Plasma uric acid remains a marker of poor outcome in hypertensive pregnancy: a retrospective cohort study.

OBJECTIVE: To examine the relationship between hyperuricaemia, haemoconcentration and maternal and fetal outcomes in hypertensive pregnancies. DESIGN: Retrospective analysis of a database of hypertensive pregnancies. SETTING: St George Hospital, a major obstetric unit in Australia. POPULATION: A cohort of 1880 pregnant women without underlying hypertension or renal disease, referred for management of pre-eclampsia or gestational hypertension. METHODS: Demographic, clinical and biochemical data at time of referral and delivery were collected for each pregnancy. Women were grouped according to diagnosis (pre-eclampsia or gestational hypertension) and logistic regression analysis was used to determine the relationship between uric acid, haemoglobin, haematocrit and adverse outcomes; an α level of P < 0.01 was used for statistical significance. MAIN OUTCOME MEASURES: Composites of adverse maternal and fetal outcomes. RESULTS: In women with 'benign' GH (without proteinuria or any other maternal clinical feature of pre-eclampsia) gestation-corrected hyperuricaemia was associated with increased risk of a small-for-gestational-age infant (OR 2.5; 95% CI 1.3-4.8) and prematurity (OR 3.2; 95% CI 1.4-7.2), but not with adverse maternal outcome. In the whole cohort of hypertensive pregnant women (those with pre-eclampsia or gestational hypertension) the risk of adverse maternal outcome (OR 2.0; 95% CI 1.6-2.4) and adverse fetal outcome (OR 1.8; 95% CI 1.5-2.1) increased with increasing concentration of uric acid. Hyperuricaemia corrected for gestation provided additional strength to these associations. Haemoglobin and haematocrit were not associated with adverse pregnancy outcome. CONCLUSIONS: Hyperuricaemia in hypertensive pregnancy remains an important finding because it identifies women at increased risk of adverse maternal and particularly fetal outcome; the latter, even in women with gestational hypertension without any other feature of pre-eclampsia.

Circadian blood pressure variability in adrenocorticotrophin-induced hypertension in the rat.

OBJECTIVES: Secondary hypertension is often characterized by loss of diurnal blood pressure variability. This study examined circadian (24 h) blood pressure variability in adrenocorticotrophin (ACTH)-induced hypertension in the Sprague-Dawley rat. METHODS: Male Sprague-Dawley rats were randomly allocated to sham (0.9% saline, s.c.), n = (9), ACTH (0.5 microg/kg per day, s.c., n = 8) or ACTH (100 microg/kg per day, s.c., n = 7) in a room with a 12 h light/dark cycle (0600 h to 1800 h). A radio telemetry transducer was used to measure blood pressure in unrestrained animals over 3 control days (C1-C3) and 10 treatment days (T1-T10). Heart rate, systolic (SBP), mean arterial (MAP) and diastolic (DBP) blood pressure were continuously recorded. Body weight was measured daily and serum corticosterone concentration ([B]) prior to death. RESULTS: Sham treatment had no effect on any parameters. ACTH 100 microg/kg per day increased SBP from 124+/-2 pooled control (PC) to 134+/-2 mmHg (T10), MAP from 105+/-2 to 115+/-2 mmHg and DBP from 87+/-1 to 99+/-2 mmHg and decreased heart rate from 305+/-6 to 249+/-5 beats/min and body weight from 299+/-6 (C3) to 280+/-8 g (T10) (all P' < 0.0036). Serum [B] was higher in ACTH- (881+/-44 ng/ml) than sham-treated rats (384+/-17 ng/ml, P < 0.001). There were no differences between sham treatment and ACTH 0.5 microg/kg per day. SBP, MAP, DBP and heart rate were consistently higher for ACTH 100 microg/kg per day and sham-treated animals during the dark cycle (1800 h to 0600 h) than the light cycle (0600 h to 1800 h). CONCLUSIONS: ACTH 100 microg/kg per day raises blood pressure in conscious unrestrained Sprague-Dawley rats without any change in normal diurnal rhythm.

The role of corticosterone in corticotrophin (ACTH)-induced hypertension in the rat.

