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Biomedical subjects

J A Whitworth

Publications and source records attributed to J A Whitworth.

At least 19 recordsLinked to original sources
PubMed1992

The kidney in hypertensive pregnancies--victim and villain.

Many changes in renal function occur in normal pregnancy. Without a proper understanding of these changes, routine clinical investigations may easily be misinterpreted. Women with preeclampsia have further alterations in renal function and, in occasional cases, develop acute renal failure. Understanding of abnormal renal physiology and hormonal changes in these women allows the clinician to interpret biochemical tests appropriately and make proper use of vasodilator therapy with careful attention to volume homeostasis. Women who undertake pregnancy with a primary renal disease, most commonly glomerulonephritis or reflux nephropathy, have a higher risk of adverse fetal and maternal outcomes. Awareness of these risks provides a basis for proper preconceptual counseling, as well as careful monitoring of maternal blood pressure and renal function and fetal growth during such pregnancies. These strategies will optimize the chances of a successful pregnancy outcome for both mother and baby.

Female↗
PubMed1992

Endothelium-derived prostacyclin: effect of serum from women with normal and hypertensive pregnancy.

1. Pregnancy-induced hypertension (or pre-eclampsia) is characterized by vasoconstriction, platelet aggregation and altered capillary permeability, implying disordered endothelial function and/or structure. Serum from women with pregnancy-induced hypertension has been reported by others to be cytotoxic to endothelial cells in vitro. We hypothesized that such serum contains a factor that limits the ability of endothelial cells to produce and/or release prostacyclin. 2. Prostacyclin production by intact and damaged cultured human umbilical vein endothelial cells was measured after incubating these cells with serum from non-pregnant and normal pregnant women and women with pregnancy-induced hypertension. Confluent human umbilical vein endothelial cell monolayers (intact and damaged) were incubated with sera for 24 h at 37 degrees C followed by 1 h of incubation with added thrombin (stimulated production) or media (basal production). Supernatants were then collected for measurement of 6-keto-prostaglandin F1 alpha by radioimmunoassay. 3. Basal production of 6-keto-prostaglandin F1 alpha was greater in response to serum from non-pregnant women than to that from pregnant women. Within each group, sub-lethally damaged cells had a similar basal production of 6-keto-prostaglandin F1 alpha to that of intact cells. 4. Basal production of 6-keto-prostaglandin F1 alpha by intact or damaged cells incubated with sera from normal pregnant women and from women with pregnancy-induced hypertension was similar. 5. In all groups the addition of thrombin to intact endothelial cells increased 6-keto-prostaglandin F1 alpha production approximately 15-30-fold over basal levels, but only three- to five-fold in damaged endothelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1992

Measurement of plasma volume in pregnancy.

1. Determination of the plasma volume in pregnant women is a useful research tool and may become an important clinical measurement. We used three methods to determine plasma volume using Evans Blue dye: (1) the 'usual' method, measuring serum absorbance at a wavelength of 610 nm, (2) a two-wavelength method, and (3) precipitation of non-albumin proteins by the addition of polyethyleneglycol before measuring serum absorbance at a wave-length of 620 nm. These were each compared with the standard 125I-human serum albumin method in 20 non-pregnant subjects. Subsequently, the polyethylene glycol method was considered the standard and the three Evans Blue dye methods were compared in 20 pregnant women. 2. In non-pregnant subjects mean plasma volumes did not differ significantly according to the method used. However, the limits of agreement with 125I-human serum albumin method were closest for the polyethyleneglycol method, for both clear and turbid sera. 3. In pregnant women, mean plasma volume values did not differ according to the Evans Blue dye method used, but the limits of agreement were significantly closer with the two-wavelength method than with the 'usual' method (P less than 0.05) largely owing to the effects of turbid sera. 4. These studies demonstrate that considerable error may occur when the Evans Blue dye concentration is determined in turbid sera by the 'usual' method. This can be overcome by the use of the two-wavelength method or the polyethyleneglycol method. The most accurate results will be obtained if the latter method is employed routinely to determine plasma volume in pregnant women.

Adult↗
PubMed1992

Coagulation abnormalities and ivermectin.

