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R J Workman

Publications and source records attributed to R J Workman.

At least 19 recordsLinked to original sources
PubMed1995

Factitious hypercortisoluria.

A case of factitious hypercortisoluria due to the presumed addition of glucocorticoid to the urine collections is presented. The discrepancy between urine and blood steroid hormone levels first suggested that the patient had tampered with the urine collections. Plasma steroid hormone levels were normal, whereas the urinary free cortisol level fluctuated in a totally random fashion. Urinary 17-hydroxycorticosteroid and urinary free corticosterone levels were normal. Partition chromatography of the urine indicated that the cortisol immunoactivity coeluted with authentic cortisol. This study illustrates the value of multiple urinary and plasma steroid determinations, especially urinary or plasma corticosterone measurements, in suspected cases of factitious Cushing's syndrome.

Adrenal Cortex Hormones↗
PubMed1994

A sensitive radioimmunoassay for fludrocortisone in human plasma.

Fludrocortisone has been a mainstay of therapy for orthostatic hypotension for many years. Clinical experience suggests that there exists a substantial interindividual variation in responsiveness to the drug. To assess this, we have developed an assay that permits measurement of the low concentrations of fludrocortisone found in human plasma. Fludrocortisone was detected by radioimmunoassay. A polyclonal rabbit antibody, raised against dexamethasone which cross-reacts strongly with fludrocortisone, was reacted with either standard or unknown samples in the presence of [125I]fludrocortisone-3-TyrNH2 (synthesized by coupling tyrosine amide to fludrocortisone-3-oxime and iodinating with chloramine T oxidation). The ED10, ED50, and ED80 were 0.34, 5.0, and 30 ng/mL of plasma, respectively. The cross reactivity with other 9-fluorinated steroids was found as follows: dexamethasone, 340%; betamethasone, 230%; and triamicinolone, 8%. To preclude an erroneous result, subjects who were pregnant or receiving any steroid medication were excluded from the study. The percent cross-reactivity with the main naturally occurring steroids was as follows: 11-desoxycortisol 3.2%, cortisol 1.1%, DOC 0.3%, pregnenolone 0.1%, corticosterone 0.06%, progesterone 0.05%, and aldosterone < 0.05%. The only compound with potential for interference, because of its high level in the circulation in the early morning, was cortisol.(ABSTRACT TRUNCATED AT 250 WORDS)

Fludrocortisone↗
PubMed1993

Serum angiotensin converting enzyme in diabetic patients.

Serum angiotensin converting enzyme (ACE) levels are higher in patients with diabetes mellitus than in many others. Techniques are available to grade different degrees of diabetic retinopathy, which can demonstrate a relationship between ACE and diabetic retinopathy. In this study, patients with diabetic retinopathy had higher serum ACE levels (6.3 +/- 0.2) than nondiabetic patients (4.3 +/- 0.5) (p < 0.001). In addition, the mean serum ACE level in diabetic patients with nonproliferative retinopathy (5.55 +/- 0.4) was less than that in diabetic patients with proliferative retinopathy (6.63 +/- 0.25) (p = 0.02). Due to the variability in individual serum ACE levels and the frequent use of ACE inhibitors by hypertensive diabetics, these techniques are not suitable for retinopathy screening programs. However, the graded relationship demonstrated by these data may have relevance for the pathophysiology of diabetic retinopathy.

Adult↗
PubMed1988

Effects of thromboxane synthase inhibitors on renal function.

In general the effects of thromboxane A2(TXA2) on renal function are opposite those produced by other prostanoids. TXA2 synthase inhibitors decrease the biosynthesis of TXA2 and may increase the production of other prostanoids by causing endoperoxide shunting. Therefore, in situations of increased kidney arachidonate mobilization, inhibition of renal TXA2 synthase might alter renal function by reducing TXA2 production and/or increasing prostaglandin (PG) biosynthesis. This hypothesis was tested by comparing the changes in renal function induced by suprarenal aortic constriction in anesthetized dogs pretreated with either a TXA2 synthase inhibitor (UK38,485; n = 7 or OKY1581; n = 7) or vehicle (0.1 M Na2CO3; n = 9). Several renal function parameters were compared in control versus treated animals by analysis of variance. Neither UK38,485 (1 mg/kg, i.v.) nor OKY1581 (10 mg/kg, i.v.) significantly altered renal artery hypotension-induced changes in mean arterial blood pressure, heart rate, renal blood flow, renal vascular resistance, glomerular filtration, filtration fraction, urine flow rate, sodium excretion rate, fractional sodium excretion, potassium excretion, or fractional potassium excretion. However, both UK38,485 and OKY1581 seemed to attenuate the increase in renal renin secretion rate induced by suprarenal aortic constriction. We conclude that acute administration of TXA2 synthase inhibitors does not modify acute renal artery hypotension-induced changes in either electrolyte excretion or renal hemodynamics. However, acute administration of TXA2 inhibitors attenuates suprarenal aortic constriction-induced increases in renin release in anesthetized dogs by unknown mechanisms.

