Biomedical subjects

B R Walker

Publications and source records attributed to B R Walker.

At least 91 records · Page 5Linked to original sources

PubMed1998

Reproducibility of the low dose dexamethasone suppression test: comparison between direct plasma and salivary cortisol assays.

BACKGROUND: The low dose dexamethasone suppression test (DST) has been used to detect subtle variations in the feedback suppression of the hypothalamic-pituitary-adrenal axis, which may contribute to the pathogenesis of several diseases including depression, the metabolic syndrome and coronary artery disease. Little is known about the reproducibility of this test, or whether the test can be combined with analysis of salivary cortisol which would offer a significant advantage over plasma in population studies. SUBJECTS AND DESIGN: A low dose DST was carried out in 29 healthy subjects (14 men, 15 women), aged 24-54 (mean 35.1) years, on two separate occasions 1-10 weeks apart. Following the administration of 0.25 mg dexamethasone (DXM) at 2200 h, plasma and saliva were sampled at 0830 h the next day. Cortisol was measured by radioimmunoassay in plasma and time-resolved immunofluorescent assay ('DELFIA') in saliva. Bland-Altman plots were produced for post-DXM plasma and salivary cortisol measures and used to derive a coefficient of repeatability for each measure, which describes the range of cortisol measurements within which 95% of repeated measurements will fall. RESULTS: The baseline, pre-DXM cortisol concentrations were far more variable for saliva (mean 16.5, range 4.4-34 nmol/l) than for plasma (mean 407.5; range 232-958 nmol/l). Following DXM both measurements showed an approximately 30% suppression from baseline but the variability of salivary cortisol was much greater. From the Bland-Altman plots the 95% range for the differences about their mean was calculated and used as an indication of repeatability. For plasma 95% of differences were within 0.78 log units, indicating that a repeated measurement was approximately half as small or twice as large as the first. For saliva 95% of differences were within 1.64, indicating that a repeated measurement was approximately five times as small or five times as large as the first. CONCLUSIONS: Assessment of dexamethasone suppression by salivary cortisol measurement is far less repeatable than the use of plasma cortisol. In the context of field studies of dexamethasone suppression, salivary cortisol measurements may only be appropriate for large numbers of subjects.

Adult↗

PubMed1998

Growth hormone replacement inhibits renal and hepatic 11 beta-hydroxysteroid dehydrogenases in ACTH-deficient patients.

OBJECTIVES: The commonest side-effects of GH replacement therapy relate to sodium retention but its mechanism is unclear. In rats, GH inhibits renal and hepatic 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) activities. In man, this action might impair inactivation of cortisol to cortisone in the distal nephron thereby allowing cortisol to activate mineralocorticoid receptors. In this study, we examined the effects of GH replacement on cortisol metabolism. DESIGN: A randomized double-blind study comparing 6 months GH replacement with placebo in adults with GH deficiency due to pituitary or hypothalamic disease. PATIENTS: 6 men and 8 women received placebo and 8 men and 9 women received GH. MEASUREMENTS: Cortisol and its metabolites were measured in overnight urine samples and in a fasting morning plasma sample at baseline and at 6 months. RESULTS: Five patients withdrew from the study, 4 because of adverse effects of GH. Amongst those who completed the study, the effects of GH on cortisol metabolism differed between patients with and without ACTH deficiency. Amongst those receiving hydrocortisone replacement (n = 18), GH had no effect on plasma cortisol/cortisone ratio, or urine tetrahydrocortisols/tetrahydrocortisone ratio, but produced a substantial reduction in total urinary cortisol metabolites (from 1326 +/- 191 to 777 +/- 229 micrograms/mmol creatinine; P < 0.01) and an increase in urinary free cortisol/cortisone ratio (from 0.88 +/- 0.10 to 2.57 +/- 0.74; P < 0.02). By contrast, GH had none of these effects in patients with normal ACTH secretion. There were no changes in blood pressure or plasma electrolytes, aldosterone, or renin activity with GH, and no changes in any variables with placebo. CONCLUSIONS: The increase in cortisol/cortisone ratio in urine but not in plasma, and the lack of effect on hepatic cortisol metabolites, suggests that GH inhibits both the conversion of cortisol to cortisone by renal 11 beta-HSD2 and the conversion of cortisone to cortisol by hepatic 11 beta-HSD1. It is unclear why this action of GH only affects patients with ACTH deficiency. The reduction in total cortisol metabolite excretion suggests that GH also affects bioavailability of hydrocortisone tablets. These observations suggest that glucocorticoid replacement therapy may need to be adjusted in hypopituitary patients who are commenced on GH replacement.

