Journal of Hypertension

Published by Lippincott, Williams & Wilkins
Online ISSN: 0263-6352
Publications
Article
A mixed solution of 0.1% sodium nitroprusside and 1% sodium thiosulphate ('SNP-thiosulphate') was given as i.v. infusion to 80 patients, 30 of whom were hypertensive emergencies and 50 were surgical cases requiring induction of hypotension. This treatment lowered the blood pressure (BP) by an average of 30% of the initial levels in the hypertensive patients and 30-40% of the initial levels in the surgical patients. The mean effective dose in the hypertensive patients was 2.4 micrograms/kg/min compared with about 3 micrograms/kg/min in 40 cases treated with sodium nitroprusside as mono-infusion. For deliberate hypotension in surgical patients the mean doses of SNP, used here in the mixed infusion with thiosulphate, were 1.0 and 2.3 micrograms/kg/min, compared with 1.3-7.5 micrograms/kg/min in 181 patients treated with SNP as monotherapy. In contrast to conventional therapy with SNP, the infusion of SNP-thiosulphate even at extremely high dose rates did not produce toxic concentrations of prussic acid in the blood. In no case was a rise observed in the cellular enzymes as an indirect indication of hypoxic cell damage. SNP-thiosulphate is thus at least as effective at lowering BP as SNP infused alone, and has a substantially lower toxicity risk.
 
Article
To evaluate ambulatory blood pressure monitoring (ABPM) parameters in a broad sample of high-risk hypertensive patients. The Spanish Society of Hypertension is developing a nationwide project in which more than 900 physicians send ABPM registries and corresponding clinical records to a central database via www.cardiorisc.com. Between June 2004 and July 2005 a 20 000-patient database was obtained; 17 219 were valid for analysis. We identified 6534 patients with high cardiovascular risk according to the 2003 European Society of Hypertension/European Society of Cardiology guidelines stratification score. Office blood pressure (BP) was 158.8/89.9 mmHg and 24-h BP was 135.8/77.0 mmHg. Patients with grade 3 BP in the office showed ambulatory systolic BP values less than 160 mmHg in more than 80%. A non-dipping pattern was observed in 3836 cases (58.7%), whereas this abnormality was present in 47.9% of patients with low-to-moderate risk [odds ratio (OR) 1.54; 95% confidence interval (CI) 1.45-1.64]. The prevalence of non-dippers was higher as ambulatory BP increased ( approximately 70% when 24-h systolic BP > 155 mmHg) and was similar in both groups. At the lowest levels of BP (24-h systolic BP < 135 mmHg) a non-dipping pattern was more prevalent in high-risk cases (56.6 versus 45.7%; OR 1.51; 95% CI 1.40-1.64). There was a remarkable discrepancy between office and ambulatory BP in high-risk hypertensive patients. The prevalence of a non-dipper BP pattern was almost 60%. In the lowest levels of ambulatory BP, high-risk patients showed a higher prevalence of non-dipping BP than lower-risk cases. These observations support the recommendation of a wider use of ABPM in high-risk hypertensive patients.
 
Article
To assess trends in blood pressure (BP) levels, prevalence, awareness, and control of hypertension in the Czech population from 1985 to 2000/01. Five independent cross-sectional population surveys conducted in 1985, 1988, 1992, 1997/98, and 2000/01. Six, mostly rural, districts of the Czech Republic (Praha-východ, Benesov, Pardubice, Chrudim, Cheb, and Jindrichův Hradec). Men and women aged 25-64 years randomly selected from six districts using the National Population Register/General Health Insurance Company Register (covering, by law, all citizens). The total number of participants was 11 726. We assessed the mean systolic BP, diastolic BP and pulse pressure, prevalence of hypertension (systolic BP > or = 140 mmHg and/or diastolic BP > or = 90 mmHg, or current treatment with antihypertensive drugs), awareness, treatment, and control of hypertension. Mean systolic BP, diastolic BP, and pulse pressure decreased significantly over a period of 15/16 years. This was associated with a significant decrease in the prevalence of hypertension (from 47.1 to 39.1%, P < 0.001) and with an increase in its awareness (from 49.5 to 67.2%, P < 0.001), use of antihypertensive medication (from 29.3 to 49.3%, P < 0.001), and hypertension control (from 3.9 to 17.0%, P < 0.001). Despite having lower BP values and prevalence of hypertension, females showed higher awareness of the disease, and were more frequently taking antihypertensive medication, and their hypertension was better controlled. The reduction in population BP and improved control of hypertension may have contributed to the decrease in cerebrovascular and coronary heart disease mortality in the Czech Republic. The positive longitudinal changes seen in the MONICA regions need not necessarily reflect the situation in the country as a whole. The situation is far from being optimal; a major problem is inadequate treatment of hypertension
 
Article
Restoring renal perfusion pressure (unclipping) of one-kidney-one-clip renal hypertensive (1 K1C) rats normalizes mean arterial pressure (MAP) rapidly. This has been attributed to salt/volume losses or release of the putative renal medullary depressor hormone (RMDH). To investigate the effects of endothelin receptor A and B (ET(A)/ET(B)) antagonism on unclipping. Telemetric devices were implanted in male Wistar 1K1C rats for measurement of conscious MAP. Hypertension was reversed by unclipping with the animal under brief anaesthesia. Seven rats were treated with the ET(A)/ET(B) antagonist, TAK-044 (two doses of 10 mg/kg intraperitoneally in 24 h), and eight rats received its vehicle. In order to investigate whether endothelin receptor antagonism could release RMDH under resting conditions, TAK-044 was administered to telemetered non-clipped intact and chemically renal medullectomized rats (BEA treatment). TAK-044 did not affect resting MAP, urine flow or sodium excretion in 1K1C rats. However, after unclipping, the TAK-044-treated group showed a more marked reduction in MAP during the first 24 h after unclipping (P< 0.01). TAK-044 also reduced urine flow and sodium excretion during the first 8 h after unclipping (P< 0.05). TAK-044 reduced resting MAP (P< 0.05) to a similar extent in intact and BEA rats. TAK-044 potentiated the reduction in MAP after unclipping, independently of changes in urine flow and sodium excretion. It also reduced MAP in normotensive rats--an effect that was not dependent on an intact renal medulla. Potentiation of the depressor response to unclipping by TAK-044 could be the result of an interaction of endogenous endothelin receptors with renal depressor mechanisms--possibly, the release, actions, or both, of the putative RMDH.
 
Article
The aim of this study was to test the effects of exogenous endothelin-1 (ET-1) on regional kidney blood flow and renal function, and the renal haemodynamic effects of endogenous ET, in anaesthetized rabbits. ET-1 was infused into the left renal artery at 2 ng/kg/min for 30 min, then at 1 ng/kg/min. Cumulative doses of TAK-044 (0.1-3 mg/kg, i.v.) or its vehicle were given at 30-min intervals. In other rabbits, an extracorporeal circuit was established to adjust renal arterial pressure (RAP) independently of systemic arterial pressure (MAP). RAP was set at 65 mmHg, and either TAK-044 (3 mg/kg, i.v.) or its vehicle was administered. In the infused kidney ET-1 (2 ng/kg/min) reduced renal blood flow (RBFprobe; 52+/-8%), cortical perfusion (37+/-7%), glomerular filtration rate (GFR; 49+/-8%), urine flow (47+/-14%) and sodium excretion (49+/-13%), but not medullary perfusion (5+/-6%). No effects of ET-1 on MAP or on the contralateral kidney were observed. TAK-044 dose-dependently reversed the effects of ET-1 on RBFprobe and cortical perfusion. TAK-044 also reduced MAP (by up to 11+/-3%) and increased effective renal blood flow in the contralateral kidney (by up to 46+/-27%). In the extracorporeal circuit model, TAK-044 decreased MAP by 12+/-2% and RAP by 10+/-3%, and increased RBF by 9+/-3%. Exogenous ET-1 reduces cortical more than medullary perfusion, and reduces GFR without affecting net tubular sodium and fluid reabsorption. TAK-044 antagonizes local renal vascular responses to ET-1. Endogenous ETs appear to contribute markedly to resting renal vasomotor tone and MAP.
 