Acrylates↗
PubMed1987

Methylene blue: a reliable and practical marker for validating compliance on the DST.

Assurance of compliance (ingestion of dexamethasone) is crucial for interpreting plasma cortisol results on the DST. In this double-blind study of 13 subjects, methylene blue (MB) 50 mg was combined with dexamethasone 1 mg in single capsules, and the resulting blue-green urinary color after ingestion was found to reliably validate compliance in 100% of patients and controls. The addition of MB did not influence DST results (i.e., plasma cortisol, plasma dexamethasone). Adding MB to dexamethasone as a marker is a reliable and safe means of validating compliance on the DST and is considerably more practical than plasma dexamethasone level determinations.

Adult↗
PubMed1986

Systemic synthesis of prostaglandin I2 following sustained infusion of angiotensin II in conscious dogs.

Acute infusion of pharmacological doses of angiotensin II stimulates the release of prostaglandin I2 (PGI2), which may modulate the vasoconstrictor response. It is uncertain whether sustained small increases in the plasma concentration of angiotensin II has the same effect. To investigate this further, low doses of angiotensin II were infused into conscious sodium replete dogs for 3 h. PGI2 synthesis was assessed by measurement of a major metabolite of PGI2, 2,3-dinor-6-keto PGF1 alpha, in urine and plasma, using gas chromatography mass spectrometry. Angiotensin II infusion (15 ng/min per kg body weight) resulted in a 3-fold increase in plasma angiotensin II (50.8 +/- 5.4 to 149 +/- 11.2 pg/ml, P less than 0.01). Mean blood pressure increased (84.8 +/- 4.3 to 108 +/- 4.7 mm Hg, P less than 0.02) and renal blood flow decreased (201 +/- 46 to 127 +/- 13 ml/min, P less than 0.01) throughout the infusion. However there was no change in either the plasma concentration (11.3 +/- 2.5 to 9.1 +/- 1.0 pg/ml) or rate of urinary excretion of dinor-6-keto PGF1 alpha (1.75 +/- 0.28 to 1.85 +/- 0.41 ng/30 min) during the angiotensin II infusion. The results suggest that small sustained elevations of the plasma concentration of angiotensin II such as are likely to occur in conscious animals, do not persistently stimulate release of PGI2 in the systemic circulation.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

A simplified method for the iodination of prostanoids for radioimmunoassay.

This paper presents a simplified method for iodination of prostanoids which combines conjugation and iodination into one brief step. The prostanoid is first coupled to histamine with EDC, and is thereafter iodinated directly without an intervening TLC step. The iodination mixture is purified on an LH-20 column, and the final iodinated product can be located unequivocally. The simplified procedure presented here should make iodinated tracers accessible to more laboratories.

Chloramines↗
PubMed1986

Dexamethasone suppression testing in chronic renal failure: pharmacokinetics of dexamethasone and demonstration of a normal hypothalamic-pituitary-adrenal axis.

The status of the hypothalamic-pituitary-adrenal axis in chronic renal failure (CRF) was examined by dexamethasone suppression testing (DST) using oral overnight, oral and iv 8-h daytime, and standard 48-h oral dosage protocols. Based on data obtained after iv administration of dexamethasone, the daytime study was used to calculate pharmacokinetic parameters for dexamethasone (clearance, volume of distribution at steady state, and terminal t1/2). None of a group of seven uremic patients had suppressed plasma cortisol concentrations after administration of 1 mg dexamethasone, orally, the night before. Six normal subjects and six patients with CRF participated in the pharmacokinetic study. There was no significant difference between the groups with respect to clearance, volume of distribution at steady state, or t1/2 of dexamethasone, indicating that patients with CRF metabolize dexamethasone in a fashion similar to that of normal subjects. Daily patterns of plasma cortisol determined between 0800-1600 h on a day when dexamethasone was not administered were similar in normal subjects and CRF patients. However, the degree of suppression of plasma cortisol after dexamethasone was significantly greater in the normal subjects (P less than 0.01), possibly due to a prolonged cortisol t1/2 in CRF. Nevertheless, the CRF patients did have decreased plasma cortisol levels from 4-8 h after iv and from 4-7 h after oral dexamethasone. The bioavailability of dexamethasone was not significantly different between the groups. When 48-h oral DSTs were performed in the CRF group, four of five patients had normal responses. The one patient who did not suppress had low levels of plasma dexamethasone, presumably due to decreased gastrointestinal absorption of dexamethasone. These results indicate that the metabolism of dexamethasone is similar in CRF patients and normal subjects, that normal suppression of plasma cortisol can be achieved in uremia if the duration of dexamethasone administration is prolonged sufficiently to compensate for the prolongation of cortisol t1/2 in CRF, and that it is essential to measure plasma dexamethasone as well as cortisol levels to interpret the results of a DST in CRF patients.

