Impulse-response studies on tracer doses of [C-14]lignocaine and its multiple metabolites in the perfused rat liver

The outflow-concentration-time profiles for lignocaine (lidocaine) and its metabolites have been measured after bolus impulse administration of [C-14]lignocaine into the perfused rat liver. Livers from female Sprague-Dawley rats were perfused in a once-through fashion with red-blood-cell-free Krebs-Henseleit buffer containing 0 or 2% bovine serum albumin. Perfusate flow rates of 20 and 30 mL min(-1) were used and both normal and retrograde flow directions were employed. Significant amounts of metabolite were detected in the effluent perfusate soon after lignocaine injection. The early appearance of metabolite contributed to bimodal outflow profiles observed for total C-14 radioactivity. The lignocaine outflow profiles were well characterized by the two-compartment dispersion model, with efflux rate << influx rate. The profiles for lignocaine metabolites were also characterized in terms of a simplified two-compartment dispersion model. Lignocaine was found to be extensively metabolized under the experimental conditions with the hepatic availability ranging between 0.09 and 0.18. Generally lignocaine and metabolite availability showed no significant change with alterations in perfusate flow rate from 20 to 30 mt min(-1) or protein content from 0 to 2%. A significant increase in lignocaine availability occurred when 1200 mu M unlabelled lignocaine was added to the perfusate. Solute mean transit times generally decreased with increasing flow rate and with increasing perfusate protein content. The results confirm that lignocaine pharmacokinetics in the liver closely follow the predictions of the well-stirred model. The increase in lignocaine availability when 1200 mu M unlabelled lignocaine was added to the perfusate is consistent with saturation of the hydroxylation metabolic pathways of lignocaine metabolism.

Differential perturbation of neuronal and glial glutamate transport systems in retinal ischaemia

Glutamate is the major excitatory neurotransmitter in the retina and is removed from the extracellular space by an energy-dependent process involving neuronal and glial cell transporters. The radial glial Muller cells express the glutamate transporter, GLAST, and preferentially accumulate glutamate. However, during an ischaemic episode, extracellular glutamate concentrations may rise to excitotoxic levels. Is this catastrophic rise in extracellular glutamate due to a failure of GLAST? Using immunocytochemistry, we monitored the transport of the glutamate transporter substrate, D-aspartate, in the retina under normal and ischaemic conditions. Two models of compromised retinal perfusion were compared: (1) Anaesthetised rats had their carotid arteries occluded for 7 days to produce a chronic reduction in retinal blood flow. Retinal function was assessed by electroretinography. D-aspartate was injected into the eye for 45 min, Following euthanasia, the retina was processed for D-aspartate. GLAST and glutamate immunocytochemistry. Although reduced retinal perfusion suppresses the electroretinogram b-wave, neither retinal histology, GLAST expression, nor the ability of Muller cells to uptake D-aspartate is affected. As this insult does not appear to cause excitotoxic neuronal damage, these data suggest that GLAST function and glutamate clearance are maintained during periods of reduced retinal perfusion. (2) Occlusion of the central retinal artery for 60 min abolishes retinal perfusion, inducing histological damage and electroretinogram suppression. Although GLAST expression appears to be normal. its ability to transport D-aspartate into Muller cells is greatly reduced. Interestingly, D-aspartate is transported into neuronal cells, i.e. photoreceptors, bipolar and ganglion cells. This suggests that while GLAST is vitally important for the clearance of excess extracellular glutamate, its capability to sustain inward transport is particularly susceptible to an acute ischaemic attack. Manipulation of GLAST function could alleviate the degeneration and blindness that result from ischaemic retinal disease. (C) 2001 Elsevier Science Ltd, All rights reserved.

