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Prenatal exposure to carbon monoxide (CO) disrupts brain development, however little is known about effects on neocortical maturation. We exposed pregnant mice to CO from embryonic day 7 (E7) until birth. To study the effect of CO on neuronal migration into the neocortex we injected BrdU during corticogenesis and observed misplaced BrdU+ cells. The majority of cells not in their proper layer colocalized with GAD65/67, suggesting impairment of interneuron migration; interneuron subtypes were also affected. We subsequently followed interneuron migration from E15 organotypic cultures of mouse neocortex exposed to CO; the leading process length of migrating neurons diminished. To examine an underlying mechanism, we assessed the effects of CO on the cellular cascade mediating the cytoskeletal protein vasodilator-stimulated phosphoprotein (VASP). CO exposure resulted in decreased cGMP and in a downstream target, phosphorylated VASP. Organotypic cultures grown in the presence of the phosphodiesterase inhibitor IBMX resulted in a recovery of the leading processes. These data support the idea that CO acts as a signaling molecule and impairs function and neuronal migration by acting through the CO/NO-cGMP pathway. In addition, treated mice demonstrated functional impairment in behavioral tests., (Published by Elsevier B.V.)

Cerebral pyruvate depletion and lactate acidosis are common metabolic characteristics of patients with traumatic brain injury (TBI) and are associated with poor prognosis. Pyruvate dehydrogenase (PDH) is the rate-limiting enzyme coupling glycolysis to mitochondrial tricarboxylic acid (TCA) cycle. Brain PDH activity is regulated by its phosphorylation status and other effectors. Phosphorylation of PDH E1α1 subunit by PDH kinase inhibits PDH activity while dephosphorylation of phosphorylated PDHE1α1 by PDH phosphatase (PDP1) restores PDH activity. In situ hybridization showed that PDP1 mRNA is highly expressed in the cerebral cortex, hippocampus and thalamus of rat. Controlled cortical impact (CCI) induced a significant increase in PDP1 mRNA expression in ipsilateral cerebral cortex at 4 h (P<0.05) and 24 h post CCI (P<0.01) that returned to basal level 72 h post CCI. PDP1 mRNA level increased transiently in ipsilateral hippocampal dentate gyrus and CA1-3 subfields 4 h post CCI (P<0.01) but decreased significantly 24 h and 72 h (P<0.01) post CCI, coinciding with a marked increase in neuronal apoptosis in ipsilateral hippocampus 24 h post CCI. PDP1 mRNA expression in thalamus and other subcortical regions decreased persistently post CCI. Contralateral CCI and craniotomy showed similar effects on PDP1 mRNA expression as ipsilateral CCI. Because GFAP mRNA expression was induced in brain regions where PDP1 expression was altered, further study should determine the potential relationship between astrocyte activation, PDP1 alteration, and pyruvate metabolism following TBI., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Dysregulated glucose metabolism and energy deficit is a characteristic of severe traumatic brain injury (TBI) but its mechanism remains to be fully elucidated. Phosphorylation of pyruvate dehydrogenase (PDH) is the rate-limiting mitochondria enzyme reaction coupling glycolysis to the tricarboxylic acid cycle. Phosphorylation of PDH E1α1 subunit catalyzed by PDH kinase (PDK) inhibits PDH activity, effectively decoupling aerobic glycolysis whereas dephosphorylation of phosphorylated PDHE1α1 by PDH phosphatase (PDP) restores PDH activity. We recently reported altered expression and phosphorylation of pyruvate dehydrogenase (PDH) following TBI. However, little is known about PDK and PDP involvement. We determined PDK (PDK1-4) and PDP isoenzyme (PDP1-2) mRNA and protein expression in rat brain using immunohistochemistry and in situ hybridization techniques. We also quantified PDK and PDP mRNA and protein levels in rat brain following TBI using quantitative real-time PCR and Western blot, respectively. Controlled cortical impact-induced TBI (CCI-TBI) and craniotomy significantly enhanced PDK1-2 isoenzyme mRNA expression level but significantly suppressed PDP1 and PDK4 mRNA expression after the injury (4h to 7days). CCI-TBI and craniotomy also significantly increased PDK1-4 isoenzyme protein expression but suppressed PDP1-2 protein expression in rat brain. In summary, the divergent changes between PDK and PDP expression indicate imbalance between PDK and PDP activities that would favor increased PDHE1α1 phosphorylation and enzyme inhibition contributing to impaired oxidative glucose metabolism in TBI as well as craniotomy., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Abstract Neurological dysfunction after traumatic brain injury (TBI) is caused by both the primary injury and a secondary cascade of biochemical and metabolic events. Since TBI can be caused by a variety of mechanisms, numerous models have been developed to facilitate its study. The most prevalent models are controlled cortical impact and fluid percussion injury. Both typically use "sham" (craniotomy alone) animals as controls. However, the sham operation is objectively damaging, and we hypothesized that the craniotomy itself may cause a unique brain injury distinct from the impact injury. To test this hypothesis, 38 adult female rats were assigned to one of three groups: control (anesthesia only); craniotomy performed by manual trephine; or craniotomy performed by electric dental drill. The rats were then subjected to behavioral testing, imaging analysis, and quantification of cortical concentrations of cytokines. Both craniotomy methods generate visible MRI lesions that persist for 14 days. The initial lesion generated by the drill technique is significantly larger than that generated by the trephine. Behavioral data mirrored lesion volume. For example, drill rats have significantly impaired sensory and motor responses compared to trephine or naïve rats. Finally, of the seven tested cytokines, KC-GRO and IFN-γ showed significant increases in both craniotomy models compared to naïve rats. We conclude that the traditional sham operation as a control confers profound proinflammatory, morphological, and behavioral damage, which confounds interpretation of conventional experimental brain injury models. Any experimental design incorporating "sham" procedures should distinguish among sham, experimentally injured, and healthy/naïve animals, to help reduce confounding factors.