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed1998

Maintained vasodilatory response to cromakalim after inhibition of nitric oxide synthesis.

Activation of vascular smooth-muscle adenosine triphosphate-sensitive potassium channels (KATP channels) causes membrane hyperpolarization, reduced entry of Ca2+ through L-type voltage-gated Ca2+ channels, and subsequent smooth-muscle relaxation. Conversely, opening of endothelial KATP channels elicits hyperpolarization but may induce Ca2+ influx and stimulation of endothelium-derived nitric oxide (EDNO) because these cells appear not to possess L-type Ca2+ channels. We therefore hypothesized that EDNO contributes to KATP channel-mediated vasodilation. To test this hypothesis, we examined vasodilatory responses to the KATP channel opener cromakalim in conscious rats, perfused rat tail artery segments, and isolated perfused rat lungs in the presence or absence of the EDNO synthesis inhibitor Nomega-nitro-L-arginine (L-NNA). Additionally, we compared the effect of cromakalim with the EDNO-dependent dilator bradykinin on NO production and intracellular Ca2+ in cultured rat pulmonary artery endothelial cells. Vasodilatory profiles to cromakalim were unaffected by L-NNA in conscious rats, tail arteries, and isolated lungs. Consistent with these results, cromakalim had no apparent effect on either NO synthesis or Ca2+ levels in cultured endothelial cells. These data suggest a lack of a role for EDNO in contributing to KATP-channel-mediated vasodilation in the rat.

Animals↗

PubMed1998

Pulmonary circulation demonstration using an isolated rat lung model.

We have developed a pulmonary circulation laboratory exercise that effectively illustrates basic concepts typically taught in a graduate physiology curriculum. The demonstration uses an isolated, perfused rat lung model to delineate the mechanisms by which pulmonary vascular resistance can be altered either passively or in an active manner by contraction or relaxation of vascular smooth muscle. The exercise further offers an opportunity to closely observe an experimental preparation commonly used to study the pulmonary circulation and allows students the opportunity to interpret the resulting physiological data. Student evaluations indicate that the demonstration was received with enthusiasm and provides an effective teaching tool for reinforcing concepts in pulmonary vascular physiology.

Animals↗

PubMed1998

Role of endothelial carbon monoxide in attenuated vasoreactivity following chronic hypoxia.

Chronic hypoxic exposure has been previously demonstrated to attenuate systemic vasoconstrictor activity to a variety of agents. This attenuated responsiveness is observed not only in conscious animals but in isolated vascular preparations as well. Because hypoxia has been documented to increase heme oxygenase (HO) levels and the subsequent production of the vasodilator CO in vitro, we hypothesized that the blunted reactivity observed with chronic hypoxia (CH) may be in part due to increased HO activity. In thoracic aortic rings from CH rats, cumulative dose-response curves to phenylephrine (PE) in the presence of the nitric oxide (NO) synthase inhibitor Nomega-nitro-L-arginine (L-NNA) and the HO inhibitor zinc protoporphyrin 9 (ZnPPIX) elicited increased contractility compared with CH rings treated with only L-NNA. Similar results were observed in rings incubated overnight with the HO-inducing agent sodium m-arsenite. In contrast, contractile responses in rings from control rats were unaffected by the HO inhibitor. Furthermore, endothelium-denuded rings from either control or CH rats did not exhibit an increase in reactivity to PE following ZnPPIX incubation. ZnPPIX had no effect on relaxant responses to the NO donor S-nitroso-N-penicillamine, suggesting that its actions were specific to HO inhibition. Finally, aortic rings exhibited dose-dependent relaxant responses to exogenous CO that were endothelium independent and blocked by an inhibitor of soluble guanylyl cyclase. The other products of HO enzyme activity, iron and biliverdin, were without effect on vasoreactivity. Thus we conclude that the attenuated vasoreactivity to PE following CH is likely to involve the induction of endothelial HO and the subsequent enhanced production of CO.

Animals↗

PubMed1998

Increased glucocorticoid activity in men with cardiovascular risk factors.

