Secondary hypertension is often characterized by loss of diurnal blood pressure variability. This... more 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. 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. 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). ACTH 100 microg/kg per day raises blood pressure in conscious unrestrained Sprague-Dawley rats without any change in normal diurnal rhythm.
In patients with hypertension associated with renovascular disease, pharmacological inhibition of... more In patients with hypertension associated with renovascular disease, pharmacological inhibition of the renin-angiotensin system effectively and safely lowers blood pressure in most patients (Level II evidence).
Atherosclerotic renovascular stenosis is a potentially progressive disease. • Risk factors for pr... more Atherosclerotic renovascular stenosis is a potentially progressive disease. • Risk factors for progressive stenosis and renal artery occlusion include:
a. At 5 years (median 34 months), correction of renal artery stenosis (RAS), by balloon angioplas... more a. At 5 years (median 34 months), correction of renal artery stenosis (RAS), by balloon angioplasty with or without stenting (no distal protection) has no beneficial effect on blood pressure (BP) compared with medical therapy and is associated with an adverse event rate of 10-25%. (Level I Evidence) b. At 5 years (median 34 months), correction of RAS, by balloon
For decades, ill-defined autosomal dominant renal diseases have been reported, which originate fr... more For decades, ill-defined autosomal dominant renal diseases have been reported, which originate from tubular cells and lead to tubular atrophy and interstitial fibrosis. These diseases are clinically indistinguishable, but caused by mutations in at least four different genes: UMOD, HNF1B, REN, and, as recently described, MUC1. Affected family members show renal fibrosis in the biopsy and gradually declining renal function, with renal failure usually occurring between the third and sixth decade of life. Here we describe 10 families and define eligibility criteria to consider this type of inherited disease, as well as propose a practicable approach for diagnosis. In contrast to what the frequently used term 'Medullary Cystic Kidney Disease' implies, development of (medullary) cysts is neither an early nor a typical feature, as determined by MRI. In addition to Sanger and gene panel sequencing of the four genes, we established SNaPshot minisequencing for the predescribed cytosine duplication within a distinct repeat region of MUC1 causing a frameshift. A mutation was found in 7 of 9 families (3 in UMOD and 4 in MUC1), with one indeterminate (UMOD p.T62P). On the basis of clinical and pathological characteristics we propose the term 'Autosomal Dominant Tubulointerstitial Kidney Disease' as an improved terminology. This should enhance recognition and correct diagnosis of affected individuals, facilitate genetic counseling, and stimulate research into the underlying pathophysiology.
Clinical and Experimental Pharmacology and Physiology, 2001
1. The nitric oxide (NO) system has been implicated in the pathogenesis of various forms of exper... more 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.
Clinical and Experimental Pharmacology and Physiology, 2001
1. The aim of the present study was to validate a telemetric blood pressure (BP) monitoring syste... more 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.
Pregnancy Hypertension: An International Journal of Women's Cardiovascular Health, 2012
Objective: Pregnancy outcome in women with transient gestational hypertension (TGH), defined as d... more Objective: Pregnancy outcome in women with transient gestational hypertension (TGH), defined as de novo blood pressure elevation after 20 weeks gestation that normalizes by subsequent evaluation in a Day Assessment Unit. Study design: Retrospective cohort analysis of hypertensive pregnancies between 2003 and 2008. Main outcome measures: Final hypertensive delivery diagnosis and composites of adverse maternal and fetal outcome. Results: Overall 1417 women were referred; 890 met criteria; 41% (65% of study population) had TGH. Twenty percent with TGH developed gestational hypertension and 19% preeclampsia. Women with TGH who developed preeclampsia had similar composite adverse maternal outcomes to other preeclamptic women (51% vs. 63%; p = 0.24) but fewer adverse fetal outcomes (50% vs. 71%; p < 0.01) due to less prematurity (30% vs. 45%; p = 0.02) and small for gestational age babies (33% vs. 51%; p = 0.02). Within the TGH population, developing gestational hypertension or preeclampsia was associated with referral at gestation <33 weeks (RRR 2.8; p < 0.01), initial average systolic blood pressure 130-139 mmHg (RRR 2.1; p < 0.01) and initial average diastolic blood pressure 80-89 mmHg (RRR 3.2; p < 0.01). Conclusion: TGH after 20 weeks is common in pregnancy. Although initial assessment implies low risk, the risk of progression to gestational hypertension or preeclampsia is substantial and warrants appropriate clinical surveillance.