Neonatal hepatic drug elimination

After the transition from in utero to newborn life, the neonate becomes solely reliant upon its own drug clearance processes to metabolise xenobiotics. Whilst most studies of neonatal hepatic drug elimination have focussed upon in vitro expression and activities of drug-metabolising enzymes, the rapid physiological changes in the early neonatal period of life also need to be considered. There are dramatic changes in neonatal liver blood how and hepatic oxygenation due to the loss of the umbilical blood supply, the increasing portal vein blood flow, and the gradual closure of the ductus venosus shunt during the first week of life. These changes which may well affect the capacity of neonatal hepatic drug metabolism. The hepatic expression of cytochromes P450 1A2, 2C, 2D6, 2E1 and 3A4 develop at different rates in the postnatal period, whilst 3A7 expression diminishes. Hepatic glucuronidation in the human neonate is relatively immature at birth, which contrasts with the considerably more mature neonatal hepatic sulfation activity. Limited in vivo studies show that the human neonate can significantly metabolise xenobiotics but clearance is considerably less compared with the older infant and adult. The neonatal population included in pharmacological studies is highly heterogeneous with respect to age, body weight, ductus venosus closure and disease processes, making it difficult to interpret data arising from human neonatal studies. Studies in the perfused foetal and neonatal sheep liver have demonstrated how the oxidative and conjugative hepatic elimination of drugs by the intact organ is significantly increased during the first week of life, highlighting that future studies will need to consider the profound physiological changes that may influence neonatal hepatic drug elimination shortly after birth.

MRI based diffusion and perfusion predictive model to estimate stroke evolution

In this study we present a novel automated strategy for predicting infarct evolution, based on MR diffusion and perfusion images acquired in the acute stage of stroke. The validity of this methodology was tested on novel patient data including data acquired from an independent stroke clinic. Regions-of-interest (ROIs) defining the initial diffusion lesion and tissue with abnormal hemodynamic function as defined by the mean transit time (MTT) abnormality were automatically extracted from DWI/PI maps. Quantitative measures of cerebral blood flow (CBF) and volume (CBV) along with ratio measures defined relative to the contralateral hemisphere (r(a)CBF and r(a)CBV) were calculated for the MTT ROIs. A parametric normal classifier algorithm incorporating these measures was used to predict infarct growth. The mean r(a)CBF and r(a)CBV values for eventually infarcted MTT tissue were 0.70 +/-0.19 and 1.20 +/-0.36. For recovered tissue the mean values were 0.99 +/-0.25 and 1.87 +/-0.71, respectively. There was a significant difference between these two regions for both measures (P

An investigation of symptom-specific muscle hyperreactivity in upper extremity cumulative trauma disorder

Objective: The study examined symptom-specific muscle hyperreactivity in patients with chronic pain with upper limb cumulative trauma disorder (CTD). Design: Four tasks were presented in counterbalanced order and included neutral, general stressor, personal stressor, and pain stressor tasks. Ratings of stressfulness and recordings of skin conductance level confirmed the effectiveness of the experimental manipulations in inducing stress experiences for all subject groups. Setting: The study was conducted in a university research center. Patients: Thirty patients with CTD were matched as closely as possible for age and gender to control groups of chronic low back pain, arthritis, and pain-Free subjects Outcome Measures: Surface electromyograph recordings were taken from the frontalis, forearm flexors, trapezius, and lower back during baseline and tasks. Results: The study found no evidence of greater muscle tension increases or extended duration of return to baseline for the CTD or low back pain patients at any of the muscle sites for any of the tasks in comparison to control groups. Conclusions: The results indicate that symptom-specific psychophysiological responses may be limited to certain subgroups rather than being characteristic of chronic musculoskeletal pain patients in general.

Influence of wall stress and left ventricular geometry on the accuracy of Dobutamine stress Echocardiography

OBJECTIVES The goal of this study was to determine whether wall stress at rest and during stress could explain the influence of left ventricular (LV) morphology on the accuracy of dobutamine stress echocardiography (DSE). BACKGROUND The sensitivity of DSE appears to be reduced in patients with concentric remodeling, but the cause of this finding is unclear. METHODS We studied 161 patients without resting wall motion abnormalities who underwent DSE and coronary angiography. Patients were classified into four groups according to relative wan thickness (normal

Determinants of tissue Doppler measures of regional diastolic function during dobutamine stress echocardiography

