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C W Leffler

Publications and source records attributed to C W Leffler.

At least 73 records · Page 4Linked to original sources
PubMed1995

Mechanisms of hypercapnia-stimulated PG production in piglet cerebral microvascular endothelial cells.

High CO2 stimulates dilator prostanoid (prostaglandin; PG) synthesis by piglet cerebral microvascular endothelial cells, but the mechanism of stimulation is unclear. We address the hypothesis that intracellular pH (pHi) and Ca2+ signaling are involved. When extracellular pH (pHe) and PCO2 were constant and pHi was rapidly reduced (propionate or nigericin), PG synthesis was stimulated. When pHe was lowered by reducing NaHCO3, pHi fell slowly, but PG synthesis was not altered. When pHe was decreased by increasing PCO2 or returned to 7.4 by increasing NaHCO3, with a constant PCO2 of 100 mmHg, pHi dropped quickly and PG synthesis was stimulated. When pHi was reduced slowly by changing CO2 slowly, or by stepwise addition of propionate, PG synthesis was increased regardless of pHe, suggesting that the rapid decline of pHi plays a central role in mediating the PG synthesis. Ca2+ signaling is a potential mechanism by which pHi increases PG synthesis. However, extracellular Ca2+ removal did not affect PG synthesis induced by propionate or hypercapnia. Furthermore, neither rapid nor slow decreases of pHi altered cytosolic free Ca2+ concentration. Therefore, Ca2+ signals do not appear to be involved in the CO2 stimulation of PG synthesis.

Acids↗
PubMed1995

Inhibitory effect of indomethacin on prostacyclin receptor-mediated cerebral vascular responses.

The present study addresses the hypothesis that indomethacin, in addition to blocking prostaglandin synthesis, directly inhibits prostacyclin receptor-mediated cerebral vascular responses. To test this hypothesis, the effects of indomethacin on pial arteriolar dilation in response to the prostacyclin receptor agonist iloprost were investigated using a cranial window technique in newborn pigs. Topically applied iloprost resulted in dose-dependent pial arteriolar dilation and concomitant increases in cortical adenosine 3',5'-cyclic monophosphate (cAMP). Indomethacin (5 mg/kg iv + 10(-4) M topically) greatly reduced both the vasodilation and the increase in cortical cAMP in response to iloprost. In contrast, indomethacin did not attenuate beta-adrenoreceptor-mediated vasodilation and the increase in cortical cAMP in response to isoproterenol. Aspirin (50 mg/kg iv + 10(-3) M topically) did not affect pial arteriolar dilation or the increase in cortical cAMP in response to iloprost. Unlike indomethacin, aspirin was not effective in inhibiting prostanoid-associated cerebral vasodilation and increase in cortical cAMP in response to hypercapnia. The present data suggest that indomethacin selectively inhibits prostacyclin receptor-mediated responses in the newborn pig cerebral circulation. The combination of highly effective inhibition of prostaglandin H synthase and prostacyclin receptor-mediated vasodilation may contribute to the increased efficacy of indomethacin compared with other prostaglandin H synthase inhibitors in blocking certain vasodilator responses associated with prostanoids.

Animals↗
PubMed1995

Lysophosphatidic acid alters cerebrovascular reactivity in piglets.

Effects of the lipid mediator lysophosphatidic acid (LPA) were studied on the cerebral circulation of newborn pigs using closed cranial windows. Topical application of synthetic LPA caused dose-dependent vasoconstriction and inhibited vasodilation to hypercapnia and isoproterenol. These vasodilators elicited a rise in the adenosine 3',5'-cyclic monophosphate (cAMP) content of the cerebrospinal fluid, which was inhibited dose dependently by LPA. Pertussis toxin (1 microgram/ml) completely abolished LPA-induced vasoconstriction and the altered vascular reactivity, and LPA no longer decreased cAMP. Electrophysiological recording of currents evoked by LPA-like lipids in Xenopus oocytes showed that cerebrospinal fluid is normally devoid of LPA-like factors. In contrast, the amount of LPA-like factors generated 4 days after intrathecal injection of autologous blood was in the range of 1-10 microM LPA equivalents. The data indicate that LPA-like bioactive mediators were generated in an intracranial hematoma model and that these phospholipids might play a role in the pathophysiology of altered vascular reactivity often found in posthemorrhagic conditions and could also contribute to the development of posthemorrhagic vasoconstriction.