Administration, Oral↗
PubMed1985

A role for the adrenal renin-angiotensin system in the regulation of potassium-stimulated aldosterone production.

Potassium is a major regulator of aldosterone production. It also increases adrenal renin. The causal relationship between potassium and adrenal renin is not known. To evaluate the role of the intraadrenal renin-angiotensin (ANG) system in potassium-stimulated aldosterone synthesis and release, specific adrenal renin activity, PRA, and plasma aldosterone were measured during potassium loading or captopril treatment in the rat. Adrenal ANGs were determined using a HPLC system combined with RIA to obtain quantitative information on the components of the adrenal renin-ANG system. In addition, the effect of pretreatment with captopril on aldosterone production by isolated adrenal glomerulosa cells was examined. In intact animals potassium loading markedly increased adrenal renin and plasma aldosterone, whereas PRA was suppressed. The administration of captopril to rats in normal potassium balance did not suppress plasma aldosterone. Captopril treatment during potassium loading inhibited the potassium-induced increase in aldosterone. Furthermore, pretreatment with captopril suppressed adrenal ANG II and reduced the response of aldosterone production to extracellular potassium concentration by isolated adrenal glomerulosa cells in vitro. These results suggest that the adrenal renin-ANG system plays a significant role in the control of aldosterone production under potassium stimulation.

Adrenal Glands↗
PubMed1985

Unilaterally nephrectomized rat with aortic ligation: a uremic model of severe hypertension.

The purpose of this study was to characterize a new animal model of severe hypertension with azotemia. Hypertension was induced in rats by complete ligation of the aorta between the origin of the renal arteries. One month later chronic renal failure was induced by removing the right kidney. The serum creatinine concentration, mean arterial blood pressure (MABP), plasma renin activity (PRA) and plasma angiotensin II levels were monitored over the next two weeks. One month after aortic ligation, but before removal of the right kidney, the MABP, PRA, and plasma angiotensin II levels were significantly greater than in controls (P less than 0.05). Following nephrectomy serum creatinine concentration rose from 0.65 +/- 0.03 mg/100 ml (X +/- SEM) to 2.75 +/- 0.40 mg/100 ml and 1.78 +/- 0.22 mg/100 ml (P less than 0.05), 3 and 14 days after the right nephrectomy, respectively. Although the elevated MABP remained unchanged, the PRA and plasma angiotensin II concentrations significantly declined to levels indistinguishable from normotensive controls. These data indicate that combining aortic ligation with right nephrectomy produces a uremic model of severe hypertension in the rat. This model may facilitate studies designed to determine the best choice of antihypertensive drugs in the situation of severe hypertension and renal insufficiency.

Angiotensin II↗
PubMed1985

Comparison of serum phospholipid fatty acids among fishing and farming Japanese populations and American inlanders.

Fatty acid compositions of phospholipids in serum were analyzed in three different populations in seaside fishing and mountain farming villages in Japan and in inland inhabitants of the United States of America. The percentage of omega-3 polyunsaturated fatty acids, i.e., eicosapentaenoic acid (20:5) and docosahexaenoic acid (22:6) was significantly low in United States inlanders with a high coronary heart disease morbidity compared with both populations in Japan with low morbidity. The level of arachidonic acid (20:4) was the same among these three inhabitant population groups. However, omega-3 polyunsaturated fatty acid levels were significantly higher in the inhabitants of fishing villages with relatively low stroke morbidity than in those of farming villages with extremely high stroke morbidity in Japan.

Agriculture↗
PubMed1985

Endothelial prostacyclin production is a late event in granulocyte migration into bovine pulmonary artery intimal explants.