Prothrombin ratios were measured 13-16 days after treatment in 148 subjects from Sierra Leone taking part in a double-blind placebo-controlled trial of ivermectin. Prolonged prothrombin ratios were observed more frequently in the ivermectin group, although this difference was not significant and no patients suffered bleeding complications. Further investigation of these patients failed to reveal any abnormality of liver function, although factor VII and II levels were reduced in most affected individuals, suggesting interference with vitamin K metabolism. Ivermectin has a minimal effect on coagulation and concern about mass treatment for this reason appears to be unjustified.

Adolescent↗
PubMed1992

Corticotropin effects on blood pressure and fluid and electrolyte homeostasis in five strains of rats.

The hemodynamic and metabolic effects of 11 days of sham (saline) and corticotropin injection were examined in five different strains of rats: Sprague-Dawley, spontaneously hypertensive (SHR), Wistar-Kyoto (WKY), Brattleboro, and Long Evans. Corticotropin significantly increased systolic blood pressure (SBP) compared with sham injection in all strains: final SBP in Sprague-Dawley was 108 +/- 5 mm Hg corticotropin, 94 +/- 4 mm Hg sham; SHR 146 +/- 6 mm Hg corticotropin, 141 +/- 3 mm Hg sham; WKY 117 +/- 3 mm Hg corticotropin, 103 +/- 3 mm Hg sham; Brattleboro 108 +/- 5 mm Hg corticotropin, 93 +/- 2 mm Hg sham; and Long Evans 103 +/- 5 mm Hg corticotropin, 90 +/- 4 mm Hg sham (P less than .001). Corticotropin also produced a decrease in body weight and increases in water intake and urine output. Increases in urine electrolyte excretion were seen in some, but not all strains. The rise in pressure in the Brattleboro rats indicated that vasopressin is not essential for the corticotropin-induced rise in pressure. Blood pressure rises in SHR were not exaggerated. Withdrawal of corticotropin in Sprague-Dawley rats led to rapid reversal of the corticotropin-induced hemodynamic and metabolic changes. Thus, strain does not appear to be an important factor in corticotropin hypertension in the rat, in contrast to deoxycorticosterone hypertension.

Adrenocorticotropic Hormone↗
PubMed1992

Renin-aldosterone relationships in pregnancy-induced hypertension.

The relationship between plasma renin (PRC) and aldosterone (PAC) concentrations was determined in 83 normal third trimester pregnant women (P), 50 women with pregnancy-induced hypertension (PIH), and 80 age-matched nonpregnant women not taking oral contraceptives (NP). Normal pregnant women had a slightly higher 24-h urine sodium: creatinine ratio than the other groups (P less than .001) (NP: 10 +/- 4 v P: 15 +/- 8 v PIH: 12 +/- 7; mean +/- SD). Both PRC and PAC were higher in normal pregnant women as was the ratio PAC:PRC [normal pregnant 195 (158 to 337) v nonpregnant 130 (101 to 209), median (interquartile range); P less than .001]. This was accompanied by a slightly reduced slope (sensitivity) of the logPRC-logPAC relationship in normal pregnant women (P less than .05). Women with PIH had reduced PRC and PAC compared with normal pregnant women but a two-fold greater increase in PAC:PRC ratio [PIH 411 (277 to 598) v normal pregnancy 195 (158 to 337), P less than .001], with a rise in the slope (sensitivity) of the logPRC-logPAC relationship in women with PIH (P less than .001). Thus there is proportionately greater aldosterone release in the third trimester of normal pregnancy than in nonpregnant women. This preferential increase in aldosterone may be due to altered adrenal sensitivity to angiotensin II or may reflect enhanced nonangiotensin stimulation of aldosterone during pregnancy. Women with PIH have reduced PRC and PAC but relatively greater stimulation of aldosterone than normal pregnant women, possibly due to enhanced sensitivity of the adrenal glands to angiotensin II.

Aldosterone↗
PubMed1992

Role of the renal medulla in adrenocorticotrophin-induced hypertension in rats.