Dysregulated brain glucose metabolism and lactate accumulation are seen following traumatic brain injury (TBI). The underlying molecular mechanism is poorly understood. Pyruvate dehydrogenase (PDH), the rate-limiting enzyme coupling cytosolic glycolysis to mitochondrial citric acid cycle, plays a critical role in maintaining homeostasis of brain glucose metabolism. PDH activity is maintained by the expression of its E1alpha1 subunit 1 (PDHE1alpha1) and is inhibited by the phosphorylation of PDHE1alpha1 (p-PDHE1alpha1). We hypothesized that PDHE1alpha1 expression and phosphorylation was altered in rat brain following controlled cortical impact (CCI)-induced TBI. Compared to naïve controls (=100%), PDHE1alpha1 protein decreased significantly ipsilateral to CCI (62%, P<0.05; 75%, P<0.05; 57%, P<0.05; and 39%, P<0.01) and contralateral to CCI (77%, 78%, 78% and 36% P<0.01) at 4h, 24h, 3- and 7-day post-CCI, respectively. PDHE1alpha1 protein phosphorylation level also decreased significantly ipsilateral to CCI (31%, P<0.01; 102%, P>0.05; 64%, P<0.05; and 14%, P<0.01) and to contralateral CCI (35%, 74%, P<0.05; 60%, P<0.05; 20%, P<0.01) at 4h, 24h, 3- and 7-day post-CCI, respectively. Similar reduction in PDHE1alpha1 and p-PDHE1alpha1 protein was found in the craniotomy (sham CCI) group. TBI-induced change in PDHE1alpha1 expression and phosphorylation could alter brain PDH activity and glucose metabolism.

Early growth response gene-1 (Egr-1) is up-regulated by hypoxia-ischemia (HI) and reactive oxygen species (ROS) in adult animals, functioning as a master switch in inflammation and thrombogenesis. We hypothesized that resuscitation from HI with 100% O2 would result in greater Egr-1 expression, ROS, and cell death (CD) in the brains of newborn piglets than 21% O2. Two control groups breathed 21% O2 for 1 h followed by 21% or 100% O2 for 1 h. Two HI groups underwent carotid artery occlusion and breathed 8-12% O2 for 1 h followed by occlusion release and 21% or 100% O2 for 1 h. Brain Egr-1 mRNA and protein were analyzed via quantitative PCR and Western blot. CD and ROS were measured by fluorescence microscopy. Egr-1 mRNA expression increased throughout the brain in response to HI with regional heterogeneity, but protein levels did not. Resuscitation with 100% oxygen did not cause any additional Egr-1 mRNA, Egr-1 protein, CD, or ROS production as compared with 21% oxygen. There was no difference in physiologic recovery after HI with room air compared with 100% O2 resuscitation. However, 100% O2 administration was associated with increased CD in the brainstem independent of HI. Therefore, 100% O2 may have been toxic to some brainstem cells and potentially have significance in long-term neurologic sequelae seen after neonatal HI/resuscitation. Egr-1 protein levels may be tightly regulated in an attempt to diminish neurotoxicity or to enhance plasticity at this stage of development.