Article
Background: Hypertension results in high morbidity and mortality. Its management is predominantly undertaken in the primary care setting. The aim of this study was to assess trends in blood pressure (BP) and hypertensive management in primary care in Australia. Methods: A retrospective analysis of patient-based electronic medical records was conducted. Antihypertensive therapy was determined by prescription data. We identified 532 050 patients (55% women, average age 54 ± 18 years) being managed by 733 general practitioners from 286 clinics Australia-wide who had at least one visit with BP recorded between 2005 and 2010. Results: Average BP did not change and men had consistently higher levels than women (132/79 vs. 127/77 mmHg, P < 0.001). At least 25% of all individuals had a visit where elevated BP more than 140/90 mmHg was recorded. Up to 50% of patients on antihypertensive therapy had a BP more than 140/90 mmHg. In any year, the odds of elevated BP more than 140/90 mmHg were three-fold to four-fold higher in treated individuals (yearly range OR 3.0-3.97; 95% CI 2.93-3.83 to 3.08-4.10). Over annual contiguous visits in 51 721 patients with BP more than 140/90 mmHg, BP decreased after two visits and then remained stable (P < 0.001) irrespective of frequency of visits or antihypertensive treatment. Individuals with more frequent visits were more likely to attain target BP less than 140/90 mmHg [OR 1.08 (three visits) to 1.29 (five visits); 95% CI range 1.03-1.38]. Conclusion: In the absence of any significant gains in the community control of hypertension since 2005, a more intensive approach to BP management in primary care is required to ensure more patients achieve BP targets.
 
Article
The C825T single nucleotide polymorphism of the G-protein beta3 (GNB3) has been implicated in susceptibility to essential hypertension, through the expression of an alternatively spliced truncated variant. In an effort to clarify earlier inconclusive results, we performed a meta-analysis of population-based case-control genetic association studies. Random-effects methods were applied on summary data in order to combine the results of the individual studies. We identified in total 34 studies, including 14,094 hypertensive cases and 17,760 controls. The TT versus CC + CT contrast yielded an overall odds ratio (OR) of 1.08 [95% confidence interval (CI): 1.01, 1.15], the contrast of TT + CT versus CC, an OR of 1.17 (95% CI: 1.06, 1.29), whereas that of the T allele versus C allele yielded a non-significant OR of 1.05 (95% CI: 0.98, 1.13). There was moderate evidence for a publication bias in the latter two contrasts, which was eliminated after excluding studies not in Hardy-Weinberg equilibrium and those performed on non-normal populations (those with a diagnosis of diabetes, obesity and myocardial infarction). Subgroup analyses revealed that non-significant estimates arose from studies on Asian populations, as opposed to the Caucasian ones. Furthermore, the frequency of the T allele was lower in Caucasians and these populations were found to inhabit higher latitudes. The findings are in agreement with a recently proposed causal model for systolic blood pressure, which correlates it with the T allele and the absolute latitude. Further studies are needed in order to fully address questions about the aetiological mechanism of the particular association, as well as to study the effect in populations of African descent.
 
Article
Whether treatment with vitamin D receptor activators contributes to cardiovascular disease in patients with chronic kidney disease is a matter of debate. We studied mechanisms involved in vitamin D-related vascular calcifications in vivo and in vitro. Aortic calcifications were induced in subtotally nephrectomized (SNX) rats by treatment with a high dose (0.25 μg/kg per day) of 1,25-dihydroxyvitamin D3 (calcitriol) given for 6 weeks. Likewise, primary rat vascular smooth muscle cells (VSMCs) were incubated with calcitriol at concentrations ranging from 10 to 10 mol/l. Immunohistochemistry revealed that the aortic expression of osteopontin, osteocalcin and bone sialoprotein was significantly increased in calcitriol-treated SNX rats compared to untreated SNX controls. In addition, aortic expression of the transient receptor potential vanilloid calcium channel 6 (TRPV6) and calbindin D9k was significantly up-regulated by treatment with calcitriol. Furthermore, calcitriol significantly increased expression of the osteogenic transcription factor osterix. In-vitro studies showed similar results, confirming that these effects could be attributed to treatment with calcitriol. High-dose calcitriol treatment induces an osteoblastic phenotype in VSMC both in SNX rats and in vitro, associated with up-regulation of proteins regulating mineralization and calcium transport, and of the osteogenic transcription factor osterix.
 
Article
Vitamin D may contribute to cardiovascular disease in the absence of hypercalcemia in patients with chronic kidney disease. We investigated the effects of long-term (6-week) treatment with 1,25(OH)2D3, at a non-hypercalcemic dosage (0.25 microg/kg per day per orally) in 5/6 nephrectomized rats: (i) vehicle-treated, sham-operated rats; (ii) 1,25(OH)2D3-treated, sham-operated rats; (iii) vehicle-treated, 5/6 nephrectomized rats; and (iv) 1,25(OH)2D3-treated, 5/6 nephrectomized rats. Creatinine clearance after 6 weeks was significantly lower and parathyroid hormone levels were significantly higher in 1,25(OH)2D3-treated uremic rats, compared with uremic controls (P < 0.01). Serum calcium levels, as well as the calcium-phosphorus product, did not differ between both groups. Mean systolic blood pressure in 1,25(OH)2D3-treated animals was significantly increased, compared with vehicle (each P < 0.01). In addition, 1,25(OH)2D3-treated uremic animals showed left ventricular hypertrophy. Diffuse aortic calcification involving the intima and media layer occurred in 1,25(OH)2D3-treated uremic animals, but not in other groups. The mean aortic wall area and lumen area were increased two-fold in 1,25(OH)2D3-treated uremic animals compared with vehicle (P < 0.01), whereas the wall/lumen ratio remained unchanged, indicating fusiform aneurysm formation. Hypertension, left ventricular hypertrophy, aortic calcification, and aneurysm, without hypercalcemia, occurred in 1,25(OH)2D3-treated, 5/6 nephrectomized rats. These data indicate a permissive effect of uremia for cardiovascular damage induced by non-hypercalcemic doses of 1,25(OH)2D3.
 
Article
To evaluate the cardiovascular effects of 1,25-dihydroxyvitamin D3 (1,25-D). Recent studies suggest that Ca-regulating hormones may contribute to the genesis of hypertension. We determined systemic and regional hemodynamics 24 h after administration of 1,25-D or vehicle to normal conscious Sprague-Dawley rats. In addition, to dissociate the vascular effects of 1,25-D from changes in serum ionized Ca2+, 1,25-D and vehicle were administered to rats maintained for 3 days on a low-Ca diet. To evaluate the effect of the slight rise in serum ionized Ca2+ with 1,25-D administration, we infused CaCl or vehicle over 1 h into normal rats to raise the serum Ca2+ to near that of rats treated with 1,25-D. The radioactive microsphere technique was used. Systemic hemodynamics (blood pressure, heart rate, cardiac output, total peripheral resistance and stroke volume) did not differ between the two groups receiving a normal-Ca diet. In these rats 1,25-D significantly decreased renal blood flow (RBF), increased renal vascular resistance (RVR) and slightly increased serum ionized Ca2+. Similarly, in rats receiving a low-Ca diet, 1,25-D administration decreased renal blood flow, increased renal vascular resistance and caused only a minimal increase in serum ionized Ca2+. A low-Ca diet also increased heart rate, cardiac blood flow and renal blood flow. Although CaCl infusion raised serum ionized Ca2+, blood pressure, renal blood flow and renal vascular resistance did not change significantly. 1,25-D may constrict the renal vasculature directly or indirectly by enhancing the vascular sensitivity to circulating vasoconstrictors.
 
Article
To investigate a possible relationship between the time courses of action of various calcium antagonists and their lipophilicity, characterized as log P-values. The functional experiments were performed in vitro in human small subcutaneous arteries (internal diameter 591 +/- 51 microm, n = 7 for each concentration), obtained from cosmetic surgery (mamma reduction and abdominoplasty). The vessels were investigated in an isometric wire myograph. The vasodilator effect of the calcium antagonists was quantified by means of log IC50-values, and the onset of the vasodilator effect for each concentration studied was expressed as time to Eeq90-values (time to reach 90% of the maximal effect). Log IC50-values were -8.46 +/- 0.09, -8.33 +/- 0.25 and -8.72 +/- 0.16 for nifedipine, felodipine and (S)-lercanidipine, respectively (not significant). On average, nifedipine reached time to Eeq90 in 11 +/- 1 min. For felodipine and (S)-lercanidipine the corresponding values were 60 +/- 11 min and 99 +/- 9 min, respectively. The differences between these values were statistically significant (P< 0.01). In spite of these differences in the in-vitro human vascular model, the three calcium antagonists are equipotent with regard to their vasodilator effects. Linear regression analysis of the correlation between the logarithm of the membrane partition coefficient (log P-values) of the calcium antagonists tested [2.50, 4.46 and 6.88 for nifedipine, felodipine and (S)-lercanidipine, respectively] and their respective values found for time to Eeq90 was highly significant. It appears that a higher log P-value is correlated with a slower onset of action.
 
