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J E Brian

Publications and source records attributed to J E Brian.

At least 19 recordsLinked to original sources
PubMed2001

Brain expression of inducible cyclooxygenase 2 messenger RNA in rats undergoing cardiopulmonary bypass.

BACKGROUND: We hypothesized that systemic proinflammatory cytokines or endotoxemia, or both, associated with cardiopulmonary bypass (CPB) would increase expression of inducible cyclooxygenase (COX-2) or inducible nitric oxide synthase (iNOS) messenger RNA (mRNA), or both, in brain. METHODS: Isoflurane-anesthetized Sprague-Dawley rats were randomly selected for CPB (n = 6) or sham surgery (n = 6). All animals underwent tracheotomy and controlled ventilation, arterial and venous pressure monitoring, insertion of a jugular venous outflow catheter, insertion of a subclavian arterial inflow catheter, systemic anticoagulation (500 U/kg heparin) and, except during CPB, servoregulation of pericranial temperature at 37.5 degrees C. Animals selected for CPB underwent 1 h of CPB at 165 ml x kg(-1) x min(-1) (31.8 +/- 0.2 degrees C), whereas animals having sham surgery underwent no intervention during this interval. Thereafter, all animals were given protamine and remained anesthetized for 4 more h. Brain and liver COX-2 and iNOS mRNA expression were determined by a ribonuclease protection assay with ribosomal L32 mRNA as a loading control. Arterial blood was analyzed for interleukin 1beta, interleukin 6, and endotoxin concentrations. RESULTS: Endotoxin concentrations did not increase above baseline values in either group. At 4 h after the CPB interval, interleukin 6 concentrations were significantly greater in CPB animals (101 +/- 45 pg/ml) versus sham animals (44 +/- 17 pg/ml) (P = 0.025). Brain COX-2 expression was significantly greater in CPB animals (0.36 +/- 0.11) versus shams (0.19 +/- 0.08) (P = 0.013). Brain COX-2 expression correlated with interleukin 6 concentration 4 h after CPB (r = 0.91; P = 5 x 10(-5)). In brain, iNOS mRNA was not detected in any animal. Cardiopulmonary bypass animals had only trace COX-2 and iNOS mRNA induction in liver. CONCLUSIONS: Cardiopulmonary bypass was associated with increased systemic interleukin 6 concentrations and increased brain COX-2 expression.

Anesthesia, Inhalation↗
PubMed2001

COX-2-dependent delayed dilatation of cerebral arterioles in response to bradykinin.

Bradykinin (BK) is released in the brain during injury and inflammation. Activation of endothelial BK receptors produces acute dilatation of cerebral arterioles that is mediated by reactive oxygen species (ROS). ROS can also modulate gene expression, including expression of the inducible isoform of cyclooxygenase (COX-2). We hypothesized that exposure of the brain to BK would produce acute dilatation, which would be followed by a delayed dilatation mediated by COX-2. To test this hypothesis in anesthetized rats, BK was placed twice in cranial windows for 7 min, after which the windows were flushed to remove residual BK. The two BK exposures were separated by 30 min. Each BK exposure produced acute dilatation of cerebral arterioles, after which diameter rapidly returned to baseline. Over the subsequent 4.5 h after the second BK exposure, arterioles dilated 48 +/- 8%. Treatment of the cranial window with NS-398, a selective COX-2 inhibitor, or dexamethasone, significantly attenuated the delayed dilatation. Aminoguanidine, a selective inhibitor of inducible nitric oxide synthase, did not alter the delayed dilatation. Cotreatment of cranial windows with BK, superoxide dismutase, and catalase also prevented the delayed dilatation. In separate experiments, exposure of the cortical surface to BK upregulated leptomeningeal expression of COX-2 mRNA. Our results suggest that acute, time-limited exposure of the brain to BK produces delayed dilatation of cerebral arterioles dependent on expression and activity of COX-2.

Animals↗
PubMed2000

Plasma viscosity and cerebral blood flow.

