Pancuronium attenuates associated hemodynamic and transcutaneous oxygen tension changes during nursery procedures.

Intermittent increases in blood pressure (BP) associated with motor activity have been implicated in the pathogenesis of intraventricular hemorrhage in premature infants. Inhibition of motor activity by pancuronium administration has also been shown to stabilize cerebral blood flow velocity (CBFV) and BP patterns. The purpose of this study was to determine whether administration of pancuronium to ill premature infants would attenuate changes in BP and transcutaneous oxygen tension (TcPO2) and the variability of CBFV pattern associated with common nursery procedures. Fourteen premature infants in the study were given a single dose of pancuronium bromide at a dose of 0.1 mg/kg intravenously. BP and TcPO2 changes were monitored during nursery procedures, that is, during radial artery blood gas sampling and a head ultrasonographic/Doppler procedure, before and during pancuronium therapy. During arterial blood gas sampling, mean percent increase in BP was significantly greater (32% +/- 21%) before pancuronium administration compared with 21% +/- 13% during pancuronium use (p < 0.05). Mean percent changes in TcPO2 were -30% +/- 21% and 5.8% +/- 7.2% before and during pancuronium use, respectively (p < 0.05). Similar significant changes in BP and TcPO2 were observed with a head ultrasonographic/Doppler procedure. Coefficients of variation of systolic and mean CBFV also decreased significantly during pancuronium therapy. We observed short-term benefits with pancuronium use on vascular dynamics and oxygenation during nursery procedures. Further studies are needed to evaluate the use of pancuronium in preterm babies supported by mechanical ventilation during the first few days of life for possible prevention of intraventricular hemorrhage, the pathophysiologic mechanism of which may be related to hemodynamic and biochemical derangement.

Permissive role of prostacyclin in cerebral vasodilation to hypercapnia in newborn pigs.

Hypercapnic cerebral vasodilation in piglets is accompanied by increased cerebral prostanoid synthesis. Interventions that prevent the increased prostanoids also interfere with the vasodilation. However, the increased prostanoids may not produce vasodilation directly; instead, they may allow or enhance function of another mechanism. The present experiments examined the hypothesis that prostacyclin can allow, but may not directly produce, cerebral vasodilation to hypercapnia. Chloralose-anesthetized piglets were equipped with closed cranial windows for measurements of pial arteriolar diameters. Hypercapnia (arterial CO2 partial pressure approximately 70 mmHg) was administered before and after indomethacin (5 mg/kg iv) in all animals. Then artificial cerebrospinal fluid (aCSF) under the cranial window was replaced for the remainder of the experiment with aCSF containing vehicle, carbaprostacyclin (60 pM), iloprost (1 pM), prostaglandin E2 (PGE2; 1.7 and 3.3 nM), isoproterenol (10 and 100 nM), or sodium nitroprusside (1 microM), and hypercapnia was repeated. The two prostacyclin receptor agonists restored cerebral vasodilation to hypercapnia that had been blocked by indomethacin (to 92 +/- 31% and 76 +/- 11% of the before-indomethacin dilation for carbaprostacyclin and iloprost, respectively.) The highest dose of PGE2 partially restored the dilation (43 +/- 7% of the pre-indomethacin response). In contrast, neither isoproterenol nor sodium nitroprusside permitted significant dilation to hypercapnia following indomethacin treatment. These data indicate that prostacyclin can allow hypercapnic vasodilation to occur, but increasing levels do not appear to be necessary to cause the dilation directly. The short half-life of prostacyclin may explain why active prostanoid synthesis appears to be necessary for hypercapnia-induced cerebral vasodilation in newborn pigs.

Indomethacin reduces ischemia-induced alteration of blood-brain barrier transport in piglets.