The association between hypertension and insulin resistance might be explained by increased activity of the principal glucocorticoid, cortisol. Recent data show that the intensity of dermal vasoconstriction after topical application of glucocorticoids is increased in patients with essential hypertension. In this report, we examine whether increased glucocorticoid sensitivity or secretion is associated with insulin resistance and is a cause or consequence of hypertension. We studied 32 men (aged 47 to 56 years) from a cross-sectional study and 105 men (aged 23 to 33 years) in whom predisposition to high blood pressure has been defined by their own blood pressure and the blood pressures of their parents. In both populations, increased dermal glucocorticoid sensitivity was associated with relative hypertension, insulin resistance, and hyperglycemia. In young men with higher blood pressure whose parents also had high blood pressure, enhanced glucocorticoid sensitivity was accompanied by enhanced secretion of cortisol, enhanced ligand-binding affinities for dexamethasone in leukocytes, and impaired conversion of cortisol to inactive metabolites (cortisone and 5beta-dihydrocortisol). Increased tissue sensitivity to cortisol, amplified by enhanced secretion of cortisol, is a feature of the familial predisposition to high blood pressure rather than a secondary effect of high blood pressure. It may be mediated by an abnormal glucocorticoid receptor, and it may contribute to the association between hypertension and insulin resistance.

Administration, Topical↗

PubMed1998

Elevated plasma cortisol concentrations: a link between low birth weight and the insulin resistance syndrome?

Recent studies have shown that reduced fetal growth is associated with the development of the insulin resistance syndrome in adult life. The mechanisms are not known. However increased activity of the hypothalamic-pituitary-adrenal axis (HPAA) may underlie this association; the axis is known to be reset by fetal growth retardation in animals, and there is evidence in humans of an association between raised HPAA activity and the insulin resistance syndrome. We have, therefore, examined the relations among size at birth, plasma cortisol concentrations, and components of the insulin resistance syndrome in a sample of healthy men. We measured 0900 h fasting plasma cortisol and corticosteroid-binding globulin levels in 370 men who were born in Hertfordshire, UK, between 1920-1930 and whose birth weights were recorded. Fasting plasma cortisol concentrations varied from 112-702 nmol/L and were related to systolic blood pressure (P = 0.02), fasting and 2-h plasma glucose concentrations after an oral glucose tolerance test (P = 0.0002 and P = 0.04), plasma triglyceride levels (P = 0.009), and insulin resistance (P = 0.006). Plasma cortisol concentrations fell progressively (P = 0.007) from 408 nmol/L in men whose birth weights were 5.5 lb (2.50 kg) or less to 309 nmol/L among those who weighed 9.5 lb (4.31 kg) or more at birth, a trend independent of age and body mass index. These findings suggest that plasma concentrations of cortisol within the normal range could have an important effect on blood pressure and glucose tolerance. Moreover, this study provides the first evidence that intrauterine programming of the HPAA may be a mechanism underlying the association between low birth weight and the insulin resistance syndrome in adult life.

Aged↗

PubMed1998

Obesity and gender influence cortisol secretion and metabolism in man.

In obesity, urinary cortisol excretion is enhanced but plasma cortisol levels are not elevated, suggesting that metabolic clearance of cortisol is increased. Cortisol is metabolised in liver and fat by A-ring reductases but also regenerated from inactive cortisone in liver, fat, and skeletal muscle by 11 beta-reductase. These enzymes are regulated by estrogen. This study addressed whether there are differences in cortisol metabolism in obesity, and whether these differences are estrogen dependent. 31 men and 37 post-menopausal women (9 on estrogen replacement therapy) aged 47-53 y supplied 24 h urine for gas chromatography/mass spectrometry. Total cortisol metabolite excretion was higher in men than women, but weakly related to indices of obesity. By contrast, metabolism of cortisol favoured 5 alpha-rather than 5 beta-reduction in obese men and obese women, and favoured cortisol rather than cortisone in obese men. In women compared with men ratios of 5 alpha-/5 beta-reduced and cortisol/cortisone metabolites were also higher but these variables were not affected by estrogen replacement therapy. We conclude that in obesity, inactivation of cortisol by 5 alpha-reductase is enhanced but this is offset by impaired metabolism of cortisol by 5 beta-reductase in women and enhanced conversion of cortisone to cortisol by 11 beta-reductase in men. These observations suggest that cortisol clearance is altered in obesity, and this may account for activation of the hypothalamic-pituitary-adrenal axis. Moreover, these data predict that obese subjects will have higher concentrations of cortisol in key target tissues including liver and visceral fat. This may contribute to the adverse metabolic consequences of obesity.