We hypothesized that the response of cerebral blood flow (CBF) to changing viscosity would be dependent on "baseline" CBF, with a greater influence of viscosity during high-flow conditions. Plasma viscosity was adjusted to 1.0 or 3.0 cP in rats by exchange transfusion with red blood cells diluted in lactated Ringer solution or with dextran. Cortical CBF was measured by H(2) clearance. Two groups of animals remained normoxic and normocarbic and served as controls. Other groups were made anemic, hypercapnic, or hypoxic to increase CBF. Under baseline conditions before intervention, CBF did not differ between groups and averaged 49.4 +/- 10.2 ml. 100 g(-1). min(-1) (+/-SD). In control animals, changing plasma viscosity to 1. 0 or 3.0 cP resulted in CBF of 55.9 +/- 8.6 and 42.5 +/- 12.7 ml. 100 g(-1). min(-1), respectively (not significant). During hemodilution, hypercapnia, and hypoxia with a plasma viscosity of 1. 0 cP, CBF varied from 98 to 115 ml. 100 g(-1). min(-1). When plasma viscosity was 3.0 cP during hemodilution, hypercapnia, and hypoxia, CBF ranged from 56 to 58 ml. 100 g(-1). min(-1) and was significantly reduced in each case (P < 0.05). These results support the hypothesis that viscosity has a greater role in regulation of CBF when CBF is increased. In addition, because CBF more closely followed changes in plasma viscosity (rather than whole blood viscosity), we believe that plasma viscosity may be the more important factor in controlling CBF.

Anemia↗
PubMed1999

Hemodilution, cerebral O2 delivery, and cerebral blood flow: a study using hyperbaric oxygenation.

Hemodilution reduces blood viscosity and O2 content (CaO2) and increases cerebral blood flow (CBF). Viscosity and CaO2 may contribute to increasing CBF after hemodilution. However, because hematocrit is the major contributor to blood viscosity and CaO2, it has been difficult to assess their relative importance. By varying blood viscosity without changing CaO2, prior investigation in hemodiluted animals has suggested that both factors play roughly equal roles. To further investigate the relationship of hemodilution, blood viscosity, CaO2, and CBF, we took the opposite approach in hemodiluted animals, i.e., we varied CaO2 without changing blood viscosity. Hyperbaric O2 was used to restore CaO2 to normal after hemodilution. Pentobarbital sodium-anesthetized rats underwent isovolumic hemodilution with 6% hetastarch, and forebrain CBF was measured with [3H]nicotine. One group of animals did not undergo hemodilution and served as controls (Con). In the three experimental groups, hematocrit was reduced from 44% to 17-19%. Con and hemodiluted (HDil) groups were ventilated with 40% O2 at 101 kPa (1 atmosphere absolute), which resulted in CaO2 values of 19.7 +/- 1.3 and 8.1 +/- 0.7 (SD) ml O2/dl, respectively. A second group of hemodiluted animals (HBar) was ventilated with 100% O2 at 506 kPa (5 atmospheres absolute) in a hyperbaric chamber, which restored CaO2 to an estimated 18.5 +/- 0.5 ml O2/dl by increasing dissolved O2. A fourth group of hemodiluted animals (HCon) served as hyperbaric controls and were ventilated with 10% O2 at 506 kPa, resulting in CaO2 of 9.1 +/- 0.6 ml O2/dl. CBF was 79 +/- 19 ml. 100 g-1. min-1 in the Con group and significantly increased to 123 +/- 9 ml. 100 g-1. min-1 in the HDil group. When CaO2 was restored to baseline with dissolved O2 in the HBar group, CBF decreased to 104 +/- 20 ml. 100 g-1. min-1. When normoxia was maintained during hyperbaric exposure in the HCon group, CBF was 125 +/- 18 ml. 100 g-1. min-1, a value indistinguishable from that in normobaric HDil animals. Our data demonstrate that the reduction in CaO2 after hemodilution is responsible for 40-60% of the increase in CBF.

Animals↗
PubMed1999

Cerebral blood flow during hemodilution and hypoxia in rats : role of ATP-sensitive potassium channels.