The discrete papular form of lichen myxedematosus (LM) is a rare idiopathic skin disorder. We present a case of this type in an 80-year-old African American woman. She was treated with pimecrolimus cream, which resulted in symptomatic relief. To our knowledge, this is the first report of the discrete papular form of LM occurring in an African American, as well as the first report on the disorder's response to pimecrolimus therapy. We also review the English medical literature on this rare disease and examine and summarize the findings.

Keratosis punctata palmoplantaris (KPPP) is a rare genodermatosis with an autosomal-dominant pattern of inheritance. We report the case of a 61-year-old woman who presented with a long history of multiple symptomatic hyperkeratotic papules on the palms and soles. In addition, we review the literature and present the current classification of the heterogeneous group of punctate palmoplantar keratoses, the cutaneous and histologic findings, the differential diagnosis, the possible association with various anomalies including malignancies, and the various treatment options.

Adult thyroid cancers express IGF and IGF-I receptor (IGF-I-R), but the clinical impact is not clear. No previous study examined any childhood thyroid cancers that are well-differentiated and have a favorable prognosis. We used immunohistochemistry to determine IGF-I and IGF-I-R in 23 papillary thyroid cancers (PTC) and 6 follicular thyroid cancers (FTC) from children and adolescents. IGF-I was detected in 45% and IGF-I-R in 43% of cancers. IGF-I and IGF-I-R were found more often in PTC (IGF-I = 9/23, IGF-I-R = 8/19) than normal surrounding thyroid (IGF-I = 0/10, p = 0.032 and IGF-I-R = 0/10, p = 0.030). There were too few FTC to support independent statistical analysis, but IGF-I was found in 4 of 6 FTC (0/10 normal), and IGF-I-R was found in 2 of 4 FTC (0/10 normal). IGF-I-R staining was more intense in aggressive (invasive, metastatic, recurrent, or persistent) than indolent tumors (confined to the gland, p = 0.029). Over time, six tumors recurred, five of which expressed IGF-I-R. Overall recurrence risk was significantly greater for tumors that expressed IGF-I-R (p = 0.05) but only approached statistical significance (p = 0.08) when disease-free survival was determined. We conclude that differentiated thyroid cancers of children and adolescents express IGF-I and IGF-I-R. Tumors that express IGF-I-R are more likely to show aggressive clinical features (invasion beyond the capsule, metastasis, or recurrence) and persistence despite treatment.

Hypoglycemic brain damage has been associated with high levels of the excitatory amino acids (EAA) aspartate and glutamate in the newborn and adult. We hypothesized that newborn piglet EAA would be different from those of older pigs when stressed with severe insulin-induced hypoglycemia (<30 mg/dl). Brain EAA were measured in piglets and adolescent pigs via microdialysis. Eleven of 12 newborn normoglycemic piglets had no detectable baseline levels (<0.5 microM) of EAA, while pigs had aspartate and glutamate concentrations of 1.78 +/- 0.44 and 3.43 +/- 1.14 microM (mean +/- SEM), respectively. Piglet aspartate and glutamate concentrations reached but did not significantly exceed normoglycemic pig levels after 2 h with plasma glucose values < or =20 mg/ml. Elevations in EAA were only detected in piglets whose EEG activity ceased. Aspartate and glutamate concentrations did not increase in insulin-treated pigs nor in control animals. We speculate that newborns with blood glucose less than clinically acceptable values (35 mg/dl) may be protected from EAA-associated neuronal damage during acute hypoglycemia. Lower normoglycemic and hypoglycemic levels of EAA in newborns when compared to older pigs provide this protection., (Copyright 2001 S. Karger AG, Basel)