Background Diastolic dysfunction induced by ischemia may alter transmitral blood flow, but this reflects global ventricular function, and pseudonormalization may occur with increased preload. Tissue Doppler may assess regional diastolic function and is relatively load-independent, but limited data exist regarding its application to stress testing. We sought to examine the stress response of regional diastolic parameters to dobutomine echocardiography (DbE). Methods Sixty-three patients underwent study with DbE: 20 with low probability of coronary artery disease (CAD) and 43 with CAD who underwent angiography. A standard DbE protocol was used, and segments were categorized as ischemic, scar, or normal. Color tissue Doppler was acquired at baseline and peak stress, and waveforms in the basal and mid segments were used to measure early filling (Em), late filling (Am), and E deceleration time. Significant CAD was defined by stenoses >50% vessel diameter. Results Diastolic parameters had limited feasibility because of merging of Em and Am waves at high heart rates and limited reproducibility. Nonetheless, compared with normal segments, segments subtended with significant stenoses showed a lower Em velocity at rest (6.2 +/- 2.6 cm/s vs 4.8 +/- 2.2 cm/s, P < .0001) and peak (7.5 +/- 4.2 cm/s vs 5.1 +/- 3.6 cm/s, P < .0001), Abnormal segments also showed a shorter E deceleration time (51 +/- 27 ms vs 41 +/- 27 ms, P = .0001) at base and peak. No changes were documented in Am. The same pattern was seen with segments identified as ischemic with wall motion score. However, in the absence of ischemia, segments of patients with left ventricular hypertrophy showed a lower Em velocity, with blunted Em responses to stress. Conclusion Regional diastolic function is sensitive to ischemia. However, a number of practical limitations limit the applicability of diastolic parameters for the quantification of stress echocardiography.

Vascular dysfunction and heart failure: Epiphenomenon or etiologic agent?

Endothelial function plays a key role in the local regulation of vascular tone. Alterations in endothelial function may result in impaired release of endothelium-derived relaxing factors or increased release of endothelium-derived contracting factors. Heart failure may impair endothelial function by means of reduced synthesis and release of nitric oxide (NO) or by increased degradation of NO and increased production of endothelin-1. Endothelial dysfunction may worsen heart function by means of peripheral effects, causing increased afterload and central effects such as myocardial ischemia and inducible nitric oxide synthase (iNOS)-induced detrimental effects. Evidence from clinical studies has suggested that there is a correlation between decreased endothelial function and increasing severity of congestive heart failure (CHF). Treatments that improve heart function may also improve endothelial dysfunction. The relationship between endothelial dysfunction and heart failure may be masked by the stage of endothelial dysfunction, the location of vessels being tested, and the state of endothelial-dependent vasodilatation response.

A compartmental model of hepatic disposition kinetics: 1. Model development and application to linear kinetics

The conventional convection-dispersion model is widely used to interrelate hepatic availability (F) and clearance (Cl) with the morphology and physiology of the liver and to predict effects such as changes in liver blood flow on F and Cl. The extension of this model to include nonlinear kinetics and zonal heterogeneity of the liver is not straightforward and requires numerical solution of partial differential equation, which is not available in standard nonlinear regression analysis software. In this paper, we describe an alternative compartmental model representation of hepatic disposition (including elimination). The model allows the use of standard software for data analysis and accurately describes the outflow concentration-time profile for a vascular marker after bolus injection into the liver. In an evaluation of a number of different compartmental models, the most accurate model required eight vascular compartments, two of them with back mixing. In addition, the model includes two adjacent secondary vascular compartments to describe the tail section of the concentration-time profile for a reference marker. The model has the added flexibility of being easy to modify to model various enzyme distributions and nonlinear elimination. Model predictions of F, MTT, CV2, and concentration-time profile as well as parameter estimates for experimental data of an eliminated solute (palmitate) are comparable to those for the extended convection-dispersion model.

