Biomedical subjects

E F Ellis

Publications and source records attributed to E F Ellis.

At least 37 records · Page 2Linked to original sources

PubMed1996

Repeated cocaine administration reduces bradykinin-induced dilation of pial arterioles.

Using the acute cranial window technique in rabbits under surgical anesthesia, we tested the vasoactivity of acetylcholine (ACh, 10(-8)-10(-5) M), bradykinin (BK, 10(-8)-10(-5) M), and asphyxia (10% O2, 9% CO2, balance N2) after subchronic pretreatment with cocaine. After repeated administration of cocaine (20 mg.kg-1.day-1 sc x 7 days), the BK-induced dilation of pial arterioles was reduced by 51%. Previous work showed that BK produces dilation of pial arterioles by a cyclooxygenase-dependent oxygen radical-mediated mechanism and that in rabbits the BK-induced dilation is dependent on both vascular and nonvascular cyclooxygenase. Selective blockade of vascular cyclooxygenase, in addition to cocaine treatment, did not produce any greater inhibition of the BK-induced dilation. The dilation in response to ACh and asphyxia was unaltered by cocaine. Levels of cerebrospinal fluid prostaglandins suggest cocaine pretreatment may inhibit cerebral vascular prostaglandin production. Together, cerebrospinal fluid prostaglandin and vasoreactivity data indicate cocaine pretreatment selectively inhibits the vascular cyclooxygenase-dependent mechanism mediating the BK-induced dilation. This decreased response to BK in cocaine-treated rabbits may result from decreased oxygen radical production concomitant with decreased vascular prostaglandin production. Alternatively, oxygen radical scavenging may be increased after cocaine treatment. We speculate that cocaine-induced alterations in cerebrovascular function and metabolism may be related to the increased incidence of stroke reported to occur in human cocaine users.

6-Ketoprostaglandin F1 alpha↗

PubMed1996

Stretch-induced injury of cultured neuronal, glial, and endothelial cells. Effect of polyethylene glycol-conjugated superoxide dismutase.

BACKGROUND AND PURPOSE: There is abundant evidence that after in vivo traumatic brain injury, oxygen radicals contribute to changes in cerebrovascular structure and function; however, the cellular source of these oxygen radicals is not clear. The purpose of these experiments was to use a newly developed in vitro tissue culture model to elucidate the effect of strain, or stretch, on neuronal, glial, and endothelial cells and to determine the effect of the free radical scavenger polyethylene glycol-conjugated superoxide dismutase (PEG-SOD; pegorgotein, Dismutec) on the response of each cell type to trauma. METHODS: Rat brain astrocytes, neuronal plus glial cells, and aortic endothelial cells were grown in cell culture wells with 2-mm-thick silastic membrane bottoms. A controllable, 50-millisecond pressure pulse was used to transiently deform the silastic membrane and thus stretch the cells. Injury was assessed by quantifying the number of cells that took up the normally cell-impermeable dye propidium iodide. Some cultures were pretreated with 100 to 300 U/mL PEG-SOD. RESULTS: Increasing degrees of deformation produced increased cell injury in astrocytes, neuronal plus glial cultures, and aortic endothelial cells. By 24 hours after injury, all cultures showed evidence of repair as demonstrated by cells regaining their capacity to exclude propidium iodide. Compared with astrocytes or neuronal plus glial cultures, endothelial cells were much more resistant to stretch-induced injury and more quickly regained their capacity to exclude propidium iodide. PEG-SOD had no effect on the neuronal or glial response to injury but reduced immediate posttraumatic endothelial cell dye uptake by 51%. CONCLUSIONS: These studies further document the utility of the model for studying cell injury and repair and further support the vascular endothelial cell as a site of free radical generation and radical-mediated injury. On the assumption that, like aortic endothelial cells, stretch-injured cerebral endothelial cells also produce oxygen radicals, our results further suggest the endothelial cell as a site of therapeutic action of free radical scavengers after traumatic brain injury.

Animals↗

PubMed1995

Effect of protein kinase C modulators on 14,15-epoxyeicosatrienoic acid incorporation into astroglial phospholipids.