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed1997

Impaired microvascular dilatation and capillary rarefaction in young adults with a predisposition to high blood pressure.

Increased vascular resistance in essential hypertension occurs mainly in microvessels with luminal diameters < 100 microm. It is not known whether abnormalities in these vessels are a cause or consequence of high blood pressure (BP). We studied 105 men (aged 23-33 yr) in whom predisposition to high blood pressure has been characterized by both their own BP and those of their parents. Factors that are secondary to high BP correlate with offspring BP irrespective of parental BP, but factors that are components of the familial predisposition to high BP are more closely associated with higher BP in offspring whose parents also have high BP. Offspring with high BP whose parents also have high BP had impaired dermal vasodilatation in the forearm following ischemia and heating (289+/-27 [n = 25] versus 529+/-40 [n = 26], 476+/-38 [n = 30], and 539+/-41 flux units [n = 24] in other groups; P < 0.0001) and fewer capillaries on the dorsum of the finger (23+/-0.8 capillaries/0.25 mm2 versus 26+/-0.8 in all other groups; P < 0.003). Except for BP, other hemodynamic indices (including cardiac output and forearm vascular resistance) were not different. The dermal vessels of men who express a familial predisposition to high BP exhibit increased minimum resistance and capillary rarefaction. Defective angiogenesis may be an etiological component in the inheritance of high BP.

Adult↗

PubMed1997

Additional value of measurement of urinary cortisone and unconjugated cortisol metabolites in assessing the activity of 11 beta-hydroxysteroid dehydrogenase in vivo.

OBJECTIVE: It has been shown recently that 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) is expressed as at least 2 isozymes. In the liver, 11 beta-HSD1 converts cortisone to cortisol; in the kidney, 11 beta-HSD2 converts cortisol to cortisone. Conventional assessment of 11 beta-HSD activity in vivo has relied on gas chromatographic measurement of the ratios of conjugated cortisol and cortisone metabolites. However, these do not permit distinction between the tissue-specific activities of the enzymes and do not reflect all forms of 11 beta-HSD deficiency. In this report, we have assessed the usefulness of measuring unconjugated cortisol metabolites and free cortisol and cortisone in urine as indices of renal 11 beta-HSD activity in man. DESIGN: Six healthy male subjects established in sodium balance were given either glycyrrhetinic acid (170 mg t.d.s., to inhibit 11 beta-HSD2), carbenoxolone (100 mg t.d.s., to inhibit both 11 beta-HSD1 and 11 beta- HSD2) or both inhibitors in combination. MEASUREMENTS: Urinary electrolytes were measured and the concentrations of total and unconjugated urinary cortisol and its metabolites were determined by gas chromatography mass spectrometry. RESULTS: Glycyrrhetinic acid and carbenoxolone inhibited renal 11 beta-HSD2 to a similar degree, as judged by similar sodium retention. As previously reported, conventional measurement of ratios of total cortisol to cortisone metabolites were influenced to a greater extent by glycyrrhetinic acid (100-200% increase in ratio from baseline) than by carbenoxolone (< 30% increase). However, the effect of carbenoxolone was readily detected by measurement of urinary unconjugated cortisol/cortisone (130-480% increase of ratio from baseline) and also by measurement of ratios of unconjugated cortisol metabolites (60-130% increase). CONCLUSIONS: Measurement of free cortisol and cortisone in urine provides the most sensitive index of renal 11 beta-HSD activity. Measurement of total and conjugated urinary steroids is insensitive in circumstances where 11 beta-HSD activity in liver or elsewhere may be abnormal.

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed1997

Selective upregulation of arterial endothelial nitric oxide synthase in pulmonary hypertension.