Cerebral ischemia-reperfusion (Isc-Rep) alters blood-brain barrier (BBB) transport properties in piglets. Pretreatment with superoxide dismutase and catalase partially attenuates these effects. Activated O2 species produced with Isc-Rep in piglets are generated via prostaglandin (PG) H synthase. This experiment determines if products of PGH synthase alter BBB transport of sodium and albumin. Piglets anesthetized with nitrous oxide and halothane were divided into four groups: 1) control, 2) indomethacin (5 mg/kg iv) with no Isc-Rep, 3) Isc-Rep alone, and 4) Isc-Rep after pretreatment with indomethacin (Indo). Regional transfer coefficients (Kin) and regional cerebral blood flow (microspheres) were measured at 2 h reperfusion after 20 min total global cerebral ischemia. Kin values are represented as absolute values and also relative to blood flow to account for any changes in perfusion caused by ischemia and/or Indo. Indo alone did not alter sodium or albumin transfer compared with control animals. Isc-Rep alone caused a significant increase in sodium and albumin transport compared with all other groups (control cerebral sodium Kin was 18.2 +/- 2.7 cm3.g-1.s-1.10(6) vs. 32.9 +/- 3.1 for Isc-Rep, P < 0.05). In contrast, there was no significant difference in sodium or albumin transfer with Isc-Rep after Indo pretreatment (e.g., cerebral sodium Kin was 22.0 +/- 2.0 for Isc-Rep after Indo) compared with the control or Indo alone groups. Indo pretreatment effectively attenuates increased BBB transport of both sodium and albumin following cerebral ischemia. We conclude that products of PGH synthase are involved in BBB alterations of protein and cation transport that follow the early stages of cerebral reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

Cyclic nucleotides and cerebrovascular tone in newborn pigs.

Relationships between cyclic nucleotides and cerebrovascular tone were investigated using closed cranial windows in anesthetized newborn pigs. Pial arteriolar diameter was monitored and cerebrospinal fluid (CSF) was collected from beneath the cranial window. Adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP) concentrations in CSF were 1,690 +/- 200 and 730 +/- 40 fmol/ml, respectively. Topically applied isozyme-selective and nonselective inhibitors [3-isobutyl-1-methylxanthine (IBMX), theophylline, Ro 201724, dipyridamole, zaprinast, calmidazolium, and W-7] of cyclic nucleotide phosphodiesterases dilated pial arterioles with concomitant increases in cAMP and/or cGMP levels in CSF. Topical application of dibutyryl-cAMP and dibutyryl-cGMP also resulted in pial arteriolar dilation. Ten-minute hypercapnia, which results in pial arteriolar dilation, increased cAMP to 5,240 +/- 900 and cGMP to 1,350 +/- 200 fmol/ml. IBMX and zaprinast potentiated the increases in cAMP and cGMP as well as the cerebrovascular dilation in response to hypercapnia. These data suggest that cyclic nucleotides contribute to regulation of cerebral vascular tone during control conditions. Furthermore, cAMP and/or cGMP appears to be involved in arterial vasodilation in response to hypercapnia in newborn pigs.

Effects of indomethacin on newborn pig pial arteriolar responses to PCO2.

The present experiments were designed to determine whether hypocapnic cerebral vasoconstriction, like hypercapnic dilation, involves prostanoids and, if not, whether alternative mechanisms are related to the absolute arterial PCO2 (PaCO2) or the direction of change. We determined effects of indomethacin (5 mg/kg iv) on pial arteriolar responses to 1) increased PCO2 from normal, 2) decreased PCO2 from normal, and 3) increased PCO2 from hypocapnia to normocapnia in anesthetized newborn pigs. Pial arterioles constricted in response to hypocapnia (PaCO2 = 15-24 Torr) similarly before (-13 +/- 3%) and after (-16 +/- 2%) indomethacin. Cortical periarachnoid cerebrospinal fluid prostanoids were not increased by hypocapnia. As previously reported, cerebral vascular responses to hypercapnia (which increases cerebrospinal fluid prostanoids) were lost after indomethacin. To determine whether the failure of indomethacin to affect the responses to hypocapnia was due to the direction of change (decreasing) or the absolute level of PCO2, piglets were hyperventilated to approximately 15 Torr PaCO2. Increasing PaCO2 in these piglets to approximately 44 Torr caused pial arteriolar dilation (46 +/- 7%) that was not blocked by indomethacin (33 +/- 5%). Cortical periarachnoid prostanoids were not altered when PaCO2 was raised from hypocapnia to normocapnia. Therefore the relationship between CO2 and piglet cerebral vascular tone appears to involve multiple mechanisms. Specifically, dilation in response to CO2 above the normal range appears to involve prostanoids but changes in pial arteriolar diameter at low PaCO2 do not.

Effects of indomethacin on cerebral vasodilator responses to arachidonic acid and hypercapnia in newborn pigs.