Our previous studies have shown that 14,15-epoxyeicosatrienoic acid (14,15-EET) is a major product of arachidonic acid metabolism in astrocytes. The purpose of this study was to investigate cellular regulation of 14,15-EET incorporation, distribution, and metabolism in primary cultures of rat brain cortical astrocytes. Incorporation of 14,15-EET into astrocytes was lower (93,390 +/- 11,121 dpm/5 x 10(6) cells) than incorporation of 8,9-EET (226,500 +/- 5,567 dpm/5 x 10(6) cells) and arachidonic acid (321,600 +/- 1,200 dpm/5 x 10(6) cells). 14,15-EET was distributed in the order neutral lipids and free fatty acids (solvent front) >> phosphatidylcholine (PC) > phosphatidylinositol (PI) > phosphatidylethanolamine. In contrast, 8,9-EET and arachidonic acid were exclusively incorporated into PC. During incubation, astroglial epoxide hydrolase selectively metabolized 14,15-EET, but not 8,9-EET, to its vic-diol. Although 4-phenylchalcone oxide, a potent inhibitor of epoxide hydrolase, completely inhibited 14,15-EET metabolism, a large amount of cell-incorporated radioactivity remained as free 14,15-EET. Long-term exposure of astrocytes to 4 beta-phorbol 12-myristate 13-acetate (4 beta-PMA) resulted in a time-dependent incorporation of 14,15-EET into PI but not in control cells exposed to 4 alpha-phorbol 12,13-didecanoate. PKC down-regulation completely inhibited epoxide hydrolase metabolism of 14,15-EET. Following recovery of down-regulated PKC, 1 week after treatment with 4 beta-PMA, astrocytes regained their normal pattern of low incorporation of 14,15-EET. Protein kinase C (PKC) inhibition by staurosporine enhanced 14,15-EET incorporation without affecting its metabolism to 14,15-dihydroxyeicosatrienoic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

8,11,14-Eicosatrienoic Acid↗

PubMed1995

Superoxide dismutase improves posttraumatic cortical blood flow in rats.

Oxygen free radicals, such as the superoxide anion, are known to mediate damage to the cerebral microcirculation following traumatic brain injury. The purpose of this study was to determine if superoxide dismutase (SOD), a scavenger of superoxide anion, could alter posttraumatic cortical blood flow. Following barbiturate anesthesia, rats were surgically prepared for moderate fluid percussion brain injury. Cortical blood flow contralateral to the site of injury was measured using laser-Doppler flowmetry. Laser-Doppler flowmetry assesses flow by measuring cell volume and velocity, which are multiplied electronically to give flow. Starting 10 min before injury, animals received either superoxide dismutase (24,000 U/kg bolus, followed by continuous infusion of 1600 U/kg/min) or an equal volume of saline. Blood pressure, heart rate, and cortical blood flow were measured up to 1 h posttrauma. Rats receiving superoxide dismutase had significantly higher cortical blood flow posttrauma (F = 6.91, p < 0.02). One hour posttrauma, the blood flow in SOD-treated rats was 89 +/- 8% of preinjury baseline, whereas this value was only 66 +/- 6% of control in saline-treated rats. SOD caused not only greater blood velocity but also less reduction in cortical blood volume after injury. There were no significant differences between the groups with respect to blood pressure or heart rate. This study further supports the role of oxygen radical-mediated cerebrovascular dysfunction following traumatic brain injury and is the first to show the beneficial effect of SOD on cortical blood flow following fluid percussion brain injury.

Animals↗

PubMed1995

A new model for rapid stretch-induced injury of cells in culture: characterization of the model using astrocytes.

