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H Richard Winn

Publications and source records attributed to H Richard Winn.

At least 19 recordsLinked to original sources
PubMed2007

Magnesium sulfate for neuroprotection after traumatic brain injury: a randomised controlled trial.

BACKGROUND: Traumatic brain injuries represent an important and costly health problem. Supplemental magnesium positively affects many of the processes involved in secondary injury after traumatic brain injury and consistently improves outcome in animal models. We aimed to test whether treatment with magnesium favourably affects outcome in head-injured patients. METHODS: In a double-blind trial, 499 patients aged 14 years or older admitted to a level 1 regional trauma centre between August, 1998, and October, 2004, with moderate or severe traumatic brain injury were randomly assigned one of two doses of magnesium or placebo within 8 h of injury and continuing for 5 days. Magnesium doses were targeted to achieve serum magnesium ranges of 1.0-1.85 mmol/L or 1.25-2.5 mmol/L. The primary outcome was a composite of mortality, seizures, functional measures, and neuropsychological tests assessed up to 6 months after injury. Analyses were done according to the intention-to-treat principle. This trial is registered with , number . FINDINGS: Magnesium showed no significant positive effect on the composite primary outcome measure at the higher dose (mean=55 average percentile ranking on magnesium vs 52 on placebo, 95% CI for difference -7 to 14; p=0.70). Those randomly assigned magnesium at the lower dose did significantly worse than those assigned placebo (48 vs 54, 95% CI -10.5 to -2; p=0.007). Furthermore, there was higher mortality with the higher magnesium dose than with placebo. Other major medical complications were similar between groups, except for a slight excess of pulmonary oedema and respiratory failure in the lower magnesium target group. No subgroups were identified in which magnesium had a significantly positive effect. INTERPRETATION: Continuous infusions of magnesium for 5 days given to patients within 8 h of moderate or severe traumatic brain injury were not neuroprotective and might even have a negative effect in the treatment of significant head injury.

Adolescent↗
PubMed2005

Effect of caffeine on cerebral blood flow response to somatosensory stimulation.

Despite caffeine's wide consumption and well-documented psychoactive effects, little is known regarding the effects of caffeine on neurovascular coupling. In the present study, we evaluated the effects of caffeine, an adenosine receptor antagonist, on intracerebral arterioles in vitro and subsequently, on the pial circulation in vivo during cortical activation induced by contralateral sciatic nerve stimulation (SNS). In our in vitro studies, we utilized isolated intracerebral arterioles to determine the effects of caffeine (10 or 50 micromol/L) on adenosine-induced vasodilatation. At the lower concentration, caffeine was without effect, but at the higher concentration, caffeine produced significant attenuation. In our in vivo studies, we determined the cerebrospinal fluid (CSF) caffeine concentrations at 15, 30, and 60 mins after intravenous administration of 5, 10 and 40 mg/kg. At the latter two concentrations, CSF levels exceeded 10 micromol/L. We then evaluated the pial arteriolar response during cortical activation caused by contralateral SNS after administering caffeine intravenously (0, 5, 10, 20 30, and 40 mg/kg). The pial circulation was observed through a closed cranial window in chloralose-anesthetized Sprague-Dawley rats. The contralateral sciatic nerve was isolated, positioned on silver electrodes and stimulated for 20 secs (0.20 V, 0.5 ms, and 5 Hz). Arteriolar diameter was quantified using an automated video dimension analyzer. Contralateral SNS resulted in a 23.8% +/-3.9% increase in pial arteriolar diameter in the hindlimb sensory cortex under control conditions. Intravenous administration of caffeine at the lowest dose studied (5 mg/kg) had no effect on either resting arteriolar diameter or SNS-induced vasodilatation. However, at higher doses (10, 20, 30, and 40 mg/kg, intravenously), caffeine significantly (P < 0.05; n = 6) attenuated both resting diameter and cerebral blood flow (CBF) responses to somatosensory stimulation. Intravenous administration of theophylline (10, 20, and 40 mg/kg), another adenosine receptor antagonist, also significantly reduced SNS-induced vasodilatation in a dose-dependent manner. Hypercarbic vasodilatation was unaffected by either caffeine or theophylline. The results of the present study show that caffeine significantly reduces cerebrovascular responses to both adenosine and to somatosensory stimulation and supports a role of adenosine in the regulation of CBF during functional neuronal activity.