BACKGROUND AND PURPOSE: Hypoxia and hemodilution both reduce arterial oxygen content (CaO(2)) and increase cerebral blood flow (CBF), but the mechanisms by which hemodilution increases CBF are largely unknown. ATP-sensitive potassium (K(ATP)) channels are activated by intravascular hypoxia, and contribute to hypoxia-mediated cerebrovasodilatation. Although CaO(2) can be reduced to equal levels by hypoxia or hemodilution, intravascular PO(2) is reduced only during hypoxia. We therefore tested the hypothesis that K(ATP) channels would be unlikely to contribute to cerebrovasodilatation during hemodilution. METHODS: Glibenclamide (19.8 microg) or vehicle was injected into the cisterna magna of barbiturate-anesthetized rats. The dose of glibenclamide was chosen to yield an estimated CSF concentration of 10(-4) M. Thirty minutes later, some animals underwent either progressive isovolumic hemodilution or hypoxia (over 30 minutes) to achieve a CaO(2) of approximately 7.5 mL O(2)/dL. Other animals did not undergo hypoxia or hemodilution and served as controls. Six groups of animals were studied: control/vehicle (n=4), control/glibenclamide (n=4), hemodilution/vehicle (n=10), hemodilution/glibenclamide (n=10), hypoxia/vehicle (n=10), and hypoxia/glibenclamide (n=10). CBF was then measured with (3)H-nicotine in the forebrain, cerebellum, and brain stem. RESULTS: In control/vehicle rats, CBF ranged from 72 mL. 100 g(-1). min(-1) in forebrain to 88 mL. 100 g(-1) x min(-1) in the brain stem. Glibenclamide treatment of control animals did not influence CBF in any brain area. Hemodilution increased CBF in all brain areas, with flows ranging from 128 mL. 100 g(-1) x min(-1) in forebrain to 169 mL. 100 g(-1) x min(-1) in the brain stem. Glibenclamide treatment of hemodiluted animals did not affect CBF in any brain area. Hypoxia resulted in a greater CBF than did hemodilution, ranging from 172 mL. 100 g(-1) x min(-1) in forebrain to 259 mL. 100 g(-1) x min(-1) in the brain stem. Glibenclamide treatment of hypoxic animals significantly reduced CBF in all brain areas (P<0.05). CONCLUSIONS: Both hypoxia and hemodilution increased CBF. Glibenclamide treatment significantly attenuated the CBF increase during hypoxia but not after hemodilution. This finding supports our hypothesis that K(ATP) channels do not contribute to increasing CBF during hemodilution. Because intravascular PO(2) is normal during hemodilution, this finding supports the hypothesis that intravascular PO(2) is an important regulator of cerebral vascular tone and exerts its effect in part by activation of K(ATP) channels in the cerebral circulation.

Adenosine Triphosphate↗
PubMed1999

Hyperbaric oxygen therapy and osteoradionecrosis.

Osteoradionecrosis of the mandible is a potentially devastating complication of head and neck radiation. Radiation causes progressive vascular occlusion with tissue hypoxia, tissue death, and failure of healing. Hyperbaric oxygen therapy is an accepted treatment for osteoradionecrosis. This article reviews the history of hyperbaric oxygen therapy, its physiologic mechanisms, its use in the management of osteoradionecrosis, and its complications and contraindications.

Contraindications↗
PubMed1998

Expression and vascular effects of cyclooxygenase-2 in brain.