Endogenous endothelin-1 limits exercise-induced vasodilation in hypertensive humans

Essential hypertension is a common disorder, associated with increased endothelin-l-mediated vasoconstrictor tone at rest. We hypothesized that increased vasoconstrictor activity of endothelin-1 might explain why the normal decrease in peripheral vascular resistance in response to exercise is attenuated in hypertensive patients. Therefore, we investigated the effect of endothelin A (ETA) receptor blockade on the vasodilator response to handgrip exercise. Forearm blood flow responses to handgrip exercise (15%, 30%, and 45% of maximum voluntary contraction) were assessed in hypertensive patients and matched normotensive subjects, before and after intra-arterial infusions of the ETA receptor antagonist BQ-123; a control dilator, hydralazine; and placebo (saline). Preinfusion (baseline) vasodilation in response to exercise was significantly attenuated at each workload in hypertensive patients compared with normotensive subjects. Intra-arterial infusions of hydralazine and saline did not increase the vasodilator response to exercise in either hypertensives or normotensives at any workload. The vasodilator response to exercise was markedly enhanced after BQ-123 at the 2 higher workloads in hypertensives (157 +/- 48%, P < 0.01; 203 &PLUSMN; 58%, P < 0.01) but not in normotensives. This suggests that the impaired vasodilator response to exercise in hypertensive patients is, at least in part, a functional limitation caused by endogenous ETA receptor-mediated vasoconstriction. Treatment with endothelin receptor antagonists may, therefore, increase exercise capacity in essential hypertension.

Working memory correlates of three symptom clusters in schizophrenia

This study was designed to examine whether discrete working memory deficits underlie positive, negative and disorganised symptoms of schizophrenia. Symptom dimension ratings were assigned to 52 outpatients with schizophrenia (ICD-10 criteria), using items drawn from the Positive and Negative Syndrome Scale (PANSS). Linear regression and correlational analyses were conducted to examine whether symptom dimension scores were related to performance on several tests of working memory function. Severity of negative symptoms correlated with reduced production of words during a verbal fluency task, impaired ability to hold letter and number sequences on-line and manipulate them Simultaneously, reduced performance during a dual task, and compromised visuospatial working memory under distraction-free conditions. Severity of disorganisation symptoms correlated with impaired visuospatial working memory under conditions of distraction, failure of inhibition during a verbal fluency task, perseverative responding on a test of set-shifting ability, and impaired ability to judge the veracity of simple declarative statements. Severity of positive symptoms was uncorrelated with performance on any of the measures examined. The present study provides evidence that the positive, negative and disorganised symptom dimensions of the PANSS constitute independent clusters, associated with unique patterns of working memory impairment. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

Limb constriction as a complication of intra-uterine vesico-amniotic shunt: Fetoscopic release

Complete fetal bladder outlet obstruction was first diagnosed in a fetus at 13.5 weeks. After sequential vesico-centesis had shown good renal function, a vesico-amniotic shunt was inserted at 17 weeks with a Rodeck catheter. The procedure was successful and amniotic fluid volume re-accumulated to normal levels. A detailed scan at 20 weeks showed that the distal free end of the catheter was wound round the left fetal thigh. As the fetus grew, there was progressive constriction of the fetal thigh by the catheter. By 29 weeks, Doppler blood flow changes to the left leg were apparent. Fetoscopic surgery was performed at 30 weeks to release the constriction. The catheter was divided successfully, but the divided end of the shunt subsequently retracted into the fetal abdomen, producing urinary ascites, bilateral hydroureter and hydronephrosis. The baby was delivered at 31.5 weeks in good condition. Endoscopic resection of anterior and posterior urethral valves was performed at 6 months of age. At 2 years, the child has normal renal function, growth parameters and developmental milestones. Mild indentation of the left thigh was still apparent, although there was no functional impairment. Copyright (C) 2002 S. Karger AG, Basel.

The therapeutic potential of dopamine modulators on the cardiovascular and renal systems