Adenosine↗
PubMed2004

Accurate intraoperative localization of spinal dural arteriovenous fistulae with embolization coil: technical note.

Spinal dural arteriovenous fistulae represent a potentially curable cause of a progressive myelopathy and therefore should be treated aggressively by either endovascular or surgical methods. In the surgical treatment of these lesions, intraoperative radiographic localization of the site of the fistula can be problematic. We describe an endovascular technique in which radiopaque microcoils are placed in the major feeding artery(ies) after completion of spinal angiography, which then provides a marker that is easily visualized with intraoperative x-rays, allowing effective localization of the site of the fistula.

Angioplasty↗
PubMed2004

Errors in compliance with federal rules and regulations relating to healthcare benefits programs: the University of Washington Department of Neurological Surgery experience.

This article details the errors in compliance with federal rules and regulations relating to the healthcare benefits programs at the University of Washington Department of Neurological Surgery from 1996 through 2002. University faculty members, regardless of the organization to which they belong, will be identified by the federal government as the individual responsible in healthcare finance inquiries. A full understanding of all regulations and an active compliance program are necessary to avoid problems, including criminal prosecution.

Academic Medical Centers↗
PubMed2004

Blood transfusion and increased risk for vasospasm and poor outcome after subarachnoid hemorrhage.

OBJECT: Nitric oxide (NO) metabolism may influence vasospasm after subarachnoid hemorrhage (SAH). It has been demonstrated in recent studies that erythrocytes carry NO for release in vessels, whereas transfused erythrocytes may lack stored NO. Several converging lines of evidence also indicate that blood transfusion may exacerbate poor outcomes in some critically ill patients. In this study the authors hypothesized that patients with SAH who received red blood cell (RBC) transfusions were at greater risk for vasospasm and poor outcome. METHODS: The authors retrospectively reviewed a prospective observational database, including hospital records, computerized tomography (CT) scans, and pre- and postoperative four-vessel angiograms, in which the management methods used in 441 patients undergoing surgery for ruptured cerebral aneurysms were described. Two hundred seventy patients (61.2%) received an RBC transfusion during their hospital stay. After adjustment for Hunt and Hess grade, SAH grade on CT scans, delay between rupture and surgery, smoking status, and intraoperative aneurysm rupture, a worse outcome was more likely in patients who received intraoperative blood (odds ratio [OR] 2.44, confidence interval [CI] 1.32-4.52; 120 patients). Intraoperative RBC transfusion did not influence subsequent angiographically confirmed vasospasm (OR 0.92, CI 0.6-1.4). Worse outcome was observed in patients who received blood postoperatively (OR 1.81, CI 1.21-2.7), but not after adjustments were made for confounding variables (OR 1.48, CI 0.83-2.63). Angiographic vasospasm was observed in 217 patients and, after adjusting for confounding variables, was more frequent among patients who received postoperative RBC transfusion (OR 1.68, CI 1.02-2.75). Among patients in whom angiographically confirmed vasospasm developed there was a tendency to have received more blood than in those with no vasospasm; however, a clear dose-dependent response was not observed. CONCLUSIONS: Development of angiographically confirmed vasospasm after SAH is associated with postoperative RBC transfusion and worse outcome is associated with intraoperative RBC transfusion. Before blood is transfused, patients with SAH should be carefully assessed to determine if they are symptomatic because of anemia.

Adolescent↗
PubMed2004

Relationship between intracranial pressure and other clinical variables in patients with aneurysmal subarachnoid hemorrhage.