Animals↗
PubMed1995

Prostacyclin receptor activation and pial arteriolar dilation after endothelial injury in piglets.

BACKGROUND AND PURPOSE: Both light/dye endothelial injury and indomethacin treatment inhibit hypercapnia-induced cerebral prostacyclin synthesis and pial arteriolar dilation in newborn pigs. Topical iloprost can allow hypercapnia-induced dilation of pial arterioles to occur in piglets treated with indomethacin. We addressed the hypothesis that prostacyclin receptor activation with iloprost can return the ability of pial arterioles with endothelial injury to respond to hypercapnia. We also examined whether the endothelial dependence and the permissive role of prostacyclin extended to histamine-induced dilation or are specific for hypercapnia. METHODS: Experiments used chloralose-anesthetized piglets equipped with closed cranial windows. Hypercapnia (PaCO2 approximately 80 mm Hg) and topically applied histamine (10(-6) and 10(-5) mol/L) dilated pial arterioles. Dilations in response to both stimuli were abolished by light/dye treatment. RESULTS: Simultaneous topical treatment with iloprost (10(-12) mol/L, which caused no residual dilation, returned dilation of pial arterioles to both hypercapnia and histamine. On removal of iloprost, responses were again absent and returned with readdition of iloprost to the cortical cerebrospinal fluid. Neither isoproterenol nor sodium nitroprusside returned responses to hypercapnia after light/dye treatment. CONCLUSIONS: These data add further support to the hypothesis that prostacyclin represents an important endothelial-derived signal in the newborn pig cerebral circulation that can permit appropriate responses by adjacent smooth muscle in response to specific stimuli.

Animals↗
PubMed1995

Hematoma-induced enhanced cerebral vasoconstrictions to leukotriene C4 and endothelin-1 in piglets: role of prostanoids.

Cerebral hematoma enhances vasoconstriction induced by topical application of the vasoconstrictor agents endothelin-1 (ET-1) and leukotriene C4 (LTC4). We investigated the influence of dilator prostanoids on vasoconstrictions induced by ET-1 and LTC4 in piglets. Newborn pigs anesthetized with alpha-chloralose were fitted with closed cranial windows 4 d after cortical subarachnoid injections of artificial cerebrospinal fluid (aCSF) (control) or blood (hematoma). The responsiveness of pial arterioles to topical application of the vasoconstrictors ET-1 and LTC4 was examined in the control and hematoma groups before and after treatment with indomethacin (5 mg/kg, i.v.). Vasoconstriction to topical application of LTC4 and ET-1 was enhanced by hematoma compared with the control (28 +/- 2% versus 21 +/- 2% for 10(-8) M LTC4 and by 25 +/- 2% versus 15 +/- 1% for 10(-8) M ET-1, respectively). The lower dose of ET-1 (10(-12) M) dilated pial arterioles in the control group by 6 +/- 2%, hematoma blocked this dilation and it was converted to constriction (10 +/- 1%). Indomethacin treatment enhanced vasoconstriction to LTC4 in the control group to a similar constriction to that observed in the hematoma group. Indomethacin treatment also enhanced vasoconstriction to ET-1 in the control group (25 +/- 1% for 10(-8) M) to similar constrictions to those observed in the hematoma group (25 +/- 2% for 10(-8) M). Dilation to the lower dose of ET-1 was blocked and converted to constriction (17 +/- 2% for 10(-12) M) by indomethacin treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Low CO2 stimulates inositol phosphate turnover and increased inositol 1,4,5-trisphosphate levels in piglet cerebral microvascular smooth muscle cells.

