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Biomedical subjects

B R Walker

Publications and source records attributed to B R Walker.

At least 19 recordsLinked to original sources
PubMed1995

Thyroid cancer management.

OBJECTIVE: Thyroid cancer is the commonest endocrine malignancy, yet management remains controversial. Many endocrinologists advocate diagnosis by fine needle aspiration (FNA), treatment by thyroidectomy, ablative radioiodine (131I) and TSH suppression, together with follow-up with 131I scans or thyroglobulin (Tg) measurements. 131I (therapy or diagnosis) is given only when TSH is > 30 mIU/I. With this strategy in mind, the aim of the present study was to audit existing clinical practice in a large Edinburgh teaching hospital to establish whether a need existed for local guidelines for the management of thyroid cancer. DESIGN AND PATIENTS: Retrospective case-note audit of 46 patients, aged 55 (range 26-86) years, admitted between 1988 and 1993 with a diagnosis of thyroid cancer. RESULTS DIAGNOSIS: Our FNA false negative rate was high (13%), aspiration technique varied considerably, and cytological reporting was not standardized. TREATMENT: Three (11%) patients received 131I despite suboptimal TSH levels because of poorly developed mechanisms to prevent this, and 7 (25%) patients had inadequate suppression of TSH as a result of poor interspecialty communication. FOLLOW-UP: Three (11%) patients were scanned despite TSH levels < 30 mIU/I, and in 5 (18%) Tg checks were incomplete. CONCLUSIONS: This audit identifies several shortcomings from what might be considered optimum management of thyroid cancer; practice was far from uniform even among the endocrinologists within a single hospital and interdisciplinary communication was poor. A locally agreed and implemented protocol should address most of these problems and improve the care of thyroid cancer patients.

Adult↗
PubMed1995

Role of endogenous opioids and serotonin in the hemodynamic response to hemorrhage during hypoxia.

Previous studies from our laboratory indicate that acute but not chronic hypoxia decreases the hemorrhage volume required to elicit reflex hypotension. Furthermore, chronically hypoxic animals exhibit an elevated hypotensive threshold during both normoxia and hypoxia compared with control animals. Because reports suggest that opioid and serotonergic mechanisms may be involved in mediating the sympathoinhibition that occurs with hemorrhage, we hypothesized that opioid and/or serotonergic systems are stimulated during hemorrhage under conditions of acute hypoxia and suppressed after chronic exposure to hypoxia and are thus responsible for the altered cardiovascular responses to hemorrhage under each condition. Control and chronically hypoxi rats were administered either the opioid receptor antagonist naltrexone (1 mg/kg), the selective 5-hydroxytryptamine receptor subtype 3 (5-HT3) serotonergic receptor antagonist MDL-72222 (0.5 mg/kg), or their respective vehicles intravenously before hemorrhage was initiated during normoxia or hypoxia (FIO2 = 0.12). In control animals, pretreatment with naltrexone increased the hemorrhage was initiated volume required to achieve hypotension in hypoxic but not normoxic conditions. Naltrexone had no effect on hypotensive threshold in chronically hypoxic animals under conditions of either normoxia or hypoxia. In addition, MDL-72222 had no effect on hypotensive threshold in either control or chronically hypoxic animals in either normoxic or hypoxic conditions. We conclude that endogenous opioids may contribute to the reflex hypotension that occurs during hypoxic hemorrhage in control rats, while no such involvement is evident in chronically hypoxic animals. Furthermore, peripheral 5-HT3 receptors are not likely involved in this response during either normoxic or hypoxic hemorrhage in control or chronically hypoxic rats.

Animals↗
PubMed1995

Carbenoxolone increases hepatic insulin sensitivity in man: a novel role for 11-oxosteroid reductase in enhancing glucocorticoid receptor activation.