Early onset pre-eclampsia (PE) is considered a worse disorder than later onset PE for the baby bu... more Early onset pre-eclampsia (PE) is considered a worse disorder than later onset PE for the baby but differences in maternal outcomes are less certain. To compare maternal and fetal outcomes amongst women with early onset PE (EOP) 37weeks. We retrospectively analysed outcomes of women with hypertension in pregnancy from our data that is collected during admission and validated by a physician at discharge. Between 1991 and 2011, 4657 pregnancies were complicated by hypertension; 2148 (45%) had pre-eclampsia. 1536 (72%) of these cases had complete data. 291 (19%) had EOP; 505 (33%) pre-term PE and 740 (48%) term PE. Maternal age was similar. Women with pre-term and term onset PE had similar maternal and fetal outcomes. Compared with term PE, women with EOP had similar rates of renal impairment (7% vs. 9%), proteinuria (76% vs. 81%), liver dysfunction (17% vs. 13%), thrombocytopenia (4.5% vs. 5%) and eclampsia (3 vs. 9/1000), but more episodes of severe hypertension (45% vs. 31%, p<0....
Women with EH are at high risk of developing PE but it is not clear whether PE in this setting is... more Women with EH are at high risk of developing PE but it is not clear whether PE in this setting is worse than in the absence of EH. We therefore compared outcomes of women with pre-eclampsia superimposed upon essential hypertension (PE/EH) with those of women with de-novo pre-eclampsia (PE). We have gathered data on pre-eclamptic pregnancies since 1991. We compared maternal outcomes (severe hypertension - BP >170/110mmHg; cerebral, renal or hepatic dysfunction or thrombocytopenia) and fetal outcomes (SGA <10% and perinatal mortality [PNM]) of women with de novo PE to those with PE/EH. PE was defined according to ISSHP 2014 criteria and required de novo proteinuria, renal, liver, platelet or neurological problems. 1947 women developed PE and 143 women had PE/EH. Women with PE/EH were older than those with PE (33 vs. 30years, p<0.05). 1st trimester BP was higher in the PE/EH group (137/84 vs. 115/70 mmHg, p<0.05). Fewer women with PE/EH were nulliparous (52% vs. 69%, p<0...
Pregnancy Hypertension: An International Journal of Women's Cardiovascular Health, 2015
A vasodilator pathway of the RAAS has been described, including the angiotensin converting enzyme... more A vasodilator pathway of the RAAS has been described, including the angiotensin converting enzyme 2 (ACE2) and the vasodilator Ang(1-7). The pressor effects of Angiotensin-II (Ang-II) are reduced in normal pregnancy, and partially restored in pre-eclampsia. To examine activity of the ACE2/Ang(1-7) axis of the RAAS in normal and hypertensive pregnancy. Women in their 3rd trimester and non-pregnant women had measurement of plasma Renin concentration (PRC), Aldosterone (PAC), ACE1 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp; ACE2, Angiotensin II (AII) and Ang(1-7) in a cross sectional study. There were five groups: normotensive pregnancy (NP, n= 16); gestational hypertension (GH, n= 40); essential hypertension (EH, n= 9), pre-eclampsia (PE, n= 7) and non-pregnant controls (C, n=23). (1) PRC was higher in NP-30mU/L than C-19mU/L, EH-19mU/L and PE-17mU/L (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05) but women with GH had similar levels to normal pregnancy (26U/L). (2) Aldosterone concentration was higher in NP-1715pmol/L compared to C-471pmol/L (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001) and compared to all hypertensive groups (GH-1287, EH-881 and PE-817pmol/L), p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05. (3) Aldo/renin ratios did not differ amongst groups (C-26, NP-71, EH-38, GH-69, PE-77). (4) ACE2 concentrations were higher in NP-276mU/L than C-119mU/L (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001), but similar to that in hypertensive pregnancies (GH-305, EH-296, PE-332mU/L). (5) Plasma angiotensin II was higher in NP-114pg/ml than C-56pg/ml (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001) but also similar to that in hypertensive pregnancies (GH-121pg/ml, EH-92pg/ml, PE-89pg/ml). (6) Neither Ang(1-7) nor ACE1 levels differed amongst groups. In normal pregnancy, as expected, PRC, PAC and AII are increased, so too is the ACE2 enzyme but without an accompanying increase in A1-7, perhaps a type 2 error or perhaps implying other physiological control of A1-7 production. In pre-eclampsia and EH there were consistent falls in PRC and PAC without a change in either ACE2 or A1-7 which may represent a compensatory shift in balance of the RAAS towards vasodilatation. F.M. Pettit: None. J. Spaan: None. G.J. Mangos: None. G. Davis: None. A. Henry: None. M.A. Brown: None.