Responses of pial arterioles to topically applied arachidonic acid, conversion of exogenous arachidonic acid to prostanoids, and pial arteriolar dilation to hypercapnia were examined before and at progressive times after treatment with indomethacin (5 mg/kg i.v.) in chloralose-anesthetized newborn pigs with closed cranial windows. Before treatment with indomethacin, arachidonic acid and hypercapnia dilated pial arterioles and increased cortical periarachnoid cerebrospinal fluid concentrations of 6-keto-prostaglandin (PG) F1 alpha and PGE2. One h after indomethacin treatment, the dilations and prostanoid synthesis were blocked. By 2 h after indomethacin treatment, hypercapnia produced significant dilation of pial arterioles, and dilation to both stimuli had returned to preindomethacin levels by 3 h. Inhibition of conversion of exogenous arachidonic acid to prostanoids as monitored by increases in 6-keto-PGF1 alpha and PGE2 in cerebrospinal fluid under the window also was reversed by 3 h after treatment with indomethacin. Repeated indomethacin treatment again blocked dilations and conversion of arachidonic acid to prostanoids on the brain surface. The possibility of short duration of vascular effectiveness of indomethacin when it is administered systemically needs to be considered, both when it is used as a probe for understanding contributions of PGH synthase products to control of cerebral circulation and when it is used therapeutically in attempts to alter the newborn cerebral circulation.

Transforming growth factor-beta attenuates ischemia-induced alterations in cerebrovascular responses.

We observed previously that 20 min of global cerebral ischemia followed by 45 min of reperfusion selectively blocked cerebral vasodilation to hypercapnia and hypotension. This study determines the effects of pretreatment with transforming growth factor-beta (TGF-beta) on cerebrovascular responses after cerebral ischemia in piglets equipped with closed cranial windows. Hypercapnia-induced pial arteriolar dilation was blocked after cerebral ischemia (20 +/- 1 vs. 2 +/- 1% dilation before and after ischemia, respectively). Similarly, the increases in periarachnoid cortical cerebrospinal fluid 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) and prostaglandin E2 (PGE2) concentration in response to hypercapnia were blocked (2.5 +/- 0.2- vs. 0.2 +/- 0.4-fold and 2.1 +/- 0.1- vs. 0.3 +/- 0.4-fold increase in 6-keto-PGF1 alpha and PGE2, respectively). Treatment with topical TGF-beta (400 ng/ml) before and during ischemia-reperfusion attenuated the loss of hypercapnia-induced cerebrovascular dilation (20 +/- 1 vs. 14 +/- 1% dilation before and after ischemia, respectively) and the loss of associated changes in cerebrospinal fluid prostanoids (2.0 +/- 0.2- vs. 1.7 +/- 0.2-fold and 2.3 +/- 0.2- vs. 2.2 +/- 0.3-fold increase in 6-keto-PGF1 alpha and PGE2 before and after ischemia, respectively). The loss of cerebrovascular dilation in response to hemorrhagic hypotension after ischemia was similarly prevented by TGF-beta. Cerebrovascular dilation to topical isoproterenol was unchanged after ischemia. TGF-beta may preserve endothelial cell function. We conclude that topical TGF-beta can attenuate cerebromicrovascular compromise caused by ischemia-reperfusion in newborn pigs.

Superoxide scavengers do not prevent ischemia-induced alteration of cerebral vasodilation in piglets.

Piglet brains generate superoxide during postischemic reperfusion, and topical application of activated oxygen species alters pial arteriolar responses. We investigated effects of pretreatment with scavengers of superoxide and H2O2 on ischemia-induced alterations of pial arteriolar responses in anesthetized newborn pigs. Four groups were studied: 1) time control, 2) untreated ischemia, 3) ischemia pretreated topically and systemically (conjugated to polyethylene glycol) with superoxide dismutase (SOD) and catalase, and 4) ischemia pretreated with Tiron. Pretreatment with SOD conjugated to polyethylene glycol alone during postischemic reperfusion effectively removed superoxide from its site of generation during postischemic reperfusion, but topical SOD was used also an insurance. Piglets were studied before and after 20 min of total cerebral ischemia caused by maintaining intracranial pressure above mean arterial pressure. As reported previously, before ischemia, hypercapnia and isoproterenol dilated pial arteries and arterioles and hypercapnia but not isoproterenol increased cortical periarachnoid cerebrospinal fluid 6-keto-prostaglandin F1 alpha, measured as an index of cerebral cortical prostacyclin synthesis. After cerebral ischemia, pial arterioles did not dilate in response to hypercapnia and 6-keto-prostaglandin F1 alpha did not increase, but dilation to isoproterenol was unchanged. The present study found that treatment with SOD/catalase or Tiron did not prevent loss of vasodilation to hypercapnia or the loss of hypercapnia-induced cerebral 6-keto-prostaglandin F1 alpha synthesis after cerebral ischemia. The postischemic loss of cerebral vasodilation to hypercapnia does not appear to involve superoxide or a subsequent reduced form of oxygen.

