(-3) M) partially restored acetylcholine- and A23187-induced dilation to indomethacin- and LNA-pretreated juvenile pigs. These data show that acetylcholine produces dilation in the juvenile pig through the production of the putative endothelium-derived relaxing factor (EDRF) nitric oxide but does not do so in the new born period. We speculate that contributions of EDRF to the acetylcholine-induced changes in pial arteriolar diameter develop with age.

1-Methyl-3-isobutylxanthine↗

PubMed1994

Different cerebral hemodynamic responses following fluid percussion brain injury in the newborn and juvenile pig.

The present study was designed to characterize the influence of early developmental changes on the relationship among systemic arterial pressure, cerebral hemodynamics, and cerebral oxygenation during the first 3 h following percussion brain injury. Anesthetized newborn (1-5 days old) and juvenile (3-4 weeks old) pigs equipped with a closed cranial window were connected to a percussion device consisting of a saline-filled cylindrical reservoir with a metal pendulum. Brain injury of moderate severity (1.9-2.3 atm) was produced by allowing the pendulum to strike a piston on the cylinder. Mean arterial blood pressure increased after brain injury in juveniles (68 +/- 4 to 93 +/- 2 mm Hg within 3 min, n = 6), whereas it decreased after injury in newborns (70 +/- 3 to 51 +/- 3 mm Hg within 3 min, n = 6). Fluid percussion brain injury decreased pial artery diameter more in newborns (132 +/- 5 to 110 +/- 5 microns within 10 min, n = 5) than in juveniles (141 +/- 3 to 133 +/- 3 microns within 10 min, n = 5). Pial arterioles constricted to a greater extent than small pial arteries following brain injury in both age groups. Within 30 sec, brain injury produced a transient increase in cerebral hemoglobin O2 saturation (27 +/- 4%, n = 5) that was reversed to a profound decrease in cerebral hemoglobin O2 saturation (45 +/- 2%, n = 5) in the newborn as measured by near infrared spectroscopy. In contrast, brain injury produced modest increases in hemoglobin O2 saturation (10 +/- 1%, n = 5), followed by mild desaturation (4 +/- 1%, n = 5) in juveniles. Additionally, regional cerebral blood flow was reduced within 10 min of injury in both newborn and juvenile pigs and remained depressed for 180 min in newborns. In contrast, cerebral blood flow returned to control values within 180 min in juveniles. These data show that the effects of comparable brain injury level were very different in newborn and juvenile pigs. Further, these data suggest that reductions in cerebral blood flow following brain injury are more dependent on changes in reactivity of arterioles. Finally, these data suggest that the decrease in cerebral oxygenation, an index of metabolism, coupled with reduced cerebral blood flow, could result in profound hypoperfusion after brain injury.

Age Factors↗

PubMed1994

Light/dye microvascular injury selectively eliminates hypercapnia-induced pial arteriolar dilation in newborn pigs.

Cerebral vasodilation in response to hypercapnia involves prostanoids in newborn pigs. This study examines the hypothesis that endothelial injury in vivo inhibits cerebral vasodilation and prostacyclin synthesis in response to hypercapnia, thus suggesting prostacyclin is a primary endothelium-derived vasodilating factor in newborn pig cerebral circulation. Anesthetized piglets with closed cranial windows were studied before and after injury caused by light/dye or before and after dye-only sham control. Light/dye injury was produced by injecting sodium fluorescein intravenously and passing filtered light from a mercury arc lamp through the cranial window. Ultrastructural changes to endothelium of pial vessels were produced that were characterized by surface pits, vacuolar cytoplasmic inclusions, and mitochondrial injury. After the light/dye injury, dilation to hypercapnia was absent while dilations to iloprost, isoproterenol, and sodium nitroprusside and constrictions to norepinephrine and acetylcholine were retained. Before light/dye treatment, hypercapnia increased cortical periarachnoid 6-keto prostaglandin F1 alpha concentration approximately threefold. However, after treatment, 6-keto-prostaglandin F1 alpha was not increased significantly in response to hypercapnia. These findings are consistent with the hypothesis that endothelial prostacyclin synthesis induced by hypercapnia participates in dilation of adjacent smooth muscle.

Animals↗