In contrast to hypercapnic dilation, hypocapnia-induced cerebral vasoconstriction does not involve prostanoids in newborn pigs. The hypothesis that increased pH or decreased CO2 tension increases inositol phosphate turnover in piglet cerebral microvascular smooth muscle (SM) cells was addressed to begin to assess the possibility that this second-messenger system is involved in hypocapnia-induced cerebral vasoconstriction. Cerebral microvascular SM cells in primary culture prelabeled with [3H]-myoinositol were stimulated for 30 sec with artificial cerebrospinal fluid of increased or normal pH, (7.80 vs 7.40), constant PCO2 36 mm Hg. Following extraction from cells, radiolabeled inositol phosphates were separated by HPLC. These metabolic alkalosis studies were repeated using an inositol 1,4,5-trisphosphate (Ins[1,4,5]P3 protein-binding assay (PBA). Respiratory alkalosis using aCSF with pH 7.60, PCO2 20 mm Hg versus control pH 7.40, PCO2 36 mm Hg was similarly tested with PBS measurement of Ins(1,4,5)P3. aCSFs of control pH 7.40, and PCO2s of 70, 36, or 25 mm Hg were studied both by [3H]-myoinositol (HPLC) and PBA to further determine the importance of CO2 tension, in the presence of fixed pH, on Ins(1,4,5)P3 production. When PCO2 was constant, inositol phosphate turnover (as measured by [3H]-Ins[1,4,5]P3 accumulation) increased when pH was increased from 7.40 to 7.80 at 30 sec of stimulation. Mean [3H]-Ins(1,4,5)P3 accumulation at pHs of 7.40 and 7.80, constant PCO2 of 36 mm Hg, were 2.9 +/- 0.7 and 4.1 +/- 0.8 cpm/micrograms protein, respectively. Ins(1,4,5)P3 levels for pH of 7.40 or 7.80 and constant PCO2 of 36 mm Hg, were 25.4 +/- 1.8 and 38 +/- 8 pmol/well, respectively, by PBA. Respiratory alkalosis also increased Ins(1,4,5)P3 levels. For pH of 7.40, PCO2 36 mm Hg and pH 7.60, PCO2 20 mm Hg, Ins(1,4,5)P3 levels were 37.6 +/- 16 and 64.1 +/- 25 pmol/well, respectively. Decreasing CO2 tension (from 70 mm Hg to 25 mm Hg) in the presence of fixed pH 7.40 failed to increase Ins(1,4,5)P3 levels. The present data demonstrate that decreased CO2 tension stimulates an increase in Ins(1,4,5)P3 production in piglet cerebral microvascular smooth muscle cells. Increasing pH via lower PCO2 increases the level of Ins(1,4,5)P3 even more than increasing pH with fixed base, but extracellular pH appears to be important since decreased PCO2 without changing extracellular pH had no effect. We conclude that the inositol phosphate second messenger system in cerebral microvascular smooth muscle responds appropriately to acute alkalosis to be involved in hypocapnia-induced cerebral vasoconstriction.

Alkalosis, Respiratory↗
PubMed1995

Dilator prostanoid-induced cyclic AMP formation and release by cerebral microvascular smooth muscle cells: inhibition by indomethacin.