OBJECTIVES: The mechanism of hypertension induced by adrenocorticotrophin (ACTH) remains unclear. The antihypertensive renomedullary lipids are vasodilators and it has been proposed that a deficiency of these lipids may contribute to the hypertension produced by destruction of the renal papilla. The aim of the present work was to study ACTH hypertension in both control and chemically renomedullectomized rats. METHODS: Renomedullectomy was produced by single intraperitoneal injection of 2-bromoethylamine (BEA) at 400 mg/kg. RESULTS: BEA-treated rats all developed increases in water intake and urine volume, with loss of papillae and medullary and cortical fibrosis. There was a significant correlation between papillary ablation and systolic blood pressure (SBP). SBP in renomedullectomized rats was higher after ACTH than sham injection, and higher than after ACTH injection in intact rats. CONCLUSION: Chemical renomedullectomy with BEA did not block or attenuate the onset or magnitude of ACTH hypertension in the rat.

Adrenocorticotropic Hormone↗
PubMed1992

Inhibition of NO synthesis has an additive effect on hypertension induced by ACTH in conscious rats.

1. The haemodynamic and metabolic effects of oral intake of approximately 30 mg/kg per day N-nitro-L-arginine (NOLA) were examined in sham and adrenocorticotrophin (ACTH, 0.5 mg/kg per day) treated conscious Sprague-Dawley rats (n = 33). 2. NOLA administration produced an increase in systolic blood pressure of 24 +/- 6 mmHg (P < 0.001), but did not alter food or water intake, urine volume or electrolyte excretion in rats not treated with ACTH. 3. Compared with sham injection, ACTH-treated rats demonstrated an increase in systolic blood pressure (water + sham, 3 +/- 1 mmHg; water + ACTH, 16 +/- 3 mmHg; P < 0.001), loss of bodyweight, and increases in water intake and urine volume. 4. The magnitude of the blood pressure rise in ACTH-treated rats was greater in those receiving NOLA than in those drinking water only (water + ACTH, 16 +/- 3 mmHg; NOLA + ACTH, 37 +/- 3 mmHg; P < 0.05). Metabolic changes were similar. 5. Inhibition of nitric oxide is unlikely to be a major determinant of ACTH-induced hypertension in the rat, since NOLA increased blood pressure whether or not ACTH was administered, indicating an additive effect of ACTH and NOLA administration.

Adrenocorticotropic Hormone↗
PubMed1992

Pressor responsiveness in corticosteroid-induced hypertension in humans.

In previous studies short-term cortisol increased cold pressor responses and the rise in forearm vascular resistance accompanying intra-arterial norepinephrine without an increase in overall resting sympathetic nervous activity. The present study examined whether these alterations in pressor response are glucocorticoid or mineralocorticoid effects, or both. Normal male subjects (n = 12) received either fludrocortisone, 0.3 mg daily (n = 6), or dexamethasone, 3 mg daily (n = 6), for 7 days. Hemodynamic studies were performed before and on day 7 of treatment. Fludrocortisone increased body weight from 69.3 +/- 1.8 to 71.1 +/- 2 kg (p less than 0.001), cardiac output from 5.0 to 6.0 l/min (+/- 0.1, p less than 0.01), mean arterial pressure from 82 +/- 1 to 91 +/- 1 mm Hg (p less than 0.001), cold pressor responsiveness from 13.0 to 39.0 mm Hg/ml per 100 ml per minute (R units) (+/- 4.3, p less than 0.01), and forearm vascular response to intra-arterial norepinephrine (F = 59.4, p less than 0.01) and angiotensin II (F = 30.8, p less than 0.01) infusions. Total peripheral resistance fell from 22.0 to 20.1 mm Hg/l per minute (+/- 0.3, p less than 0.05). Dexamethasone did not increase cardiac output, 5.1 to 5.2 l/min (+/- 0.1), or body weight but did increase mean arterial pressure from 82 +/- 3 to 91 +/- 3 mm Hg (p less than 0.001), cold pressor responsiveness from 8.6 to 17.1 R units (+/- 2.8, p less than 0.05), and forearm vascular response to intra-arterial norepinephrine (F = 33.0, p less than 0.01) and angiotensin II (F = 54.9, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Preservation of renal function in chronic renal failure.