OBJECTIVE: Corticotrophin (ACTH)-induced hypertension in the rat is prevented by L- but not D-arginine. We examined the effects of exogenous corticosterone in the male Sprague Dawley (SD) rat to determine whether ACTH-induced hypertension is mediated by corticosterone. METHODS: Exogenous corticosterone (10, 20 or 40 mg/kg per day) or sham (polyethylene glycol (PEG) 1 ml/kg per day) was injected subcutaneously in divided doses (s/c b.d.) over 15 treatment days to 40 SD rats (n = 10 each group). Subsequently, the effects of L-arginine, D-arginine or L-arginine + N-nitro-L-arginine (NOLA) on corticosterone-induced hypertension (corticosterone 20 mg/kg per day) were examined. Systolic blood pressure (SBP) and metabolic parameters were measured every two days. RESULTS: Twenty and 40 mg/kg per day of corticosterone increased SBP compared with sham (P< 0.01, P< 0.05 respectively, sham versus respective group). Forty mg/kg per day of corticosterone raised serum corticosterone concentration compared with sham (502 +/- 20 versus 364 +/- 25 ng/ml, P < 0.001). L-arginine prevented the rise in SBP produced by corticosterone (131 +/- 3 to 131 +/- 2 mmHg, control versus day 10) but D-arginine did not (129 +/- 3 to 142 +/- 4 mmHg on day 8, P < 0.01). NOLA blocked the effect of L-arginine and amplified the rise in blood pressure produced by corticosterone (130 +/- 3 to 171 +/- 6 mmHg on day 10, P < 0.001). CONCLUSIONS: The haemodynamic features of ACTH-induced hypertension were reproduced by corticosterone excess, at concentrations of corticosterone similar to those in studies of exogenous ACTH administration. It is likely that ACTH-stimulated adrenal production of corticosterone accounts for the features of ACTH-induced hypertension in the rat

Cortisol inhibits cholinergic vasodilation in the human forearm.

Exogenous cortisol raises blood pressure (BP) in humans and there is accumulating evidence of abnormalities of glucocorticoid activity in essential hypertension. In this study we tested the hypothesis that exogenous cortisol attenuates the cholinergic dilator response in the forearm circulation. Fourteen healthy normotensive men were studied. Using bilateral forearm venous plethysmography, we examined forearm blood flow responses to intra-arterial acetylcholine (ACh) and sodium nitroprusside (SNP) pre- and post-NG-monomethyl-L-arginine (LNMMA) after 2 or 5 days of oral cortisol or placebo in a randomized, double-blind crossover study. Exogenous cortisol increased supine systolic (P < .05) and standing systolic (P < .05) BP and produced expected metabolic changes and suppressed serum cortisol concentration (P < .001). Baseline forearm blood flow did not differ between placebo and cortisol treatments at 2 or 5 days. Cholinergic vasodilatation was impaired after cortisol administration, reaching statistical significance at 5 days (P < .05). Cortisol did not affect responses to SNP. NG-monomethyl-L-arginine inhibited cholinergic vasodilatation in placebo-treated groups but had no additional effect in the presence of cortisol. These results support our hypothesis and suggest that the mechanism of impaired cholinergic dilatation in glucocorticoid-treated subjects involves abnormalities of the endothelial nitric oxide system.

Characteristics of hypertensive disorders in twin versus singleton pregnancies.

OBJECTIVE: To determine the characteristics of hypertensive disorders of pregnancy in twin compared with singleton pregnancies. STUDY DESIGN: Analysis of a prospectively recorded database of 4976 hypertensive pregnancies. MAIN OUTCOME MEASURES: Comparison of progression to pre-eclampsia and maternal and neonatal outcomes. RESULTS: There were 3942 singleton and 214 twin pregnancies. De novo hypertension in twin pregnancy was diagnosed earlier (p<0.001). In singleton pregnancies with de novo hypertension (n=3161), 60% had an initial diagnosis of gestational hypertension (GH) and 40% had pre-eclampsia (PE). In twin pregnancies with de novo hypertension (n=199), 35% of women were initially diagnosed with GH and 65% with PE (p<0.001). At delivery, 46% of the singletons had GH and 54% had PE, compared with twin pregnancies where 23% had GH and 77 % had PE (p<0.001). The progression from GH to PE for twins was twice that of singleton pregnancies (p<0.001). There were 781 singleton and 15 twin pregnancies with chronic hypertension (CH). Twin pregnancies complicated by CH were more likely to progress to PE than singletons (p<0.01). The gestation at delivery was earlier for twin pregnancies (p<0.001) and there were more twins that were smaller for gestational age (p<0.001). There were no differences in maternal outcomes. CONCLUSION: Women carrying twins with de novo hypertension are more likely to present earlier, have initial PE and to subsequently progress from GH to PE. Neonatal outcomes are worse in such pregnancies.

Nitric oxide synthase activity in adrenocorticotrophin-induced hypertension in the rat.