OBJECT: Increased intracranial pressure (ICP) is well known to affect adversely patients with head injury. In contrast, the variables associated with ICP following aneurysmal subarachnoid hemorrhage (SAH) and their impact on outcome have been less intensely studied. METHODS: In this retrospective study the authors reviewed a prospective observational database cataloging the treatment details in 433 patients with SAH who had undergone surgical occlusion of an aneurysm as well as ICP monitoring. All 433 patients underwent postoperative ICP monitoring, whereas only 146 (33.7%) underwent both pre- and postoperative ICP monitoring. The mean maximal ICP was 24.9 +/- 17.3 mm Hg (mean +/- standard deviation). During their hospital stay, 234 patients (54%) had elevated ICP (> 20 mm Hg), including 136 of those (48.7%) with a good clinical grade (Hunt and Hess Grades I-III) and 98 (63.6%) of the 154 patients with a poor grade (Hunt and Hess Grades IV and V) on admission. An increased mean maximal ICP was associated with several admission variables: worse Hunt and Hess clinical grade (p < 0.0001), a lower Glasgow Coma Scale (GSC) motor score (p < 0.0001); worse SAH grade based on results of computerized tomography studies (p < 0.0001); intracerebral hemorrhage (p = 0.024); severity of intraventricular hemorrhage (p < 0.0001); and rebleeding (p = 0.0048). Both intraoperative cerebral swelling (p = 0.0017) and postoperative GCS score (p < 0.0001) were significantly associated with a raised ICP. Variables such as patient age, aneurysm size, symptomatic vasospasm, intraoperative aneurysm rupture, and secondary cerebral insults such as hypoxia were not associated with raised ICP. Increased ICP adversely affected outcome: 71.9% of patients with normal ICP demonstrated favorable 6-month outcomes postoperatively, whereas 63.5% of patients with ICP between 20 and 50 mm Hg and 33.3% with ICP greater than 50 mm Hg demonstrated favorable outcomes. Among 21 patients whose raised ICP did not respond to mannitol therapy, all experienced a poor outcome and 95.2% died. Among 145 patients whose elevated ICP responded to mannitol, 66.9% had a favorable outcome and only 20.7% were dead 6 months after surgery (p < 0.0001). According to results of multivariate analysis, however, ICP was not an independent outcome predictor (odds ratio 1.26, 95% confidence interval 0.28-5.68). CONCLUSIONS: Increased ICP is common after SAH, even in patients with a good clinical grade. Elevated ICP post-SAH is associated with a worse patient outcome, particularly if ICP does not respond to treatment. This association, however, may depend more on the overall severity of the SAH than on ICP alone.

Adult↗
PubMed2003

Adenosine receptors mediate glutamate-evoked arteriolar dilation in the rat cerebral cortex.

We tested the hypothesis that adenosine (Ado) mediates glutamate-induced vasodilation in the cerebral cortex by monitoring pial arteriole diameter in chloralose-anesthetized rats equipped with closed cranial windows. Topical application of 100 microM glutamate and 100 microM N-methyl-d-aspartate (NMDA) dilated pial arterioles (baseline diameter 25 +/- 2 microm) by 17 +/- 1% and 18 +/- 4%, respectively. Coapplication of the nonselective Ado receptor antagonist theophylline (Theo; 10 microM) significantly reduced glutamate- and NMDA-induced vasodilation to 4 +/- 2% (P < 0.01) and 6 +/- 2% (P < 0.05), whereas the Ado A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (0.1 microM) had no effect. Moreover, application of the Ado A(2A) receptor-selective antagonist 4-(2-[7-amino-2-(2-furyl)(1,2,4)triazolo(2,3-a)(1,3,5)triazin-5-ylamino]ethyl)phenol (ZM-241385), either by superfusion (0.1 microM, 1 microM) or intravenously (1 mg/kg), significantly inhibited the pial arteriole dilation response to glutamate. Neither Theo nor ZM-241385 affected vascular reactivity to mild hypercapnia induced by 5% CO(2) inhalation. These results suggest that Ado contributes to the dilation of rat cerebral arterioles induced by exogenous glutamate, and that the Ado A(2A) receptor subtype may be involved in this dilation response.

Animals↗
PubMed2003

Effect of valproate on hemostatic function in patients with traumatic brain injury.