Prostanoids modulate opioid-induced increases in cerebrospinal fluid vasopressin concentration.

Topical dynorphin and beta-endorphin produce increases in both prostanoid and vasopressin concentrations in cortical periarachnoid fluid of newborn pigs. The present study, in anesthetized piglets with cranial windows implanted, investigated the role of these prostanoids in the mediation of this vasopressin release by opioids. Topical prostaglandin (PG) I2 (100 ng/ml) increased pial arteriolar diameter from 145 +/- 4 to 178 +/- 4 microns and also increased cerebrospinal fluid (CSF) vasopressin from 1.1 +/- 0.1 to 4.1 +/- 0.5 microU/ml, but CSF vasopressin was not changed by PGE2, PGF2 alpha, and U-46619. Therefore, it is possible that PGI2 causes the increase in CSF vasopressin produced by opioids. Consistent with this concept, indomethacin and aspirin blocked dynorphin- and beta-endorphin-induced vasopressin release. The present data indicate that PGI2 contributes to opioid-induced changes in CSF vasopressin concentration and, thereby, to vasopressinergic contributions to opioid-induced cerebral vascular responses.

Cerebral vasoconstriction in response to hypocapnia is maintained after ischemia/reperfusion injury in newborn pigs.

BACKGROUND AND PURPOSE: Hypocapnic cerebral vasoconstriction is used therapeutically to reduce elevated intracranial pressure caused by cerebral edema. Because cerebral ischemia/reperfusion injury causes a selective loss of prostanoid-dependent responses, including vasodilation to hypercapnia, we designed these experiments to examine the effect of ischemia/reperfusion on hypocapnic cerebral vasoconstriction. METHODS: Microvascular responses were studied in 10 newborn pigs (closed cranial window) in response to hyperventilation-induced hypocapnia (PaCO2, 22 +/- 2 mm Hg) both before and 45 minutes after 20 minutes of global cerebral ischemia. Responses to hypercapnia (PaCO2, 63 +/- 3 mm Hg), topical isoproterenol (10(-7) M), and norepinephrine (10(-4) M) were also studied before and after ischemia in the same animals for comparison. RESULTS: Before ischemia/reperfusion, pial arterioles vasoconstricted to hypocapnia (-17 +/- 2%) and norepinephrine (-35 +/- 4%) and vasodilated to CO2 (37 +/- 7%) and isoproterenol (25 +/- 2%). After ischemia/reperfusion, the constriction of pial arterioles to hypocapnia (-19 +/- 2%) was similar to that before ischemia. This is in contrast to the loss of dilation to hypercapnia. Dilation to isoproterenol and constriction to norepinephrine were not affected by ischemia. CONCLUSIONS: Hypocapnic cerebral vasoconstriction is maintained after ischemia/reperfusion. Since prostanoid-dependent responses, such as hypercapnic dilation, are lost following cerebral ischemia, these data suggest that hypocapnic constriction is not dependent on an intact prostanoid system and that cerebral vascular responses to CO2 involve multiple mechanisms, depending on whether CO2 is increasing or decreasing from baseline.

Topical arachidonic acid restores pial arteriolar dilation to hypercapnia of postischemic newborn pig brain.

In the newborn pig, cerebral vasodilator responses to hypercapnia are lost after cerebral ischemia. We examined the effect of topical application of arachidonic acid (30 micrograms/ml, 20 min) to the postischemic piglet brain on subsequent pial arteriolar dilated in response to hypercapnia (10% CO2 ventilation) and topical isoproterenol (10(-6), 10(-7) M). After 20 min cerebral ischemia, pial arterioles did not dilate to hypercapnia but responded to isoproterenol in a fashion similar to before ischemia. Treatment with arachidonic acid after ischemia restored pial arteriolar dilation to hypercapnia. Hypercapnia caused an increase in cortical periarachnoid concentration of 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) before but not after ischemia. After postischemic treatment with arachidonic acid, the increase in cortical periarachnoid fluid 6-keto-PGF1 alpha during hypercapnia was restored. Therefore, topical application of arachidonic acid to cerebral vessels restores cerebral prostanoid synthesis and pial arteriolar dilation in response to hypercapnia that has been abolished by ischemia.