The purpose of this study was to develop a simple, reproducible model for examining the morphologic, physiologic, and biochemical consequences of stretch-induced injury on tissue-cultured cells of brain origin. Rat cortical astrocytes from 1- to 2-day-old rats were cultured to confluency in commercially available 25-mm-diameter tissue culture wells with a 2-mm-thick flexible silastic bottom. A cell injury controller was used to produce a closed system and exert a rapid positive pressure of known amplitude (psi) and duration (msec). The deformation of the membrane, and thus the stretch of the cells growing on the membrane, was proportional to the amplitude and duration of the air pressure pulse. Extent of cell injury was qualitatively assessed by light and electron microscopy and quantitatively assessed by nuclear uptake of the fluorescent dye propidium iodide, which is excluded from cells with intact membranes. Lactate dehydrogenase (LDH) enzyme release was measured spectrophotometrically. Cell injury was found to be proportional to the extent of the silastic membrane deformation. Increasing cell stretch caused mitochondrial swelling and vacuolization as well as disruption of glial filaments. Stretching also caused increased dye uptake, with maximum dye uptake occurring with a 50 msec pressure pulse duration, whereas deformations produced over longer periods of time (seconds) caused little dye uptake. With increasing postinjury survival fewer cells took up dye, implying cell repair. LDH release was also proportional to the amplitude of cell stretch, with maximum release occurring within 2 h of injury. In summary we have developed a simple, reproducible model to produce graded, strain-related injuries in cultured cells. Our continuing experiments suggest that this model can be used to study the biochemistry and physiology of injury as well as serve as a tool to examine the efficacy of therapeutic agents.

Air Pressure↗

PubMed1995

The effect of acute cocaine or lidocaine on behavioral function following fluid percussion brain injury in rats.

One of the goals of our laboratory is to examine how the presence of drugs of abuse will influence traumatic brain injury. Previous studies in our laboratory have shown that cocaine or lidocaine treatment before experimental fluid percussion brain injury in rats reduces the cortical hypoperfusion normally found in the early posttraumatic period. The purpose of the current study was to determine if pretreatment with cocaine or lidocaine is also associated with changes in trauma-induced suppression of reflexes and motor and cognitive dysfunction that occurs following traumatic brain injury (TBI). Twenty-four hours after surgical preparation, rats were randomly assigned to a saline or drug pretreatment group, cocaine (0.5, 2, or 5 mg/kg) or lidocaine (2 mg/kg), which was injected via the tail vein. None of the drug pretreatments worsened injury. Lidocaine and cocaine decreased the duration of suppression of some neurological reflexes and reduced posttraumatic body weight losses. Lidocaine and cocaine both decreased postinjury motor deficits. Lidocaine and cocaine did not affect cognitive function on days 11-15 postinjury. The mechanism by which lidocaine improves acute neurological and motor function following brain injury is unknown, but may involve improved posttraumatic cortical blood flow, as seen in our previous study. Our results, along with other studies showing lidocaine to be neuroprotective in animal models of ischemia, suggest that studies of the effect of posttraumatic administration of lidocaine are warranted.

Animals↗

PubMed1995

Endothelial and nonendothelial cyclooxygenase mediate rabbit pial arteriole dilation by bradykinin.

Aspirin (acetylsalicylic acid, ASA) was administered to rabbits in an attempt to inhibit selectively endothelial cyclooxygenase activity and therefore to determine its role in bradykinin-induced radical-mediated dilation of cerebral arterioles. With the use of the cranial window technique in anesthetized rabbits, pial arteriolar diameters were recorded in response to topically applied bradykinin, acetylcholine, and ventilation with 10% O2-9% CO2 gas mixture. Prostaglandins were measured in isolated cerebral microvessels and cerebrospinal fluid (CSF) using radioimmunoassay. Microvessel prostaglandin production was reduced significantly by 90 mg/kg i.v. ASA, whereas acetylcholine-stimulated increases of CSF prostaglandins were not similarly affected. This treatment reduced bradykinin-induced dilation of pial arterioles by 47%. After concurrent 90 mg/kg i.v. ASA plus 300 microM ASA topically applied to the brain, stimulated increases of CSF prostaglandins were reduced by 79%, while bradykinin-induced dilation was reduced by 78%. ASA did not reduce the dilator activity of either acetylcholine or ventilation with 10% O2-9% CO2. Acetylcholine- but not bradykinin-induced dilation was reduced by NG-nitro-L-arginine methyl ester. These results indicate intravenous ASA produced a relatively selective inhibition of cerebral microvascular cyclooxygenase and partial inhibition of bradykinin-induced dilation. Further inhibition of dilation occurred following ASA administered both systemically and topically to the brain. This indicates two sources of cyclooxygenase, endothelial and nonendothelial, mediate the bradykinin-induced dilation of rabbit pial arterioles. Furthermore, systemic doses of ASA do not eliminate brain prostaglandin formation.