Exogenous cortisol raises blood pressure (BP) in humans and there is accumulating evidence of abn... more 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-N Gmonomethyl-L-arginine (LNMMA) after 2 or 5 days of oral cortisol or placebo in a randomized, double-blind crossover study.
Cushing's syndrome is a consequence of primary or, more commonly, secondary oversecretion of cort... more Cushing's syndrome is a consequence of primary or, more commonly, secondary oversecretion of cortisol. Cardiovascular disease is the major cause of morbidity and mortality in Cushing's syndrome, and excess risk remains even in effectively treated patients. The cardiovascular consequences of cortisol excess are protean and include, inter alia, elevation of blood pressure, truncal obesity, hyperinsulinemia, hyperglycemia, insulin resistance, and dyslipidemia. This review analyses the relationship of cortisol excess, both locally and at tissue level, to these cardiovascular risk factors, and to putative mechanisms for hypertension. Previous studies have examined correlations between cortisol, blood pressure, and other parameters in the general population and in Cushing's syndrome. This review also details changes induced by short-term cortisol administration in normotensive healthy men.
rapid decline in eGFR (p = 0.007, 0.033, and 0.003, respectively). On multivariate analysis: gend... more rapid decline in eGFR (p = 0.007, 0.033, and 0.003, respectively). On multivariate analysis: gender, age, prescription of ESA and phosphate binders, and baseline eGFR were significantly associated with CKD progression (p = 0.003, 0.004, ! 0.001, 0.029, and ! 0.001, respectively). Conclusions: This study identifies potential factors associated with CKD progression in a population referred to nephrologists, but current data quality may result in bias. Implementation of changes in the format of data collection is required so that busy clinicians record essential information to enable this to become a more accurate and reliable research tool.
went valve surgery, none of these variables were significantly associated with the development of... more went valve surgery, none of these variables were significantly associated with the development of ARF or Background. Acute renal failure requiring dialysis (ARF-D) occurs in 1-5% of patients following cardiac ARF-D in this group of patients.
Darbepoetin alfa, an erythropoiesis-stimulating protein, has a longer serum half-life than recomb... more Darbepoetin alfa, an erythropoiesis-stimulating protein, has a longer serum half-life than recombinant human erythropoietin, allowing less-frequent administration. This study aimed to demonstrate that once-monthly (QM) darbepoetin alfa administration would maintain haemoglobin (Hb) concentrations in subjects with chronic kidney disease (CKD) not receiving dialysis who had previously been administered darbepoetin alfa every 2 weeks (Q2W). Methods: This was a multicentre study in which subjects with CKD receiving stable Q2W darbepoetin alfa doses and with stable Hb (100-130 g/L) were started on QM darbepoetin alfa dosing. The initial QM darbepoetin alfa dose was equivalent to the cumulative darbepoetin alfa dose administered during the month preceding enrolment. Darbepoetin alfa doses were titrated to maintain Hb concentrations between 100 and 130 g/L. The primary endpoint was the proportion of subjects maintaining mean Hb 3 100 g/L during the evaluation period (weeks 21-33). Results: Sixty-six subjects were enrolled in the study and all received at least one dose of darbepoetin alfa; 55 (83%) had mean Hb 3 100 g/L during evaluation. Mean (SD) Hb concentrations at baseline and during the evaluation period were 119 (8.7) g/L and 114 (9.8) g/L, respectively. The median QM darbepoetin alfa dose at baseline and during the evaluation period was 80 mg. Darbepoetin alfa was considered to be well-tolerated. Conclusion: Patients with CKD not receiving dialysis who are receiving darbepoetin alfa Q2W can be safely and effectively extended to darbepoetin alfa QM. Dosing QM may simplify anaemia management for patients and health-care providers.