The purpose of the present study was to investigate the role of nitric oxide (NO) in modulating the resting vascular tone of the choroidal and anterior uveal circulations and the autoregulatory gain of the retina. Blood flow (ml/min/100 gm dry weight) to tissues was determined in 23 anesthetized piglets (3-4 kg) using radiolabelled microspheres. Ocular Perfusion Pressure (OPP) was defined as mean arterial pressure minus intraocular pressure (IOP) which was manipulated hydrostatically by cannulation of the anterior eye chamber. The OPP was decreased during intravenous infusion (30 mg/kg/hr) of either the NO-synthase inhibitor L-NAME or the inactive enantiomer D-NAME. Blood flows were determined at OPP of 60, 50, 40, 30, and 20 mmHg following initial ocular blood flow measurements. Mean initial choroidal and anterior uveal blood flows with L-NAME showed a 47+/-12% and a 43+/-6% reduction (p <.001), respectively. Mean choroidal blood flows were significantly reduced (p<.01) in the L-NAME treated animals at an OPP of 60 and 50 when compared to D-NAME. Uveal blood flows were linearly correlated with OPP in the L-NAME and D-NAME treated groups. Uveal blood flow was greater following exogenous administration of L-arginine (180 mg/kg). Mean initial retinal blood flow did not differ significantly in either group. Retinal blood flow with L-NAME was reduced at OPP of 60 mmHg and below compared to D-NAME (p<.05). The degree of compensation in the autoregulatory gain of the retinal vasculature was reduced in the presence of L-NAME at an OPP of 50 mmHg and below compared to D-NAME. These data support the hypothesis that NO may be a primary mediator in maintaining resting vascular tone to the choroid and anterior uvea in vivo and that NO blockade reduces the degree of compensation in the autoregulatory gain of the retinal vasculature within a specific range of ocular perfusion pressures.

The US National Institute on Alcohol Abuse and Alcoholism (NIAAA) recognizes two forms of problematic drinking: 'willful alcohol abuse', a behavioural problem, and 'alcohol dependence', a true medical disorder, which includes a genetic component, that can be scientifically understood and medically treated. Current biomedical research has linked specific neurotransmitters to certain effects of alcohol that are unique to alcoholics. An inadequate flow of information between the victims of alcoholism, researchers, and the public has impeded further exploration of the genetic and neurochemical underpinnings of alcohol dependence. This is due in part to continuing misconceptions about alcohol dependence, not only among the general public, but within the scientific and medical communities as well. Consequently. compared to other diseases, research in alcohol dependence is proceeding with less urgency despite its relatively high economic and social costs. Incorporating the input of recovering alcoholics into future research agendas can help to ensure relevant scientific investigation and the delivery of a more accurate and consistent message to the public with regard to alcoholism.

Objective: To determine whether tolazoline reduces pulmonary vascular resistance (PVR) by means of endogenous nitric oxide production., Design: Thirty newborn lambs (2 to 7 days of age) were anesthetized with pentobarbital, and their lungs were ventilated through an endotracheal tube. Intravascular catheters were placed in the left ventricle, descending aorta, right atrium, and pulmonary artery for continuous monitoring of intravascular pressures. Cardiac output was measured with radiolabeled microspheres. Arterial carbon dioxide pressure and pH were maintained in a normal range throughout the experiments. Animals were randomly assigned to the following groups: group 1, lungs ventilated with a hypoxic gas mixture and administered tolazoline; group 2, given N omega-nitro-L-arginine (L-NA) (5 mg/min intravenously for 60 minutes) and tolazoline; group 3, given L-NA with hypoxia and tolazoline. Acetylcholine (0.5 microgram/kg) was injected into the right atrium to assess pulmonary nitric oxide synthase activity before and after the L-NA infusion. Data were analyzed by analysis of variance., Results: L-NA inhibited the acetylcholine-induced reduction in mean pulmonary artery pressure (MPAP) by more than 75%. Hypoxia and L-NA increased both MPAP and PVR. Tolazoline produced immediate reductions in both MPAP and PVR in all three groups (group 1, 27% +/- 3% and 50% +/- 5%; group 2, 34% +/- 5% and 50% +/- 6%; and group 3, 31% +/- 4% and 46% +/- 5%, respectively)., Conclusions: These results suggest that tolazoline produces vasodilation independent of nitric oxide production. Understanding the mechanism by which tolazoline produces pulmonary vasodilation may provide insight into the clinical use of this drug and information regarding other potential endogenous mediators of pulmonary vasomotor tone in the neonate.