The effect of indomethacin on dilator prostanoid receptor-mediated cAMP formation was investigated using primary cultures of vascular smooth muscle cells from the newborn pig cerebral microvessels. Cerebral microvascular smooth muscle cells responded to dilator prostanoids (iloprost > PGE2) by increasing cAMP formation and release into the media (EC50 = 2 x 10(-8) M and 2 x 10(-7) M for iloprost and PGE2, respectively). Indomethacin inhibited iloprost- and PGE2-evoked increases in cAMP formation (IC50 = 10(-4) M) and release (IC50 = 10(-6) M) by microvascular smooth muscle cells (maximal inhibition 80-90%), whereas isoproterenol-induced cAMP formation was only slightly attenuated at the highest concentration of indomethacin used (10(-3) M). Aspirin was much less effective in inhibiting dilator prostanoid-induced cAMP formation and release by the cells. Direct analysis of prostacyclin receptor sites using [3H]iloprost as the ligand revealed saturable, high affinity (ED50 = 2 x 10(-8) M) and reversible binding to the membranes isolated from cerebrovascular smooth muscle cells. Indomethacin dose-dependently inhibited [3H]iloprost receptor binding (ID50 = 10(-4) M; maximal inhibition, 70%). The present data suggest that combination of highly effective inhibition of prostaglandin H synthase and receptor binding resulting in inhibition of dilator prostanoid-mediated cAMP formation in target cells may contribute to the increased efficacy of indomethacin compared with other prostaglandin H synthase inhibitors in blocking certain vasodilator responses associated with prostanoids.

6-Ketoprostaglandin F1 alpha↗
PubMed1995

Light/dye microvascular injury eliminates pial arteriolar dilation in hypotensive piglets.

Cerebral vasodilation in response to hypotension is necessary to maintain adequate cerebral blood flow. This study in newborn pigs examines the hypothesis that endothelial injury in vivo inhibits cerebral vasodilation in response to hypotension in newborn pigs, thus suggesting that this response is endothelium dependent. Chloralose-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 i.v. and passing filtered light from a mercury arc lamp through the cranial window. Measurements of pial arteries and arterioles were made during normotensive and hypotensive periods. Hemorrhagic hypotension (to 50% of the mean arterial control value) caused pial arterial and arteriolar diameters to increase 49 +/- 8% and 66 +/- 8%, respectively. After the light/dye injury, dilation in response to hypotension was absent, whereas dilations in response to isoproterenol and constriction in response to hypertension (3.33 to 4.0 kPa increase in arterial pressure) and hypocapnia were retained. These findings are consistent with the hypothesis that hypotension-induced cerebral arteriolar vasodilation is dependent on endothelial signals influencing adjacent smooth muscle.

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

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↗
PubMed1994

CO2 and cerebral circulation in newborn pigs: cyclic nucleotides and prostanoids in vascular regulation.

The role of cyclic nucleotides and prostanoids in cerebrovascular reactivity to increased carbon dioxide was investigated in anesthetized and artificially ventilated newborn pigs equipped with closed cranial windows. Pial arteriolar diameter was measured, and cortical periarachnoid cerebrospinal fluid (CSF) was collected from beneath the cranial window for determination of adenosine 3',5'-cyclic monophosphate (cAMP), guanosine 3',5'-cyclic monophosphate (cGMP), and prostanoids. Progressively increasing arterial PCO2 (PaCO2) from normocapnia (33 +/- 1 mmHg) to hypercapnia (final PaCO2, 83 +/- 2 mmHg) resulted in dose-dependent pial arteriolar dilation and concomitant increases in cAMP, cGMP, and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) in cortical CSF. N omega-methyl-L-arginine, N omega-nitro-L-arginine, N omega-nitro-L-arginine methyl ester, methylene blue, and LY 83583 did not inhibit cerebral vasodilation or the increases in cortical cAMP/cGMP induced by hypercapnia. Indomethacin abolished the vasodilatory response to hypercapnia and attenuated the hypercapnia-induced increases in cAMP and cGMP. Prostacyclin analogues increased both cAMP and cGMP levels in cortical CSF and induced pial arteriolar dilation (iloprost > carbaprostacyclin). The present data suggest that in newborn pigs cyclic nucleotides are involved in cerebral vasodilation in response to hypercapnia via a prostanoid-dependent mechanism.