6-Ketoprostaglandin F1 alpha↗

PubMed1995

Acute cocaine administration alters posttraumatic blood pressure and cerebral blood flow in rats.

Cocaine abuse is widespread, and it is possible that its two main pharmacological actions, sympathomimetic and local anesthetic, could influence the blood pressure and cerebral blood flow response to brain injury, which occurs with increased frequency in drug abusers. We tested this hypothesis in ventilated barbiturate-anesthetized rats. Brain injury was induced using the fluid-percussion method, and cortical blood flow was measured using laser-Doppler flowmetry. Saline, cocaine, methamphetamine, or lidocaine was administered 10 min before injury. Upon injury, both cocaine- and saline-pretreated rats showed a similar acute hypertensive phase, which was followed by a period of more pronounced hypotension in the cocaine group (68 +/- 4 vs. 100 +/- 6 mmHg). Cortical blood flow increased dramatically 3-15 s following injury-induced hypertension in both the cocaine and saline groups (approximately 230-260%), but then fell below preinjury values within minutes. At 1 h postinjury, the blood flow in the saline group was 53 +/- 6% of the preinjury value, while in the cocaine group, flow was 74 +/- 7% of preinjury baseline. Similar to the cocaine-treated animals, methamphetamine also caused a more pronounced hypotensive event, but blood flow was not significantly different from saline controls. Lidocaine did not alter posttraumatic blood pressure but did significantly elevate blood flow throughout the 1-h postinjury period. At 60 min posttrauma, blood flow in the lidocaine group was 80 +/- 10% of the preinjury value. The mechanism by which cocaine alters blood pressure and blood flow after injury is not entirely certain.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Anandamide and delta 9-THC dilation of cerebral arterioles is blocked by indomethacin.

Anandamide (AN, arachidonyl ethanolamide) has been isolated from the brain and shown to be an endogenous ligand for the delta 9-tetrahydrocannabinol (delta 9-THC) receptor. The purpose of these studies was to determine whether AN or delta 9-THC can affect the cerebral circulation. With the use of the closed cranial window AN and delta 9-THC (10(-13)-10(-3) M) were topically applied to rabbit cerebral arterioles and effects on diameter were measured with a microscope. AN and delta 9-THC similarly induced a dose-dependent dilation starting at concentrations as low as 10(-12) M. Maximum dilation for AN was 25% and that for delta 9-THC 22%. Topical coapplication of indomethacin, a cyclooxygenase inhibitor, completely blocked dilation, whereas the free radical scavengers superoxide dismutase and catalase or the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) had no effect on AN-induced dilation. The cerebrospinal fluid level of prostaglandin E2 increased only in response to 10(-7) M and greater AN and was not affected by delta 9-THC. [3H]AN superfused through the cranial window was 20% converted to arachidonic acid. These results show that AN and delta 9-THC can modulate cerebral arterioles, likely by stimulating release and metabolism of endogenous arachidonic acid. Whether dilation is due to vasodilator eicosanoids, or other vasoactive agents whose synthesis or release is cyclooxygenase dependent, is uncertain.

Administration, Topical↗

PubMed1995

Mechanical perturbation of cultured cortical neurons reveals a stretch-induced delayed depolarization.

1. An in vitro cellular model of injury was used to elucidate mechanisms contributing to traumatic brain injury (TBI). Neonatal rat cortical neurons cultured on a flexible silastic membrane were stretched rapidly and reversibly by a 50-ms pulse of pressurized air. 2. Sublethal cell stretch depolarized neuronal resting membrane potential by approximately 10 mV but only if cells were incubated for 1 h after injury. Stretch-induced delayed depolarization (or SIDD) returned to baseline values within 24 h. 3. SIDD was dependent on the degree of cell stretch and required neuronal firing, calcium entry, and N-methyl-D-aspartate receptor activation for its induction but not its maintainance. 4. Similarities between SIDD and TBI suggest that SIDD may play a role in brain injury.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1993

Cocaine potentiates the blood pressure and cerebral blood flow response to norepinephrine in rats.