We have previously demonstrated that arterial, but not venous, vasodilatory responses to endothelium-derived nitric oxide (EDNO)-dependent agonists are enhanced in lungs isolated from rats with chronic hypoxia (CH)-induced pulmonary arterial hypertension. These data suggest that CH is associated with increased endothelial nitric oxide synthase (eNOS) activity within the pulmonary arterial vasculature. In addition, the correlation of increased pulmonary arterial pressure with selectively enhanced arterial responsiveness to EDNO-mediated agonists suggests that arterial hypertension, rather than hypoxia per se, is a contributing factor in this response. Therefore, we hypothesized that 1) CH selectively upregulates eNOS within the pulmonary arterial vasculature and 2) monocrotaline (MC)-induced pulmonary arterial hypertension selectively enhances pulmonary arterial dilation to EDNO-dependent dilators and upregulates arterial eNOS. We examined the responses to the EDNO-dependent dilators arginine vasopressin and ionomycin in U-46619-constricted isolated perfused lungs from control and MC-treated rats. Microvascular pressure was assessed by the double-occlusion technique, allowing calculation of segmental resistances. Lungs from MC-treated rats exhibited augmented arterial dilation to arginine vasopressin compared with control lungs. However, the responses to ionomycin were not different between the two groups. Quantitative immunocytochemistry was used to compare pulmonary eNOS immunoreactivity in vessels from control, CH, and MC-treated rats. eNOS staining was more intense in the arteries of CH and MC-treated rats compared with those of control animals, whereas CH and MC treatment had no effect on eNOS staining in veins. We conclude that pulmonary arterial hypertension, or altered vascular mechanical forces associated with hypertension, may be responsible for the augmented EDNO-dependent arterial dilation and upregulation of arterial eNOS in lungs from CH and MC-treated rats.

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

PubMed1997

Myogenic contribution to agonist-induced renal vasoconstriction during normoxia and hypoxia.

Acute hypoxia attenuates agonist-induced constrictor and pressor responses in conscious rats, and a recent report suggests that hypoxia may also diminish myogenic reactivity in isolated, perfused rat kidneys. Thus we hypothesized that the diminished responsiveness to pressor agents during hypoxia is caused by an impairment of myogenic reactivity. Male Sprague-Dawley rats were instrumented with a pulsed Doppler flow probe on the left renal artery, an aortic vascular occluder cuff immediately above the left renal artery to control renal perfusion pressure, and catheters were inserted to measure systemic arterial blood pressure and renal arterial pressure (RAP) and for administration of agents. Animals were studied under normoxic or acute hypoxic (fractional concentration of O2 in inspired gials = 0.12) conditions and were administered phenylephrine, arginine vasopressin, or angiotensin II. To determine the myogenic (pressure-dependent) component of agonist-induced vasoconstriction, renal vascular resistance was calculated during agonist infusion with RAP uncontrolled and with RAP controlled to preinfusion levels. Significant myogenic components of agonist-induced renal vasoconstriction were evident with all pressor agents used. However, hypoxia did not attenuate agonist-induced, pressure-dependent increases in renal vascular resistance. We conclude that the reduced vasoreactivity associated with acute hypoxia is not caused by diminished myogenic reactivity.

Angiotensin II↗

PubMed1997

Seasonal variation in glucocorticoid activity in healthy men.

Many endocrine systems are subject to seasonal variation. However, studies of the hypothalamic-pituitary-adrenal axis in man have been limited to patients with psychiatric illness with conflicting results. We studied 105 healthy men, age 24-33 yr, during a 15-month period that included two winters. We measured cortisol and its metabolites by gas chromatography/mass spectrometry in plasma and urine and the intensity of dermal blanching after overnight topical application of beclomethasone dipropionate. There were no differences between subjects studied during the two winter periods, but marked differences between subjects studied in winter and summer. In winter, 0900-h plasma cortisol concentrations were higher (73 +/- 10 ng/mL, n = 41 vs. 35 +/- 4, n = 25 in summer; P < 0.01), total cortisol metabolite excretion was lower (678 +/- 67 micrograms/mmol creatinine vs. 900 +/- 98; P < 0.05), the ratio of metabolites of cortisol to those of cortisone was higher (3.0 +/- 0.2 vs. 2.1 +/- 0.1; P < 0.01), and dermal glucocorticoid sensitivity was higher (7.2 +/- 0.4 arbitrary units vs. 5.6 +/- 0.5; P < 0.02). Although blood pressure and fasting insulin/glucose relationships were not measurably different between seasons, these correlated with dermal vasoconstriction and cortisol metabolite excretion rate. We conclude that plasma cortisol and tissue sensitivity to glucocorticoids are higher in winter, but cortisol production rate is reduced. This could be explained by a reduction in cortisol clearance rate: urinary free cortisol/cortisone ratios were not different but A-ring-reduced metabolites of cortisol were higher in winter, suggesting that conversion of cortisone to cortisol by hepatic 11 beta-hydroxysteroid dehydrogenase 1 is enhanced. It is an intriguing possibility that increased glucocorticoid activity contributes to the increased prevalence of disease during the winter.