BACKGROUND AND PURPOSE: Cyclooxygenase-2 (COX-2) is an inducible isoform of cyclooxygenase. Several types of brain cells in culture can express COX-2 when treated with lipopolysaccharide (LPS) or some cytokines. LPS produces dilatation of cerebral arterioles in vivo through a mechanism that is partially inhibited by indomethacin. In the present study we examined the hypothesis that LPS causes increased expression of COX-2 in brain as well as COX-2-dependent dilatation of cerebral arterioles. METHODS: Cranial windows were implanted in anesthetized rats and used to measure diameter of cerebral arterioles under control conditions and during topical application of various agonists and antagonists. Windows were flushed every 30 minutes for 4 hours with vehicle (artificial cerebrospinal fluid; n=5), LPS (100 ng/mL; n=8), LPS and NS-398 (100 micromol/L; n=8), a selective inhibitor of COX-2, or LPS and dexamethasone (1 micromol/L; n=5), which attenuates expression of COX-2. To examine expression of COX-2 protein in vivo, other animals were injected intracisternally with artificial cerebrospinal fluid (n=3) or LPS (40 ng; n=4). Four hours after injection, the leptomeninges were harvested and analyzed by Western blot for expression of COX-2 protein. In a third group of experiments, COX-2 expression and prostaglandin E2 (PGE2) production were determined in leptomeningeal tissue treated for 4 hours ex vivo with vehicle (n=4), LPS (100 ng/mL; n=4), LPS and NS-398 (100 micromol/L; n=4), or LPS and dexamethasone (1 micromol/L; n=4). RESULTS: LPS caused marked, progressive dilatation of cerebral arterioles, with a maximum increase in diameter of 55+/-9% (mean+/-SEM) at 4 hours. Coapplication of either NS-398 or dexamethasone with LPS reduced dilatation of cerebral arterioles at hours 2 through 4 (P<0.05). In contrast, NS-398 did not inhibit dilatation of cerebral arterioles in response to bradykinin or ADP. In animals injected intracisternally with vehicle, COX-2 protein was expressed at a very low level in leptomeningeal tissue. Intracisternal injection of LPS increased COX-2 protein expression by approximately 20-fold (P<0.05). In leptomeningeal tissue treated ex vivo with LPS, there was also expression of COX-2. Both dexamethasone and NS-398 markedly reduced COX-2 protein expression in ex vivo LPS-treated tissue. PGE2 production was detectable under control conditions in leptomeningeal tissue incubated in vehicle ex vivo for 4 hours (6.5+/-1.1 pmol/mg protein). LPS treatment significantly increased PGE2 production to 12.8+/-1.1 pmol/mg protein (P<0.05). Both dexamethasone and NS-398 significantly attenuated LPS-induced PGE2 production (P<0.05). CONCLUSIONS: LPS increased expression of COX-2 protein in leptomeningeal tissue and caused COX-2-dependent dilatation of cerebral arterioles in vivo. Ex vivo, both NS-398 and dexamethasone suppressed LPS-induced PGE2 production and COX-2 expression in leptomeningeal tissue. Inhibition of LPS-induced dilatation of cerebral arterioles in vivo by NS-398 and dexamethasone suggests that the dilatation was dependent on expression and activity of COX-2. These findings support the concept that exposure of brain to LPS causes cerebral vasodilatation that is dependent in part on expression and activity of COX-2.

Adenosine Diphosphate↗
PubMed1998

Tumor necrosis factor-alpha-induced dilatation of cerebral arterioles.

BACKGROUND AND PURPOSE: In brain, several cell types produce tumor necrosis factor-alpha (TNFalpha) after injury or exposure to endotoxin. TNFalpha alone or in combination with endotoxin or other cytokines can cause expression of inducible nitric oxide (NO) synthase. We have previously demonstrated that endotoxin caused NO-dependent dilatation of cerebral arterioles in vivo. In the present study we examined the hypothesis that TNFalpha causes NO-mediated dilatation of cerebral arterioles in vivo. METHODS: Cranial windows were implanted in anesthetized rats and used to measure the diameter of cerebral arterioles. Windows were flushed every 30 minutes for 4 hours with artificial cerebrospinal fluid (aCSF) (n=6); aCSF with TNFalpha (100 ng/mL; n=10); aCSF with TNFalpha and aminoguanidine (0.3 mmol/L; n=5), an inhibitor of inducible NO synthase; or aCSF with TNFalpha and dexamethasone (1 micromol/L; n=6), which attenuates expression of inducible NO synthase. In some animals, brain from beneath the cranial window was examined by immunocytochemistry for inducible NO synthase expression. RESULTS: Application of TNFalpha caused marked, progressive dilatation of cerebral arterioles, with a maximum increase in diameter of 46+/-9% (mean+/-SEM) at 4 hours. Coapplication of either aminoguanidine or dexamethasone with TNFalpha prevented dilatation of cerebral arterioles compared with TNFalpha alone (4+/-2% and 1+/-1% dilatation at 4 hours, respectively; P<.05). Dexamethasone did not inhibit dilatation of cerebral arterioles in response to adenosine diphosphate. However, 2 hours of aminoguanidine treatment produced moderate inhibition of adenosine diphosphate-induced dilatation of cerebral arterioles. After treatment with TNFalpha, immunocytochemistry for inducible NO synthase demonstrated expression in perivascular and arachnoid cells but not brain cells. There was no detectable expression of inducible NO synthase after treatment with aCSF. CONCLUSIONS: The present study indicates that TNFalpha causes cerebral vasodilatation and expression of inducible NO synthase in perivascular and arachnoid cells. Inhibition of TNFalpha-induced dilatation by aminoguanidine and dexamethasone suggests that the vasodilatation was due predominantly to expression of inducible NO synthase. These findings support the concept that cerebral vasodilatation that occurs during pathophysiological conditions associated with increased TNFalpha production in brain is mediated by expression of inducible NO synthase.