The ability of newborn animals to autoregulate cerebral blood flow (CBF) has been documented. Most studies of the cerebral vascular response to hypotension utilize hemorrhage, generally confounded with anemia. We studied the cerebral blood flow and metabolic response of chloralose and urethane anesthetized newborn lambs to regulated hypotension. Lambs (< or = 7 days old) were catheterized for radioactive microsphere determinations of CBF. The dorsal sagittal sinus was catheterized to obtain cerebral blood samples for the calculation of oxygen uptake. Cerebral perfusion pressure was reduced in a step-wise fashion with hemorrhagic hypotension. Animals spontaneously became anemic with hypotension (AH; n = 8). In a group of animals (NH; n = 6), anemia was prevented by infusion of autologous red blood cells. Arterial pressure was reduced from control to 50, 40, and 30 mm Hg. In the AH group hematocrit fell 37% but was not different from control in the NH group. Total CBF was maintained in all groups. The lowest perfusion pressures studied were 25 +/- 1 and 22 +/- 1 mm Hg in AH and NH groups respectively. Oxygen delivery decreased (37%) only in the AH group, secondary to anemia. Calculated oxygen consumption was maintained in the AH group but increased (approximately 50%) in the NH group at 50 and 40 mm Hg. The ratio of oxygen uptake to oxygen delivery (fractional oxygen extraction) increased linearly in both groups as arterial pressure decreased. The major findings of these experiments are (i) The anesthetized newborn lamb can maintain CBF when perfusion pressure falls to 25 mm Hg and this autoregulatory capacity (classically defined) is not dependent on a change in hematocrit and, presumably, viscosity; (ii) Cerebral hypotension, anemic or not, appears to be accompanied by an increase in fractional extraction of oxygen.

Study Objective: To compare the pulmonary and systemic vascular responses to intravenously (IV) and endotracheally (ET) administered tolazoline (Tz) in newborn lambs with hypoxia-induced pulmonary hypertension., Design: Randomized, controlled study design., Methods: Twenty lambs, 2 to 7 days of age, were anesthetized, intubated, and surgically catheterized for continuous physiologic monitoring and cardiac output measurements using radiolabeled microspheres. After a postoperative stabilization period, the lambs were ventilated with a hypoxic gas mixture which was titrated to increase mean pulmonary artery pressure (MPAP) 30% to 50% above baseline. Each animal was randomly assigned to receive either IV-Tz (2 mg/kg), ET-Tz (4 mg/kg), or ET-saline (Sal, control group)., Results: ET-Tz significantly (P < .05) reduced MPAP, PVRI (pulmonary vascular resistance index), MPAP/mean artery pressure (MAP) and PVRI/systemic vascular resistance index (SVRI), but not SVRI. IV-Tz lowered (P < .05) MPAP, PVRI, and PVRI/SVRI but also produced significant reductions in MAP and SVRI while only transiently decreasing MPAP/MAP: MPAP/MAP and PVRI/SVRI ratios were consistently lower in the ET-Tz animals than either the IV-Tz or ET-Sal animals., Conclusions: Our results suggest that ET-Tz produced a more selective pulmonary vascular response than IV-Tz and may warrant further investigation for potential clinical applications.

The feasibility of stenting the ductus arteriosus with a balloon-expandable vascular endoprosthesis was tested in 8 newborn lambs. Tantalum wire and stainless steel mesh coronary stents were implanted antegrade or retrograde by percutaneous transfemoral catheterization. One lamb died during the procedure from perforation of the aorta. In 7 lambs, the ductus arteriosus was crossed using endhole catheters and wires, and stents mounted on angioplasty catheters were expanded in the ductus arteriosus. Six lambs had successful implantation and had maintained a sizeable patent ductus arteriosus at 2 h. We conclude that the feasibility of percutaneous stenting of the newborn ductus was demonstrated. By providing patency of the ductus arteriosus, stents may offer nonsurgical alternatives for palliation of cyanotic congenital heart disease and hypoplastic left heart syndrome.