Article
To analyse the efficacy of indapamide sustained-release (SR) 1.5 mg in reducing blood pressure versus amlodipine 5 mg and hydrochlorothiazide 25 mg, in elderly hypertensive patients. Double-blind, randomized, 12 week study using three parallel groups. European teaching hospitals and general practices. Randomized patients, (n = 524) including 128 patients with isolated systolic hypertension (ISH); mean age: 72.4 years; mean systolic/diastolic blood pressures (SBP/DBP): 174.5/97.9 mmHg. Clinic systolic and diastolic blood pressure variations. Indapamide SR 1.5 mg demonstrates a similar efficacy to that of amlodipine 5 mg, as well as to that of hydrochlorothiazide 25 mg (equivalence P < 0.001); the mean decreases in SBP/DBP were -22.7/-11.8 mmHg, -22.2/-10.7 mmHg and -19.4/-10.8 mmHg, respectively. In the ISH subgroup, indapamide SR 1.5 mg tends to have greater efficacy than hydrochlorothiazide 25 mg in reducing the SBP (-24.7 versus -18.5 mmHg, respectively; equivalence P = 0.117), while similar results are obtained with amlodipine 5 mg (-23 mmHg, equivalence P < 0.001). The normalization rate was relatively high for indapamide SR 1.5 mg (75.3%), when compared with amlodipine (66.9%) and hydrochlorothiazide (67.3%), especially in the subgroup of isolated systolic hypertensive patients: 84.2 versus 80.0% for amlodipine, and versus 71.4% for hydrochlorothiazide. Indapamide SR 1.5 mg shows similar antihypertensive efficacy to amlodipine 5 mg and hydrochlorothiazide 25 mg in elderly hypertensive patients, while in patients with isolated systolic hypertension, indapamide SR 1.5 mg shows a similar efficacy to amlodipine 5 mg but a greater efficacy than hydrochlorothiazide 25 mg.
 
Article
To compare the efficacy of indapamide sustained release (SR) 1.5 mg and enalapril 20 mg at reducing left ventricular mass index (LVMI) in hypertensive patients with left ventricular hypertrophy (LVH). The LIVE study (left ventricular hypertrophy regression, indapamide versus enalapril) was a 1 year, prospective, randomized, double-blind study. For the first time, a committee validated LVH before inclusion, provided on-going quality control during the study, and performed an end-study reading of all echocardiograms blinded to sequence. European hospitals, general practitioners and cardiologists. Hypertensive patients aged > or = 20 years with LVH (LVMI in men > 120 g/m2; LVMI in women > 100 g/m2). Data were obtained from 411 of 505 randomized patients. Indapamide SR 1.5 mg, or enalapril 20 mg, daily for 48 weeks. LVMI variation in the perprotocol population. Indapamide SR 1.5 mg significantly reduced LVMI (-8.4 +/- 30.5 g/m2 from baseline; P< 0.001), but enalapril 20 mg did not (-1.9 +/- 28.3 g/m2). Indapamide SR 1.5 mg reduced LVMI significantly more than enalapril 20 mg: -6.5 g/m2, P = 0.013 (-4.3 g/m2 when adjusted for baseline values; P = 0.049). Both drugs equally and significantly reduced blood pressures (P< 0.001), without correlation with LVMI changes. Indapamide SR progressively reduced wall thicknesses throughout the 1-year treatment period. In contrast, the effect of enalapril observed at 6 months was not maintained at 12 months. Indapamide SR 1.5 mg was significantly more effective than enalapril 20 mg at reducing LVMI in hypertensive patients with LVH.
 
Article
In accordance with international recommendations on the need to decrease doses of antihypertensive drugs, a low-dose (1.5 mg) sustained-release (SR) formulation of indapamide was developed to optimize the drug's efficacy : safety ratio. The aim of this work was to evaluate the benefit of a low-dose diuretic by consolidating the efficacy and safety results of two clinical trials with a similar design. Clinical data were obtained in two European randomized double-blind studies with 690 mild to moderate hypertensive patients (95 mmHg < or = supine diastolic blood pressure < or = 114 mmHg using a mercury sphygmomanometer) treated respectively for 2 and 3 months, with a mean age of 53 and 57 years, 44 and 57% males, mean supine diastolic blood pressure of 100.6 and 102.5 mmHg and mean supine systolic blood pressure of 161.0 and 164.5 mmHg. The first study, a dose-finding study with indapamide SR at 1.5, 2 and 2.5 mg versus placebo and the immediate-release (IR) formulation of indapamide, showed that the 1.5 mg dosage of the new indapamide formulation had an improved antihypertensive efficacy : safety ratio. The second study confirmed the equivalence of blood pressure reductions with 1.5 mg indapamide SR and 2.5 mg indapamide IR, and better acceptability with 1.5 mg indapamide SR, particularly in the number of patients with serum potassium levels < 3.4 mmol/l, which was reduced by more than 50%. The long-term efficacy of 1.5 mg indapamide SR was observed through a 9-month open-treatment follow-up to the second study. The 1.5 mg SR formulation of indapamide has an improved antihypertensive efficacy : safety ratio, which is in accordance with international recommendations for the use of low-dose antihypertensive drugs and diuretics in first-line therapy of hypertension.
 
Article
In the previous studies, we indicated that a gene (or genes) responsible for exaggerated sympathetic response to stress was located in a chromosome 1 QTL for blood pressure (BP) in stroke-prone spontaneously hypertensive rat (SHRSP). In this study, we narrowed down the candidate region to a 1.8-Mbp fragment between D1Rat171 and D1Wox33, and established reciprocal congenic strains for this region. Reciprocal congenic strains were established by introgressing the chromosomal segment from SHRSP/Izm into WKY/Izm (Wpch1.21) and vice versa (SPwch1.72). The urinary norepinephrine excretion (u-NE) was quantified with high-performance liquid chromatography in the urine collected under 6 h of cold stress (4°C). ECG was recorded using the telemetry under 3 h of restraint stress, and the relative sympathetic activity was evaluated as the low frequency/high frequency ratio by the power spectral analysis. BP under the stresses was evaluated by the telemetry. The increases in the u-NE during the cold stress and in the low frequency/high frequency ratio under the restraint stress were significantly greater in Wpch1.21 when compared with Wistar-Kyoto (WKY) rat. The increases in BP both under the cold and the restraint stresses were significantly greater in Wpch1.21 than in WKY. In the reciprocal congenic strain, SPwch1.72, the effects of the transferred fragment on the sympathetic stress responses were confirmed as lower u-NE and low frequency/high frequency in this strain than in SHRSP. Further, the BP responses both to the cold and the restraint stresses were significantly greater in SHRSP than in SPwch1.72. These results indicated that a small fragment on chromosome 1 harbored a gene (or genes) influencing the sympathetic response to different stresses.
 
Article
To investigate the effects of the dual angiotensin-converting enzyme (ACE) + neutral endopeptidase (NEP) inhibitor, MDL-100,240 (MDL), on hypertension and cardiovascular damage in male heterozygous transgenic Ren2 rats. Blood-pressure-matched 5-week-old transgenic rats were allocated to receive a placebo, MDL (40 mg/kg body weight) or ramipril (5 mg/kg body weight) for 8 weeks. During the last 4 weeks, the bradykinin B2 receptor antagonist, icatibant (0.5 mg/kg body weight), was also administered subcutaneously via osmotic minipumps to 50% of the transgenic rats receiving MDL or ramipril. We measured blood pressure, heart weight, structural changes in the aorta and small resistance mesenteric arteries, and the plasma concentrations of adrenomedullin, aldosterone, atrial natriuretic peptide and cGMP. To verify if MDL could regress long-standing hypertension and full-blown cardiovascular damage, 3-month-old transgenic rats received MDL subcutaneously (3 and 10 mg/kg body weight, osmotic minipumps) for 4 weeks. Compared with placebo, MDL decreased blood pressure (P < 0.001) and prevented left ventricular hypertrophy (P < 0.001), being as effective as ramipril. Hypertrophy and dilatation of the aorta and hypertrophy of the resistance arterioles were all prevented by MDL. Plasma aldosterone was decreased by MDL (P < 0.001), but not by ramipril. Icatibant blunted the decrease in blood pressure (P < 0.001), decreased cGMP concentrations and blunted the decrease in cross-sectional area of the resistance arteries in MDL-treated, but not in ramipril-treated, transgenic rats. In 3-month-old transgenic rats, MDL normalized blood pressure, regressed left ventricular hypertrophy and decreased adrenomedullin concentrations. The dual ACE+NEP inhibitor MDL prevented and regressed severe hypertension and cardiovascular damage, even in this model of severe angiotensin II-dependent hypertension with pronounced cardiovascular damage. Enhancement of the effects of bradykinin has a role in such favourable outcomes.
 