In the periphery, physiological dopamine increases renal blood flow, decreases renal resistance and acts on the kidney tubule to enhance natriuresis and diuresis. The loss of dopamine function may be involoved in the deterioration in kidney function associated with ageing and may have a role in the pathogenesis of hypertension and diabetes. Intravenous dopamine is used as a positive inotrope in the treatment of acute heart failure and cardiogenic shock and as a diuretic in renal failure. The clinical uses of dopamine are limited, as it must be given intravenously, and also has widespread effects. The levels of peripheral dopamine can be increased by the administration of L-dopa to increase synthesis, prodrugs to release dopamine (docarpamine, glu-dopa) or by inhibiting the breakdown of dopamine (nitecapone). Preliminary clinical trials suggest that docarpamine may be useful in patients with low cardiac output syndrome after cardiac surgery and in refractory cirrhotic ascites. Ibopamine is an agonist at dopamine D1 and D2 receptors, which may retard the progression of chronic renal failure. Gludopa is selective for the kidney thus avoiding widespread side effects. The early clinical studies with ibopamine as a diuretic in heart failure were favourable but the subsequent large mortality study showed that ibopamine increased mortality. Fenoldopam is a selective dopamine D1 receptor agonist. Intravenous fenoldopam may be useful in the treatment of hypertension associated with coronary artery bypass surgery or in hypertensive emergencies. Although our understanding of physiological and pathological roles of peripheral dopamine has been increasing rapidly in recent times, we still need more information to allow the design of clinically useful drugs that modify these roles. One priority is an orally-active selective dopamine D1 receptor agonist.

Facilitation of renal autoregulation by angiotensin II is mediated through modulation of nitric oxide

Aims: This study was designed to investigate the influence of angiotensin II (Ang II) and nitric oxide (NO) on autoregulation of renal perfusion. Methods: Autoregulation was investigated in isolated perfused kidneys (IPRK) from Sprague-Dawley rats during stepped increases in perfusion pressure. Results: Ang II (75-200 pM) produced dose-dependent enhancement of autoregulation whereas phenylephrine produced no enhancement and impaired autoregulation of GFR. Enhancement by Ang II was inhibited by the AT(1) antagonist, Losartan, and the superoxide scavenger, Tempol. Under control conditions nitric oxide synthase (NOS) inhibition by 10 muM N-omega-nitro-L-arginine methyl ester (L-NAME) facilitated autoregulation in the presence of non-specific cyclooxygenase (COX) inhibition by 10 muM indomethacin. Both COX and combined NOS/COX inhibition reduced the autoregulatory threshold concentration of Ang II. Facilitation by 100 pM Ang II was inhibited by 100 muM frusemide. Methacholine (50 nM) antagonised Ang II-facilitated autoregulation in the presence and absence of NOS/COX inhibition. Infusion of the NO donor, 1 muM sodium nitroprusside, inhibited L-NAME enhancement of autoregulation under control conditions and during Ang II infusion. Conclusions: The results suggest than an excess of NO impairs autoregulation under control conditions in the IPRK and that endogenous and exogenous NO, vasodilatory prostaglandins and endothelium-derived hyperpolarizing factor (EDHF) activity antagonise Ang II-facilitated autoregulation. Ang II also produced a counterregulatory vasodilatory response that included prostaglandin and NO release. We suggest that Ang II facilitates autoregulation by a tubuloglomerular feedback-dependent mechanism through AT(1) receptor-mediated depletion of nitric oxide, probably by stimulating generation of superoxide.

Capillaries within compartments: Microvascular interpretation of dynamic positron emission tomography data

Measurement of exchange of substances between blood and tissue has been a long-lasting challenge to physiologists, and considerable theoretical and experimental accomplishments were achieved before the development of the positron emission tomography (PET). Today, when modeling data from modern PET scanners, little use is made of earlier microvascular research in the compartmental models, which have become the standard model by which the vast majority of dynamic PET data are analysed. However, modern PET scanners provide data with a sufficient temporal resolution and good counting statistics to allow estimation of parameters in models with more physiological realism. We explore the standard compartmental model and find that incorporation of blood flow leads to paradoxes, such as kinetic rate constants being time-dependent, and tracers being cleared from a capillary faster than they can be supplied by blood flow. The inability of the standard model to incorporate blood flow consequently raises a need for models that include more physiology, and we develop microvascular models which remove the inconsistencies. The microvascular models can be regarded as a revision of the input function. Whereas the standard model uses the organ inlet concentration as the concentration throughout the vascular compartment, we consider models that make use of spatial averaging of the concentrations in the capillary volume, which is what the PET scanner actually registers. The microvascular models are developed for both single- and multi-capillary systems and include effects of non-exchanging vessels. They are suitable for analysing dynamic PET data from any capillary bed using either intravascular or diffusible tracers, in terms of physiological parameters which include regional blood flow. (C) 2003 Elsevier Ltd. All rights reserved.