Adult↗

PubMed1997

Dexamethasone and 11-dehydrodexamethasone as tools to investigate the isozymes of 11 beta-hydroxysteroid dehydrogenase in vitro and in vivo.

Dexamethasone is used in the clinic to test the sensitivity of the hypothalamic-pituitary-adrenal axis to negative feedback. It has also been proposed that metabolism of dexamethasone might differentiate between the activities of the two isozymes of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD1 and 11 beta HSD2). We have developed a gas chromatographic mass spectrometric assay for dexamethasone and 11-dehydrodexamethasone and have confirmed in vitro that dexamethasone is a substrate for 11 beta-HSD2 but not 11 beta-HSD1 (conversion to 11-dehydrodexamethasone 0.6 +/- 0.3% in homogenates of rat liver with NADP+ for 11 beta-HSD1, and 29.4 +/- 10.3% and 40.0 +/- 2.0% in homogenates of rat and human kidney respectively with NAD+ for 11 beta-HSD2). However, we have also made the novel observation that 11-dehydrodexamethasone is a substrate for both isozymes (conversion to dexamethasone 65.0 +/- 20.4% for 11 beta HSD1 and 53.5 +/- 20.8% and 69.0 +/- 4.5% for 11 beta HSD2, rat and human respectively). In healthy humans, the concentrations of 11-dehydrodexamethasone in plasma after an intravenous bolus of dexamethasone were less than 10% of those of dexamethasone, and 11-dehydrodexamethasone was detected (at 0.8-65.0 nM) in plasma from only 11 of 20 subjects at 0900 h on the morning after oral dexamethasone (0.1-1 mg taken at 2400 h). Concentrations of 11-dehydrodexamethasone did not correlate with the degree of suppression of plasma cortisol. Thus dexamethasone is not useful in differentiating the activities of the isozymes of 11 beta-HSD in vivo and variations in 11 beta-HSD activity do not explain the interindividual variability in suppression of plasma cortisol by low doses of dexamethasone.

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed1997

Testis sparing surgery for steroid unresponsive testicular tumors of the adrenogenital syndrome.

PURPOSE: Surgical management of steroid unresponsive testicular tumors of the adrenogenital syndrome has been orchiectomy. Magnetic resonance imaging (MRI) of these tumors accurately delineates the extent of disease. Testis sparing surgery is an important consideration, since male individuals with congenital adrenal hyperplasia are potentially fertile. We present our results of surgical management of this tumor based on MRI findings. MATERIALS AND METHODS: Four boys with steroid unresponsive testicular tumors of the adrenogenital syndrome were evaluated with MRI, testicular ultrasound and color flow Doppler examinations preoperatively and postoperatively. Three patients had 21-hydroxylase deficiency and 1 had 3-beta-hydroxysteroid dehydrogenase deficiency. Contralateral testicular abnormalities included a vanished testis, testicular atrophy due to trauma and bilateral tumors in 1 boy each. Bilateral orchiectomy and surgical enucleation were performed in 1 and 3 patients, respectively. Followup ranged from 8 to 18 months. RESULTS: Postoperative MRI of the testis in 2 of 3 patients showed no evidence of recurrent tumor. Postoperative testicular sonography revealed no tumor and vascular flow in 2 of 3 patients. All 3 patients who underwent testis sparing surgery have a viable testis in the scrotum without evidence of recurrent disease. CONCLUSIONS: MRI of the testis in patients with testicular tumors of the adrenogenital syndrome accurately defines the extent of disease. Surgical enucleation of this tumor has been performed successfully without recurrent disease. This surgical approach should be considered for any patient with a steroid unresponsive tumor and contralateral abnormalities. We believe that surgical enucleation is the procedure of choice for all patients with this tumor, since it maximizes future fertility potential.

Adolescent↗

PubMed1996

Abnormal glucocorticoid activity in subjects with risk factors for cardiovascular disease.