Article
To investigate the endocrine and renal effects of the dual inhibitor of angiotensin converting enzyme and neutral endopeptidase, MDL 100,240. A randomized, placebo-controlled, crossover study was performed in 12 healthy volunteers. MDL 100,240 was administered intravenously over 20 min at single doses of 6.25 and 25 mg in subjects with a sodium intake of 280 (n = 6) or 80 (n = 6) mmol/day. Measurements were taken of supine and standing blood pressure, plasma angiotensin converting enzyme activity, angiotensin II, atrial natriuretic peptide, urinary atrial natriuretic peptide and cyclic GMP excretion, effective renal plasma flow and the glomerular filtration rate as p-aminohippurate and inulin clearances, electrolytes and segmental tubular function by endogenous lithium clearance. Supine systolic blood pressure was consistently decreased by MDL 100,240, particularly after the high dose and during the low-salt intake. Diastolic blood pressure and heart rate did not change. Plasma angiotensin converting enzyme activity decreased rapidly and dose-dependently. In both the high- and the low-salt treatment groups, plasma angiotensin II levels fell and renin activity rose accordingly, while plasma atrial natriuretic peptide levels remained unchanged. In contrast, urinary atrial natriuretic peptide excretion increased dose-dependently under both diets, as did urinary cyclic GMP excretion. Effective renal plasma flow and the glomerular filtration rate did not change. The urinary flow rate increased markedly during the first 2 h following administration of either dose of MDL 100,240 (P < 0.001) and, similarly, sodium excretion tended to increase from 0 to 4 h after the dose (P = 0.07). Potassium excretion remained stable. Proximal and distal fractional sodium reabsorption were not significantly altered by the treatment. Uric acid excretion was increased. The safety and clinical tolerance of MDL 100,240 were good. The increased fall in blood pressure in normal volunteers together with the preservation of renal hemodynamics and the increased urinary volume, atrial natriuretic peptide and cyclic GMP excretion distinguish MDL 100,240 as a double-enzyme inhibitor from inhibitors of the angiotensin converting enzyme alone. The differences appear to be due, at least in part, to increased renal exposure to atrial natriuretic peptide following neutral endopeptidase blockade.
 
Article
The effects of 3 weeks treatment with CGS 10078B (30 mg/kg orally) on systemic and regional haemodynamics and cardiac mass were studied in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. The significant decrease in mean arterial pressure (MAP) (174 +/- 3 versus 156 +/- 4 mmHg, P less than 0.002) in SHR was associated with a significantly slower heart rate. No significant alteration in systemic haemodynamics was observed in WKY rats. The reduced MAP in SHR was related to the preserved blood flow to the vital organs, and therefore reduced renal and cerebrovascular resistances. Left ventricular mass index was reduced in both rat strains of treated animals. Therefore, the reduced MAP and heart rate in the SHR without haemodynamic changes in the WKY indicates that CGS 10078B was an effective antihypertensive agent that decreased cardiac mass in rats through mechanisms that may be dissociated from their haemodynamic effects.
 
Article
To investigate ambulatory blood pressure in elderly people, including 'old elderly' subjects, aged over 80 years. Cross-sectional study of community-dwelling, elderly subjects. Subjects were healthy, self-caring, and living independently. Those who were taking medication affecting blood pressure were excluded. Conventional blood pressure was the mean of two measurements. Ambulatory blood pressure monitoring was performed using the SpaceLabs 90207 device. Daytime and night-time blood pressure were defined by fixed clock intervals. Seventy-five 'young elderly', aged 60-79 years, (39 men, 36 women) and 81 'old elderly' aged 80 years and older (37 men, 44 women) underwent 24-h ambulatory blood pressure monitoring. Systolic blood pressure (SBP) was related to age, correlation coefficients between age and SBP were 0.31, 0.25 and 0.31, respectively, for conventional SBP, daytime SBP and night-time SBP (P < 0.01 for all). There was no correlation between age and diastolic blood pressure. Blood pressure levels were similar in men and women. Mean conventional blood pressure, daytime blood pressure and night-time blood pressure were found to be 149/81, 138/82 and 119/69 mmHg, respectively, in the 'young elderly' and 162/82, 147/83, and 133/71 mmHg, respectively, in the 'old elderly (P < 0.01 for SBP). The night : day SBP ratio was significantly higher in the 'old' elderly compared with the 'young' elderly (0.90 versus 0.86, respectively; P < 0.01). Ambulatory blood pressure levels in healthy, community-dwelling 'old elderly' are higher than those reported for younger adults and reflect the prominent age-related rise in SBP associated with advanced old age. Advanced old age is associated with a diminished nocturnal dip in blood pressure.
 
Article
In our previous linkage analysis of Chinese hypertensive families, a hypertension susceptibility region on chromosome 17 was located at D17S1878, which encompasses the inducible nitric oxide synthase (iNOS) gene. The aim of this study was to investigate the association between variant in the human iNOS gene and susceptibility to hypertension in Chinese Han. We detected the -1026C/A polymorphism of the iNOS promoter in 463 hypertensive patients and 432 normotensive individuals for purposes of an association analysis and in 76 hypertensive families with 318 members for purposes of transmission disequillibrium test analysis via real-time PCR with a Taqman-minor groove binder probe. There were significant differences in the genotype and allele frequencies of the iNOS-1026C/A (P<0.05); the genotype CC was associated with hypertension after adjusting for environmental risk factors via a nonconditional logistic regression analysis [adjusted odds ratio, 2.90; 95% confidence interval, 2.14-3.93]. A transmission disequillibrium test-sib transmission disequillibrium test analysis demonstrated that the allele C was preferentially transmitted within a pedigree (combined Z score 2.257, P<0.05). The iNOS-1026C/A was identified by a construct reporter assay as a functional variant, and the transcriptional activity of the promoter with allele C was 4.73-fold lower than that with allele A. Furthermore, electrophoresis mobility shift assay showed that the -1026C/A changed the Y in Yang 1 (YY1)-binding pattern in vitro, whereas chromatin immunoprecipitation showed that transcription factor YY1 was bound to the -1026C element in vivo. Lipopolysaccharide, an inflammatory stimulating factor, could induce YY1 to augment DNA-binding affinity; it could also be involved in the inhibited transcriptional activity of the iNOS promoter with allele C. We thus conclude that iNOS-1026C/A with a change in YY1-binding affinity is associated with hypertension under the affect of inflammatory-stimulating factors.
 
Article
To examine the chronic effects of a newly synthesized, potent and selective endothelin (ET) ETA receptor antagonist, J-1 05859, on mortality in salt-loaded Dahl salt-sensitive (DS) rats and to confirm the potential of this compound as an ETA antagonist Vehicle and J-105859 were administered to salt-loaded DS rats for 12 weeks. Throughout the experimental period, blood pressure was measured continuously using a telemetry system and the survival rate was determined. The surviving animals were subsequently sacrificed and autopsy was performed. Binding and functional assays were also carried out to characterize J-1 05859. The Ki values of J-1 05859 for cloned human ETA and ETB were 0.025 and 48 nmol/l, respectively. J-105859 inhibited ET-1-induced contractions in rabbit iliac artery (pA2 = 10.08) and BQ-3020 (ETB agonist)-induced contractions in pulmonary artery (pA2 = 7.63). The pressor response to intravenous (i.v.) ET-1 (0.5 nmol/kg) was significantly inhibited by J-1 05859 at a dose of 0.03 mg/kg i.v. Chronic treatment with J-1 05859 [0.1 and 1 mg/kg per day orally (p.o.)] from the prehypertensive stage decreased the mortality of salt-loaded DS rats and markedly inhibited the development of brain lesions. The survival rates in the control and J-1 05859 (0.1 and 1 mg/kg per day) groups were 34, 80 and 100%, respectively. Development of hypertension was markedly inhibited at a dose of 1 mg/kg per day. J-105859 is a selective, potent, orally active ETA-selective antagonist ETA antagonists may reduce morbidity as well as mortality in salt-sensitive hypertension.
 