Whether migration of granulocytes across pulmonary vascular endothelium in the absence of structural evidence of endothelial injury causes increased production of thromboxane or prostacyclin is not known. Using bovine pulmonary artery intimal explants mounted in Boyden chambers and homologous separated granulocytes, concentrations of thromboxane B2 and 6-keto-PGF1 alpha in the upper-well fluid were measured by radioimmunoassay over a three-hour period under the following conditions: (1) granulocyte chemotaxis (zymosan-activated plasma in the lower well, granulocytes in the upper well); (2) unstimulated granulocyte migration (serum or plasma in the lower well, granulocytes in the upper well); (3) granulocyte activation without migration (zymosan-activated plasma and granulocytes in the upper well); (4) granulocyte chemotaxis in the absence of endothelium (identical to condition 1 above except that endothelium was scraped from the explant surface); and (5) explants incubated in the absence of granulocytes. Minimal increases in thromboxane B2 concentrations in upper-well fluid occurred under all conditions. In contrast, granulocyte chemotaxis was accompanied by large increases in concentrations of 6-keto-PGF1 alpha evident by two hours of incubation and increasing markedly by three hours, to 524.3 +/- 69.0 ng/mL (m +/- SEM). Unstimulated migration of granulocytes toward serum or plasma and granulocyte activation without migration were accompanied, at three hours, by more modest increases in 6-keto-PGF1 alpha (296.5 +/- 46.4; 128.0 +/- 38.6, and 236.7 +/- 47.0 ng/mL, respectively) and, in the absence of granulocytes or in the absence of endothelium, only minimal increases in this prostacyclin metabolite occurred (137.2 +/- 16.9 and 53.9 +/- 12.6 ng/mL, respectively). The large rises in prostacyclin metabolite occurred at a time when the majority of granulocytes had migrated through the endothelial layer rather than during their adherence or transendothelial passage. We conclude that chemotaxis of granulocytes through pulmonary vascular endothelium causes endothelial production of large amounts of prostacyclin, but this occurs late in the chemotactic process, after granulocytes have transversed the endothelium.

Animals↗
PubMed1984

Pleiotropic activities of human interferons are mediated by multiple response pathways.

Among the pleiotropic effects of human interferon are the inhibition of viral replication, the activation of natural killer cells, and the inhibition of cellular growth. Oxyphenbutazone, a nonsteroidal antiinflammatory agent, is a potent inhibitor of the antiviral activity of human alpha and beta interferons as determined by cytopathic effect and vesicular stomatitis virus synthesis and release in human foreskin fibroblasts. The inhibition of interferon activity is dose dependent with maximal inhibition at 25-50 microM and minimal inhibition at 1 microM. In contrast, oxyphenbutazone at concentrations as high as 100 microM has no effect on the activation of natural killer cells by human interferon. Similarly, oxyphenbutazone has no inhibitory effect on interferon-induced antigrowth activity in the human breast carcinoma cell line MDA-MB-231. This cell line is sensitive to oxyphenbutazone inhibition of interferon-induced antiviral activity in vitro. In another human cell line, the vulvar carcinoma A431, oxyphenbutazone apparently augments the antigrowth activity of interferon. Although oxyphenbutazone inhibits the fatty acid cyclooxygenase enzyme in these systems, other inhibitors of cyclooxygenase fail to inactivate the antiviral activity of human interferon. Thus, oxyphenbutazone appears to inhibit the interferon antiviral cascade at a site distinct from prostaglandin biosynthesis. Moreover, the failure to inhibit natural killer cell activation or cellular antigrowth effects of human interferon suggests a pathway different from that associated with the antiviral effect of human interferon.

Breast Neoplasms↗
PubMed1983

A functional cyclooxygenase enzyme is not required for mediation of the pleiotropic effects of human alpha or beta interferon.

Aspirin, indomethacin, and phenbutazone at 50 microM concentration inhibit cyclooxygenase in cultured human foreskin fibroblasts as evidenced by the suppression of the major prostaglandin species which accumulate in the culture medium. In contrast to data reported for mouse interferon on target mouse cells, these agents have no effect on the induction of antiviral activity by human alpha or beta interferons. Similarly, these agents have no effect on interferon induced inhibition of cell growth in vitro or on interferon induced natural killer cell activity.

Aspirin↗
PubMed1983

Prostaglandin biosynthesis does not participate in hypercapnia-induced cerebral vasodilatation in the dog.