Amino Acid Oxidoreductases↗
PubMed1994

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)

Animals↗
PubMed1994

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.

Animals↗
PubMed1994

Subarachnoid hematoma attenuates vasodilation and potentiates vasoconstriction induced by vasoactive agents in newborn pigs.

The effects of perivascular blood on pial arteriolar vasoreactivity to selected vasodilators and vasoconstrictors were examined in vivo in a newborn pig model. alpha-Chloralose-anesthetized newborn pigs were fitted with closed cranial windows 4 d after cortical subarachnoid injections of autologous blood. The responsiveness of pial arterioles to topical application of dilator agents [iloprost, prostaglandin E2 (PGE2), histamine, and sodium nitroprusside (SNP)] and vasoconstrictor agents [leukotriene C4 and endothelin-1 (ET-1) in artificial cerebrospinal fluid was studied in control and blood-injected piglets. Pial arterioles dilated dose dependently in response to topical application of iloprost, PGE2, histamine, and SNP in the control group, with increases in diameter of 54, 44, 67, and 50% at 10(-8) M, 10(-5) M, 10(-5) M, and 10(-5) M, respectively. These dilations in response to iloprost, PGE2, and histamine in the blood-injected piglets were significantly attenuated to 23, 18, and 34%, respectively, whereas the dilation in response to SNP was not changed (64%). Constrictions in response to 10(-8) M leukotriene C4 and ET-1 were 16 and 26% and were potentiated by hematoma to 36 and 43%, respectively. The lowest dose of ET-1 (10(-12) M) significantly dilated pial arterioles in the control but not in the blood-treated group. We conclude that prolonged exposure of pial arterioles to perivascular blood attenuates cerebrovascular dilation in response to selected vasoactive agents (iloprost, PGE2, and histamine) but not to SNP, suggesting that blood-induced attenuation of vasodilation and the generalized vasoconstriction may involve inhibiting the prostanoid/cAMP signaling pathway.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Cerebral blood flow responses to indomethacin in awake newborn pigs.

The prostaglandin H-synthase inhibitor indomethacin decreases cerebral blood flow (CBF) in newborn pigs. The duration of this effect on CBF has not been established in piglets in the awake state. The purpose of the study was to determine in awake piglets the duration of cerebral vascular responses to a single dose of indomethacin and the CBF responses to a second dose of indomethacin. Two groups of animals were studied. Newborn pigs 3-5 d old were instrumented the day before experiments. On the next day, sagittal sinus catheters were placed after the piglets were given local anesthesia. The experiments were performed on unanesthetized piglets that were put in a cloth sling and fed via an orogastric tube. In the first group of piglets (n = 8), the baseline CBF (microspheres) and cerebral metabolic rate for oxygen (CMRO2) measurements were made 30 min after sagittal sinus catheter placement. Indomethacin (5 mg/kg i.v.) was then given slowly over a 5-min period, and CBF and CMRO2 measurements were made at 10, 60, 120, and 240 min. Total CBF (mean +/- SEM) decreased significantly after indomethacin administration from 98 +/- 12 mL.min-1.100 g-1 to 50 +/- 3, 56 +/- 7, and 70 +/- 11 mL.min-1.100 g-1 at 10, 60, and 120 min, respectively. The total CBF returned to baseline levels at 240 min (101 +/- 16 mL-1.min-1.100 g-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Recent advances and controversies in cerebrovascular physiology in the newborn.

Important differences exist between adult and newborn responses to different cerebrovascular influences. This review discusses the important influence that the prostanoid system has in newborn cerebral hemodynamics. Activated oxygen species and their generation through different cerebral insults are discussed. The role of several radical scavengers as modes of therapy is reviewed. The endothelium-derived relaxing factor system and its major influence in the adult is compared with its lesser role in the newborn. Finally, the pathophysiology of the alterations in newborn cerebral hemodynamics seen with experimentally induced seizures is reviewed.

Acetylcholine↗