Article
Effects of catastrophic stress on blood pressure are well documented, but usually few measurements were taken before the event occurred, and the people studied were directly involved or geographically close to the disaster. The impact of the 11 September 2001 (9/11) attacks in New York City had far greater reach, and has been sustained by subsequent events. To test the hypothesis that, after the 9/11 attacks, blood pressures in the population affected would be increased compared with that in both the preceding months and the same period during the previous year. We used data available from a current study of blood pressure in four sites in the USA that enabled us to examine them from two perspectives: a mixed (within and between groups) analysis that tested the overall differences in blood pressure before and after 9/11, and a within-subjects model to examine the more focused issue of individual change in blood pressure after 9/11. The blood pressures of 427 hypertensive individuals were telemonitored at four sites. An additional 101 patients had been monitored at two sites during the same period in the previous year. Mean systolic blood pressure was significantly greater during the 2 months after 9/11, across the four sites, compared with that assessed during the previous 2 months (range of observed differences 1.7-3.8 mmHg). At the two sites for which data were available for the same period in the year 2000, there was also a significant effect for the same period during the preceding year for systolic blood pressure. However, at both these sites the effect at 2000 was significantly smaller than the effect at 2001. Blood pressure also generally increased among those individuals in whom monitoring overlapped the 9/11 event. The World Trade Center attacks produced a substantial and sustained increase in blood pressure that appears to be independent of seasonal effects, and which has important implications for morbidity and financial burden. The ubiquitous continuing reference to the events in the news reports may contribute to the sustained effects.
 
Article
To examine the hypothesis that hyperinsulinaemia is associated with the development of borderline hypertension or hypertension. Blood pressure status in non-obese normotensives (< 140/90 mmHg, n = 135) people were re-examined after 11 years after the baseline examination. Participants were selected from a 1981 population-based health examination and had a high blood glucose level or more than a trace of glucose in their urine. Out of 319 people recruited for further examination of glucose tolerance status, 135 normotensive participants with body mass index < 26 kg/m2 and without diabetes according to World Health Organization criteria were re-examined at the follow-up survey. Sixty-two (46%) out of 135 normotensive participants were hypertensive (defined as blood pressure > or = 140/90 mmHg) or receiving antihypertensive medication (n = 8) at the follow-up survey. Significant associations between the development of hypertension and baseline parameters were observed for systolic and diastolic blood pressure, serum triglycerides, high-density lipoprotein (HDL)-cholesterol, fasting and 60 min post-load insulin levels, and the sum of insulin concentrations from fasting to 180 min after glucose challenge after adjustments for age and sex. Odds ratios (95% confidence intervals) for the future development of hypertension between the highest and the lowest tertiles of insulin levels were 4.06 (1.40-11.76) for fasting insulin, 4.25 (1.45-12.45) for 60 min post-glucose load insulin, and 3.88 (1.34-11.20) for the sum of insulin concentrations, after adjustment for age, sex, systolic blood pressure, body mass index and alcohol consumption. Further adjustments for serum triglycerides and serum creatinine did not affect the insulin-hypertension relationship. The present study suggests that hyperinsulinemia is significantly related to the development of hypertension in non-obese and non-diabetic Japanese people.
 
Article
Although 24-h urinary measure to estimate sodium and potassium excretion is the gold standard, it is not practical for large studies. We compared estimates of 24-h sodium and potassium excretion from a single morning fasting urine (MFU) using three different formulae in healthy individuals. We studied 1083 individuals aged 35-70 years from the general population in 11 countries. A 24-h urine and MFU specimen were obtained from each individual. A subset of 448 individuals repeated the measures after 30-90 days. The Kawasaki, Tanaka, and INTERSALT formulae were used to estimate urinary excretion from a MFU specimen. The intraclass correlation coefficient (ICC) between estimated and measured sodium excretion was higher with Kawasaki (0.71; 95% confidence interval, CI: 0.65-0.76) compared with INTERSALT (0.49; 95% CI: 0.29-0.62) and Tanaka (0.54; 95% CI: 0.42-0.62) formulae (P <0.001). For potassium, the ICC was higher with the Kawasaki (0.55; 95% CI: 0.31-0.69) than the Tanaka (0.36; 95% CI: -0.07 to 0.60; P <0.05) formula (no INTERSALT formula exists for potassium). The degree of bias (vs. the 24-h urine) for sodium was smaller with Kawasaki (+313 mg/day; 95% CI: +182 to +444) compared with INTERSALT (-872 mg/day; 95% CI: -728 to -1016) and Tanaka (-548 mg/day; 95% CI: -408 to -688) formulae (P <0.001 and P = 0.02, respectively). Similarly for potassium, the Kawasaki formula provided the best agreement and least bias. Blood pressure correlated most closely and similarly with the 24-h and Kawasaki estimates for sodium compared with the other two formulae. In a diverse population, the Kawasaki formula is the most valid and least biased method of estimating 24-h sodium excretion from a single MFU and is suitable for population studies.
 
Article
The 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) catalyzes the conversion of cortisol (F) to cortisone (E), avoiding the interaction of cortisol with the mineralocorticoid receptor. If it fails, cortisol will stimulate sodium and water reabsorption, increasing the intravascular volume that suppresses renin and secondarily increase the blood pressure. To look for the possible contribution of a decreased ability of 11betaHSD2 to convert cortisol to its inactive metabolite cortisone in the pathogenesis of low renin hypertension (LREH). We studied 64 LREH patients (plasma renin activity, PRA < 1 ng/ml per h), eighty normo-renin essential hypertensives (NREH) (PRA: 1-2.5 ng/ml per h) and 74 normotensives. Serum aldosterone (SA), F, E and serum F/E ratio was determined in all patients. A serum F/E ratio was considered high when it was higher than X + 2SD from the normotensive value. Cytosine-adenine (CA)-repeat microsatellite region in intron 1 of HSD11B2 gene was genotyped in all patients and normotensives volunteers. In 13 LREH with high F/E ratio we performed HSD11B2 gene sequencing. LREH had serum F/E ratio higher than NREH and normotensive controls (3.6 (2.9-4.3) versus 2.9 (2.2-4.3) versus 3.0 (2.4-3.7) (P = 0.004), respectively). We observed an inverse relation between F/E ratio and SA and PRA. In NREH and normotensives we did not find correlation between these variables. In the LREH subset the longer 155 bp CA-allele showed the highest serum F/E ratio. No mutations in coding region or short introns were found in LREH patients. In this study we show that low-renin essential hypertensives had increased serum cortisol/cortisone ratios as compared with normotensive subjects. This suggest that some essential hypertensives, with suppressed renin activity, may have an impairment in the cortisol inactivation catalyzed by the enzyme 11betaHSD2, whose low activity in LREH patients could be associated with the length of CA-repeat microsatellite in intron 1 of the HSD11B2 gene.
 
Article
11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD), by converting the active steroids cortisol and corticosterone to their inactive metabolites, regulates steroid exposure to the mineralocorticoid and glucocorticoid receptors. We explored the hypothesis that a defect in 11 beta-HSD could result in overstimulation of either the mineralocorticoid or glucocorticoid receptors with subsequent hypertension in an established animal model of hypertension, the Bianchi-Milan hypertensive (BMH) rat. Groups of BMH rats with established hypertension (42-46 days old) and prehypertensive rats (22 days old) were compared with age-matched normotensive control rats. Kidney and liver 11 beta-HSD and glucocorticoid receptor messenger RNA (mRNA) levels were assessed by Northern and dot-blot analyses, and 11 beta-HSD activity as percentage conversion of [3H]-corticosterone to [3H]11-dehydrocorticosterone by tissue homogenate. Hepatic 11 beta-HSD activity and gene expression were significantly reduced in the hypertensive BMH rat compared with its normotensive genetic control. 11 beta-HSD activity was also reduced in the prehypertensive BMH rat (aged 25 days) from hypertensive parents, excluding hypertension per se as the cause of the abnormality. Plasma corticosterone was higher in the hypertensive rats. There was no difference in renal 11 beta-HSD activity or gene expression between hypertensive and normotensive BMH rats, or in glucocorticoid receptor gene expression in the liver or kidney. Normal levels of renal 11 beta-HSD mRNA and activity are found in the BMH rat. However, the hypertensive BMH rat does demonstrate impaired hepatic 11 beta-HSD activity which occurs at a pretranslational level, although it is not clear how this relates to the pathogenesis of hypertension in this model.
 