Secondary hypertension is often characterized by loss of diurnal blood pressure variability. This... more 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. 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. 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&#39; &lt; 0.0036). Serum [B] was higher in ACTH- (881+/-44 ng/ml) than sham-treated rats (384+/-17 ng/ml, P &lt; 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). ACTH 100 microg/kg per day raises blood pressure in conscious unrestrained Sprague-Dawley rats without any change in normal diurnal rhythm.
In patients with hypertension associated with renovascular disease, pharmacological inhibition of... more In patients with hypertension associated with renovascular disease, pharmacological inhibition of the renin-angiotensin system effectively and safely lowers blood pressure in most patients (Level II evidence).
Atherosclerotic renovascular stenosis is a potentially progressive disease. • Risk factors for pr... more Atherosclerotic renovascular stenosis is a potentially progressive disease. • Risk factors for progressive stenosis and renal artery occlusion include:
a. At 5 years (median 34 months), correction of renal artery stenosis (RAS), by balloon angioplas... more a. At 5 years (median 34 months), correction of renal artery stenosis (RAS), by balloon angioplasty with or without stenting (no distal protection) has no beneficial effect on blood pressure (BP) compared with medical therapy and is associated with an adverse event rate of 10-25%. (Level I Evidence) b. At 5 years (median 34 months), correction of RAS, by balloon
For decades, ill-defined autosomal dominant renal diseases have been reported, which originate fr... more For decades, ill-defined autosomal dominant renal diseases have been reported, which originate from tubular cells and lead to tubular atrophy and interstitial fibrosis. These diseases are clinically indistinguishable, but caused by mutations in at least four different genes: UMOD, HNF1B, REN, and, as recently described, MUC1. Affected family members show renal fibrosis in the biopsy and gradually declining renal function, with renal failure usually occurring between the third and sixth decade of life. Here we describe 10 families and define eligibility criteria to consider this type of inherited disease, as well as propose a practicable approach for diagnosis. In contrast to what the frequently used term &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;Medullary Cystic Kidney Disease&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; implies, development of (medullary) cysts is neither an early nor a typical feature, as determined by MRI. In addition to Sanger and gene panel sequencing of the four genes, we established SNaPshot minisequencing for the predescribed cytosine duplication within a distinct repeat region of MUC1 causing a frameshift. A mutation was found in 7 of 9 families (3 in UMOD and 4 in MUC1), with one indeterminate (UMOD p.T62P). On the basis of clinical and pathological characteristics we propose the term &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;Autosomal Dominant Tubulointerstitial Kidney Disease&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; as an improved terminology. This should enhance recognition and correct diagnosis of affected individuals, facilitate genetic counseling, and stimulate research into the underlying pathophysiology.
Clinical and Experimental Pharmacology and Physiology, 2001
1. The nitric oxide (NO) system has been implicated in the pathogenesis of various forms of exper... more 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.
Clinical and Experimental Pharmacology and Physiology, 2001
1. The aim of the present study was to validate a telemetric blood pressure (BP) monitoring syste... more 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 &lt; 0.001) compared with 14 mmHg (P &lt; 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.
Pregnancy Hypertension: An International Journal of Women's Cardiovascular Health, 2012
Objective: Pregnancy outcome in women with transient gestational hypertension (TGH), defined as d... more Objective: Pregnancy outcome in women with transient gestational hypertension (TGH), defined as de novo blood pressure elevation after 20 weeks gestation that normalizes by subsequent evaluation in a Day Assessment Unit. Study design: Retrospective cohort analysis of hypertensive pregnancies between 2003 and 2008. Main outcome measures: Final hypertensive delivery diagnosis and composites of adverse maternal and fetal outcome. Results: Overall 1417 women were referred; 890 met criteria; 41% (65% of study population) had TGH. Twenty percent with TGH developed gestational hypertension and 19% preeclampsia. Women with TGH who developed preeclampsia had similar composite adverse maternal outcomes to other preeclamptic women (51% vs. 63%; p = 0.24) but fewer adverse fetal outcomes (50% vs. 71%; p < 0.01) due to less prematurity (30% vs. 45%; p = 0.02) and small for gestational age babies (33% vs. 51%; p = 0.02). Within the TGH population, developing gestational hypertension or preeclampsia was associated with referral at gestation <33 weeks (RRR 2.8; p < 0.01), initial average systolic blood pressure 130-139 mmHg (RRR 2.1; p < 0.01) and initial average diastolic blood pressure 80-89 mmHg (RRR 3.2; p < 0.01). Conclusion: TGH after 20 weeks is common in pregnancy. Although initial assessment implies low risk, the risk of progression to gestational hypertension or preeclampsia is substantial and warrants appropriate clinical surveillance.