Acute drug-induced hypertension is known to have adverse consequences on the cerebral vasculature. Cocaine abuse has been reported to be associated with an increased frequency of hemorrhagic or ischemic stroke. The purpose of this study was to determine whether cocaine alters the blood pressure or cerebral blood flow response to exogenous norepinephrine. A craniectomy was made over the parietal cortex in rats and cortical blood flow changes were measured using laser-Doppler flowmetry. Ten minutes after cocaine (1 mg/kg, i.v.) or saline, increasing doses of norepinephrine (0.01-10 micrograms/kg, i.v.) were given by bolus injection and changes in blood pressure and flow were monitored. Cocaine produced a transient 27 +/- 5% increase in blood pressure and a 38 +/- 9% increase in blood flow. Cocaine significantly potentiated the blood pressure and cerebral blood flow responses produced by submaximal pressor doses of norepinephrine (0.01-0.6 microgram/kg, i.v.). In summary, cocaine causes a rapid, transient increase in blood pressure and cortical blood flow and potentiates the magnitude and duration of the pressure and flow response to norepinephrine. Repetitive blood pressure elevations in cocaine abusers is one of the proposed mechanisms leading to damage of cerebral vessels. These results may be relevant to an increased frequency of cerebrovascular accidents in cocaine-abusing individuals.

Analysis of Variance↗

PubMed1993

Antinociceptive activity of intrathecal ketorolac is blocked by the kappa-opioid receptor antagonist, nor-binaltorphimine.

Systemic and intrathecally administered ketorolac produced antinociception in the p-phenylquinone test, but not in the tail-flick or hot-plate tests. Antagonists of the subtypes of opioid receptors were used to evaluate the interaction of ketorolac with these receptors. Intrathecally administered kappa-opioid receptor antagonist nor-binaltorphimine dihydrochloride blocked the antinociceptive effects of systemic ketorolac and intrathecally administered ketorolac. Naloxone and ICI 174,864 failed to block the effects of ketorolac. Activation of nor-binaltorphimine-sensitive receptors appears to be an integral element in the mechanism of antinociception of ketorolac at the spinal level. Ketorolac did not precipitate withdrawal jumping in morphine-tolerant mice demonstrating that ketorolac does not act as a mixed agonist-antagonist at the opioid receptor. We suggest that neuraxial placement of ketorolac may prove useful in the clinical setting for the management of acute pain in humans.

Analgesics↗

PubMed1993

Metabolism of arachidonic acid to epoxyeicosatrienoic acids, hydroxyeicosatetraenoic acids, and prostaglandins in cultured rat hippocampal astrocytes.

We have recently shown that brain slices are capable of metabolizing arachidonic acid by the epoxygenase pathway. The purpose of this study was to begin to determine the ability of individual brain cell types to form epoxygenase metabolites. We have examined the astrocyte epoxygenase pathway and have also confirmed metabolism by the cyclooxygenase and lipoxygenase enzyme systems. Cultured rat hippocampal astrocyte homogenate, when incubated with radiolabeled [3H]arachidonic acid, formed products that eluted in four major groups designated as R17-30, R42-50, R51-82, and R83-90 based on their retention times in reverse-phase HPLC. These fractions were further segregated into as many as 13 peaks by normal-phase HPLC and a second reverse-phase HPLC system. The principal components in each peak were structurally characterized by gas chromatography/electron impact-mass spectrometry. Based on HPLC retention times and gas chromatography/electron impact-mass spectrometry analysis, the more polar fractions (R17-30) contained prostaglandin D2 as the major cyclooxygenase product. Minor products included 6-keto prostaglandin F1 alpha, prostaglandin E2, prostaglandin F2 alpha, and thromboxane B2. Fractions R42-50, R51-82, and R83-90 contained epoxygenase and lipoxygenase-like products. The major metabolite in fractions R83-90 was 5,6-epoxyeicosatrienoic acid (EET). Fractions R51-82 contained 14,15- and 8,9-EETs, 12- and 5-hydroxyeicosatetraenoic acids, and 8,9- and 5,6-dihydroxyeicosatrienoic acids (DHETs). In fractions R42-50, 14,15-DHET was the major product. When radiolabeled [3H]14,15-EET was incubated with astrocyte homogenate, it was rapidly metabolized to [3H]14,15-DHET. The metabolism was inhibited by submicromolar concentration of 4-phenylchalcone oxide, a potent inhibitor of epoxide hydrolase activity. Formation of other polar metabolites such as triols or epoxy alcohols from 14,15-DHET was not observed. In conclusion, astrocytes readily metabolize arachidonic acid to 14,15-EET, 5,6-EET, and their vicinal-diols. Previous studies suggest these products may affect neuronal function and cerebral blood flow.