OBJECTIVES: To evaluate whether valproate (VPA) resulted in laboratory or clinical evidence of a change in bleeding-related measures associated with VPA therapy in patients sustaining a traumatic brain injury. METHODS: Fibrinogen, platelet count and clot elastic shear modulus using the Thrombelastograph (TEG) coagulation analyzer were measured at baseline, 4, 14, 30, and 180 days post-injury. Clinically significant events, defined as the trigger for requiring a transfusion, were identified and evaluated as to possible treatment effects. RESULTS: Compared to baseline, the platelet count in the VPA groups was decreased on day 4, increased by 100% on day 14, and returned to baseline levels by day 30. Fibrinogen was significantly increased by day 4 and returned to baseline by day 30. The platelet count was correlated with an increase in the maximum amplitude or width of the TEG tracing; a measure of strength of the clot, suggesting that valproate did not alter the clot strength contributed by platelets. None of the clinical events requiring transfusions appeared to be treatment related. CONCLUSIONS: No serious hemostatic adverse events occurred in the trauma patients receiving VPA or phenytoin that could be attributed to treatment.

Adult↗
PubMed2003

Hippocampal injury and neurobehavioral deficits are improved by PD 81,723 following hyperglycemic cerebral ischemia.

We investigated the effects of PD 81,723, an allosteric enhancer for the adenosine A(1) receptor subtype, on hippocampal injury and Morris water maze (MWM) performance following hyperglycemic cerebral ischemia and reperfusion (4-VO, 10 min) in the rat. PD 81,723 (3 or 10 mg/kg) or the equivalent volume of saline was administered intraperitoneally 30 min prior to ischemia. Moderate hyperglycemia was achieved by administration of D-glucose (3g/kg, i.p.) 15 min prior to induction of ischemia. Morris water maze trials were performed on the 6th, 7th, and 8th days after the ischemic insult. The rat brains were sectioned (8 microm), stained with cresyl violet/acid fuchsin, and evaluated for hippocampal ischemic injury by an experimenter blinded to the treatment conditions. At the higher dose, PD 81,723 (10 mg/kg) had no effect on hippocampal injury or MWM performance following hyperglycemic ischemia compared to corresponding saline-treated animals. In contrast, a lower dose of PD 81,723 (3 mg/kg) resulted in significant (P < 0.05, n = 8) reduction of hippocampal injury following hyperglycemic ischemia. Furthermore, corresponding Morris water maze performance (latency, learning index, and cumulative distance swum) was significantly improved by PD 81,723 (P < 0.05, n = 8). The results of the present study suggest that, in the presence of PD 81,723, an A(1) allosteric enhancer, endogenously produced adenosine is sufficient to exert significant neuroprotection during hyperglycemic ischemia. Moreover, the present study provides further evidence for a neuromodulatory role of adenosine during hyperglycemic ischemia.

Animals↗
PubMed2003

cGMP-dependent and not cAMP-dependent kinase is required for adenosine-induced dilation of intracerebral arterioles.

Adenosine (ADO) is a potent cerebral vasodilator and has been proposed as a metabolic regulator of cerebral blood flow. However, the signal transduction pathway by which ADO causes vasodilation in cerebral microvessels is currently unknown. The current study was designed to investigate the role of cyclic nucleotides and cyclic nucleotide-dependent protein kinases in ADO-induced dilation of resistance-sized rat cerebral arterioles that develop spontaneous tone. Arterioles were cannulated and perfused intraluminally at constant flow (2 microl/min) and pressure (60 mm Hg). ADO (29.7 +/- 2.0%; 1 microM), CGS-21680 (16 +/- 4%, 1 microM), 8-bromo-cyclic guanosine monophosphate (8 Br-cGMP; 29.9 +/- 3.9%; 100 microM), sodium nitroprusside (SNP; 30.6 +/- 3.3%, 1 microM), cyclic guanine monophosphate-dependent protein kinase activator (Sp-8-pCPT-cGMPS, 25.9 +/- 4.2%; 10 microM), forskolin (30.5 +/- 5.9%; 0.1 microM), and pH 6.8 all produced large dilations. The selective cGMP-dependent protein kinase inhibitor, Rp-8-pCPT-cGMPS (10 microM), had no effect on resting diameter or reactivity to acidic pH, but significantly ( < 0.05) attenuated arteriolar dilations to ADO (59%, n = 8), CGS-21680 (60%, n = 4), SNP (62%, n = 3), 8 Br-cGMP (88%, n = 3), and Sp-8-pCPT-cGMPS (98%, n = 3). H8, the less-selective cyclic nucleotide-dependent protein kinase inhibitor, had similar effects as Rp-8-pCPT-cGMPS. Additionally, the inhibitor of the soluble guanylate cyclase, 1H-[1,24]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), blocked the response to SNP (70% inhibition) and significantly inhibited the ADO response (43% inhibition). In contrast, inhibition of the cyclic ADO monophosphate (cAMP)-dependent protein kinase Rp-8-CPT-cAMPS had no effect on the ADO, SNP, or pH responses, but significantly blocked forskolin-induced vasodilation (53%). It is concluded that ADO-induced vasodilation in cerebral microvessels, at least in part, involves cGMP and cGMP-dependent protein kinase, but not cAMP or cAMP-dependent kinase. Our data therefore provides a new insight into mechanisms by which ADO invokes vasodilation in cerebral microvascular arterioles.