In the kidney, conversion of cortisol to cortisone by the enzyme 11 beta-hydroxysteroid dehydrogenase protects mineralocorticoid receptors from cortisol. In the liver, a different isoform of the enzyme favors 11 beta-reductase conversion of cortisone to cortisol. We have tested the hypothesis that hepatic 11 beta-reductase enhances glucocorticoid receptor activation in the liver by inhibiting the enzyme with carbenoxolone and observing effects on insulin sensitivity. Seven healthy males took part in a double blind randomized cross-over study in which oral carbenoxolone (100 mg every 8 h) or placebo was administered for 7 days. Euglycemic hyperinsulinemic clamp studies were then performed, including measurement of forearm glucose uptake. Carbenoxolone increased whole body insulin sensitivity (M values for dextrose infusion rates, 41.1 +/- 2.4 mumol/kg.min for placebo vs. 44.6 +/- 2.3 for carbenoxolone; P < 0.03), but had no effect on forearm insulin sensitivity. We infer that carbenoxolone, by inhibiting hepatic 11 beta-reductase and reducing intrahepatic cortisol concentration, increases hepatic insulin sensitivity and decreases glucose production. Thus, plasma cortisone provides an inactive pool that can be converted to active glucocorticoids at sites where 11 beta-reductase is expressed, abnormal hepatic 11 beta-reductase activity might be important in syndromes of insulin resistance, and manipulation of hepatic 11 beta-reductase may be useful in treating insulin resistance.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1994

Enhanced pulmonary arterial dilation to arginine vasopressin in chronically hypoxic rats.

Chronic hypoxic exposure elicits pulmonary vascular remodeling and may alter normal pulmonary endothelial function. We examined the vasodilatory response to the receptor-mediated endothelium-dependent dilator arginine vasopressin (AVP), the non-receptor-mediated endothelium-dependent dilator A-23187, and the nitric oxide (NO) donor sodium nitroprusside in lungs isolated from control or chronically hypoxic rats. Lungs were isolated from male Sprague-Dawley rats and perfused with a physiological saline solution containing 4% albumin. Arterial and venous pressures were monitored and microvascular pressure was estimated by double occlusion, allowing assessment of segmental resistances. After equilibration, lungs were constricted with the thromboxane mimetic U-46619. Upon development of a stable pressor response, lungs were dilated with one of the above agents. A series of doses of AVP was administered to separate groups of lungs from control or chronically hypoxic rats. Lungs from chronically hypoxic rats exhibited an augmented dilatory response to AVP compared with control lungs, and this effect was due to enhanced dilation of precapillary segments. The total and segmental vasodilatory responses to A-23187 and sodium nitroprusside were not different between the two groups of lungs, suggesting that chronic hypoxia did not upregulate the enzyme NO synthase or enhance the vascular smooth muscle responsiveness to NO. Thus our data suggest that the augmented total and pulmonary arterial dilation to AVP after chronic hypoxia is most likely due to altered receptor-mediated processes of the hormone.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1993

Inhibition of nitric oxide synthesis increases blood pressure in healthy humans.

OBJECTIVE: To examine whether endogenous production of the endothelium-derived vasodilator nitric oxide influences blood pressure in healthy humans. METHODS: After preliminary pilot dose-ranging studies, 3 mg/kg NG-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide synthase, and saline placebo were infused intravenously over 5 min to eight healthy subjects in a two-phase, randomized, single-blind crossover study. Blood pressure and cardiac and renal function were measured. RESULTS: Compared with placebo, L-NMMA increased mean arterial pressure by 10%, decreased heart rate by 19%, decreased cardiac index by 25% and increased calculated total peripheral resistance by 46%. Effects were maximal 10-15 min after starting L-NMMA infusion. Urinary sodium and fractional sodium excretions were increased by L-NMMA, but creatinine clearance was unchanged. CONCLUSIONS: Basal generation of nitric oxide influences total peripheral resistance and blood pressure in healthy humans. The natriuresis induced by L-NMMA may be related to the increase in blood pressure, or arise from inhibition of the intrarenal actions of nitric oxide. Any decrease in nitric oxide generation, as has been postulated to occur in essential hypertension, could have substantial effects on blood pressure and tissue blood flow.

