T. Naicker

Drug management of hypertensive disorders of pregnancy

Drugs used in the acute and long-term management of hypertension in pregnancy and the preeclampsia-eclampsia syndrome have been reviewed and their therapeutic effects and maternal and fetal adverse effects have been considered. The review also focuses on recent developments in the areas of prevention and management of pre-eclampsia-eclampsia syndrome. Although a number of new drugs have emerged, as potentially useful in the management of hypertension in pregnancy and pre-eclampsia-eclampsia syndrome, some remain at the cornerstone of therapy; for example, methyldopa for long-term treatment of chronic hypertension, hydralazine or nifedipine for rapid reduction of severely elevated blood pressure, and magnesium sulphate for eclampsia. Some of these agents, especially the calcium antagonists, show promise in that their use is associated with fewer side effects. Safety for the fetus, however, has not been adequately evaluated yet. Neither aspirin nor calcium supplements appear to improve the outcome in pregnancy. Currently, the dilemma whether to treat hypertension in pregnancy and pre-eclampsia-eclampsia syndrome with old, established, cost-effective drugs or the promising newer drugs provides an interesting academic challenge.

Transforming growth factor β 1 levels in platelet depleted plasma in African women with pre-eclampsia

Recently it has been suggested that TGF- g 1 may play an important role in trophoblast invasion of spiral arteries in pre-eclampsia. This study was designed to investigate TGF- g 1 levels in pre-eclampsia. Platelet depleted plasma TGF- g 1 levels were measured by ELISA in 43 normotensive healthy non-pregnant women, 30 normotensive healthy pregnant and 42 pre-eclamptic women: TGF- g 1 levels were increased significantly in the pre-eclamptics (4·9 - 0·9 ng/ml) compared to the normotensive pregnant (1·9 - 0·54 ng/ml; P <0·001) and normotensive non-pregnant groups (2·1 - 0·41 ng/ml; P <0·0001). There was no significant difference in TGF- g 1 levels between normotensive pregnant and non-pregnant groups (1·9 - 0·54 vs. 2·1 - 0·41 ng/ml; P =0·2). There was a highly significant correlation between neonatal weight ( r =0·63; P <0·0001) and TGF- g 1 levels. The finding of increased levels of plasma TGF- g 1 suggests an aetiological role of this peptide in pre-eclampsia.

Endothelin-1 activity in pregnancy.

Plasma endothelin-1 activity was measured by radioimmunoassay in 24 normotensive non-pregnant women and in 24 normotensive pregnant, 24-aproteinuric hypertensive and 24 pre-eclamptic women. Endothelin-1 activity was increased in the pre-eclamptic group (2·7 - 06 pg/ml) compared to the normotensive non-pregnant (1·0 - 0·8 pg/ml; P < 0·0001), normotensive pregnant (1·2 - 0·4 pg/ml; P < 0·0001) group and the aproteinuric hypertensive group (1·4 - 0·7 pg/ml; P < 0·0001). There was no difference in endothelin-1 activity between the normotensive non-pregnant and normotensive pregnant group (1·0 - 0·8 vs. 1·2 - 0·4 pg/ml; P = 0·3). However, there was a difference between the aproteinuric hypertensive group (1·4 - 0·7 pg/ml) and both the normotensive non-pregnant (1·0 - 0·8 pg/ml; P < 0·01) and the normotensive pregnant group (1·2 - 0·4 pg/ml; P < 0·06). The birth weight in the pre-eclamptic group (2·48 - 0·61kg) was significantly lower than that of the normotensive pregnant group (2·85 - 0·33 kg ; P < 0·001) and the aproteinuric hypertensive group (2·99 - 0·46 kg; P < 0·001). In addition, there was no difference in birth weight between the normotensive pregnant group and aproteinuric hypertensive group (2·85 - 0·33 vs. 2·99 - 0·46 kg; P = 0·3). A significant Pearsons correlation of plasma endothelin-l versus birth weight in the pre-eclamptic group was obtained ( r = 0·64; P < 0·0001). Endothelin-1 activity is increased with pre-eclampsia in black African women with pre-eclampsia. The results of our study also suggests an ethnic difference in plasma endothelin-1 activity when compared to result of studies carried out in Caucasian women with hypertensive disorders of pregnancy.