Adenosine↗
PubMed2003

Blood pressure and outcome after severe pediatric traumatic brain injury.

BACKGROUND: The relationship between systolic blood pressure and outcome in children after severe traumatic brain injury (TBI) is unclear. We examined the relationship between age-appropriate systolic blood pressure (AASBP) percentile and outcome after severe pediatric TBI. METHODS: We examined the association between AASBP percentiles and outcome in 172 children younger than 14 years of age with a Glasgow Coma Scale score < 9. Outcome was evaluated using discharge Glasgow Outcome Scale score. Poor outcome was defined as a Glasgow Outcome Scale score < 4. RESULTS: Poor outcome was associated with AASBP < 75th percentile (odds ratio, 4.2; 95% confidence interval, 2.1-8.3). Patients with systolic blood pressure (SBP) > or = 90 mm Hg and AASBP < 75th percentile had a higher odds for poor outcome compared with patients with SBP > or = 90 mm Hg and AASBP > or = 75th percentile (odds ratio, 3.5; 95% confidence interval, 1.7-7.3). CONCLUSION AASBP < 75th percentile was associated with poor outcome after severe pediatric TBI, even when SBP was > or = 90 mm Hg.

Academic Medical Centers↗
PubMed2003

Adenosine-A2a receptor down-regulates cerebral smooth muscle L-type Ca2+ channel activity via protein tyrosine phosphatase, not cAMP-dependent protein kinase.

Adenosine acting via A2a receptors (A2aR) is a potent cerebral vasodilator that relaxes vascular smooth muscle cells (VSMCs) by a mechanism attributed to activation of cAMP-dependent protein kinase (cAK). We examined effects of adenosine and its mechanism of action on L-type Ca2+ channels in native VSMCs from rat basilar artery. Reverse transcription-polymerase chain reaction and immunofluorescence imaging confirmed transcription and expression of A2aR, and in situ hybridization confirmed presence of mRNA for L-type Cav1.2b channels. In patch-clamp experiments, adenosine down-regulated Ca2+ channel currents in a concentration-dependent manner, with receptor-subtype-specific antagonists [4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo-[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM-241385) versus 1,3-dipropyl-8-cyclopentyl-1,3-dipropylxanthine] showing that this was caused by action of A2aR. Down-regulation of channel currents was mimicked by stimulation of cGMP-dependent protein kinase (cGK; 8-Br-cGMP) and by inhibition of tyrosine kinase (AG-18) but not by stimulation of cAK [forskolin and 8-bromo-cAMP (8-Br-AMP)]. Down-regulation of currents by the A2aR agonist 2-[p-(2-carboxyeth yl)phenylethylamino]-5'-N-ethyolcarboxamidoadenosine (CGS-21680) was blocked by inhibiting protein tyrosine phosphatase (PTP; orthovanodate and dephostatin), but not by inhibiting cGK (KT-5823 and H-7). Western blots of lysate or of immunoisolated Ca2+ channels from arterial segments incubated with CGS-21680 showed 1) increased phosphorylation of vasodilator-stimulated phosphoprotein that was blocked by inhibiting cAK (KT-5720), consistent with activation of cAK by A2aR; and 2) decreased tyrosine phosphorylation of immunoisolated alpha1c subunit of the Ca2+ channel. Our data show that cAK, although activated, was not germane to down-regulation of Ca2+ channel activity by A2aR, and they delineate a novel signaling mechanism involving reduced tyrosine phosphorylation of Ca2+ channels by A2aR probably caused by PTP activation.