Adult↗
PubMed1992

Glucocorticoids and blood pressure: a role for the cortisol/cortisone shuttle in the control of vascular tone in man.

1. 11 beta-Hydroxysteroid dehydrogenase converts cortisol to inactive cortisone in man. In distal renal tubules, this inactivation protects mineralocorticoid receptors from cortisol. Congenital 11 beta-hydroxysteroid dehydrogenase deficiency and inhibition of 11 beta-hydroxysteroid dehydrogenase by liquorice or carbenoxolone result in cortisol-dependent hypokalaemia and hypertension. 2. 11 beta-Hydroxysteroid dehydrogenase is expressed in vascular smooth muscle. Both glucocorticoids and mineralocorticoids potentiate vascular responses to noradrenaline. 11 beta-Hydroxysteroid dehydrogenase activity may therefore influence vascular tone. 3. Experiments were performed in healthy subjects with and without 7 days of oral administration of 11 beta-hydroxysteroid dehydrogenase inhibitors (liquorice or carbenoxolone), and in a patient with congenital 11 beta-hydroxysteroid dehydrogenase deficiency. We measured the following parameters: dermal vasoconstriction after topical application of cortisol, forearm blood flow during brachial artery infusion of cortisol or noradrenaline, and blood pressure during systemic infusion of noradrenaline. 4. Cortisol-induced dermal vasoconstriction was increased by liquorice (23 +/- 6 to 52 +/- 7 units; P < 0.04) and in congenital 11 beta-hydroxysteroid dehydrogenase deficiency (87 units). In congenital 11 beta-hydroxysteroid dehydrogenase deficiency intraarterial infusion of cortisol caused vasoconstriction (20% reduction in blood flow in the infused arm) and accentuated the response to application of lower-body negative pressure, which stimulates sympathetically mediated vasoconstriction (35% reduction). However, intra-arterial infusion of cortisol had no effect in healthy subjects either with or without administration of liquorice. 5. Carbenoxolone potentiated both noradrenaline induced forearm vasoconstriction (P < 0.01) and pressor response (P < 0.001). 6. We conclude that 11 beta-hydroxysteroid dehydrogenase modulates the access of cortisol to vascular receptors and thereby influences vascular sensitivity to noradrenaline.(ABSTRACT TRUNCATED AT 250 WORDS)

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1992

Mineralocorticoid excess and inhibition of 11 beta-hydroxysteroid dehydrogenase in patients with ectopic ACTH syndrome.

OBJECTIVE: 11 beta-Hydroxysteroid dehydrogenase protects renal mineralocorticoid receptors from cortisol by converting cortisol to inactive cortisone. We hypothesize that 11 beta-dehydrogenase is inhibited by ACTH, providing a mechanism whereby cortisol induces hypokalaemic alkalosis in ectopic ACTH syndrome. DESIGN/MEASUREMENTS: The principal sources of plasma cortisone were assessed by selective venous catheterization with measurement of cortisol and cortisone by radioimmunoassays. The effect of ACTH on peripheral plasma cortisol/cortisone ratio was assessed in healthy volunteers during circadian rhythm, insulin induced hypoglycaemia, and infusions with exogenous ACTH or cortisol. In patients with Cushing's syndrome plasma cortisol/cortisone ratios were related to plasma potassium, corticosterone, and 11-deoxycorticosterone concentrations. PATIENTS: Catheterization was performed in 24 patients with valvular or ischaemic heart disease. Cushing's syndrome patients included: 15 with pituitary adenoma; two with adrenal adenoma; and nine with ectopic ACTH secretion. RESULTS: Plasma cortisol/cortisone ratios were low in renal vein and high in hepatic vein. In healthy volunteers plasma cortisone increased during cortisol infusion but did not change with increases in endogenous or exogenous ACTH. Plasma cortisol/cortisone ratios were higher in ectopic ACTH syndrome than in other forms of Cushing's syndrome. However, the cortisol/cortisone ratio was no better a predictor of hypokalaemia than the levels of 11-deoxycorticosterone or corticosterone. CONCLUSIONS: Peripheral conversion of cortisol to cortisone occurs mainly in the kidney and is inhibited by ACTH. In ectopic ACTH syndrome the characteristic mineralocorticoid excess can be accounted for by a combination of increased secretion of cortisol, corticosterone and of 11-deoxycorticosterone and decreased inactivation of cortisol and corticosterone by 11 beta-dehydrogenase.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1992

Role of nitric oxide in vasopressinergic pulmonary vasodilatation.

