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Biomedical subjects

A Calver

Publications and source records attributed to A Calver.

18 recordsLinked to original sources
PubMed2001

Epileptogenesis and enhanced prepulse inhibition in GABA(B1)-deficient mice.

The recent cloning of two GABA(B) receptor subunits, GABA(B1) and GABA(B2), has raised the possibility that differences in GABA(B) receptor subunit composition may give rise to pharmacologically or functionally distinct receptors. If present, such molecular diversity could permit the selective targeting of GABA(B) receptor subtypes specifically involved in pathologies such as drug addiction, spasticity, pain, and epilepsy. To address these issues we have developed a GABA(B1) subunit knockout mouse using gene targeting techniques. In the brains of GABA(B1) null mice, all pre- and postsynaptic GABA(B) receptor function was absent demonstrating that the GABA(B1) subunit is essential for all GABA(B) receptor-mediated mechanisms. Despite this, GABA(B1) null mice appeared normal at birth, although by postnatal week four their growth was retarded and they developed a generalized epilepsy that resulted in premature death. In addition, GABA(B1) heterozygote animals showed enhanced prepulse inhibition responses compared to littermate controls, suggesting that GABA(B1) deficient mice exhibit increased sensorimotor gating mechanisms. These data suggest that GABA(B) receptor antagonists may be of benefit in the treatment of psychiatric and neurological disorders in which attentional processing is impaired.

Action Potentials↗
PubMed1997

Migration of pectus excavatum correction bar into the left ventricle.

We present the case of a 19-year-old student who underwent correction of a pectus excavatum deformity using a pectus bar. At least 6 months following surgery, one end of the bar had migrated into his right ventricle, across the interventricular septum, to lie with its free end in the left ventricular cavity. This acted as a source of thrombus formation and lead to several systemic embolic events. The patient made a full recovery after removal of the bar. A review of the literature demonstrates that this has not been reported before.

Adult↗
PubMed1995

Measuring forearm blood flow and interpreting the responses to drugs and mediators.

Venous occlusion plethysmography has been widely used to study forearm blood flow. The principle of the technique is straightforward: the rate of swelling of the forearm during occlusion of venous return is used to assess the rate of arterial inflow. Provided that perfusion pressure (arterial blood pressure) remains constant, changes in flow reflect changes in smooth muscle tone in small arteries and arterioles. Local infusion into the brachial artery allows assessment of the direct effect of drugs on vascular tone and has been used to probe the roles of endogenous mediators. The technique is at its most powerful when dose-response relationships to different drugs or mediators within a single study are being compared but can also be used for comparison of responses to drugs between healthy control subjects and patient populations. However, when responses between groups are being compared, it is important to take into account the starting conditions of baseline blood flow and pressure. This article describes venous occlusion plethysmography, discusses the presentation and analysis of data (dose of drug or concentration? forearm blood flow or resistance?), and highlights certain potential problems and limitations of the technique as a means of studying disease states.

Blood Pressure↗
PubMed1994

Effect of local inhibition of nitric oxide synthesis on forearm blood flow and dorsal hand vein size in patients with alcoholic cirrhosis.

1. Nitric oxide (NO) is a potent endogenous vasodilator and plays a role in the control of resting vascular tone. Patients with cirrhosis have a hyperdynamic circulation with reduced blood pressure and decreased peripheral resistance, and it is possible that increased production of NO due to induction of NO synthase may be involved in maintaining this vasodilatation. We have examined this possibility by studying the effects of local infusions of NG-monomethyl-L-arginine (an inhibitor of NO synthase) in the forearm arteriolar bed and the superficial dorsal hand veins of patients with alcoholic cirrhosis. 2. Drugs were either infused locally into the brachial artery and forearm blood flow was measured by venous occlusion plethysmography, or into a vein on the back of the hand and vein diameter was measured using a linear displacement technique. 3. Basal forearm blood flow was increased and vascular resistance was decreased in the patients with alcoholic cirrhosis compared with healthy control subjects. Noradrenaline and NG-monomethyl-L-arginine caused dose-dependent falls in forearm blood flow in both healthy control subjects and patients with cirrhosis. There was no significant difference in the responses to either noradrenaline or NG-monomethyl-L-arginine between the two groups. 4. In the superficial hand veins there was no change in vein size in response to NG-monomethyl-L-arginine infused alone, and venoconstriction to local infusion of noradrenaline was unaffected by co-infusion with NG-monomethyl-L-arginine. 5. Our results confirm that patients with alcoholic cirrhosis are vasodilated compared with healthy control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Forearm blood flow responses to a nitric oxide synthase inhibitor in patients with treated essential hypertension.