1. The nitric oxide (NO) system has been implicated in the pathogenesis of various forms of experimental hypertension. We studied nitric oxide synthase (NOS) activity as a possible indicator of NO production in adrenocorticotrophin (ACTH)-induced hypertension in the rat. 2. Haemodynamic, metabolic and biochemical parameters were examined in sham (saline)- and ACTH (100 microg/kg per day)-treated male Sprague-Dawley rats (n = 20). 3. Adrenocorticotrophin treatment increased systolic blood pressure, serum corticosterone, adrenal NOS activity and adrenal nitrate and nitrite concentrations and decreased bodyweight and plasma nitrate/nitrite. 4. Previous observations of diminished NO production in ACTH- and corticosterone-induced hypertension in the rat were confirmed, but could not be explained by reduced NOS activity in the present study.

Cushing, cortisol, and cardiovascular disease.

Cushing's syndrome of glucocorticoid excess is named after the eminent Boston neurosurgeon Harvey W. Cushing (1869-1939). The recognition that glucocorticoid excess produces hypertension led to examination of the role of cortisol in essential hypertension, but it is only over the last decade that evidence has emerged to support the concept. Despite the widespread assumption that cortisol raises blood pressure as a consequence of renal sodium retention, there are few data consistent with the notion. Although it has a plethora of actions on brain, heart and blood vessels, kidney, and body fluid compartments, precisely how cortisol elevates blood pressure is unclear. Candidate mechanisms currently being examined include inhibition of the vasodilator nitric oxide system and increases in vasoconstrictor erythropoietin concentration.

Difficulties in detecting parathyroid hypertensive factor in the rat.

1. Parathyroid hypertensive factor (PHF) has been implicated in the pathogenesis of several forms of hypertension. We aimed to establish a PHF bioassay using spontaneously hypertensive rat (SHR) plasma. 2. Spontaneously hypertensive rats were confirmed hypertensive and their plasma was dialysed and injected into anaesthetized normotensive rats. 3. Haemodynamic responses to injected SHR plasma were uninterpretable during pentobarbital anaesthesia due to blood pressure (BP) fluctuation. Under halothane anaesthesia, BP was stable but did not rise following SHR plasma injection. Using filtered, undialysed plasma and a different brand of pentobarbital, no consistent BP response was observed following SHR plasma injection. 4. We were unable to detect PHF in the SHR.

Comparison of telemetric and tail-cuff blood pressure monitoring in adrenocorticotrophic hormone-treated rats.

1. The aim of the present study was to validate a telemetric blood pressure (BP) monitoring system against tail-cuff blood pressure in both adrenocorticotrophic hormone (ACTH)- and sham-treated rats. In the statistical analyses, we first tested whether there was a detectable effect on systolic blood pressure (SBP) of 10 days treatment with ACTH compared with saline. Second, we compared results of telemetered and tail-cuff measurements and, third, we developed a novel method for estimating the relative power of the two techniques. 2. Twenty-three male Sprague-Dawley rats were randomly divided into two groups: (i) ACTH (100 microg/kg per day, s.c; n = 12) treated; or (ii) sham treated (0.9% saline, s.c; n = 11). Systolic BP was measured by the telemetric system (sampled for 10 s every 2 min) continuously for 4 h (n = 16) or for 30 min (n = 23) and also by the indirect tail-cuff method daily (n = 23). Data were compared within and between groups; ordinary least products (OLP) regression analysis was then performed to test for bias between the two methods. Sample size/power estimations were also performed. 3. Adrenocorticotrophic hormone treatment raised telemetered SBP by 11 mmHg (P < 0.001) compared with 14 mmHg (P < 0.001) using the tail-cuff method. There was no fixed or proportional bias between the two methods of measurement, as shown by regression analysis. Power calculations indicate that a minimum sample size of six gives a power of telemetered to tail-cuff of 0.84/0.86 = 0.98. The power of 4 h versus 30 min BP measurements was 0.99/0.82 = 1.2. 4. Telemetry gave very similar results to the tail-cuff method. Telemetry allows for a longer period of measurement, giving greater power to the study so that fewer animals are needed.

Telemetric monitoring of adrenocorticotrophin-induced hypertension in mice.