Alterations in cerebrovascular reactivity after positive pressure ventilation.

Pressure ventilation of the newborn can adversely affect the cardiovascular system. Increasing airway pressure increases cerebral venous pressure, thus stressing brain vasculature. To test the hypothesis that cerebral venous distension caused by mechanical ventilation alters cerebral microvascular responses, we studied cerebrovascular responses before, during, and after positive pressure ventilation. Anesthetized newborn pigs were ventilated with a standard time-cycled, pressure-limited infant respirator. Pial arterioles were measured in response to hypercapnia, topical isoproterenol, and topical norepinephrine during control [mean airway pressure (Paw) = 0.9 +/- 0.05 kPa (4.8 +/- 0.3 cm H2O)] conditions, during 40-60 min of increased Paw [2.5 +/- 0.2 kPa (13.9 +/- 1.3 cm H2O)], and when the Paw was lowered again. Pial arteriolar dilation in response to hypercapnia was not changed by increasing Paw. Similarly, responses to isoproterenol and norepinephrine were unaltered during raised Paw. However, a significant decrease in responses to topical isoproterenol and norepinephrine was observed after increased Paw. These experiments show that specific prostanoid-independent cerebrovascular responses are altered subsequent to pressure ventilation, whereas prostanoid-dependent dilation to hypercapnia was not affected. These changes suggest that the newborn cerebral vasculature is affected by positive pressure ventilation, further raising the possibility that ventilation-induced alterations in microvascular responses could make the brain more vulnerable to added stresses after pressure ventilation.

Polyethylene glycol superoxide dismutase and catalase attenuate increased blood-brain barrier permeability after ischemia in piglets.

BACKGROUND AND PURPOSE: Transport of urea across the blood-brain barrier is increased during postischemic cerebral reperfusion in the piglet. Ischemia/reperfusion also has been observed to increase apparent superoxide anion generation on the surface of the brain. The present study was designed to address the hypothesis that the increased transfer of urea into the brain after ischemia/reperfusion could be due to superoxide anion-induced alterations in blood-brain barrier permeability. METHODS: Blood-to-brain transfer of carbon-14-labeled urea was measured in four groups (n = 7 each) of newborn pigs: 1) control (no ischemia, no pretreatment), 2) pretreatment with polyethylene glycol superoxide dismutase (1,000 IU/kg) and polyethylene glycol catalase (10,000 IU/kg i.v.) but no ischemia, 3) no pretreatment and 20 minutes of ischemia followed by 2 hours of reperfusion, and 4) pretreatment with polyethylene glycol superoxide dismutase and polyethylene glycol catalase in addition to ischemia/reperfusion. The following brain regions were investigated: cerebrum, caudate, midbrain, pons, medulla, and cerebellum. RESULTS: Polyethylene glycol superoxide dismutase inhibited generation of superoxide anion by the brain during reperfusion after ischemia. Regional transfer of [14C]urea from blood to brain increased at 2 hours' reperfusion. This ischemia-induced increase in blood-to-brain transfer of [14C]urea was attenuated by pretreatment with polyethylene glycol superoxide dismutase and polyethylene glycol catalase: e.g., cerebrum Kin was 28 +/- 2 in the control group, 26 +/- 3 in the pretreated/no ischemia group, 67 +/- 5 in the untreated/ischemia group, and 40 +/- 2 ml.g-1.s-1.10(6) in the pretreated/ischemia group. After ischemia/reperfusion, cerebral blood flow was unchanged by pretreatment with polyethylene glycol superoxide dismutase and polyethylene glycol catalase. CONCLUSIONS: These data suggest that production of a partially reduced species of oxygen contributes to the increased urea transfer across the blood-brain barrier after ischemia in the newborn pig.

Influence of opioids on CSF vasopressin concentration in newborn pigs.

