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Biomedical subjects

B R Walker

Publications and source records attributed to B R Walker.

At least 127 records · Page 7Linked to original sources
PubMed1994

Cardiovascular responses to hemorrhage during acute and chronic hypoxia.

Previous work from our laboratory had demonstrated attenuation of systemic vasoreactivity to pressor agents in rats after acute or chronic exposure to hypoxia. Therefore we hypothesized that hemorrhage of acutely hypoxic (12% O2) or chronically hypoxic (barometric pressure 380 mmHg for 3 wk) rats would deter the normal increase in total peripheral resistance (TPR) and thus decrease the ability to maintain blood pressure. Progressive hemorrhage (2% of blood volume per min) was performed under conditions of either normoxia or acute hypoxia in conscious rats. In control animals, the increase in TPR observed during normoxic hemorrhage was absent when hemorrhage was performed in acute hypoxia. Furthermore, the amount of blood removal required to achieve hypotension was reduced under conditions of acute hypoxia. In contrast, chronically hypoxic rats exhibited no difference in the threshold for hypotension between conditions of acute normoxia and hypoxia and demonstrated an increased hypotensive threshold under both normoxic and hypoxic conditions compared with control animals. We next hypothesized that the prolonged threshold for hypotension observed in chronically hypoxic rats might be due to hypoxia-induced right ventricular hypertrophy. Such ventricular hypertrophy may minimize stimulation of ventricular volume receptors thought to elicit the reflex fall in heart rate and TPR occurring in extreme underfill conditions. Therefore we compared the cardiovascular responses to hemorrhage in rats with right ventricular hypertrophy resulting from administration of monocrotaline with those from rats treated with vehicle.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1994

Regulation of 11 beta-hydroxysteroid dehydrogenase activity by the hypothalamic-pituitary-adrenal axis in the rat.

11 beta-Hydroxysteroid dehydrogenase (11 beta-OHSD) inactivates glucocorticoids and thereby modulates their access to both mineralocorticoid and glucocorticoid receptors. Since 11 beta-OHSD activity influences the biological responses of the hypothalamic-pituitary-adrenal axis, it might be regulated by components of this axis. We examined 11 beta-OHSD activity in adrenalectomized rats treated for 9 days with dexamethasone and with or without ACTH. Adrenalectomy and low-dose (2 micrograms/day) dexamethasone had no effect on 11 beta-OHSD activity in renal cortex, hippocampus or heart, and reduced enzyme activity in aorta. High-dose dexamethasone (50 micrograms/day) had no effect in renal cortex but increased enzyme activity by at least 50% in all other sites. This effect of dexamethasone was unaffected by the co-administration of ACTH. We also examined the metabolism of dexamethasone by 11 beta-OHSD in homogenized rat tissues. Only in kidney, in the presence of NAD rather than NADP, was dexamethasone converted to a more polar metabolite previously identified as 11-dehydrodexamethasone. We conclude that: dexamethasone induction of 11 beta-OHSD is tissue-specific, and includes vascular tissues and hippocampus but not kidney; this tissue-specificity may be explained by contrasting metabolism of dexamethasone by the isoforms of 11 beta-OHSD; fluctuations of glucocorticoid levels within the physiological range may not have a biologically significant effect on 11 beta-OHSD activity; and the inhibitory effect of ACTH, observed previously in humans, is likely to depend on the presence of intact adrenal glands.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1994

Licorice-induced hypertension and syndromes of apparent mineralocorticoid excess.

Excessive ingestion of licorice induces a syndrome of hypokalemia and hypertension that reflects increased activation of renal mineralocorticoid receptors by cortisol. A similar syndrome of cortisol-dependent mineralocorticoid excess occurs in congenital deficiency of the enzyme 11 beta-hydroxysteroid dehydrogenase, which normally inactivates cortisol to cortisone. It has been shown that licorice inhibits 11 beta-dehydrogenase, preventing local inactivation of cortisol and allowing cortisol inappropriate access to intrinsically nonspecific renal mineralocorticoid receptors. Further studies with licorice and its derivatives have revealed a widespread role for 11 beta-dehydrogenase in regulating tissue sensitivity to cortisol. Deficient 11 beta-dehydrogenase activity provides a novel pathogenetic mechanism for hypertension, and current research suggests that several common forms of hypertension can be explained by the mechanisms that operate in licorice-induced hypertension.

Adrenal Hyperplasia, Congenital↗
PubMed1994

Direct and indirect effects of carbenoxolone on responses to glucocorticoids and noradrenaline in rat aorta.