Adenosine Diphosphate↗
PubMed1995

Mechanisms of endotoxin-induced dilatation of cerebral arterioles.

Lipopolysaccharide (LPS; endotoxin) produces dilatation of cerebral arterioles in vivo which may be due, in part, to expression of inducible nitric oxide (NO) synthase. We tested the hypothesis that aminoguanidine, an inhibitor of inducible NO synthase, would reduce endotoxin-induced dilatation of cerebral arterioles. Because mechanisms other than expression of inducible NO synthase may contribute to endotoxin-induced dilatation of cerebral arterioles, we also tested the hypothesis that calcitonin gene-related peptide (CGRP) contributes to vascular responses to endotoxin. Cerebral arteriolar diameter was measured using a closed cranial window in anesthetized rabbits under control conditions [77 +/- 3 (SE) microns] and during topical application of endotoxin (100 micrograms/ml). After 4 h, diameter of cerebral arterioles increased by 41 +/- 5%. Coapplication of aminoguanidine (0.3 mM) with endotoxin reduced vasodilatation at all time points (30 min to 4 h). Relative to control values, endotoxin treatment increased guanosine 3',5'-cyclic monophosphate (cGMP) concentration in cerebrospinal fluid (CSF) by approximately 20 fold at 4 h. Aminoguanidine attenuated the endotoxin-induced increased in CSF cGMP concentration. Aminoguanidine (0.3 mM) did not alter acetylcholine-mediated dilatation of cerebral arterioles. Coapplication of CGRP-(8-37) (0.5 microM), a specific blocker of CGRP receptors, with endotoxin significantly reduced vasodilatation in response to endotoxin at 2, 3, and 4 h. Thus 1) aminoguanidine inhibits endotoxin- but not acetylcholine-mediated dilatation of cerebral arterioles, and 2) activation of CGRP receptors mediates a portion of endotoxin-induced dilation of cerebral arterioles.

Acetylcholine↗
PubMed1995

Response of cerebral blood vessels to an endogenous inhibitor of nitric oxide synthase.

We examined effects of NG,NG-dimethyl-L-arginine (asymmetric dimethylarginine, ADMA), an endogenous inhibitor of nitric oxide (NO) synthase, on cerebral vascular responses using cranial windows in anesthetized rats and rabbits. Under control conditions in rats, topical application of 10 and 100 microM ADMA constricted the basilar artery by 9 +/- 2 and 19 +/- 1% (SE; P < 0.05, n = 8), respectively, from a baseline diameter of 213 +/- 19 microns. ADMA (10 and 100 microM) produced marked inhibition of vasodilation in response to acetylcholine without inhibiting vasodilatation in response to nitroprusside. ADMA (1-100 microM) inhibited activity of brain NO synthase (measured as the conversion of L-[14C]arginine to L-[14C]citrulline). In cerebrum and cerebellum, 50% inhibition of activity of NO synthase was produced by 2.3 +/- 0.4 and 1.8 +/- 0.1 microM ADMA, respectively. In rabbits, treatment with ADMA (300 microM) decreased baseline diameter of cerebral arterioles (control diameter = 93 +/- 10 microns) by 11 +/- 2% (P < 0.05, n = 10). In response to 1 microM acetylcholine, cerebral arterioles dilated by 36 +/- 6 and 13 +/- 4% (P < 0.05 vs. control) in the absence and presence of ADMA, respectively. Effects of ADMA were prevented by L-arginine. Thus ADMA inhibits activity of brain NO synthase and relaxation of cerebral blood vessels in response to acetylcholine. Because ADMA is produced in relatively high concentrations in brain, it may be an important endogenous modulator of cerebral vascular tone under resting conditions and in response to vasoactive stimuli.