Article
High blood pressure (BP) is a major public health issue, both in the United Kingdom and worldwide. Although BP levels in UK adults are declining, there is little published information on BP trends in children, a particular concern in the context of the rising levels of childhood adiposity. Our aims are to determine whether BP in children has changed over time and whether the change reflected trends in adiposity. We collated data from seven population-based BP studies conducted in the United Kingdom between 1980 and 2008. Children of white European origin were included (9-11 years, mean 10.3 years). Adjustments were made to account for differences in mean ages, BP devices and cuff sizes used in different studies. Mean SBP increased over time both in boys and girls: annual increases were 0.45 mmHg (95% CI: 0.43, 0.48) for boys; 0.51 mmHg (0.49, 0.53) for girls. Mean BMI increased by 0.064 kg/m(2) (0.060, 0.068) per year for boys; 0.070 kg/m(2) (0.065, 0.074) for girls; the prevalence of overweight/obesity increased from 5.7 to 21.1% and from 9.7 to 24.1%, respectively. The SBP trends occurred both in children with low and high BMI, but were more marked in low BMI group; BMI explained only 15.3% (15.1%, 15.6%) of increases in SBP for boys and 14.9% (14.6%, 15.1%) for girls. The BMI/SBP association appeared to become weaker over time (P < 0.001 for negative interaction from 1984). There was only a modest annual increase in DBP (<0.1 mmHg). SBP levels have increased with time, but the increase is not explained by increased BMI. Further research is needed to identify the factors responsible.
 
Article
To test the hypothesis that insulin resistance of the spontaneously hypertensive rat (SHR) and adrenocorticotropin-hypertensive rat is related to a difference in the proportion of the functionally different, alternatively spliced exon 11 isoforms of the insulin receptor. We determined the proportions of mRNA for the exon 11+ and exon 11- isoforms in various tissues of SHR and Wistar-Kyoto rats aged 3, 6, 9 and 12 weeks, which span the pre-hypertensive phase through to established hypertension, as well as in Sprague-Dawley rats with adrenocorticotropin-induced hypertension and Sprague-Dawley controls. Detection of mRNA involved a reverse-transcriptase polymerase chain reaction technique specific for each isoform and quantification was by slot and dot blot hybridization. Mean proportions of exon 11+ mRNA in SHR, Wistar-Kyoto rats, adrenocorticotropin-hypertensive rats and Sprague-Dawley control rats at each age were 95% for liver, 82% for adipose tissue, 77% for kidney, 66% for adrenal, 53% for heart, 26% for cerebral cortex, 23% for hypothalamus, and 3% for skeletal muscle. There was also no difference in concentration of total insulin receptor mRNA. The absence of any difference in proportions of insulin receptor mRNA isoforms argues against the hypothesis that an alteration of differential splicing plays a role in the models of hypertension studied.
 
Article
Epoxygenase metabolites produced by the kidney affect renal blood flow and tubular transport function and 11,12-epoxyeicosatrienoic acid (11,12-EET) has been putatively identified as an endothelium-derived hyperpolarizing factor. The current studies were performed to determine the influence of 11,12-EET on the regulation of afferent arteriolar diameter in angiotensin II-infused hypertensive rats. Male Sprague-Dawley rats received angiotensin II (60 ng/min) or vehicle via an osmotic minipump. Angiotensin II-infused hypertensive and vehicle-infused normotensive rats were studied for 2 weeks following implantation of the minipump. Renal microvascular responses to the sulfonimide analog of 11,12-EET (11,12-EET-SI) and angiotensin II were observed utilizing the in-vitro juxtamedullary nephron preparation. Renal cortical epoxygenase enzyme protein levels were quantified by Western blot analysis. Renal microvessels were also isolated and epoxygenase metabolite levels measured by negative ion chemical ionization (NICI)/gas chromatography-mass spectroscopy. Systolic blood pressure averaged 118 +/- 2 mmHg prior to pump implantation and increased to 185 +/- 7 mmHg in rats infused with angiotensin II for 2 weeks. Afferent arteriolar diameters of 2-week normotensive animals averaged 22 +/- 1 microm. Diameters of the afferent arterioles were 17% smaller in hypertensive rats (P< 0.05); however, arterioles from both groups responded to 11,12-EET-SI (100 nmol) with similar 15-17% increases in diameter. As we previously demonstrated, the afferent arteriolar reactivity to angiotensin II was enhanced in angiotensin II-infused animals. Interestingly, elevation of 11,12-EET-SI levels to 100 nmol reversed the enhanced vascular reactivity to angiotensin II associated with angiotensin II hypertension. Renal microvascular EET levels were not different between groups and averaged 81 +/- 9 and 87 +/- 13 pg/mg per 30 min in normotensive and hypertensive animals, respectively. Renal cortical microsomal levels of the epoxygenase CYP2C23 and CYP2C11 proteins were also similar in normotensive and angiotensin II hypertensive rats. Taken together, these data support the concept that renal microvascular 11,12-EET activity and levels may not properly offset the enhanced angiotensin II renal vasoconstriction during angiotensin II hypertension.
 
Article
To assess the prognostic value of a history of hypertension in patients with acute myocardial infarction (AMI) treated with thrombolysis. Retrospective adjusted analysis of outcome data of patients with AMI randomly allocated to treatment in a controlled study of alteplase versus streptokinase and heparin versus no heparin. A highly representative sample (about 90%) of Italian Coronary Care Units. Patients with (n = 3306) and without (n = 7406) a history of treated hypertension. Morbidity and mortality during hospital stay and the next 6 months. Patients with a history of hypertension had a significantly higher mortality, both in hospital and during the next 6 months. The difference persisted also after a multivariate analysis including all major prognostic factors for in-hospital and 6-month mortality, respectively. Left ventricular failure and recurrent ischaemic events (angina and re-infarction) were also significantly more frequent in hypertensives both during their hospital stay and during follow-up study. A history of hypertension is a negative independent prognostic factor after acute myocardial infarction treated with thrombolysis.
 
Article
Although it is recognized that the cause of hypertension can be various, once blood pressure has become established structural changes emerge in the systemic vasculature. In medium- and large-sized vessels, as in the left ventricle, there is clear histological evidence of hypertrophy of the medial smooth muscle layers but, downstream in small arteries, which modulate vascular resistance, other changes occur. In essential hypertension, the smooth muscle cells of small vessels are restructured around a smaller lumen, but there is no evidence of hypertrophy or hyperplasia of the vascular wall. In secondary forms of hypertension, which tend to be representative of severer forms of the disease, hypertrophic remodelling is observed. Similarly, in non-insulin-dependent diabetes mellitus, irrespective of whether blood pressure accompanies this disorder or not, hypertrophy is also seen. The presence of architectural alterations in the vascular wall of small arteries may have a strong prognostic significance in patients, and this may be over and above all other known cardiovascular risk factors. Although it is yet to be established whether regression of such changes should be a goal of effective antihypertensive therapy, there is a body of evidence emerging indicating that different classes of antihypertensive drug have a varied effect on reversing vascular structure both in humans and animal models of genetic and experimental hypertension. However, at present, there are no data available concerning the prognostic impact of regressing vascular structural alterations in hypertension, and this must be an urgent research priority.
 