Early onset pre-eclampsia (PE) is considered a worse disorder than later onset PE for the baby bu... more Early onset pre-eclampsia (PE) is considered a worse disorder than later onset PE for the baby but differences in maternal outcomes are less certain. To compare maternal and fetal outcomes amongst women with early onset PE (EOP) 37weeks. We retrospectively analysed outcomes of women with hypertension in pregnancy from our data that is collected during admission and validated by a physician at discharge. Between 1991 and 2011, 4657 pregnancies were complicated by hypertension; 2148 (45%) had pre-eclampsia. 1536 (72%) of these cases had complete data. 291 (19%) had EOP; 505 (33%) pre-term PE and 740 (48%) term PE. Maternal age was similar. Women with pre-term and term onset PE had similar maternal and fetal outcomes. Compared with term PE, women with EOP had similar rates of renal impairment (7% vs. 9%), proteinuria (76% vs. 81%), liver dysfunction (17% vs. 13%), thrombocytopenia (4.5% vs. 5%) and eclampsia (3 vs. 9/1000), but more episodes of severe hypertension (45% vs. 31%, p<0....
Women with EH are at high risk of developing PE but it is not clear whether PE in this setting is... more Women with EH are at high risk of developing PE but it is not clear whether PE in this setting is worse than in the absence of EH. We therefore compared outcomes of women with pre-eclampsia superimposed upon essential hypertension (PE/EH) with those of women with de-novo pre-eclampsia (PE). We have gathered data on pre-eclamptic pregnancies since 1991. We compared maternal outcomes (severe hypertension - BP >170/110mmHg; cerebral, renal or hepatic dysfunction or thrombocytopenia) and fetal outcomes (SGA <10% and perinatal mortality [PNM]) of women with de novo PE to those with PE/EH. PE was defined according to ISSHP 2014 criteria and required de novo proteinuria, renal, liver, platelet or neurological problems. 1947 women developed PE and 143 women had PE/EH. Women with PE/EH were older than those with PE (33 vs. 30years, p<0.05). 1st trimester BP was higher in the PE/EH group (137/84 vs. 115/70 mmHg, p<0.05). Fewer women with PE/EH were nulliparous (52% vs. 69%, p<0...
Pregnancy Hypertension: An International Journal of Women's Cardiovascular Health, 2015
A vasodilator pathway of the RAAS has been described, including the angiotensin converting enzyme... more A vasodilator pathway of the RAAS has been described, including the angiotensin converting enzyme 2 (ACE2) and the vasodilator Ang(1-7). The pressor effects of Angiotensin-II (Ang-II) are reduced in normal pregnancy, and partially restored in pre-eclampsia. To examine activity of the ACE2/Ang(1-7) axis of the RAAS in normal and hypertensive pregnancy. Women in their 3rd trimester and non-pregnant women had measurement of plasma Renin concentration (PRC), Aldosterone (PAC), ACE1 &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp; ACE2, Angiotensin II (AII) and Ang(1-7) in a cross sectional study. There were five groups: normotensive pregnancy (NP, n= 16); gestational hypertension (GH, n= 40); essential hypertension (EH, n= 9), pre-eclampsia (PE, n= 7) and non-pregnant controls (C, n=23). (1) PRC was higher in NP-30mU/L than C-19mU/L, EH-19mU/L and PE-17mU/L (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05) but women with GH had similar levels to normal pregnancy (26U/L). (2) Aldosterone concentration was higher in NP-1715pmol/L compared to C-471pmol/L (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001) and compared to all hypertensive groups (GH-1287, EH-881 and PE-817pmol/L), p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05. (3) Aldo/renin ratios did not differ amongst groups (C-26, NP-71, EH-38, GH-69, PE-77). (4) ACE2 concentrations were higher in NP-276mU/L than C-119mU/L (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001), but similar to that in hypertensive pregnancies (GH-305, EH-296, PE-332mU/L). (5) Plasma angiotensin II was higher in NP-114pg/ml than C-56pg/ml (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001) but also similar to that in hypertensive pregnancies (GH-121pg/ml, EH-92pg/ml, PE-89pg/ml). (6) Neither Ang(1-7) nor ACE1 levels differed amongst groups. In normal pregnancy, as expected, PRC, PAC and AII are increased, so too is the ACE2 enzyme but without an accompanying increase in A1-7, perhaps a type 2 error or perhaps implying other physiological control of A1-7 production. In pre-eclampsia and EH there were consistent falls in PRC and PAC without a change in either ACE2 or A1-7 which may represent a compensatory shift in balance of the RAAS towards vasodilatation. F.M. Pettit: None. J. Spaan: None. G.J. Mangos: None. G. Davis: None. A. Henry: None. M.A. Brown: None.