Animals↗
PubMed2002

Methods for isolation and characterization of intracerebral arterioles in the C57/BL6 wild-type mouse.

Vascular control mechanisms have been studied extensively in mice. However, an in vitro characterization of penetrating intracerebral arterioles has not been reported. We describe methods for isolation and cannulation for mouse intracerebral arterioles. This technique allows analysis of mouse cerebral arteriolar physiology and pharmacology without the confounding influences of the surrounding brain elements. Penetrating intracerebral arterioles from adult C57/BL6 wild-type (WT) mice were isolated at 4 degrees C, transferred to an inverted microscope and cannulated at both ends using a dual glass micropipette system, wherein intraluminal flow (0.2 microl/min) and pressure (60 mmHg) were maintained. The arterioles developed spontaneous tone when the chamber was warmed to 37 degrees C, with the resulting diameter reaching 68.4+/-0.9% of passive diameter (29.8+/-1.1 microm). After the development of spontaneous tone, incremental changes in luminal pressure from 20 to 140 mmHg induced myogenic responses. Acidosis (pH 6.8) and alkalosis (pH 7.6) caused dilation (20.0+/-1.4%) and constriction (17.2+/-1.4%), respectively. Extraluminal adenosine (ADO (10 microM); 24.3+/-3.6%) and sodium nitroprusside (SNP (10 microM); 28.6+/-4.1%) and intraluminal adenosine 5'-triphosphate (ATP (10 microM); 20.0+/-3.9%) resulted in vasodilation similar in magnitude to that observed in rat arterioles. This information provides a foundation for elucidating cerebral vascular control mechanisms in genetically engineered mice.

Acidosis↗
PubMed2002

High-intensity focused ultrasound selectively disrupts the blood-brain barrier in vivo.

High-intensity focused ultrasound (HIFU) has been shown to generate lesions that destroy brain tissue while disrupting the blood-brain barrier (BBB) in the periphery of the lesion. BBB opening, however, has not been shown without damage, and the mechanisms by which HIFU induces BBB disruption remain unknown. We show that HIFU is capable of reversible, nondestructive, BBB disruption in a targeted region-of-interest (ROI) (29 of 55 applications; 26 of 55 applications showed no effect); this opening reverses after 72 h. Light microscopy demonstrates that HIFU either entirely preserves brain architecture while opening the BBB (18 of 29 applications), or generates tissue damage in a small volume within the region of BBB opening (11 of 29 applications). Electron microscopy supports these observations and suggests that HIFU disrupts the BBB by opening capillary endothelial cell tight junctions, an isolated ultrastructural effect that is different from the mechanisms through which other (untargeted) modalities, such as hyperosmotic solutions, hyperthermia and percussive injury disrupt the BBB.

Animals↗
PubMed2002

Bilateral multiple cervical root avulsions without skeletal or ligamentous damage resulting from blast injury: case report.

OBJECTIVE AND IMPORTANCE: We describe a unique case of multiple bilateral cervical root injuries without ligamentous or bony injury secondary to a sandblast accident. CLINICAL PRESENTATION: A 19-year-old man sustained a sandblast injury to his face, neck, chest, and upper extremities, with immediate loss of motor and sensory function occurring in both of his upper extremities. Cervical spine x-rays, computed tomography, and magnetic resonance imaging demonstrated no fracture, soft tissue abnormality, or malalignment. The restriction of deficits to the patient's upper extremities suggested a central cervical spinal cord injury, bilateral brachial injuries, or a conversion disorder. INTERVENTION: Cervical computed tomographic myelography revealed multiple bilateral nerve root injuries. CONCLUSION: This case report is unique in the literature in that it describes a patient with multiple cervical nerve root injuries secondary to sandblast injury without ligamentous or bony injury. Although magnetic resonance imaging remains the diagnostic modality of choice in patients with acute spinal cord injury, it is deficient in demonstrating cervical root injury in the acute setting. In this setting, computed tomographic myelography is superior.