This study was designed to determine the influence of opioids on periarachnoid cortical cerebrospinal fluid (CSF) vasopressin concentration in newborn pigs equipped with closed cranial windows. Topical dynorphin-(1-13) produced tone-dependent pial arterial responses (dilation during normotension, constriction when cerebrovascular tone was decreased by hypotension). Dynorphin-(1-13) increased periarachnoid cortical CSF vasopressin concentrations in both normotensive and hypotensive piglets (5 +/- 1, 11 +/- 1, and 233 +/- 27 microU/ml for control, 10(-10), and 10(-6) M dynorphin-(1-13) during normotension, respectively). Dynorphin-(1-8) and U 50488H, a purported selective kappa-opioid receptor agonist, produced similar tone-dependent responses associated with smaller increases in CSF vasopressin concentration. beta-Endorphin caused only cerebral vasoconstriction associated with modest increases in CSF vasopressin (3 +/- 1, 5 +/- 1, 9 +/- 2 microU/ml for control, 10(-10), and 10(-6) M beta-endorphin, respectively). In contrast, methionine enkephalin- and leucine enkephalin-induced dilations were not associated with changes in CSF vasopressin concentration. Naloxone (1 mg/kg i.v.) blocked both the opioid-induced vascular effects and associated changes in CSF vasopressin concentration. Naloxone also attenuated the increase in CSF vasopressin concentration in response to hemorrhagic hypotension. These data show that dynorphin- and beta-endorphin-induced cerebrovascular effects are associated with increased CSF vasopressin concentration. Furthermore, these data indicate that opioids could contribute to the increase in CSF vasopressin concentration observed in response to hemorrhagic hypotension.

Vasopressin modulates cerebrovascular responses to opioids in newborn pigs.

Vasopressin receptor blockade has been observed to attenuate the systemic vascular effects of dynorphin. This study was designed to determine the ability of vasopressin to modulate cerebrovascular responses to opioids in newborn pigs equipped with closed cranial windows. Topical dynorphin 13 increased pial arteriolar diameter during normotension (151 +/- 5, 171 +/- 4, 183 +/- 4 and 187 +/- 4 microns for control, 10(-10), 10(-8) and 10(-6) M dynorphin 13, respectively). During hypotension, however, responses to dynorphin 13 were reversed to concentration-dependent decreases in pial arteriolar diameter (184 +/- 3, 169 +/- 4, 165 +/- 4 and 159 +/- 4 microns for control 10(-10), 10(-8) and 10(-6) M dynorphin 13, respectively). Dynorphin 13-induced pial arteriolar dilation was potentiated by the V1 receptor antagonist [1-(beta-mercapto-beta beta-cyclopentamethylene propionic acid) 2(o-methyl)-Tyr-AVP] (MEAVP; 5 micrograms/kg i.v.; 14 +/- 1, 22 +/- 1 and 24 +/- 1% vs. 19 +/- 1, 26 +/- 1 and 30 +/- 1% increase for 10(-10), 10(-8) and 10(-6) M dynorphin 13 before and after MEAVP, respectively). In contrast, dynorphin 13-induced constriction during hypotension was markedly reduced by MEAVP (10 +/- 1, 15 +/- 1 and 16 +/- 2% vs. 1 +/- 1, 4 +/- 1 and 9 +/- 1% decrease for 10(-10), 10(-8) and 10(-6) dynorphin 13 before and after MEAVP, respectively). Dynorphin 8 and the synthetic kappa-opioid selective agonist, U5O,488H, elicited similar tone-dependent responses that were modified by MEAVP in a similar fashion.(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of opioids on local cerebral glucose utilization in the newborn pig.

Topical methionine enkephalin, leucine enkephalin, and dynorphin (10(-6)M) previously have been observed to produce prominent pial arteriolar dilation. Dilation to these opioids could be caused directly by opioids acting on vascular receptors, or indirectly, as a consequence of increased metabolism. Therefore, we examined this possibility by determining the influence of opioids on cerebral glucose utilization in piglets with closed cranial windows using the [14C]deoxyglucose method. Qualitatively, the autoradiographic images expressed as a change in relative optical density from vehicle were unchanged by these opioids. Quantitatively, the opioids similarly had no effect on cerebral glucose utilization (53 +/- 5, 70 +/- 8, 63 +/- 5, and 52 +/- 3, mumol.100 g-1.min-1 for vehicle, methionine enkephalin, leucine enkephalin, and dynorphin, respectively). In contrast, topical glutamate (10(-3) M) produced similar dilation but increased cerebral glucose utilization (41 +/- 3 vs 89 +/- 8 mumol.100 g-1.min-1 for vehicle and glutamate, respectively). Therefore, these opioids do not appear to produce vascular effects through a change in cerebral metabolic utilization of glucose.