Animals↗
PubMed1995

7-Nitroindazole inhibits brain nitric oxide synthase and cerebral vasodilatation in response to N-methyl-D-aspartate.

BACKGROUND AND PURPOSE: N-Methyl-D-aspartate (NMDA) produces dilatation of cerebral arterioles that is dependent on production of nitric oxide (NO). In these experiments we examined the hypothesis that cerebral vasodilatation in response to NMDA is mediated by the neuronal isoform of NO synthase. METHODS: We measured diameters of cerebral arterioles (baseline diameter, 89 +/- 7 microns) using a closed cranial window in anesthetized rabbits that received either vehicle (10 mL/kg IP peanut oil) or 7-nitroindazole (7-NI; 50 mg/kg IP). 7-NI is reported to be a selective inhibitor of neuronal NO synthase. RESULTS: Two hours after administration of 7-NI, activity of brain NO synthase (measured by conversion of L-arginine to L-citrulline) was reduced by 33% compared with vehicle (24 +/- 1 versus 16 +/- 3 pmol/min per milligram protein; n = 7; P < .05). Dilatation of cerebral arterioles in response to NMDA (100 and 300 mumol/L) was inhibited by 30% to 40% by 7-NI compared with responses in the presence of vehicle (23 +/- 6% versus 14 +/- 5% and 30 +/- 4% versus 21 +/- 5%, respectively; P < .05 for both concentrations; n = 10). In contrast, vasodilatation in response to acetylcholine (1 mumol/L) was similar in vehicle- and 7-NI-treated animals (17 +/- 5% versus 21 +/- 4%; P > .05). CONCLUSIONS: These findings suggest that vasodilatation in response to NMDA is mediated by neuronally derived NO. 7-NI appears to produce selective inhibition of brain NO synthase but not endothelial NO synthase.

Animals↗
PubMed1995

Dilatation of cerebral arterioles in response to lipopolysaccharide in vivo.

BACKGROUND AND PURPOSE: Bacterial lipopolysaccharide can increase nitric oxide (NO) production by expression of an inducible form of NO synthase. Bacterial infections of the central nervous system dilate cerebral vessels and increase blood flow. We hypothesized that topical application of bacterial lipopolysaccharide would increase production of NO, causing dilatation of cerebral arterioles. METHODS: Cranial windows were implanted in anesthetized rabbits. Windows were flushed with artificial cerebrospinal fluid, artificial cerebrospinal fluid with lipopolysaccharide, or artificial cerebrospinal fluid with lipopolysaccharide and NG-monomethyl-L- arginine (an inhibitor of NO synthase) for 4 hours. Other rabbits received either dexamethasone or indomethacin intravenously 1 hour before lipopolysaccharide treatment of cranial windows. RESULTS: Application of lipopolysaccharide in cranial windows produced marked, progressive vasodilation, with diameter increased by 58 +/- 7% (mean +/- SEM) after 4 hours. The cerebral vasodilator response was inhibited by NG-monomethyl-L-arginine, dexamethasone, or indomethacin. Excess L-arginine reversed the inhibitory effect of NG-monomethyl-L-arginine. CONCLUSIONS: Inhibition of lipopolysaccharide-induced dilatation of cerebral arterioles by NG-monomethyl-L-arginine and dexamethasone suggests that a portion of the vasodilation was mediated by inducible NO synthase. Indomethacin also inhibited lipopolysaccharide-induced vasodilatation. These findings suggest an important role for both nitric oxide and cyclooxygenase products in lipopolysaccharide-induced cerebral arteriolar dilatation in vivo.