We studied the effects of positive end expiratory pressure (PEEP) on vascular pressure flow relationships in atelectatic lobes in the closed-chest pigs and compared our results to measurements we previously obtained in sublobar atelectasis. Regional hemodynamic responses to lung inflation were significantly different between lobes and sublobar regions. PEEP caused marked increase in the fraction of cardiac output perfusing the atelectatic lobe from 16.5 +/- 2.0% (SE) to 32.5 +/- 2.0% at similar pulmonary vascular transmural pressures. In contrast, similar levels of PEEP failed to redistribute blood flow to the atelectatic sublobar regions. We propose that distortion of the sublobar region with inflation of the surrounding lung may be responsible for the failure of redistribution of pulmonary blood flow with application of PEEP.

Regional central nervous system and peripheral hemodynamic effects of the intrathecal (i.t.) administration of a substance P (SP) receptor antagonist, [D-Arg1, D-Pro2, D-Trp7,9, Leu11]-substance P ([D-Arg]-SP), were studied in anesthetized rats. It was found that [D-Arg]-SP (3.3 nmol i.t.) reduced mean arterial pressure and cardiac output due to a reduction in stroke volume. Total peripheral resistance was not altered. Whereas most vascular beds showed no alterations in vascular resistance, a renal vasoconstriction was noted. The hypotensive effect of [D-Arg]-SP was blocked by phentolamine (10 mg/kg i.v.) but not by propranolol (1 mg/kg i.v.). In the absence of changes in vascular arterial resistance due to [D-Arg]-SP, it appears that a change in venous return may contribute to the [D-Arg]-SP-induced reduction in stroke volume. These data provide evidence that a spinal cord SP system may tonically affect sympathetic neurons controlling venous, but not arterial, vasomotor tone. [D-Arg]-SP (i.t.) did not alter brain blood flow but significantly decreased blood flow in the thoracolumbar spinal cord 15 to 20 min after administration. The reduction in spinal cord flow did not appear to be responsible for the [D-Arg]-SP-induced hypotension because kainic acid (i.t.), an agent that interacts with glutamate receptors, produced similar pressor responses in the presence and absence of [D-Arg]-SP. In addition, whereas the pressor effect of low doses of a SP agonist [pGlu5, MePhe8, MeGly9]-substance P (5-11) were blocked by [D-Arg]-SP, a higher dose produced the typical pressor effect.(ABSTRACT TRUNCATED AT 250 WORDS)

A potential role for cerebrovascular nerves containing vasoactive intestinal polypeptide (VIP) was examined in 24 anesthetized, ventilated dogs. Cerebral blood flow (CBF) was measured by either the cerebral venous outflow or microsphere method. Plasma VIP concentration was measured by radioimmunoassay. Hypercapnia (5% and 10% CO2) and hypoxia (7% O2) produced significant increases in cerebral venous outflow, but had no affect on arterial or cerebral venous VIP concentrations. Measurements of VIP in cerebrospinal fluid (CSF) made during 5% and 8% CO2 breathing also were not different from control values. VIP produced large dose-dependent increases in common carotid artery and temporalis muscle blood flow when injected or infused intraarterially; however, VIP had no effect on total or regional cerebral blood flow (rCBF) within the brain when administered in a similar manner. Unilateral perfusion of the cerebral ventricles with VIP produced significant increases (range: 11-80%) in rCBF. These data are consistent with the possibility that local release of VIP from perivascular nerve endings could affect CBF. The unresponsiveness of canine cerebral vessels to blood-borne VIP may be due to the blood-brain barrier, since VIP dilates cerebral vessels when the barrier is bypassed by intraventricular infusion. These studies do not support the hypothesis that CBF changes induced during hypercapnia or hypoxia are mediated by VIP.

We studied the effects of sublobar atelectasis on regional blood flow in anesthetized paralyzed pigs. Following the washout of nitrogen from the lung with oxygen, a sublobar airway was obstructed and a peripheral segment of lung allowed to collapse. Blood flow to the atelectatic region fell from a control of 140.0 +/- 20.5 to 16.6 +/- 2.9 ml/(min . g). Basilar regions that became atelectatic spontaneously during the course of the studies had similar decreases in blood flow. Inflation of the surrounding lung by the application of positive end-expiratory pressure failed to increase blood flow and vascular conductance within the atelectatic regions. These results indicate that mechanical and hypoxic effects on vessels perfusing sublobar atelectatic regions limit the effects of interdependence from the surrounding lung. Furthermore, with inflation of the surrounding lung, increases in pulmonary shunting of blood are small.