There are striking similarities between Cushing's syndrome and the 'metabolic syndrome X' since both are characterised by hypertension, insulin resistance, glucose intolerance, hyperlipidaemia, and central obesity. The possibility that cortisol contributes to the associations between multiple risk factors for cardiovascular disease was rejected when it was demonstrated that there was no elevation in cortisol secretion or circulating concentration in patients with essential hypertension or type 2 diabetes mellitus. However, in recent years the enormous variability in tissue sensitivity to cortisol has become apparent. We have measured tissue sensitivity to glucocorticoids using an assay of skin vasoconstriction and have demonstrated its relationship with high blood pressure, insulin resistance, glucose intolerance, and hypertriglyceridaemia. Our data suggest that the increase in dermal glucocorticoid sensitivity is not a secondary phenomenon and may be explained by increased glucocorticoid receptor affinity together with impaired inactivation of cortisol by 11 beta-hydroxysteroid dehydrogenase. Importantly, we have not found that enhanced peripheral glucocorticoid sensitivity is associated with compensatory suppression of cortisol secretion, so that the maintenance of normal circulating cortisol concentrations in patients with cardiovascular risk factors may be paradoxical and inappropriate.

Cardiovascular Diseases↗

PubMed1996

Chronic hypoxia selectively augments endothelium-dependent pulmonary arterial vasodilation.

We have previously demonstrated that chronic hypoxia (CH) augments pulmonary arterial dilation to the endothelium-derived nitric oxide (EDNO)-dependent pulmonary vasodilator arginine vasopressin (AVP). The present study examined 1) whether this enhanced vasoreactivity is observed with other agents that act by stimulating constitutive NO synthase (cNOS), 2) whether CH increases arterial vascular smooth muscle sensitivity to NO, and 3) whether endogenous endothelin (ET) or an endothelium-derived hyperpolarizing factor (EDHF) contributes to this altered arterial reactivity following CH. We examined responses to the receptor-mediated EDNO-dependent dilators histamine and ET-1, the nonreceptor-mediated EDNO-dependent dilator ionomycin, and the NO donors 1, 3-propanediamine, N-4-[1-(3-aminopropyl)-2-hydroxy-2-nitrosohydrazino] butyl (spermine NONOate) and S-nitroso-N-acetylpenicillamine (SNAP) in U-46619-constricted, isolated perfused lungs from control and CH rats. Additional experiments examined responses to AVP in the presence of the ET-receptor antagonist PD-145065 or the K+ channel blockers glibenclamide or tetraethylammonium (TEA) in lungs from each group. Microvascular pressure was assessed by double occlusion, allowing calculation of segmental resistances. Total and arterial vasodilatory responses to histamine, ET-1, and ionomycin were augmented in lungs from CH vs. control animals. However, CH did not alter the vasodilation to spermine NONOate or SNAP. PD-145065, glibenclamide, and TEA had no effect on responses to AVP in either group. We conclude that increased activity of arterial cNOS may be responsible for the augmented pulmonary arterial dilation to EDNO-dependent vasodilators following CH.

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

PubMed1996

Nitric oxide and cGMP do not affect fluid flux in isolated rat lungs.

We sought to examine the influence of nitric oxide (NO) and the second messengers guanosine 3',5'-cyclic monophosphate (cGMP) and intracellular Ca2+ on fluid flux in lungs isolated from male Sprague-Dawley rats and perfused with saline (containing 4% albumin) or with whole blood. Lungs were allowed to equilibrate for a period of 30 min without treatment (control group) or with one of the following agents: the exogenous NO donor spermine NONOate, the nitric oxide synthase inhibitor N omega-nitro-L-arginine (L-NNA), 8-BrcGMP, the Ca2- ionophore ionomycin, or the endothelial injurious agent protamine. After equilibration, perfusate reservoir height was increased to five incremental settings to increase pulmonary venous pressure and enhance fluid flux. Perfusate reservoir weight was monitored continuously as an index of fluid flux. The lung wet-to-dry weight ratio was determined on completion of the experiments. Increasing reservoir height was associated with an increase in pulmonary arterial, pulmonary capillary, and pulmonary venous pressures and an increase in fluid flux. However, treatment with exogenous NO or inhibition of endogenous NO was without effect on fluid flux in saline lungs at two different flow rates or in whole blood-perfused lungs. Similarly, treatment with cGMP and ionomycin did not alter fluid flux. Protamine pretreatment resulted in a significant increase in fluid flux at the highest reservoir setting, although exogenous NO and L-NNA pretreatments were without further effect on the protamine-treated lungs. Thus a role for NO and the second messengers cGMP and Ca2+ in modulating fluid flux could not be demonstrated in the isolated rat lung.

Animals↗