Adult↗
PubMed2002

Pial arteriole dilation during somatosensory stimulation is not mediated by an increase in CSF metabolites.

Pial arterioles supplying the hindlimb somatosensory cortex dilate in response to contralateral sciatic nerve stimulation. The mechanism of this pial vasodilation is not well understood. One possibility is that vasoactive metabolites released during brain activation may diffuse to subarachnoid cerebrospinal fluid (CSF) to dilate pial vessels. To test this hypothesis, we implanted closed cranial windows in rats and measured pial arteriolar dilation to sciatic nerve stimulation during constant rate superfusion of the pial surface with artificial CSF. We reason that flushing the pial surface with CSF should quickly dissipate vasoactive substances and prevent these substances from dilating pial arterioles. CSF flow (1 and 1.5 ml/min) significantly reduced pial arteriole dilation induced by 5% CO2 inhalation, but the same flow rates did not affect dilator responses to sciatic nerve stimulation. We conclude that brain-to-CSF diffusion of vasoactive metabolites does not play a significant role in the dilation of pial arterioles during somatosensory activity.

Animals↗
PubMed2002

Differential role of KIR channel and Na(+)/K(+)-pump in the regulation of extracellular K(+) in rat hippocampus.

Little information is available on the specific roles of different cellular mechanisms involved in extracellular K(+) homeostasis during neuronal activity in situ. These studies have been hampered by the lack of an adequate experimental paradigm able to separate K(+)-buffering activity from the superimposed extrusion of K(+) from variably active neurons. We have devised a new protocol that allows for such an analysis. We used paired field- and K(+)-selective microelectrode recordings from CA3 stratum pyramidale during maximal Schaffer collateral stimulation in the presence of excitatory synapse blockade to evoke purely antidromic spikes in CA3. Under these conditions of controlled neuronal firing, we studied the [K(+)]o baseline during 0.05 Hz stimulation, and the accumulation and rate of recovery of extracellular K(+) at higher frequency stimulation (1-3 Hz). In the first set of experiments, we showed that neuronal hyperpolarization by extracellular application of ZD7288 (11 microM), a selective blocker of neuronal I(h) currents, does not affect the dynamics of extracellular K(+). This indicates that the K(+) dynamics evoked by controlled pyramidal cell firing do not depend on neuronal membrane potential, but only on the balance between K(+) extruded by firing neurons and K(+) buffered by neuronal and glial mechanisms. In the second set of experiments, we showed that di-hydro-ouabain (5 microM), a selective blocker of the Na(+)/K(+)-pump, yields an elevation of baseline [K(+)]o and abolishes the K(+) recovery during higher frequency stimulation and its undershoot during the ensuing period. In the third set of experiments, we showed that Ba(2+) (200 microM), a selective blocker of inwardly rectifying K(+) channels (KIR), does not affect the posttetanus rate of recovery of [K(+)]o, nor does it affect the rate of K(+) recovery during high-frequency stimulation. It does, however, cause an elevation of baseline [K(+)]o and an increase in the amplitude of the ensuing undershoot. We show for the first time that it is possible to differentiate the specific roles of Na(+)/K(+)-pump and KIR channels in buffering extracellular K(+). Neuronal and glial Na(+)/K(+)-pumps are involved in setting baseline [K(+)]o levels, determining the rate of its recovery during sustained high-frequency firing, and determining its postactivity undershoot. Conversely, glial KIR channels are involved in the regulation of baseline levels of K(+), and in decreasing the amplitude of the postactivity [K(+)]o undershoot, but do not affect the rate of K(+) clearance during neuronal firing. The results presented provide new insights into the specific physiological role of glial KIR channels in extracellular K(+) homeostasis.

Animals↗