OBJECTIVE: There is evidence that basal NO mediated vasodilatation is abnormal in patients with essential hypertension. Studies in animals suggest that treatment of hypertension may restore the nitric oxide system towards normal. The objective of this study was to examine basal nitric oxide mediated vasodilatation in patients with treated essential hypertension. METHODS: The forearm blood flow response to noradrenaline and NG-monomethyl-L-arginine (L-NMMA), a stereospecific inhibitor of nitric oxide synthesis, was compared in 11 patients with treated essential hypertension and 18 normotensive healthy controls. The results in the treated hypertensive patients were also compared with those in a previously reported group of seven untreated patients with essential hypertension. Drugs were infused locally into the brachial artery and forearm blood flow measured using venous occlusion plethysmography. RESULTS: In the healthy controls noradrenaline (60, 120, and 240 pmol.min-1) and L-NMMA (1, 2, and 4 mumol.min-1) produced similar reductions in resting forearm blood flow. In the patients with treated essential hypertension, at the same doses, noradrenaline and L-NMMA also produced similar reductions in forearm blood flow. There was no significant difference in the response to either noradrenaline or L-NMMA between the healthy controls and the treated hypertensive patients. There was also no significant difference in the response to noradrenaline or L-NMMA between the treated patients and the patients with untreated essential hypertension. However, the response to L-NMMA in all subjects correlated significantly with blood pressure, such that the responses in the treated patients lay between those of the healthy controls and the untreated patients. CONCLUSIONS: Basal nitric oxide mediated vasodilatation appears to be a continuum that varies with blood pressure. Reduction in blood pressure with medication moves the L-NMMA response nearer to that seen in healthy subjects. These results suggest that treatment of hypertension may restore NO mediated vasodilatation towards normal.

Adult↗
PubMed1992

Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure.

Nitric oxide (NO), synthesised from L-arginine, contributes to the regulation of blood pressure and to host defence. We describe in-vitro and in-vivo evidence that NO synthesis can be inhibited by an endogenous compound, NG,NG-dimethylarginine (asymmetrical dimethylarginine, ADMA). In man, this inhibitor is found in plasma and more than 10 mg is excreted in urine over 24 h. However, in patients with end-stage chronic renal failure, who have little or no urine output, elimination is blocked and circulating concentrations of the inhibitor rise sufficiently to inhibit NO synthesis. Accumulation of endogenous ADMA, leading to impaired NO synthesis, might contribute to the hypertension and immune dysfunction associated with chronic renal failure.

Adult↗
PubMed1992

Effect of acute plasma volume expansion on peripheral arteriolar tone in healthy subjects.

1. Using venous occlusion plethysmography, we have investigated the forearm blood flow response in healthy subjects to the acute plasma volume expansion caused by a rapid intravenous infusion of saline. The contribution made to this response by nitric oxide has been investigated using local intra-arterial infusions of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine. 2. The infusion of 1000 ml of saline over 25 min caused plasma volume to increase by about 7%, and resulted in a rise in forearm blood flow, with no change in arterial blood pressure. The onset of the blood flow response occurred within 10 min and blood flow remained elevated above baseline 20 min after the end of the saline infusion. 3. Local intra-arterial infusion of NG-monomethyl-L-arginine alone caused a reduction in forearm blood flow which was maximal at the end of the infusion and gradually recovered to baseline levels over 40 min. 4. When local intra-arterial infusion of NG-monomethyl-L-arginine was followed by plasma volume expansion, the calculated effect of NG-monomethyl-L-arginine was such as to abolish the vasodilator response to saline. 5. The effect of local intra-arterial infusion of NG-monomethyl-L-arginine on forearm blood flow was greater when the drug was given after volume expansion had occurred, than when it was given before the administration of saline. However, in control experiments the vasoconstrictor response to noradrenaline was also enhanced after the administration of the volume load in comparison with the response to noradrenaline given alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Arginine↗
PubMed1992

The vascular endothelium in diabetes and hypertension.

PURPOSE: To review recent research into the function of endothelial cells in relation to diabetes and hypertension, and the implications for cardiovascular control. ENDOTHELIAL FUNCTIONS: Endothelial cells extract and inactive circulating hormones, convert inactive precursors into vasoactive products, and synthesize and secrete vasodilator and vasoconstrictor mediators, which also modify platelet function and cell growth. DIABETES: Abnormalities in endothelial cell morphology and function are recognized features of diabetes. Diminished endothelium-dependent relaxation and enhanced endothelium-dependent contraction have been described. HYPERTENSION: Similar defects in endothelial cell function have been demonstrated in animal and human hypertension. These might lead to increased vascular tone, vasospasm, platelet activation and atheroma. THERAPY: Certain drugs modify or mimic endothelium-derived mediators. Endothelial dysfunction may contribute to cardiovascular pathology, but the precise clinical and therapeutic significance of modifying endothelial function remains to be determined.

Blood Platelets↗
PubMed1992

Endogenous dimethylarginine as an inhibitor of nitric oxide synthesis.

Nitric oxide (NO) is a widespread biological mediator with myriad functions. We have demonstrated that methylated arginines capable of inhibiting NO synthesis circulate in the plasma of healthy volunteers and are excreted unchanged in the urine. Up to 10 mg of asymmetric dimethylarginine is excreted in the urine every day, and this compound inhibits NO synthesis in vitro and in vivo, in animals and in humans. This finding raises the possibility that these compounds may act as endogenous regulators of the L-arginine:NO pathway in health and disease.