8,11,14-Eicosatrienoic Acid↗

PubMed1992

The effect of dietary n-3 fatty acids on in vivo platelet aggregation in the cerebral microcirculation.

Diets enriched in n-3 fish oil have been suggested to decrease coronary artery disease in part through their ability to decrease cyclooxygenase-dependent platelet aggregation. However little is known concerning the effect of n-3 fatty acids on in vivo platelet aggregation. The purpose of these experiments was to determine whether dietary n-3 fatty acids affect the rate at which platelet aggregation occurs in cerebral arterioles. Fish oil (200 mg eicosapentaenoic acid + 143 mg docosahexaenoic acid/kg), corn oil or water was given daily by gavage to mice (n = 30) for six weeks and then in vivo platelet aggregation was induced by the light plus dye method, which injuries the endothelium. Two additional groups of mice were acutely treated with saline or indomethacin (0.5 mg/kg, ip), with the latter serving as a positive control for therapeutic inhibition of platelet aggregation. Serum thromboxane B2 was analyzed by RIA. All fed groups gained weight equally. Serum thromboxane B2 was decreased by 40% in the fish oil group (p = 0.05 vs. corn oil, p = 0.07 vs. water). The mean (+/- SE) time to first aggregate in pial arterioles was 101 +/- 6, 91 +/- 6 and 101 +/- 9 seconds in the fish corn oil and water groups, respectively. Indomethacin significantly increased the time to first arteriolar aggregate by 35% (p < 0.002) and caused an 80% reduction in serum thromboxane. These studies show dietary fish oil produces a moderate reduction in serum TxB2 level and does not affect arteriolar platelet aggregation whereas indomethacin produces a drastic TxB2 reduction and significantly slows platelet aggregation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Monoclonal antibody to tumor necrosis factor alpha attenuates cardiopulmonary dysfunction in porcine gram-negative sepsis.

Tumor necrosis factor (TNF) is implicated in the pathophysiology of gram-negative sepsis. This study examined physiologic and biochemical effects of pretreatment with an anti-TNF alpha monoclonal antibody immediately before the onset of sepsis. Three groups of anesthetized ventilated pigs were studied for 300 minutes. Groups 1 (n = 12) and 2 (n = 6) received a 1-hour infusion of live Pseudomonas aeruginosa. Group 2 was pretreated with anti-TNF alpha monoclonal antibody (15 mg/kg). Group 3 (n = 8) received intravenous sterile saline. Group 1 exhibited a significant rise in plasma TNF activity, which was abolished in group 2. Cardiac index was reduced in both groups 1 and 2 in the first hour but recovered in group 2 (3.3 +/- 0.4 l/min per square meter at 300 minutes in group 2 vs 1.3 +/- 0.2 L/min per square meter in group 1). Metabolic acidosis was attenuated (arterial pH, 7.39 +/- 0.01 in group 2 vs 7.16 +/- 0.03 at 300 minutes in group 1). Increased extravascular lung water was also attenuated (5.9 +/- 0.7 in group 2 vs 13.2 +/- 1.5 mL/kg at 300 minutes in group 1). However, pulmonary hypertension and hypoxemia, which are known cyclooxygenase effects, were not affected. In the early phase of the study, plasma thromboxane B2 levels were elevated in both groups 1 and 2. We conclude that anti-TNF alpha monoclonal antibody offered significant protection against the effects of sepsis, but that other mediators may be responsible for the early changes seen in this model.

Animals↗

PubMed1992

Long-term comparison of three combinations of albuterol, theophylline, and beclomethasone in children with chronic asthma.