Mechanisms of progression of chronic renal failure (CRF) have been well documented in the rat but may not be relevant in man. Factors which may modify clinical CRF include underlying disease, diet, hypertension, intercurrent events, and adverse or beneficial effects of drug therapy. It has been argued that progression in many forms of renal disease is inexorable below a certain level of renal function. In other diseases, eg primary malignant hypertension, analgesic nephropathy, function frequently improves in both the short and long term with appropriate management. Thus knowledge of the nature of the underlying disease is essential in assessing progression. The value of diet in preserving renal function has been debated, particularly the relative roles of protein and phosphate control. In our own unit, a prospective randomized study showed a benefit of protein restriction. Development of accelerated hypertension is an important cause of progression of renal disease and clinical and experimental evidence supports the view that non-accelerated hypertension is also a factor in progression, amenable to treatment. Various intercurrent events may accelerate progression and function may be lost permanently following sepsis, urinary tract obstruction, renal arterial or venous obstruction, hypotension and in some cases pregnancy. Numerous drugs can have deleterious effects on the kidney. The possibility that converting enzyme inhibitors might preserve renal function is attracting attention but in view of their side effects their place in therapy should be determined by prospective controlled studies in which the above factors are carefully considered.

Animals↗
PubMed1992

Glomerulosclerosis and hyalinosis in rabbits.

Histological appearances of remnant kidney in female New Zealand white rabbits undergoing left nephrectomy at 6 mths were studied. All 20 rabbits had evidence of previous Encephalitozoon cuniculi (E. cuniculi) infection. Half of the 10 uninephrectomized and 10 control animals completed 3 pregnancies before sacrifice (15 mths). Twelve of 30 kidneys at sacrifice showed focal and segmental hyalinosis and sclerosis (FSHS), a lesion not previously reported in rabbits. Four of 5 kidneys in both uninephrectomized pregnant and uninephrectomized virgin animals showed FSHS compared with 2 of 10 in both control pregnant and non-pregnant rabbits (p = 0.0026). More glomeruli were sclerosed in control pregnant (median 3.5%) than non pregnant animals (median 0.4%) (p < 0.005). Median right kidney weights per kilogram body weight were greater in previously nephrectomized animals (3.9 gm/kg) than controls (2.6 gm/kg), (p < 0.001). Absolute glomerular area was increased in hypertrophied kidneys, however, after correction for kidney weight, glomerular area was smaller in previously uninephrectomized animals than controls (p < 0.0001).

Animals↗
PubMed1992

ACTH hypertension in the rat: role of sodium chloride.

Adrenocorticotrophin (ACTH) produces adrenally dependent increases in both blood pressure and salt (NaCl) appetite in the rat. The present study examines the effect of free access to a high intake of NaCl on ACTH hypertension in the rat to test the hypothesis that high NaCl intake would amplify the rise in blood pressure. Either water or 1%NaCl were offered to sham or ACTH treated Sprague-Dawley rats. Subcutaneous injections of synthetic ACTH (0.5 mg/kg/day) for 10 days caused large increases in the intake of both 1%NaCl (+240 +/- 6 ml/day) and water (+45 +/- 4 ml/day), urine volume (1%NaCl + ACTH +182 +/- 4 ml/day, ACTH + water +36 +/- 2 ml/day), adrenal weight (ACTH + water 176 +/- 18, ACTH + 1%NaCl 367 +/- 129 mg/100 g body weight) and maximum systolic blood pressure (SBP) (ACTH + water +18 +/- 5 mmHg; 1%NaCl + ACTH +16 +/- 3 mmHg). Some ACTH + 1%NaCl rats developed severe edema. Thus, free access to NaCl in ACTH treated Sprague Dawley rats did not potentiate the hypertension, but was associated with edema in some animals.

Adrenal Glands↗
PubMed1992

Haemodynamic and metabolic effects of short term administration of synthetic sex steroids in humans.