Tissue kallikrein in transplant kidney

Literature survey, thus far, has shown a decrease in the excretion of urinary tissue kallikrein (TK) in transplant patients with a further reduction of the enzyme during episodes of acute rejection. The study aims were to compare, at cellular and subcellular levels, the localisation of tissue kallikrein in biopsies of the transplant kidney to autopsy derived normal renal tissue. Renal biopsies from eighteen transplant patients with deteriorating renal function were obtained. Immunolabelling for tissue kallikrein, using a polyclonal goat anti-TK, antibody raised against recombinant TK, was performed following routine enzymatic, immunofluorescence and electron microscopic techniques. In normal kidney tissue, TK was immunolocalised in the distal connecting tubules and collecting ducts. By comparison the renal transplant tissue showed a reduction in the intensity of label, but maintained the sites of localisation. In the sections examined by electron microscopy, although TK was confined mainly at the luminal side of the cell, some label was noted along the basolateral membranes. In the transplant kidneys, there was a reduction in the overall number of gold particles counted, which correlated with the decreased intensity observed on immunocytochemistry. In addition, there was a shift to a basolateral orientation of the immunolabel. Acute rejection is characterised by oedema, tubulitis and vasculitis. Destruction of the tubule cells and leakage of TK into the interstitial tissue space and the resultant effect of the formed kinins on renal capillary vasculature could explain the observed renal parenchymal oedema and transplant rejection.

Immunolocalisation and endothelin-1 values In pre-eclampsia: an immunocytochemical study

Maternal plasma ET-1 levels and the immunolocalisation of ET1 in the fetal membranes of pre-eclamptic primigravidae at >/=28 weeks, gestation were studied. The levels of maternal plasma ET1 and immunoreactive ET-1 were increased in pre-eclampsia. Immunoreactive ET-1 was localised in the amnion, chorion and decidua of normal pregnant women as well as those with preeclampsia-eclampsia. Intense labelling was observed in moderate pre-eclampsia (BP 140/90 - 170/110 mmHg) with very intense labelling in severe pre-eclampsia (BP >170/110 mmHg), especially in the amniotic epithelium, chorionic villi, maternal blood vessels, cytotrophoblasts and giant cells of the decidua. The increased ET-1 levels demonstrated in fetal membranes of pre-eclamptic women are probably produced in a paracrine and/or autocrine manner, contributing to the hypertension, vasospasm and fetal growth restriction characteristic of the syndrome. A larger study would be required to show significant change in endothelin production in pre-eclampsia.Maternal plasma ET-1 levels and the immunolocalisation of ET1 in the fetal membranes of pre-eclamptic primigravidae at S 28 weeks, gestation were studied. The levels of maternal plasma ET1 and immunoreactive ET-1 were increased in pre-eclampsia. Immunoreactive ET-1 was localised in the amnion, chorion and decidua of normal pregnant women as well as those with preeclampsia-eclampsia. Intense labelling was observed in moderate pre-eclampsia (BP 140/90 - 170/110 mmHg) with very intense labelling in severe pre-eclampsia (BP >170/110 mmHg), especially in the amniotic epithelium, chorionic villi, maternal blood vessels, cytotrophoblasts and giant cells of the decidua. The increased ET-1 levels demonstrated in fetal membranes of pre-eclamptic women are probably produced in a paracrine and/or autocrine manner, contributing to the hypertension, vasospasm and fetal growth restriction characteristic of the syndrome. A larger study would be required to show significant change in endothelin production in pre-eclampsia.

Localisation of Tissue Kallikrein in the Kidney of Black African Women With Early Onset Pre-Eclampsia: A Pilot Study

Increased renal production of vasodilator mediators like kinins would counteract the vasospasm of pre-eclampsia. This study examines the cellular localisation of tissue kallikrein (TK), the potent kinin forming enzyme within the nephron of patients with early onset pre-eclampsia. Using the peroxidase-antiperoxidase immunoenzyme complex, TK was immunolocalised in the principal cells of the distal connecting tubule and the cortical collecting duct cells of the distal nephron of control tissue. Moderate reactivity was observed in the epithelial cells lining the Bowmans capsule. In early onset pre-eclampsia, TK was additionally localised in the proximal tubule cells, however, the intensity of reactivity was reduced when compared to that of the distal tubule cells. In patients with hypertension of pregnancy, the occurrence of TK in the proximal tubule suggests either gene induction or emiocytosis of TK.

PLASMA AND RED CELL MAGNESIUM LEVELS IN BLACK AFRICAN WOMEN WITH HYPERTENSIVE DISORDERS OF PREGNANCY

Objective: To measure plasma and red cell magnesium levels in black African women with hypertensive disorders of pregnancy.Methods: Plasma and red cell magnesium levels were analyzed using atomic absorption spectrophotometer in 27 patients presenting with severe hypertension in pregnancy, 27 patients with mild hypertension in pregnancy, and 27 healthy normotensive pregnant women.Results: There were no significant differences in plasma magnesium concentrations between the hypertensive groups compared to the normotensive group [mild vs. normotensive (0.82 ± 0.03 vs. 0.84 ± 0.03 mmol/L; P = 0.12); severe hypertension vs. normotensive (0.80 ± 0.03 vs. 0.84 ± 0.03 mmol/L; P = 0.15)]. There were not statistical differences in plasma magnesium levels between the hypertensive groups.There was a significant difference in the red cell magnesium concentrations between normotensive women and those with mild hypertension (2.3 ± 0.3 vs. 2.6 ± 0.5 mmol/L; P < 0.05) and those with severe hypertension in pregnancy (1.35 ±...