Article
To investigate, for the first time, the frequency of recurrences of angiotensin-converting enzyme inhibitor (ACE-I)-related angioedema after the discontinuation of ACE-I. This retrospective study was conducted in an outpatient tertiary-level centre for a total period of 173 months (about 14 years). Consecutive patients with recurrent angioedema symptoms, initiated during treatment with an ACE-I, who had been followed for at least 12 months after discontinuation of the drug were eligible. The primary study variable was the incidence of recurrences of angioedema after ACE-I discontinuation. Angioedema location, type of ACE-I and indication for this treatment and the drugs prescribed after the discontinuation of ACE-I were also evaluated. In total, 111 patients were followed; 54 of them (49%) were on enalapril. After discontinuation from ACE-I, 51 patients (46%) had further recurrences of angioedema; in 18 relapsers (16% of the total), the frequency of angioedema recurrences remained unchanged when compared with that reported during ACE-I treatment. The large majority of relapsers (88%) had the first recurrence of angioedema within the first month since ACE-I discontinuation. The switch to a different antihypertensive therapy did not seem associated with a reduction in the frequency of angioedema attacks. Even with all the limitations on any observational analysis, this long-term study suggests for the first time that patients with angioedema started while on ACE-I treatment seem to have a condition predisposing to angioedema that is elicited by the treatment with these drugs. Further studies in this field appear advocated due to the potential severity of angioedema attacks.
 
Article
Albuminuria predicts cardiovascular risk, but its function as a marker of endothelial damage and atherosclerosis is uncertain, as is the complex relationship with hypertension and diabetes. To determine whether hypertension contributes to albuminuria across levels of atherosclerosis and type 2 diabetes. Cross-sectional associations of cardiovascular risk factors and albuminuria were examined in 10,113 middle-aged participants in the atherosclerosis risk in communities study divided into four subgroups: type 2 diabetes with marked atherosclerosis, type 2 diabetes without marked atherosclerosis, without diabetes with marked atherosclerosis, and without diabetes without marked atherosclerosis. Marked atherosclerosis was defined as high levels of carotid atherosclerosis or prevalent coronary heart disease. Hyperglycemia and hypertriglyceridemia were associated with albuminuria, but only among patients with type 2 diabetes. In multivariate models, increasing blood pressure levels (but not albuminuria) were significantly associated (P-trend <0.001) with carotid atherosclerosis when stratified by prevalent coronary heart disease. Excluding individuals on hypertension medication, higher blood pressure was associated with albuminuria in all groups (P-trend<0.05). The association was strong even for high-normal blood pressure among individuals without diabetes without marked atherosclerosis (odds ratio 2.7, 95% confidence interval 1.6-4.6) and patients with type 2 diabetes with marked atherosclerosis (12.0, 1.3-108.2). Blood pressure, even at high-normal levels, is consistently associated with albuminuria across categories of type 2 diabetes and atherosclerosis. Our results suggest that the effects of blood pressure on albuminuria are not solely mediated through generalized vascular damage, as represented by degree of atherosclerosis.
 
Article
Viprostol [(dl)-15-deoxy-16-hydroxy-16(alpha/beta)-vinyl-prostaglandin E2 methyl ester; CL 115 347], injected directly into coronary, renal, mesenteric, femoral and carotid arteries of the anaesthetized beagle dogs at doses which did not lower the systemic arterial blood pressure, increased blood flow of the vascular beds being studied. Viprostol was as potent as I-prostaglandin E2 (I-PGE2) in the renal bed, but less potent in the other vascular beds. Viprostol was as potent as I-PGE2 in relaxing smooth muscle of the perfused isolated central ear artery of the rabbit. Viprostol maintained its antihypertensive effect in spontaneously hypertensive rats (SHR) pretreated with indomethacin, chlorpheniramine plus cimetidine, atropine or propranolol, suggesting that the vasodilating effects of viprostol were not mediated through the endogenous prostaglandin, histamine, cholinergic nervous system or beta-adrenergic nervous system. The antihypertensive effects of viprostol were not altered in SHR with bilateral nephrectomy or bilaterally ligated ureters, suggesting that the action of viprostol was not dependent on the secretory or excretory functions of the kidneys. In conclusion, viprostol exerts its antihypertensive action mainly by vasodilation in a way similar to the natural PGE2.
 
Article
Viprostol [(dl)-15-deoxy-16-hydroxy-16(alpha/beta)-vinyl-prostaglandin E2 methyl ester; CL 115 347] is a new orally and transdermally active antihypertensive agent that exerts its major antihypertensive action by vasodilation. The present studies were conducted to examine its effects on the adrenergic nervous system. In cats, viprostol did not inhibit renal sympathetic nerve discharge (RSND) monitored at the postganglionic region, indicating that nerve transmission or conduction was not blocked at the ganglion or the pre- or postganglionic fibres. In cat nictitating membrane preparations in situ, viprostol partially blocked the membrane contractile response to exogenous epinephrine and norepinephrine, as well as to electrical stimulation of pre- and postganglionic fibres. In spontaneously hypertensive rats (SHR), viprostol partially blocked the vasopressor response of exogenous norepinephrine and epinephrine specifically without influencing that of angiotensin II. All these suggest that viprostol produced weak alpha-adrenoceptor blockade. Viprostol did not antagonize the tachycardia induced by stimulation of the discrete segments at C7-T1 (cardio-accelerator) of the spinal cord in pithed SHR, suggesting that viprostol did not activate the presynaptic alpha-adrenoceptors. Viprostol significantly inhibited the increase in blood pressure induced by electrical stimulation of the spinal cord at T7-T9 in pithed SHR, probably due to postsynaptic alpha-adrenoceptor blockade. In conclusion, viprostol produced weak, but statistically significant alpha-adrenoceptor blockade which may contribute partially to its antihypertensive action.
 
Article
To examine whether chronic oral treatment with an angiotensin-converting enzyme inhibitor imidapril and an angiotensin II type 1 receptor antagonist TCV-116 would alter the response to angiotensin II in the rostral ventrolateral medulla. Twelve-week-old spontaneously hypertensive rats (SHR) were treated with imidapril (20 mg/kg per day, n = 7), TCV-116 (5 mg/kg per day, n = 8) or vehicle (n = 8) for 4 weeks. Wistar- Kyoto rats (WKY) (n = 8) served as normotensive controls. At 16 weeks of age, angiotensin II (100 pmol) was microinjected into the rostral ventrolateral medulla of anaesthetized rats. Blood pressure decreased significantly in the rats treated with either imidapril or TCV-116. Pressor responses to angiotensin II microinjected into the rostral ventrolateral medulla were comparable in the untreated SHR, the imidapril-treated SHR and WKY (12 +/- 2, 15 +/- 4 and 10 +/- 1 mmHg, respectively), but were abolished in SHR treated with TCV-116 (0 +/- 2 mmHg, P< 0.01). Angiotensin-converting enzyme activity in the brain stem was significantly lower in SHR treated with imidapril (0.70 +/- 0.06 nmol/mg per h), but significantly higher in SHR treated with TCV-116 (1.62 +/- 0.04 nmol/mg per h) than in the untreated SHR (1.37 +/- 0.05 nmol/mg per h). Chronic oral treatment with imidapril and TCV-116 may have divergent influences on the renin-angiotensin system within the brain stem. TCV-116, but not imidapril, abolishes the pressor effect of angiotensin II in the rostral ventrolateral medulla.
 
Article
Most of the known actions of angiotensin II are mediated by the angiotensin II type 1 receptor (AGT1R). The adenine/cytosine(1166) (A/C(1166)) polymorphism of the AGT1R gene has been shown to be associated with hypertension and hypertension-related diseases. Thus, it may have the potential to predict the blood pressure response of patients with hypertension to angiotensin-converting enzyme inhibitors (ACEIs). To investigate the association between the A/C(1166) polymorphism and the blood pressure response to ACEIs in a hypertensive cohort. After a 2-week, single-blind, placebo run-in period, ACEIs were administered for 6 weeks to 509 hypertensive patients. The polymorphism was determined by PCR followed by restriction enzyme digestion. The AA genotype, AC genotype, and CC genotype were present in 464 (91.2%), 44 (8.6%), and 1 (0.2%) of patients, respectively. As the frequency of the C allele was quite low (0.05), the genotypes were classified according to the presence or absence of the C allele. After 6 weeks of treatment, the systolic blood pressure reductions in patients with the AA genotype and AC + CC genotype were 14.3 +/- 12.6 and 14.1 +/- 12.2 mmHg, respectively (P = 0.908). The diastolic blood pressure reductions in patients with the AA genotype and AC + CC genotype were 8.6 +/- 7.1 and 8.8 +/- 6.9 mmHg, respectively (P = 0.816). There were no differences in the changes in systolic or diastolic blood pressure after treatment among the two genotype groups. The AGT1R A/C(1166) polymorphism does not predict the response to antihypertensive treatment with ACEIs in Chinese hypertensive patients.
 