Amino Acid Oxidoreductases↗
PubMed1992

Inhibition and stimulation of nitric oxide synthesis in the human forearm arterial bed of patients with insulin-dependent diabetes.

Patients with insulin-dependent diabetes mellitus have an increased mortality and morbidity due to vascular complications. Nitric oxide from the vascular endothelium contributes to the control of normal vascular tone, and endothelial dysfunction has been implicated in the pathogenesis of diabetic vascular disease. In this study we have examined basal and stimulated nitric oxide-mediated vasodilatation in insulin-dependent diabetics and age- and sex-matched healthy controls. Drugs were infused locally into the brachial artery and forearm blood flow measured using venous occlusion plethysmography. Noradrenaline and NG-monomethyl-L-arginine produced similar reductions in resting forearm blood flow in healthy controls. However, in the diabetics, NG-monomethyl-L-arginine was significantly less effective than noradrenaline. Comparing between groups, the response to NG-monomethyl-L-arginine was also significantly less in the diabetics compared with the healthy controls. The response to sodium nitroprusside was significantly less in the diabetics compared with the healthy controls, whereas the responses to both acetylcholine and verapamil were the same in the two groups. The results provide evidence for an abnormality of basal nitric oxide-mediated dilatation in the forearm arterial bed of patients with insulin-dependent diabetes mellitus, and suggest that the vascular smooth muscle is less sensitive to nitric oxide.

Acetylcholine↗
PubMed1992

Effect of local intra-arterial NG-monomethyl-L-arginine in patients with hypertension: the nitric oxide dilator mechanism appears abnormal.

OBJECTIVE: There is indirect evidence that the nitric oxide system may be impaired in hypertensive patients. The objective of this study was to examine basal nitric oxide-mediated dilation in hypertensive patients. DESIGN: The forearm blood flow (FBF) response to noradrenaline and NG-monomethyl-L-arginine (L-NMMA), a stereospecific inhibitor of nitric oxide synthesis, was compared in seven untreated hypertensive patients and 17 normotensive controls. METHODS: Drugs were infused locally into the brachial artery and FBF measured using venous occlusion plethysmography. RESULTS: In normotensives noradrenaline (60, 120 and 240 pmol/min) and L-NMMA (1,2 and 4 mumol/min) produced similar reductions in resting FBF. In the hypertensives L-NMMA was significantly less effective than noradrenaline, such that the threshold dose for L-NMMA vasoconstriction was increased and the overall response to L-NMMA reduced. Furthermore, when noradrenaline was used as an internal control there was a significant negative relationship between the response to L-NMMA and blood pressure. When the responses to L-NMMA and noradrenaline were compared between groups, the response to L-NMMA was significantly less in hypertensives compared with normotensives, whereas there was no statistical difference in the response to noradrenaline between the two groups. CONCLUSIONS: The results suggest an abnormality of basal nitric oxide-mediated dilation in the forearm arteriolar bed of patients with untreated essential hypertension.

Adult↗
PubMed1991

Dilator actions of arginine in human peripheral vasculature.

1. L-Arginine is the physiological precursor for the formation of endothelium-derived nitric oxide. The synthesis of nitric oxide is stereospecific: D-arginine is not a substrate for nitric oxide synthase. It is possible that the provision of excess L-arginine substrate might increase the vascular synthesis of nitric oxide. We have examined this possibility by studying the effects of local infusion of L- and D-arginine in the forearm resistance bed and the superficial dorsal hand veins of healthy subjects. 2. Drugs were either infused locally into a vein on the back of the hand and then the vein diameter was measured using a linear displacement technique, or into the brachial artery and then the forearm blood flow was measured by venous occlusion plethysmography. 3. In the superficial hand veins, L- and D-arginine free base and L- and D-arginine hydrochloride (all four preparations at a dose of 5 mumol/min) all caused a significant increase in venous diameter. The responses of the L- and D-enantiomers did not differ significantly from one another. 4. In the forearm resistance bed, L- and D-arginine free base and L- and D-arginine hydrochloride were without effect at doses of 10 and 40 mumol/min. However, at doses of 160 mumol/min all three preparations of arginine caused a significant increase in forearm blood flow compared with control values. The responses to the three preparations of arginine did not differ significantly from one another. 5. These results show that arginine in high dose is a vasodilator in both human resistance vessels and superficial veins in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMedDate not supplied

Riverbed permeabilities: information from pooled data.

Numerical values of hydraulic conductivities of river channel-lining materials are assembled from published and unpublished sources. These are found to cover a range from below 1.0 x 10(-9) to above 1.0 x 10(-2) m sec-1 and to be concentrated in the region 1.0 x 10(-7) to 1.0 x 10(-3) m sec-1. Variability within a site can be large. Assessment of the values in relation to sediment, scale, and method of determination presents a complex picture, and generalization is not straightforward. Hydraulic conductivity determinations from numerical modeling, which tends to be associated with averaging at larger spatial scales, are associated with a more conservative range of values than those derived from field and laboratory analyses. The sample of determinations provides a guideline basis of representative values for hydrological and hydrogeological assessment where specific investigation is not possible.

Environmental Monitoring↗