Changes in urinary tissue kallikrein excretion in black African women with hypertensive disorders of pregnancy.

The aim of this study was firstly to establish whether tissue kallikrein (TK) was involved in the aetiology of hypertensive disorders of pregnancy. Secondly, to assess whether tissue kallikrein:creatinine ratios may differentiate normotensive pregnant women from those with hypertensive disorders of pregnancy and have a predictive value. Random untimed urine samples were collected from all women (n = 264) recruited to this study. Urine specimens were analyzed for urinary tissue kallikrein using a selective, synthetic chromogenic tripeptide substrate (H-D-Val-Leu-Arg-pNA). Urinary creatinine levels were measured using standard methods. There was a significant difference in the excretion of urinary tissue kallikrein between normotensive pregnant women (2.91 ng TK/microgram protein) and women with mild (2.52 ng TK/microgram protein; p < 0.0001) and severe (1.53 ng TK/microgram protein; p < 0.0001) hypertension in pregnancy. No statistical difference was observed with regard to urinary tissue kallikrein excretion between normotensive pregnant and normotensive non-pregnant women (2.87 ng TK/microgram protein; p = 0.16). A positive correlation was observed between the diastolic blood pressure and urinary tissue kallikrein excretion in women with hypertensive disorders of pregnancy. When compared to the normotensive pregnant group, the urinary kallikrein:creatinine ratios were significantly lower in the mild (0.6 versus 0.3; p < 0.0001) and severe (0.6 versus 0.12; p < 0.0001) hypertensive groups. The urinary creatinine excretion was significantly higher in the mild (9.55 +/- 2.6 mmol/l; p < 0.0001) and in severe (15.62 +/- 5.48 mmol/l; p < 0.0001) hypertensives when compared to normotensive pregnant values (5.65 +/- 2.6 mmol/l). The reduced urinary tissue kallikrein excretion in hypertensive disorders of pregnancy may be a significant factor in the development of the hypertension in pregnancy. Measurement of urinary tissue kallikrein: creatinine ratios may represent a simple and practical predictive test to differentiate women with hypertensive disorders of pregnancy from normotensive pregnant women.

Tissue kallikrein activity in pregnancy.

Summary: To determine tissue kallikrein (TK) activity in black African women with hypertensive disorders of pregnancy; 140 women were recruited and divided into the following groups: group A – 35 preeclamptic women, group B – 35 mild to moderate hypertensive pregnant women and group C – 35 normotensive pregnant women, and group D – 35 normotensive non‐pregnant healthy women. The activity of tissue kallikrein was determined from a random untimed urine sample using a selective, synthetic chro‐mogenic tripeptide substrate having the sequence H‐D‐Val‐Leu‐Arg‐pNA (S‐2266). Urinary sodium and potassium levels was determined by flame photometry. Tissue kallikrein activity was decreased in women with preeclampsia (1.54 ± 0.95 vs 3.05 ± 0.83 ngTK/μg protein; p < 0.0001) and mild to moderate hypertensive group (2.03 ± 0.76 vs 3.05 ± 0.83 ngTK/μg protein; p < 0.0001) compared with normotensive pregnant women. There was also a significant difference in tissue kallikrein activity between the pregnancy groups (1.54 ± 0.95 vs 2.03 ± 0.76 ngTK/μg protein; p < 0.001). No difference in tissue kallikrein activity was observed between normotensive pregnant and normotensive non‐pregnant healthy women (3.05 ± 0.83 vs 3.14 ± 0.88 ngTK/μg protein; p = 0.51). There was no difference in the excretion of urinary sodium and potassium in pregnancy groups compared to normotensive pregnant group. Tissue kallikrein activity is decreased in hypertensive disorders of pregnancy.

The effect of therapeutic doses of paracetamol on liver function in the rat perfused liver.

Abstract— The isolated liver perfusion technique was used to study the effect of therapeutic doses of paracetamol on hepatic gluconeogenesis and bromosulphthalein clearance from the perfusate and biliary excretion of the dye in the rat. Six groups of rats were studied; those in the three experimental groups were given 0·02 g kg−1 paracetamol daily for ninety days. The livers of animals in the control group and in one of the experimental groups were perfused with a medium containing pyruvate. The animals in the second experimental and control group were perfused with a medium containing bromosulphthalein (10 mg/100 mL). The livers of the third experimental and control group were subjected to histological examination. The rate of glucose formation and glucose concentrations were decreased, while, lactate levels and lactate: pyruvate ratios were increased in paracetamol‐treated rats. The mean concentration of bromosulphthalein in the perfusate and biliary excretion of the dye were decreased. Macro and micro vesicular fatty change was present in the livers of paracetamol‐treated rats. This study demonstrates that chronic administration of therapeutic doses of paracetamol to rats adversely affects liver function, as evidenced by impaired gluconeogenesis and bromosulphthalein clearance from the perfusate, and excretion of the dye into the bile, and provides histological evidence of hepatic damage in rats.