Laser-Doppler flowmetry (LDF) is a non-invasive method for continuous on-line monitoring of microvascular blood flow. LDF has previously been validated with established methods in various tissues, yet its validity and resolution in the central nervous system (CNS) remain unclear. We compared LDF with the microsphere method (MS) using two independent laser probes placed on the dorsal lumbar spinal cord (L5 laminectomy) of anesthetized rabbits (n = 9). After base-line flow measurements, spinal cord blood flow (SCBF) was increased (up to 50%) with phenylephrine (10-80 micrograms.kg-1.min-1 iv) and decreased (up to 50%) with chlorisondamine (10 mg/kg iv) or other stimuli. The percentage changes of lumbar SCBF and vascular resistance (VR) from the base line obtained by LDF and MS excellently agreed (rBF = 0.86, rVR = 0.94, P less than 0.0001). LDF estimated also the absolute SCBF values parallel to MS (r = 0.77, P less than 0.001). In conclusion, the validity of LDF in estimating the SCBF and dynamic changes of BF and VR is confirmed. Therefore, LDF may prove useful for monitoring CNS microcirculation in normal or pathophysiological states.

In the present study we sought evidence for the hypothesis that norepinephrine (NE) can cause constriction of lymph vessels in the canine forelimb perfused at constant flow. Mechanical venous compression (small-vein pressure approximately equal to 45 mmHg), intra-arterial infusion of histamine (16 micrograms base/min), and intra-arterial infusion of NE (16 micrograms base/min) caused the limbs to gain weight at similar rates due to edema formation; the first two maneuvers caused a sustained increase in skin lymph flow, but the increase in lymph flow with NE was only transient. Similar changes were seen during infusion of NE at 1 and 2 micrograms/min, and studies with radioactive microspheres indicated that NE increased capillary blood flow. When venous pressure was elevated and held constant at 45 mmHg. NE (4 micrograms base/min ia) antagonized and phentolamine (400 micrograms/min ia) potentiated the increase in skin lymph flow. Finally, NE (16 micrograms base/min ia) caused a reduction in histamine (16 micrograms base/min)-elevated skin lymph flow, despite the fact that capillary pressure was greatly increased due to active venous constriction. We conclude that intra-arterial infusion of norepinephrine in the dog forelimb perfused at constant flow causes constriction of lymphatic trunk vessels in skin, resulting in increased resistance to the flow of lymph.

To examine the possible role of adenosine in the vasoactivity of acetate, acetate and adenosine were injected into the renal artery of the dog while measuring renal blood flow. Low (9-28 mg) doses of acetate produced vasodilation, but higher doses (28-94 mg), like adenosine, produced vasoconstriction followed by vasodilation. Theophylline, a competitive inhibitor of the vascular action of adenosine, inhibited the vasodilator action of adenosine but not that of acetate. Secondly, theophylline inhibited the vasoconstrictor effect of adenosine and acetate but the latter to a much lesser extent. These findings suggest that adenosine mediates the vasoconstriction effect of acetate in the canine kidney.

Regional CNS and peripheral hemodynamic effects of the intrathecal (i.t.) administration of a substance P receptor agonist, [pGlu5,MePhe8,MeGly9]-substance P5-11 ([DiMe]-SP), were studied in anesthetized rats with the radioactive microsphere technique. It was previously shown that [DiMe]-SP caused a sympathetically mediated increase in mean arterial pressure (MAP) by an action within the spinal cord. In this study, [DiMe]-SP (5 and 33 nmol, i.t.) increased MAP. The 5 nmol dose increased resistance in cutaneous, renal, splanchnic, and adrenal vascular beds but decreased resistance, and increased blood flow in some skeletal muscle beds. Total peripheral resistance was unchanged. The 33 nmol dose increased resistance in each peripheral vascular bed analyzed and increased total peripheral resistance. Whereas each dose increased heart rate, stroke volume and cardiac output were unchanged with the 5 nmol dose and were reduced with the 33 nmol dose. Neither dose of [DiMe]-SP significantly altered regional brain or spinal cord blood flows. These data show that the i.t. administration of the SP agonist, [DiMe]-SP, increased vascular tone to most peripheral vascular beds whereas the low dose caused a vasodilation of skeletal muscle. These effects are consistent with the notion of a dose-related activation of SP receptors in the spinal cord affecting sympathetic outflow to the adrenals and to the vasculature.