1. The mouse is the animal of choice for studies involving genetic manipulation and transgenic and knockout mice are valuable tools for physiological studies. We have studied adrenocorticotrophin (ACTH)- and steroid-induced hypertension in both rat and humans. The aim of the present study was to develop a model of ACTH-induced hypertension in the mouse and to assess a chronically implanted telemetric device for measurement of blood pressure (BP). 2. Male Swiss Outbred and Quackenbush Swiss (QS) mice (35-45 g) were implanted with TA11PA-C20 BP devices (Data Sciences International, St Paul, MN, USA) under isoflurane anaesthesia. Seven to 10 days later, mice were monitored telemetrically for baseline BP for 4 days. Mice were then randomly allocated to: (i) sham treatment with normal saline s.c.; or (ii) ACTH at 500 microg/kg per day, s.c. Mice were monitored 24 h/day for 10 days. 3. Sham treatment (n = 7) did not affect BP (114 +/- 2/84 +/- 1 to 115 +/- 2/84 +/- 1 mmHg; P = NS). Adrenocorticotrophin treatment (n = 5) raised BP from 112 +/- 7/82 +/- 4 to 138 +/- 3/104 +/- 4 mmHg, which was significantly different from sham treatment (P = 0.0021 for systolic BP; P < 0.0001 diastolic BP). The increase in BP with ACTH was comparable with that seen in previous studies in humans, sheep and rat. Sham and ACTH-treated animals each lost 3% bodyweight. 4. Administration of ACTH (500 microg/kg per day) raises BP in two strains of mice, measured using a telemetry system. This model will allow the selective use of transgenic and/or knockout mice to further elucidate the mechanism of ACTH- and steroid-induced hypertension.

Glucocorticoid-induced hypertension: from mouse to man.

1. Adrenocorticotrophic hormone (ACTH) raises blood pressure in humans, sheep, rat and mouse. In rat and humans, but not sheep, the hypertension can be explained by glucocorticoid excess. 2. In both rat and humans, the hypertension is associated with a rise in cardiac output and renal vascular resistance. 3. In both rat and humans, the nitric oxide system is implicated in glucocorticoid hypertension. 4. In both rat and humans, hypertension due to naturally occurring glucocorticoids is not prevented by drugs that block classical glucocorticoid or mineralocorticoid receptors. 5. Abnormalities in glucocorticoid metabolism may contribute to some forms of 'essential' hypertension.

Adrenocorticotrophic hormone-induced hypertension in the rat: effects of the endothelin antagonist bosentan.

1. The effects of the endothelin antagonist bosentan on adrenocorticotrophic hormone (ACTH)-induced hypertension were examined in the conscious male Sprague-Dawley rat. 2. In order to confirm endothelin antagonism, 18 rats were randomly divided into two groups: receiving either (i) endothelin-1 (0.125, 0.25, 0.5 and 1 nmol/kg, i.v.); or (ii) endothelin-1 at these doses following bosentan (100 mg/kg gavage) and mean arterial pressure recorded (study A). Subsequently, 40 male rats (320 +/- 5 g) were randomly divided into four groups (n = 10): (i) Sham (0.9% saline, s.c.) + 5% acacia gum gavage; (ii) ACTH (500 micrograms/kg per day, s.c.) + 5% acacia gum gavage; (iii) Sham injection + bosentan (100 mg/kg per day) gavage; or (iv) ACTH + bosentan. Six control days (C1-C6) were followed by 11 treatment days (T0-T10). Systolic blood pressure, water intake, urine volume, food intake and bodyweight were measured every second day (study B). 3. Bosentan significantly attenuated the endothelin-1-induced blood pressure rise at 0.125 nmol/kg (P < 0.05), but not at higher doses. 4. Bosentan at a dose which attenuated endothelin-1-induced blood pressure increase had no effect on either blood pressure or metabolic parameters in ACTH-treated rats. 5. These results suggest that endothelin does not play a major role in ACTH-induced hypertension.

The role of the parathyroid glands in adrenocorticotrophin-induced hypertension in the rat.

The aim of this study was to determine whether parathyroidectomy (PTx) would modify hypertension secondary to adrenocorticotrophin (ACTH) administration. Male Sprague Dawley (SD) rats were randomly assigned to one of five groups; (i) sham (saline) treatment (NaCl 0.9% s/c 0.5 ml/kg/day), (ii) ACTH treatment (Synacthen Depot 0.5 mg/kg/day), (iii) saline/PTx/1% CaCl2 in water, (iv) ACTH/PTx/1% CaCl2 in water and (v) ACTH/1% CaCl2 in water. Tail cuff systolic blood pressure (SBP) and metabolic parameters were measured on alternate days for 4 control (C) and 11 treatment days (T0-T10). There was no change in SBP in the sham and saline/PTx/CaCl2 groups over T0-10. SBP increased in the ACTH treated groups. PTx did not modify ACTH-induced increases in SBP or metabolic effects. These results do not support a role for the parathyroids in the genesis of ACTH-induced hypertension in the rat.