Amino Acid Oxidoreductases↗
PubMed1994

Nitric oxide has no chronotropic effect in right atria isolated from rat heart.

This study was designed to determine if nitric oxide (NO) has direct effects on heart rate or if it is involved in the chronotropic actions of adrenergic or cholinergic stimulation. Right atria were isolated from hearts of adult male rats, bathed in Krebs-Henseleit buffer (37 degrees C), and used to monitor spontaneous rate. For comparison, ring segments of thoracic aorta were also suspended in the Krebs-Henseleit solution and used to examine vascular actions of various agents. The dose-dependent chronotropic effects of acetylcholine (10(-7)-10(-3) M) and norepinephrine (10(-8)-3 x 10(-4) M) in right atria were not affected by pretreatment with 10(-4) M N-nitro-L-arginine or 10(-3) M N-nitro-L-arginine-methyl ester, inhibitors of L-arginine-derived NO production. SIN-1 (3-morpholino-sydnonimine), an agent which releases NO in aqueous solution, elicited a dose-dependent (0.3-100 microM) vasorelaxation in aortic preparations constricted with 60 mM KCl; the ED50 value for this effect was increased by pretreatment with methylene blue (10 microM) and LY-83,583 (6-(phenylamino)-5,8- quinolinedione; 1 and 3 microM), compounds which inhibit NO-induced stimulation of guanylate cyclase. SIN-1 produced a negative chronotropic effect in right atria; however, this action was not observed at concentrations less than 300 microM and was not antagonized by methylene blue or LY-83,583. 8-Bromo cyclic GMP produced a dose-dependent (10-3000 microM) decrease in KCl-induced tension in aortic rings. In right atria, 8-bromo cyclic GMP elicited a positive chronotropic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1994

The effect of age on halothane-induced alterations of contractility in isolated rat aorta.

Aging is implicated as a factor which increases the susceptibility to volatile anesthetic-induced depression of the cardiovascular system. However, little is known regarding mechanisms responsible for this enhanced depression. Current experiments examined the effects of 1.2 and 2.4 vol.% halothane on norepinephrine-induced contractility in endothelium-intact and -denuded aortic preparations isolated from 4-, 14-, and 24-month-old Fisher-344 rats. Prior to exposure to halothane, endothelium removal significantly enhanced the sensitivity to norepinephrine in all age groups without altering the maximum tension. Additionally, in endothelium-intact preparations, increasing age from 4 to 24 months decreased the sensitivity to norepinephrine. Exposure to 2.4 vol.% halothane caused a significant decline in the maximum tension generated in response to norepinephrine in all groups. There were no differences in the amount of depression seen with 2.4 vol.% halothane either within age groups or between endothelium-intact and -denuded preparations of the same age. Halothane at 1.2 vol.% caused a significant reduction in the amount of tension generated in the 4-month-old, endothelium-denuded group. However, all age groups with and without endothelium tended to decrease to a similar degree at 1.2 vol.% halothane, and there were no differences either within age groups or between endothelium-intact and -denuded preparations of the same age. In the 4- and 14-month-old endothelium-intact groups, both 1.2 and 2.4 vol.% halothane decreased the sensitivity to norepinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1994

Effect of carbon monoxide on rabbit cerebral arteries.