Exogenous cortisol raises blood pressure (BP) in humans and there is accumulating evidence of abn... more 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-N Gmonomethyl-L-arginine (LNMMA) after 2 or 5 days of oral cortisol or placebo in a randomized, double-blind crossover study.
Cushing's syndrome is a consequence of primary or, more commonly, secondary oversecretion of cort... more Cushing's syndrome is a consequence of primary or, more commonly, secondary oversecretion of cortisol. Cardiovascular disease is the major cause of morbidity and mortality in Cushing's syndrome, and excess risk remains even in effectively treated patients. The cardiovascular consequences of cortisol excess are protean and include, inter alia, elevation of blood pressure, truncal obesity, hyperinsulinemia, hyperglycemia, insulin resistance, and dyslipidemia. This review analyses the relationship of cortisol excess, both locally and at tissue level, to these cardiovascular risk factors, and to putative mechanisms for hypertension. Previous studies have examined correlations between cortisol, blood pressure, and other parameters in the general population and in Cushing's syndrome. This review also details changes induced by short-term cortisol administration in normotensive healthy men.
rapid decline in eGFR (p = 0.007, 0.033, and 0.003, respectively). On multivariate analysis: gend... more rapid decline in eGFR (p = 0.007, 0.033, and 0.003, respectively). On multivariate analysis: gender, age, prescription of ESA and phosphate binders, and baseline eGFR were significantly associated with CKD progression (p = 0.003, 0.004, ! 0.001, 0.029, and ! 0.001, respectively). Conclusions: This study identifies potential factors associated with CKD progression in a population referred to nephrologists, but current data quality may result in bias. Implementation of changes in the format of data collection is required so that busy clinicians record essential information to enable this to become a more accurate and reliable research tool.
went valve surgery, none of these variables were significantly associated with the development of... more went valve surgery, none of these variables were significantly associated with the development of ARF or Background. Acute renal failure requiring dialysis (ARF-D) occurs in 1-5% of patients following cardiac ARF-D in this group of patients.
Darbepoetin alfa, an erythropoiesis-stimulating protein, has a longer serum half-life than recomb... more Darbepoetin alfa, an erythropoiesis-stimulating protein, has a longer serum half-life than recombinant human erythropoietin, allowing less-frequent administration. This study aimed to demonstrate that once-monthly (QM) darbepoetin alfa administration would maintain haemoglobin (Hb) concentrations in subjects with chronic kidney disease (CKD) not receiving dialysis who had previously been administered darbepoetin alfa every 2 weeks (Q2W). Methods: This was a multicentre study in which subjects with CKD receiving stable Q2W darbepoetin alfa doses and with stable Hb (100-130 g/L) were started on QM darbepoetin alfa dosing. The initial QM darbepoetin alfa dose was equivalent to the cumulative darbepoetin alfa dose administered during the month preceding enrolment. Darbepoetin alfa doses were titrated to maintain Hb concentrations between 100 and 130 g/L. The primary endpoint was the proportion of subjects maintaining mean Hb 3 100 g/L during the evaluation period (weeks 21-33). Results: Sixty-six subjects were enrolled in the study and all received at least one dose of darbepoetin alfa; 55 (83%) had mean Hb 3 100 g/L during evaluation. Mean (SD) Hb concentrations at baseline and during the evaluation period were 119 (8.7) g/L and 114 (9.8) g/L, respectively. The median QM darbepoetin alfa dose at baseline and during the evaluation period was 80 mg. Darbepoetin alfa was considered to be well-tolerated. Conclusion: Patients with CKD not receiving dialysis who are receiving darbepoetin alfa Q2W can be safely and effectively extended to darbepoetin alfa QM. Dosing QM may simplify anaemia management for patients and health-care providers.
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Papers by George Mangos