Twenty-four-hour automated blood pressure monitoring as a predictor of preeclampsia.

OBJECTIVE: The purpose of this study was to determine the predictive ability of parameters of 24-hour ambulatory blood pressure monitoring for the development of preeclampsia or gestational hypertension in women who are already considered at risk for these disorders. STUDY DESIGN: One hundred twenty-two pregnant women who were considered high risk for the development of preeclampsia underwent 24-hour ambulatory blood pressure monitoring between 18 and 30 weeks gestation, while their condition was normotensive according to routine mercury sphygmomanometry. One hundred sixty-four healthy primigravid women who were considered at usual risk for preeclampsia underwent the same tests as a parallel study. Routine blood pressure, awake and sleep average blood pressure, and 24-hour mean average blood pressure were entered into multiple logistic regression as predictors of either preeclampsia or gestational hypertension; significant variables were then tested by a series of receiver operator curves. RESULTS: Eight percent of usual risk and 45% of high risk women experienced the development of preeclampsia or gestational hypertension. In both groups, the average routine mercury blood pressure and awake, sleeping, and 24-hour ambulatory blood pressure monitoring-derived blood pressure were significantly higher in women who later experienced the development of preeclampsia or gestational hypertension. In usual risk women, 24-hour systolic blood pressure of >or=115 mm Hg and sleeping systolic blood pressure of >or=106 mm Hg were predictive of later preeclampsia or gestational hypertension, but sensitivities were low (77% and 54%, respectively). In high risk women, sleeping diastolic blood pressure of >or=62 mm Hg and sleeping mean arterial pressure of >or=79 mm Hg were predictive of preeclampsia or gestational hypertension, but again sensitivities were low (70% and 65%, respectively). CONCLUSION: Awake and sleeping blood pressure are higher in midpregnancy in women who later experience the development of preeclampsia or gestational hypertension. Twenty-four-hour ambulatory blood pressure monitoring provides a noninvasive method of selecting some of these women, but this test has a sensitivity no better than that of other predictive tests, even in women at high risk for preeclampsia.

Acute renal failure following cardiac surgery: incidence, outcomes and risk factors.

BACKGROUND: Acute renal failure (ARF) is a recognised complication following cardiac surgery, but the incidence varies widely in the published literature and there are no Australian data available to help predict the risks of ARF in patients with pre-existing renal disease. AIM: To determine the incidence, outcome and risk factors for ARF following cardiac surgery. METHODS: A retrospective case control analysis of 903 consecutive patients who had cardiac surgery (795 CABG, 68 valve/septal surgery, 40 combined valve/CABG) in 1992-93. ARF was defined as doubling of serum creatinine concentration (Cr) to > 0.13 mmol/L if serum Cr was < or = 0.13 mmol/L pre-operatively, or else a rise in serum Cr of > or = 0.10 mmol/L after cardiac surgery. For each subject with ARF, two case control subjects were matched for date of surgery, surgeon, age, sex, type of surgery and pre-operative serum Cr to permit analysis of the influence of pre-operative factors (hypertension, diabetes mellitus, left ventricular systolic dysfunction) and for the comparison of cardiopulmonary bypass time upon the development of ARF. Subsidiary endpoints were mortality, need for dialysis and length of hospital stay. RESULTS: ARF developed in only 1.1% of patients with 'normal' pre-operative renal function (creatinine < or = 0.13 mmol/L) and none required dialysis. ARF developed in 16% of those with impaired pre-operative renal function, 20% of whom required dialysis. Mortality from ARF was 13%. The risk of ARF rose from 10.4% in those with pre-operative serum Cr 0.14-0.20 mmol/L to 36.8% if the serum Cr was > 0.20 mmol/L (p < 0.01). Mortality was higher (4.2% vs 0.7%, p < 0.01) and length of hospital stay longer (14.5 vs nine days [median], p < 0.001) in those with impaired pre-operative renal function. ARF was more likely in those over 65 years, if valve surgery was included and where there was prolonged cardiopulmonary bypass time. CONCLUSIONS: These data confirm that ARF following cardiac surgery is uncommon without pre-operative impairment of renal function but currently carries a mortality rate of 13%. Impaired renal function alone is associated with higher mortality and prolonged hospital stay. Studies to prevent ARF in this setting should focus on the high risk subsets described in this study.