The participation of cerebral prostaglandin biosynthesis in hypercapnia-induced cerebral vasodilation was assessed in pentobarbital-anesthetized dogs using the radioactive microsphere technique. In five dogs, administration of 5% CO2 increased pCO2 from 31.0 +/- 0.8 to 53.4 +/- 2.4 mm Hg (P less than .001) and decreased total cerebral vascular resistance from 11.2 +/- 3.0 to 2.6 +/- 0.6 mm Hg . min . 100 g . ml-1 (P less than .001). The observed increases in pCO2 and the decreases in cerebral vascular resistance during 5% CO2 inhalation were unchanged 1 hr after administration of an i.v. bolus of 0.1 M Na2CO3 (vehicle). In another group of five dogs, 5% CO2 increased pCO2 from 30.4 +/- 0.58 to 55.2 +/- 4.2 mm Hg (P less than .01) and decreased total cerebral vascular resistance from 5.7 +/- 0.6 to 1.8 +/- 0.4 mm Hg . min . 100g . ml-1 (P less than .001). In these dogs, the CO2-induced decrease in cerebral vascular resistance 1 hr after a bolus dose of indomethacin (10 mg/kg i.v.) dissolved in 0.1 M Na2CO3 was also unchanged. In both groups of dogs the patterns described for total cerebral vascular resistance were also observed in the cerebrum, cerebellum and brainstem. The dose of indomethacin used in this study abolished the vasodepressor responses to i.v. arachidonic acid and suppressed the total brain secretion rate of immunoreactive 6-keto-prostaglandin F1 alpha. Furthermore, the administration of 5% CO2 did not increase the total brain secretion rate of immunoreactive 6-keto-prostaglandin F1 alpha. We conclude that cerebral prostaglandin biosynthesis does not mediate or modulate hypercapnia-induced cerebral vasodilation in the dog.

Animals↗
PubMed1982

Attenuation of the development of hypertension in spontaneously hypertensive rats by the thromboxane synthetase inhibitor, 4'-(imidazol-1-yl) acetophenone.

The compound 4'-(imidazol-1-yl) acetophenone was demonstrated to be a selective thromboxane (Tx) synthetase inhibitor in spontaneously hypertensive rats (SHR). Serum TxB2 concentrations (from clotted blood) were suppressed by 89.1% (p less than 0.001) and 41.2% (p less than 0.01) at 3 and 24 hours, respectively, following a single subcutaneous injection of 100 mg/kg of 4'-(Imidazol-1-yl) acetophenone suspended in olive oil. In contrast, plasma 6-keto-PGF1 alpha levels were not significantly altered at 3 hours following injection - a time when suppression of TXB2 was maximal. From 4 to 10 weeks of age, SHR were treated with daily injections of either 4'-(Imidazol-1-yl) acetophenone (100 mg/kg) in olive oil or olive oil alone. By 8 weeks of age systolic blood pressures in the treated group were 140.6 +/- 3.2 vs 156.6 +/- 4.5 mmHg in the control group (p less than 0.01). At ten weeks of age the separation was even more pronounced: 155.3 +/- 3.7 vs. 184.8 +/- 4.6 mmHg for treated vs. control animals (p less than 0.001). This data supports the hypothesis that thromboxanes may be involved in the development of SHR hypertension; however, alternative mechanisms are discussed.

6-Ketoprostaglandin F1 alpha↗
PubMed1981

Proteinase activity of human renin preparations: the International Reference Preparation (Renin Standard 68/356).

1. Several commonly used preparations of human renin, including the International Reference Preparation (Renin Standard 68/356), were examined for the presence of contaminating proteinase activity by using a 14C-glycinated bovine haemoglobin substrate assay. 2. All of the human renin preparations tested cleaved haemoglobin even in the presence o di-isopropylfluorophosphate and ethylenediaminetetra-acetate (EDTA). For a given amount of renin activity, varying amounts of proteinase activity were seen. The pH optimum also varied between preparations. 3. Small peptide inhibitors of human renin were not able to inhibit the proteinase activity. Furthermore a diazoacyl reagent and pepstatin, both potent inhibitors of aspartic acid-active site proteinases, were only partially inhibitory. 4. These and other observations suggest that the proteinase activity of the human renin preparations is not due to renin itself, but to contaminating proteinases of different types. Since these enzymes may produce angiotensin I or peptides which may interfere in renin assays, crude preparations of renin which contain proteinase activity, including the International Reference Preparation, should be used with caution or replaced by proteinase-free human renin which can be easily prepared by use of suitable affinity chromatography.

Chromatography, Affinity↗