Experiments were performed to determine the mechanism of vasopressinergic pulmonary vasodilation in isolated, salt-perfused rat lungs. Administration of a 50-ng bolus of arginine vasopressin (AVP) to lungs preconstricted with the synthetic thromboxane analogue U-46619 resulted in a 66% reversal of pulmonary vasoconstriction. Administration of the known endothelium-dependent vasodilator ATP resulted in a parallel decrease in pressure. The vasodilatory responses to both agents were significantly attenuated by pretreatment with the nitric oxide synthesis inhibitor N omega-nitro-L-arginine (L-NNA). In addition to attenuating the vasodilatory response to these agents, L-NNA pretreatment caused a significant augmentation of the pressor response to U-46619 without affecting baseline pulmonary arterial pressure. The attenuation of vasopressinergic pulmonary vasodilation by L-NNA was completely reversed by addition of excess substrate for NO production (50 mM L-arginine) but was unaffected by addition of equimolar amounts of D-arginine. Finally, L-NNA pretreatment failed to attenuate the vasodilatory actions of sodium nitroprusside and isoproterenol. We conclude that AVP dilates the preconstricted pulmonary vasculature via the release of nitric oxide.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1992

Role of vasopressin in cardiovascular responses to acute and chronic hyperosmolality.

Experiments were performed in conscious chronically instrumented rats to determine the role of arginine vasopressin (AVP) in the cardiovascular adjustments to acute and chronic increases in plasma osmolality. Animals were implanted with pulsed Doppler flow probes and arterial and venous catheters for the determination of cardiac output, mean arterial blood pressure (MABP), and heart rate and for the calculation of total peripheral resistance and baroreflex sensitivity (BRS). Before and after raising plasma osmolality by either 48-h water deprivation or acute hypertonic saline infusion, specific V1- or V2-vasopressinergic receptor antagonists or vehicle were administered to the animals, and the cardiovascular responses were noted. MABP was significantly elevated in water-deprived animals. These animals also exhibited significantly increased BRS, which was further increased by administration of the V1-receptor antagonist. Animals subjected to acute hypertonic saline infusion also demonstrated increased MABP, although the infusion, unlike water deprivation, did not affect BRS. We observed no significant effects on any other variable measured. We conclude that AVP plays a relatively minor role in the cardiovascular adjustments to acute and chronic hyperosmolality.

Animals↗
PubMed1992

Pulmonary vasodilatory response to neurohypophyseal peptides in the rat.

Experiments were performed on isolated salt-perfused rat lungs to determine the receptor type(s) responsible for the pulmonary vascular effects of the neurohypophyseal peptides arginine vasopressin (AVP) and oxytocin. Bolus administration of AVP to lungs preconstricted with the thromboxane mimetic U-46619 resulted in a dose-dependent vasodilatory response (approximately 65% reversal of U-46619-induced vasoconstriction at the highest dose tested) that was blocked by pretreatment with a selective V1- but not by a selective V2-vasopressinergic receptor antagonist. Administration of a selective V1-agonist to the preconstricted pulmonary vasculature resulted in a vasodilatory response similar to that observed with AVP (approximately 55% reversal of U-46619 vasoconstriction), which was blocked by prior administration of the selective V1-receptor antagonist. Administration of the selective V2-receptor agonist desmopressin to the preconstricted pulmonary vasculature resulted in a small (approximately 8% reversal of U-46619 vasoconstriction) vasodilatory response that was, nevertheless, greater than that produced by addition of vehicle alone and was attenuated by pretreatment with a selective V2-receptor antagonist. Finally, oxytocin also caused vasodilation in the preconstricted pulmonary vasculature; however, the potency of oxytocin was approximately 1% of AVP, and the vasodilation produced by oxytocin was blocked by prior administration of a selective V1-receptor antagonist, suggesting that oxytocin acts via V1-vasopressinergic receptor stimulation. We conclude from these experiments that AVP and oxytocin dilate the preconstricted pulmonary vasculature primarily via stimulation of V1-vasopressinergic receptors. V2-receptor stimulation results in a minor vasodilatory response, although its physiological significance is unclear.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1992