Three combination regimens, (1) inhaled albuterol (ALB) with oral theophylline (THEO), (2) inhaled ALB with inhaled beclomethasone dipropionate (BDP), or (3) inhaled ALB, inhaled BDP, and oral THEO, were evaluated and compared as optimal pharmacotherapy for chronic asthma in 111 children. In this double-blind, parallel-group, multicenter study, children, aged 6 to 16 years with moderately severe asthma (unstable despite daily medications), were treated with one of the combinations for 12 weeks. Patients were evaluated every 4 weeks by spirometry and serum THEO measurement. Patients kept daily symptom diaries, measured peak flow rates twice daily, and recorded adverse events. Treatment groups did not differ in disease or demographic characteristics at study entry. All three combination treatments provided and maintained significant improvement in FVC, FEV1, and FEF25%-75% volume points, and compared with that of pretreatment, with no significant differences between treatments. Throughout the 12-week treatment period, however, patients receiving BDP had lower symptom scores, fewer had more than one asthma attack, fewer required "bursts" of prednisone (p = 0.001), and fewer required rescue medication (p = 0.009). Significantly more patients receiving BDP said that they felt better than they did at the beginning of the study compared with the number of patients not receiving BDP (p = 0.002). Adverse events were similar among treatment groups.

Administration, Inhalation↗

PubMed1992

The endothelium-dependent effects of thimerosal on mouse pial arterioles in vivo: evidence for control of microvascular events by EDRF as well as prostaglandins.

Thimerosal causes synthesis and/or release of both endothelium-derived relaxing factor (EDRF) and prostaglandins from conductance vessels in vitro. We tested its effects and mechanism of action on mouse pial arterioles in vivo using intravital microscopic techniques. Topical thimerosal dilated pial arterioles. This effect was eliminated by endothelial injury produced by a laser/Evans blue technique. Dilation was also eliminated by topical L-NMMA, a reported inhibitor of EDRF synthesis. Topical thimerosal also reduced the incidence of platelet adhesion/aggregation ("capture") at a site of minimal endothelial damage. This effect was eliminated by L-NMMA pretreatment. The ability of thimerosal to dilate arterioles was eliminated not only by treatments thought to eliminate synthesis/release of EDRF, but also by cyclooxygenase inhibitors. However, inhibition of platelet adhesion/aggregation was not affected by cyclooxygenase inhibition. Thimerosal significantly increased production of prostaglandin E2 recovered from a closed cranial window. We conclude that the dilating effects of thimerosal on diameter require two endothelium-derived agents: EDRF and one or more prostaglandins acting in concert. However, the inhibiting effect of thimerosal on local platelet adhesion/aggregation appears to be caused only by an increase in EDRF at the injured site.

6-Ketoprostaglandin F1 alpha↗

PubMed1992

Continuous monitoring of posttraumatic cerebral blood flow using laser-Doppler flowmetry.

Traumatic brain injury causes alterations in cerebral blood flow that are thought to influence secondary pathophysiology and neurologic outcome in humans. Since it is difficult to study early changes in blood flow in head-injured patients, animal models of brain injury must be employed. However, techniques to monitor brain blood flow in animals are labor intensive and generally provide discontinuous flow measurements. The present study examines the application of laser-Doppler flowmetry for measurement of cerebral blood flow following experimental brain injury. This method allows continuous monitoring of local cerebral blood flow before, during, and after injury. Rats (n = 9) were prepared for lateral fluid percussion injury under barbiturate anesthesia. Injury (2.10 +/- 0.02 atm) was induced over the right parietal cortex, and blood flow was monitored in the contralateral cortex. Seconds after the peak hypertension after injury, blood flow in the left parietal cortex increased 226% +/- 18% (means +/- SEM). This increase was transient, with blood flow falling below control values within minutes. Five minutes after injury, blood flow was 83% +/- 8% of control, and at 1 h, this value had fallen to 56% +/- 6%. Blood flow at 60 min was 93% +/- 5% of control in the sham-injured group (n = 10). The reduction in cerebral blood flow in our laser-Doppler study was of similar magnitude as previously reported in rats injured at a similar intensity when blood flow was examined with radiolabeled microspheres. Given these results, we believe laser-Doppler flowmetry can be used to continuously monitor posttraumatic blood flow following experimental brain injury.

Animals↗