BACKGROUND: In the kidney carbenoxolone impairs inactivation of glucocorticoids and facilitates their access to mineralocorticoid receptors by inhibiting 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD). 11 beta-OHSD is also expressed in vascular smooth muscle, and, in humans, carbenoxolone potentiates vasoconstrictor sensitivity to cortisol and noradrenaline. OBJECTIVE: To establish in vitro whether the vascular effects of carbenoxolone are mediated by inhibition of 11 beta-OHSD. METHODS: Noradrenaline-induced vasoconstriction was measured in helical de-endothelialized rat aortic strips following 2-5 h exposure to one or more of: carbenoxolone, corticosterone, a mineralocorticoid-receptor antagonist (spironolactone) and a glucocorticoid- and progesterone-receptor antagonist (RU 38486). RESULTS: Carbenoxolone potentiated noradrenaline-induced vasoconstriction in aortae from adrenalectomized rats, an effect which was prevented by spironolactone but not by RU 38486. By contrast, when corticosterone was added or when aortae from non-adrenalectomized rats were studied, carbenoxolone attenuated noradrenaline-induced vasoconstriction. CONCLUSIONS: Carbenoxolone has a direct effect, independent of 11 beta-OHSD, which potentiates noradrenaline-induced vasoconstriction and might be mediated by activation of mineralocorticoid receptors. Carbenoxolone also has an indirect effect, attenuating noradrenaline-induced vasoconstriction dependent on corticosterone and, therefore, mediated by inhibition of 11 beta-OHSD. Although experiments with carbenoxolone must be interpreted with caution because of its direct effect, the present data confirm that 11 beta-OHSD modulates vascular sensitivity to glucocorticoids and noradrenaline. Therefore, 11 beta-OHSD activity might influence blood pressure by effects in both the kidney and the vasculature.

Adrenalectomy↗
PubMed1993

Kainic acid lesions increase reafferentation of the striatum by substantia nigra grafts.

Effects of kainic acid lesions of the striatum on reafferentation of the striatum produced by intraventricular substantia nigra (SN) grafts were investigated. Rats with unilateral 6-hydroxydopamine lesions of the SN received intrastriatal kainic acid lesions or sham lesions, and then received fetal (E16) SN or sciatic nerve grafts in the lateral ventricle. The depth of reafferentation of the striatum by catecholaminergic neurites from SN grafts was significantly increased in rats with kainic acid-induced striatal lesions, as compared to the sham-lesioned controls. No reafferentation was seen in the control animals with sciatic nerve grafts. These data suggest that striatal injury promotes the growth of dopaminergic neurites from SN grafts.

Afferent Pathways↗
PubMed1993

Steroid hormones and hypertension: the cortisol-cortisone shuttle.

The role of adrenal steroid hormones in hypertension has, until recently, focused on disorders of secretion. We describe a new form of mineralocorticoid hypertension which arises from impaired metabolism of physiological glucocorticoid. 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) is responsible for the inactivation of cortisol to cortisone. Congenital absence of this enzyme (the syndrome of apparent mineralocorticoid excess) results in cortisol acting as a potent mineralocorticoid. Furthermore, inhibition of this enzyme by glycyrrhizic and glycyrrhetinic acids also accounts for the mineralocorticoid excess states seen following licorice and carbenoxolone ingestion. Whilst impaired 11 beta-HSD activity has been shown in patients with "essential" hypertension, the significance of this finding remains unknown. These clinical studies, however, have uncovered a novel physiological mechanism, whereby the mineralocorticoid receptor (which in vitro has an equal affinity for cortisol and aldosterone) is protected from cortisol excess by the action of 11 beta-HSD. Thus 11 beta-HSD plays a crucial role in determining the in vivo specificity for this receptor.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1993

Congenital and acquired syndromes of apparent mineralocorticoid excess.

The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) interconverts cortisol and cortisone. Congenital deficiency of the renal isoform of the enzyme results in hypertension, hypokalemia and suppression of the renin-angiotensin-aldosterone system--the apparent mineralocorticoid excess syndrome (AME). In these patients cortisol acts as a potent mineralocorticoid. Suppression of plasma cortisol with dexamethasone results in natriuresis, potassium retention and reduction in blood pressure. Ingestion of excess liquorice or taking carbenoxolone produces an acquired form of AME. The active component of liquorice is glycyrrhetinic acid (GE) and carbenoxolone is the hemisuccinate derivative. Both GE and carbenoxolone are potent inhibitors of 11 beta-OHSD. In vitro studies have shown that 11 beta-OHSD is present in aldosterone-selective tissues and acts as an autocrine mechanism which prevents cortisol from gaining access to the non-specific mineralocorticoid receptor (MR). Congenital or acquired absence of this enzyme allows cortisol to bind to MR resulting in AME. 11 beta-OHSD also appears to be important in controlling cortisol access to glucocorticoid receptors. Variable placental 11 beta-OHSD may alter foetal exposure to maternal cortisol and affect growth as indicated by the correlation between foetal weight and placental 11 beta-OHSD. Thus the tissue-specific distribution, ontogeny and modulation of this enzyme allows it to dictate glucocorticoid effects in addition to its key role in ensuring the specificity of the MR.