Tissue-specific distribution of the NAD(+)-dependent isoform of 11 beta-hydroxysteroid dehydrogenase.

11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) converts the active glucocorticoid corticosterone to inactive 11-dehydrocorticosterone in rat (or cortisol to cortisone in man), thereby protecting renal mineralocorticoid receptors from corticosterone or cortisol and allowing preferential access for aldosterone. Recent work suggests that a nicotinamide adenine dinucleotide (NAD+)-dependent 11 beta-OHSD isoform is expressed in distal renal tubule, in contrast with the hepatic isoform which is NAD(+)-phosphate (NADP+)-dependent. To establish the distribution of the NAD(+)-dependent isoform we measured in vitro conversion of [3H]corticosterone to [3H]11-dehydrocorticosterone in homogenized rat tissues in the presence of NADP+ or NAD+. In most tissues (liver, testis, hippocampus, heart, aorta, mesenteric artery) NADP+ increased activity and NAD+ was without effect. However, in whole renal cortex, colon, placenta, and lung both NADP+ and NAD+ increased activity. No difference in cofactor utilization was demonstrated between proximal and distal renal tubules following density gradient separation. This distribution of NAD(+)-dependent activity corresponds with: (i) the distribution of multiple mRNA and/or protein species of 11 beta-OHSD; (ii) the distribution of aldosterone-specific mineralocorticoid receptors; and (iii) the equilibrium between active and inactive glucocorticoids in each tissue. We suggest that the tissue-specific expression of isoforms of 11 beta-OHSD with different kinetic properties confers on them diverse roles in modulating corticosteroid receptor activation.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1992

Clonidine therapy for Shapiro's syndrome.

Shapiro's syndrome comprises agenesis of the corpus callosum in association with episodic hyperhidrosis and hypothermia. We describe a 25-year-old man who is the twentieth case to be reported. There was no evidence of epilepsy, sympathetic nervous system dysfunction or inappropriate vasopressin release. However, investigation demonstrated a central defect in temperature regulation with an abnormally low hypothalamic set-point and normal homeothermic reflexes. Therapy with clonidine, an alpha 2-adrenoceptor agonist, was associated with remission of symptoms: these recurred on four occasions when clonidine was withdrawn. Clonidine therapy was also associated with a return to normal central temperature regulation. We suggest that the efficacy of clonidine reflects an action on hypothalamic thermoregulation rather than on peripheral catecholamine release. These findings have implications for the use of clonidine in other patients with Shapiro's syndrome and in more common disorders of temperature control, including perimenopausal flushing.

Adult↗
PubMed1991

Attentuation of systemic vasoreactivity in chronically hypoxic rats.

Experiments were performed to assess the effects of chronic hypoxia on systemic vasoreactivity in conscious unrestrained rats and in abdominal aortic rings. Two groups of rats were used: normoxic controls and chronically hypoxic rats that were maintained in a hypobaric chamber (380 mmHg) for 4 wk before experimentation. In conscious animals instrumented with pulsed Doppler cardiac output probes and arterial and venous catheters, mean arterial pressure and mean cardiac output were measured before and during graded continuous infusions of phenylephrine (PE), angiotensin II, and arginine vasopressin (AVP). Measurements were made while the animals breathed either room air or 12% O2. Acute exposure to 12% O2 significantly reduced pressor and vasoconstrictor responses for all three agents. These responses were also attenuated in the chronically hypoxic rats in 12% O2; however, acute return to room air conditions did not return pressor or vasoconstrictor responses to normoxic control levels. In abdominal aortic rings from both groups of animals, cumulative dose-response curves to PE and AVP were completed in 21 and 3% O2 conditions. Neither acute nor chronic hypoxia caused a shift in the dose-response curves. In rings from control rats, maximum tension responses to AVP were significantly diminished in 3% O2. Rings from chronically hypoxic rats exhibited less maximum tension to AVP in 21% O2 than did rings from control rats. We conclude that acute hypoxia reversibly attenuates systemic vasoreactivity and that chronic hypoxia induces a more sustained decrease in reactivity. In addition, at least part of the mechanism may reside within the vasculature.