Synthetic sex steroid administration is a major cause of iatrogenic hypertension but little is known of the haemodynamic or metabolic consequences of these steroids. This study examined the short term blood pressure, volume and metabolic consequences of 5 day administration of synthetic androgen to normal men and synthetic oestrogen or progestogen to normal women. Healthy subjects (8 women, 6 men) on a constant diet took part in each of 3 studies. Males received testosterone undecanoate 120 mg/day (n = 6) and females either ethinyloestradiol 0.3 mg/day (n = 5) or norethisterone 15 mg/day (n = 6) for 5 days in the last week of the cycle. Norethisterone increased lying (+7 mmHg) and standing (+8 mmHg) systolic pressure but the other steroids did not alter blood pressure. All 3 treatments increased body weight. There were no consistent changes in plasma electrolytes or glucose with any steroid, and no urinary sodium retention or changes in urine Na:K ratio. Haematocrit fell on ethinyloestradiol but no steroid significantly increased plasma volume (measured as volume of distribution of 125I human serum albumin). Renin substrate and cortisol rose and renin concentration fell on ethinyloestradiol. These studies suggest that the progestogen component may contribute to the blood pressure raising effects of oral contraceptives.

Adult↗
PubMed1992

The effect of repeated doses of ivermectin on adult female Onchocerca volvulus in Sierra Leone.

The effects of single and multiple doses of ivermectin on mortality and morphology were assessed in over 700 female Onchocerca volvulus worms and the effects on embryogenesis were assessed in 490. Nodules were surgically removed from Sierra Leoneans recruited from a double-blind placebo controlled study of ivermectin given at six-monthly intervals. Nodules were digested in collagenase to isolate whole adult worms. After four or five doses of ivermectin there were significant increases in the numbers of discoloured and calcified worms and possibly a trend towards increased mortality, but this was not seen consistently. There was no evidence of a prophylactic effect of the drug. Worms were then homogenised and embryograms constructed. A single dose of ivermectin produced large numbers of degenerating intrauterine microfilariae, but embryonic development occurred normally. After multiple doses we observed almost complete cessation of embryogenesis, with a highly significant decrease in the numbers of viable multicellular embryonic stages, while oocytes appeared to be produced normally. Development is probably impeded at the single cell stage, possibly because of reduced fertilization. In planning the future role of ivermectin as a control measure for onchocerciasis it is crucial to determine if these effects on embryogenesis are reversible.

Adolescent↗
PubMed1992

Adrenocorticotrophin and steroid-induced hypertension in humans.

ACTH and adrenocortical steroids have been known to raise blood pressure since their introduction into clinical practice. Our experimental studies in normal subjects show that ACTH reproducibly increases blood pressure in association with a rise in cardiac output, plasma and extracellular fluid volumes and exchangeable sodium. The rise in pressure is adrenally dependent and appears due to ACTH-induced increases in cortisol secretion. When ACTH is given by constant intravenous infusion, rates as low as 50 micrograms/day raise pressure. The increase in blood pressure is not dependent on, but modified by, dietary sodium content. Synthetic steroids (prednisolone, methylprednisolone, triamcinolone, dexamethasone) raise pressure in the absence of any increase in plasma volume or urinary sodium retention. Cortisol increases pressor responsiveness to endogenous and exogenous catecholamines, without evidence of any increase in sympathetic nervous activity. The role of this increased pressor responsiveness in ACTH/steroid-induced hypertension remains to be determined. There is some evidence from human studies that steroids may raise pressure by a hypertensinogenic mechanism, distinct from classical mineralocorticoid or glucocorticoid effects.

Adrenocorticotropic Hormone↗
PubMed1992

Immunological studies on onchocerciasis in Sierra Leone. 2. Cell-mediated immune responses after repeated treatment with ivermectin.

Cell mediated responses of peripheral blood lymphocytes were tested by incorporation of I-125 dideoxyuridine in a standard proliferation assay. The cells were collected from age and sex-matched patients selected on the basis of their clinical and parasitological status. These patients were treated with either ivermectin or placebo at 6-monthly intervals for two years. For the purpose of comparison, the patients were divided into three groups: children aged 5-9 years; 10-19 year olds; and, those older than 20 years. Repeated drug treatment over the two year period had no effect on either mitogenic or non-parasite antigen (PPD) responses in a majority of individuals. However, in younger children (5-9 years) repeated treatment with ivermectin resulted in some enhancement of Onchocerca-specific responses measured 6 months after administration of the drug. This effect was more pronounced in children presenting with positive skin-snips. An age related decline in mitogenic responses was observed.

Adolescent↗