11-beta-Hydroxysteroid Dehydrogenases↗
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↗
PubMed1993

Deficient inactivation of cortisol by 11 beta-hydroxysteroid dehydrogenase in essential hypertension.

OBJECTIVE: 11 beta-Hydroxysteroid dehydrogenase protects renal mineralocorticoid receptors from cortisol by converting cortisol to inactive cortisone. 11 beta-Dehydrogenase deficiency, either congenital or after inhibition by liquorice and carbenoxolone, results in cortisol-dependent mineralocorticoid excess and hypertension. We tested the hypothesis that the same mechanism occurs in some patients with essential hypertension. DESIGN/PATIENTS: Twenty patients with essential hypertension were compared with 19 matched healthy controls. MEASUREMENTS: 11 beta-Hydroxysteroid dehydrogenase activity was assessed by the half-life of 11 alpha-3H-cortisol, and by the ratios of cortisol to cortisone in plasma and of their metabolites in urine. Renal mineralocorticoid receptor activation was assessed by plasma potassium, renin activity and aldosterone. RESULTS: Half-lives of 11 alpha-3H-cortisol were prolonged in a subgroup of hypertensives (mean +/- SE 53.2 +/- 3.6 min in hypertensives vs 42.3 +/- 2.3 in controls, P < 0.05; seven of the 20 hypertensives had half-lives exceeding 2 SD of controls). Ratios of cortisol to cortisone in plasma and of their metabolites in urine were not different. 11 alpha-3H-Cortisol half-lives correlated with blood pressure but not with indices of renal mineralocorticoid receptor activation. CONCLUSIONS: 11 beta-Dehydrogenase is defective in a proportion of patients with essential hypertension. The normal ratios of cortisol to cortisone in plasma and of their metabolites in urine, also seen after carbenoxolone administration, suggest that 11 beta-reductase conversion of cortisone to cortisol is also defective. Unlike other syndromes of 11 beta-dehydrogenase deficiency, the defect was not associated with mineralocorticoid excess. We suggest that it may cause hypertension by increasing exposure of vascular steroid receptors to cortisol.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1993

Maintained endothelium-dependent pulmonary vasodilation following chronic hypoxia in the rat.

We have previously demonstrated that arginine vasopressin (AVP) dilates the preconstricted pulmonary vasculature via the release of nitric oxide (NO). However, recent evidence suggests that NO release in response to other agents may be suppressed in lungs from animals that have been chronically exposed to hypoxia. The purpose of the present experiment was to determine whether vasopressinergic pulmonary vasodilation is similarly affected by chronic exposure to hypoxia (barometric pressure = 380 Torr for 4 wk). Inhibition of NO synthesis with N omega-nitro-L-arginine (L-NNA) had no effect on baseline perfusion pressure in isolated salt-perfused lungs from either control or chronically hypoxic rats. Similarly, pulmonary vasodilatory responses to AVP and the calcium ionophore A23187 were unaffected by chronic hypoxic exposure. Pretreatment with the cyclooxygenase inhibitor meclofenamate did not alter vasopressinergic pulmonary vasodilation in lungs from either control or chronically hypoxic animals, ruling out involvement of vasodilator prostaglandins in the response to AVP. In contrast, vasodilatory responses to both AVP and A23187 were inhibited by L-NNA pretreatment not only in lungs from control animals but also in lungs from chronically hypoxic rats, suggesting the involvement of NO in the vasodilatory response. The inhibition by L-NNA was reversible by prior addition of excess L-arginine but not by D-arginine. In addition, vasodilatory responses to the endothelium-independent vasodilators sodium nitroprusside and isoproterenol were unaffected by chronic hypoxic exposure. We conclude that endothelium-dependent vasodilation remains intact in male Sprague-Dawley rats after chronic hypoxic exposure.

Air Pressure↗
PubMed1993

Pressure natriuresis following therapy for "one-clip one-kidney" hypertension in man.

Decreased renal tubular reabsorption of sodium in response to increased renal artery perfusion pressure, or "pressure natriuresis", has been demonstrated directly in animal experiments but not in man. In bilateral or single-kidney renovascular hypertension, hypertension has been attributed to reduced pressure natriuresis, and a similar mechanism may operate in chronic renal failure. We report a patient who presented with bilateral renovascular disease and was treated initially by unilateral nephrectomy. At a second operation the remaining ischemic kidney was revascularised. There followed a dramatic natriuresis, sufficient to cause clinical and biochemical features of hypovolemia. However, despite the natriuresis, systemic blood pressure remained elevated in the few weeks following surgery. We attribute the natriuresis to increased renal artery perfusion pressure, and conclude that acute pressure natriuresis sufficient to over-ride neurohormonal antinatriuretic mechanisms does occur in man. However, the failure to normalize blood pressure acutely following the natriuresis suggests that decreased sodium excretion is not the only mechanism which maintains hypertension in this unusual syndrome.

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↗