Angiotensin II↗
PubMed1991

Role of vasopressin in acutely altered baroreflex sensitivity during hemorrhage in rats.

Experiments were performed to examine the potential role of circulating arginine vasopressin (AVP) on baroreflex sensitivity during hypotensive and nonhypotensive hemorrhage in the conscious rat. Animals were chronically instrumented for measurement of cardiac output, blood pressure, and heart rate (HR). Three potential stimuli for release of AVP were utilized: 1) rapid 20% arterial hemorrhage that resulted in hypotension, 2) nonhypovolemic hypotension induced by intravenous infusion of nitroprusside, and 3) nonhypotensive hemorrhage (rapid 10% arterial blood withdrawal). Hypotensive hemorrhage was associated with significant reductions in blood pressure, cardiac output, HR, and calculated total peripheral resistance, an increase in baroreflex (BRR) bradycardia in response to pressor infusions of phenylephrine, and a moderate elevation in circulating AVP. Prior intravenous administration of a specific V1-vasopressinergic antagonist augmented the hypotensive response to hemorrhage; however, neither V1- nor V2-blockade affected hemorrhage-induced augmentation of the BRR. Inducement of hypotension by infusion of nitroprusside did not alter subsequent BRR sensitivity. Finally, nonhypotensive hemorrhage was associated with an increase in resting HR and augmented BRR sensitivity. However, in contrast to hypotensive hemorrhage, either V1- or V2-antagonism attenuated the increase in BRR sensitivity seen with 10% hemorrhage. These data suggest that, although AVP may play a role in blood pressure maintenance via its direct vasoconstrictor actions during hypotensive hemorrhage, the observed augmentation of BRR sensitivity associated with severe blood loss is not attributable to a vasopressinergic mechanism activated by circulating AVP. However, blood-borne AVP may contribute to BRR sensitivity alterations in response to mild blood loss.

Animals↗
PubMed1991

Vasopressin-induced bradycardia in barodenervated rats.

Experiments were performed on conscious chronically instrumented rats to determine the contribution of baroreceptor reflex (BRR)-independent mechanisms in the bradycardia associated with intravenous administration of arginine vasopressin (AVP). At least 2 wk prior to experimentation, the aortic and carotid baroreceptors were denervated in six rats. Following recovery, the maximum bradycardic responses to pressor doses of phenylephrine (PE) or AVP were determined on separate days in each animal. Pulse interval (PI) was calculated from heart rate (HR), and the slopes of PI vs. mean arterial blood pressure (MABP) and PI vs. dose were determined for each experiment by linear regression. There was no significant correlation of PI vs. MABP in response to bolus PE in these barodenervated rats. However, there was a significant correlation of PI vs. MABP and PI vs. dose in response to AVP in five of the six barodenervated rats. These data suggest that pressor levels of AVP may elicit bradycardia independent of the BRR. Another group of experiments was performed in the Langendorff-isolated rat heart preparation to assess the direct chronotropic effect of AVP. Hearts were not paced, and the coronary arteries were perfused at a constant flow. HR was determined at various concentrations of AVP (n = 4 at each dose). In addition, because unpaced hearts exhibited low intrinsic rates, the same protocol was performed in hearts receiving isoproterenol to elevate basal HR (n = 4 at each AVP dose). There was no chronotropic effect of AVP in isolated hearts with or without isoproterenol administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