BACKGROUND AND PURPOSE: Carbon monoxide produces relaxation in some peripheral arteries. Recently it has been suggested that carbon monoxide may be generated in brain tissue. In the present study we examined the hypothesis that carbon monoxide directly relaxes cerebral blood vessels. METHODS: The aorta and basilar and middle cerebral arteries were removed from New Zealand White rabbits and mounted for tension recording in vitro. Canine basilar arteries were also studied. After precontraction, cumulative relaxation concentration-response curves to carbon monoxide, nitric oxide, sodium nitroprusside, acetylcholine (rabbit arteries), and ATP (dog basilar artery) were obtained. Maximum relaxation and the concentration of agonists that induced half-maximal relaxation (ED50) were determined. RESULTS: Carbon monoxide (10(-6) to 3 x 10(-4) mol/L) did not affect tension in rabbit or dog cerebral arteries. In rabbit aorta, carbon monoxide induced 29 +/- 4% (mean +/- SEM) relaxation at the highest concentration used (3 x 10(-4) mol/L). In contrast, nitric oxide produced 80% to 100% relaxation of all arteries, with ED50 values ranging from 7.1 to 7.4 -log mol/L. Nitroprusside, acetylcholine, and ATP also produced 80% to 100% relaxation of the arteries. CONCLUSIONS: Carbon monoxide does not appear to have significant effect on tone in cerebral arteries. In contrast, at high concentrations carbon monoxide produces concentration-dependent relaxation in rabbit aorta. Factors that account for this regional heterogeneity are not clear. Although neurons may produce both nitric oxide and carbon monoxide, our findings suggest that only nitric oxide has direct effects on cerebral vascular tone.

Analysis of Variance↗
PubMed1994

Nitric oxide and the cerebral circulation.

BACKGROUND: Nitric oxide (NO) is a potent vasodilator that was initially described as the mediator of endothelium-dependent relaxation (endothelium-derived relaxing factor, EDRF). It is now known that NO is produced by a variety of other cell types. SUMMARY OF REVIEW: Endothelium produces NO (EDRF) under basal conditions and in response to a variety of vasoactive stimuli in large cerebral arteries and the cerebral microcirculation. Endothelium-dependent relaxation is impaired in the presence of several pathophysiological conditions. This impairment may contribute to cerebral ischemia or stroke. Activation of glutamate receptors appears to be a major stimulus for production of NO by neurons. Neuronally derived NO may mediate local increases in cerebral blood flow during increases in cerebral metabolism. NO synthase-containing neurons also innervate large cerebral arteries and cerebral arterioles on the brain surface. Activation of parasympathetic fibers that innervate cerebral vessels produces NO-dependent increases in cerebral blood flow. Increases in cerebral blood flow during hypercapnia also appear to be dependent on production of NO. Astrocytes may release some NO constitutively, but astrocytes and microglia can release relatively large quantities of NO after induction of NO synthase in response to endotoxin or some cytokines. Expression of inducible NO synthase, perhaps in response to local production of cytokines, may exert cytotoxic effects in brain during or after ischemia. CONCLUSIONS: Because endothelium, neurons, and glia can all produce NO in response to some stimuli, the influence of NO on the cerebral circulation appears to be very important. Under normal conditions, constitutively produced NO influences basal cerebral vascular tone and mediates vascular responses to a diverse group of stimuli. The inducible form of NO synthase produces much greater amounts of NO that may be an important mediator of cytotoxicity in brain.

Amino Acid Oxidoreductases↗
PubMed1993

Modulation of cerebral arterial tone by endothelium-derived relaxing factor.

This study was designed to further elucidate the role of the endothelium in regulation of cerebral vascular smooth muscle tone. Dose-dependent vasoconstrictive effects of serotonin (5-HT) were examined in endothelium-intact and endothelium-denuded ring segments prepared from canine basilar and middle cerebral arteries. Some preparations were pretreated with 10(-5) M N omega-nitro-L-arginine (L-NNA), an agent that inhibits the production of L-arginine-derived nitric oxide, one of the compounds proposed to be endothelium-derived relaxing factor. L-NNA alone elicited marked dose-dependent increases in tension in endothelium-intact preparations; a significantly smaller response was seen in endothelium-denuded preparations. The effects of L-NNA on endothelium-intact preparations were partially reversed by washing and treatment with L-arginine. The maximum tension induced by 5-HT was approximately doubled by removal of the endothelium as well as by L-NNA treatment of endothelium-intact preparations; a slight increase in maximum tension occurred in endothelium-denuded preparations treated with L-NNA. The concentration of 5-HT producing half-maximal contraction (ED50) was not affected by L-NNA. These data suggest that L-arginine-derived nitric oxide modulates canine cerebral arterial tone in both the resting state and during contraction with 5-HT.

Animals↗