Article
To investigate whether the angiotensin II (Ang II) subtype 1 receptor (AT1) antagonist CV-11974 had a similar effect to angiotensin converting enzyme inhibitors on cerebral blood flow autoregulation in normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). Sixteen WKY rats and 16 SHR were given CV-11974 0.1 mg/kg intravenously and compared with two control groups (n = 16). Their cerebral blood flow was measured with the intracarotid xenon-133 injection method and blood pressure was raised by noradrenaline infusion and lowered by controlled haemorrhage in separate groups of rats. The limits of autoregulation were determined by computed least-sum-of-squares analysis. The dose of CV-11974 given lowered blood pressure but did not influence baseline cerebral blood flow. In WKY rats the lower limit of autoregulation in control rats was 60 +/- 3 mmHg, whereas after CV-11974 administration it was 48 +/- 2 mmHg (P < 0.01). In SHR the corresponding values were 85 +/- 2 and 78 +/- 2 mmHg, respectively (P < 0.05). In WKY rats the upper limit of autoregulation in control rats was 144 +/- 5 mmHg, whereas after CV-11974 administration it was 126 +/- 7 mmHg (P < 0.05). In SHR the corresponding figures were 174 +/- 8 and 144 +/- 6 mmHg, respectively (P < 0.01). Thus, the AT1 receptor antagonist, although it did not influence baseline cerebral blood flow, shifted the autoregulation curve towards lower blood pressure. This effect is similar to that of angiotensin converting enzyme inhibitors, and might be due to release of Ang II-dependent tone in the larger cerebral resistance vessels.
 
Article
The 11 beta-hydroxysteroid dehydrogenase type 2 (11 PHSD2) enzyme inactivates 11 betahydroxy steroids in sodium-transporting epithelia such as the kidney, thus protecting the non-selective mineralocorticoid receptor (MR) from occupation by cortisol in humans. Inhibition by xenobiotics such as liquorice or mutations in the HSD11 B2 gene, as occur in the rare monogenic hypertensive syndrome of apparent mineralocorticoid excess (AME), result in a compromised 11 betaHSD2 enzyme activity, which in turn leads to overstimulation of the MR by cortisol, sodium retention, hypokalaemia, low plasma renin and aldosterone concentrations, and hypertension. Whereas the first patients described with AME had a severe form of hypertension and metabolic derangements, with an increased urinary ratio of cortisol (THF+5alphaTHF) to cortisone (THE) metabolites, more subtle effects of mild 11 beta HSD2 deficiency on blood pressure have recently been observed. Hypertension with no other characteristic signs of AME was found in the heterozygous father of a child with AME, and we described a girl with a homozygous gene mutation resulting in only a slightly reduced 11 beta HSD2 activity causing 'essential' hypertension. Thus, depending on the degree of loss of enzyme activity, 11 beta HSD2 mutations can cause a spectrum of phenotypes ranging from severe, life-threatening hypertension in infancy to a milder form of the disease in adults. Patients with essential hypertension usually do not have overt signs of mineralocorticoid excess, but nevertheless show a positive correlation between blood pressure and serum sodium levels, or a negative correlation with potassium concentrations, suggesting a mineralocorticoid influence. Recent studies revealed a prolonged half-life of cortisol and an increased ratio of urinary cortisol to cortisone metabolites in some patients with essential hypertension. These abnormalities may be genetically determined. A genetic association of a HSD11 B2 flanking microsatellite and hypertension in black patients with end-stage renal disease has been reported. A recent analysis of a CA-repeat allele polymorphism in unselected patients with essential hypertension did not find a correlation between this marker and blood pressure. Since steroid hormones with mineralocorticoid action modulate renal sodium retention, one might hypothesize that genetic impairment of 11 beta HSD2 activity would be more prevalent in salt-sensitive as compared with salt-resistant subjects. Accordingly, we found a significant association between the polymorphic CA-microsatellite marker and salt-sensitivity. Moreover, the mean ratio of urinary cortisol to cortisone metabolites, as a measure for 11betaHSD2 activity, was markedly elevated in salt-sensitive subjects. These findings suggest that variants of the HSD11 B2 gene may contribute to the enhanced blood pressure response to salt in some humans.
 
Article
Prenatal glucocorticoid excess programs hypertension in adulthood. The underlying mechanisms are unknown. Here, we tested whether hypertension in this model is due to increased renal mineralocorticoid activity. Pregnant rats were injected daily with the synthetic glucocorticoid dexamethasone (DEX) or vehicle during the last week of pregnancy. Blood pressure, electrolytes and target gene expression were measured in the offspring. Adult DEX-treated offspring were hypertensive (SBP, 140.1 ± 2.4 vs. 128.6 ± 3.2 mmHg; P = 0.009), hypokalemic (4.5 ± 0.2 vs. 5.1 ± 0.2 mmol/l; P = 0.03) and had suppressed plasma renin concentration (23.6 ± 4.8 vs. 43.8 ± 5.9 ng/ml; P = 0.017). DEX programming had similar effects in younger rats (age 2 months), but only when fed a high-salt diet. Although these data are consistent with excess mineralocorticoid activity, plasma aldosterone levels were unaffected and daily urinary aldosterone values were decreased (136.1 ± 27.0 vs. 303.6 ± 47.0 ng/kg; P = 0.008). Accordingly, we assessed renal factors that might influence mineralocorticoid responsiveness. Renal expression of mineralocorticoid receptor and glucocorticoid receptor mRNAs was unaltered, as was 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) which regenerates active glucocorticoids. However, renal mRNA for 11β-HSD2, which catalyses inactivation of glucocorticoids in the distal nephron and thus protects mineralocorticoids from glucocorticoids, was decreased by 45% in both new born and adult rats (P < 0.01). The functional significance of this reduction was confirmed by measurements of renal 11β-HSD activity and by demonstrating that the mineralocorticoid properties of cortisol were enhanced in DEX-programmed rats. Additionally, the difference in blood pressure between DEX and control groups was abolished upon administration of spironolactone, a mineralocorticoid receptor antagonist. The blood pressure phenotype of DEX-programmed rats may in part be explained by a life-long reduction in renal 11β-HSD2 activity. Salt-sensitive hypertension could be programmed by prenatal stress.
 
Article
Mutations of the 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) gene cause the syndrome of apparent mineralocorticoid excess, a rare autosomal recessive form of hypertension. We therefore investigated the question of whether variants of the 11beta-HSD2 gene can contribute to genetic susceptibility to essential hypertension. We performed a linkage study in 162 French hypertensive sibships using the affected sib-pair method on 347 sibling pairs and a polymorphic microsatellite marker that we identified in a 30 kb cosmid clone containing the 11beta-HSD2 gene. The coding sequence, introns 2-4 and 350 bp of the 5'-flanking region of the 11beta-HSD2 gene were screened for polymorphisms by polymerase chain reaction/single-strand conformation polymorphism, and a single polymorphism, Glu178/Glu (G534A), was identified in exon 3, which did not change the encoded amino acid sequence. A case-control study was conducted on 370 hypertensive subjects with a positive family history of hypertension and 783 French subjects with hypertension with or without a family history of hypertension, compared with 313 normotensive control subjects, all of whom were analyzed for the newly identified bi-allelic polymorphism. Statistical analyses using the affected sib-pair method did not show significant linkage between the 11beta-HSD2 microsatellite marker and hypertension. Furthermore, no positive association with hypertension was found with the Glu178/Glu (G534A) polymorphism. Our data do not suggest that variants of the 11beta-HSD2 gene contribute substantially to essential hypertension in Caucasians.
 
Article
To identify telmisartan doses that are more effective than placebo and non-inferior to hydrochlorothiazide (HCTZ) 12.5 mg, and are well tolerated, in lowering systolic blood pressure (SBP) in patients with isolated systolic hypertension (ISH). A 2-4-week single-blind placebo run-in was followed by randomization of 1039 patients (age 36-84 years) with ISH [seated SBP 150-179 mmHg and seated diastolic blood pressure (DBP) < 90 mmHg] to once-daily double-blind treatment with telmisartan 20, 40 or 80 mg, HCTZ 12.5 mg, or placebo. The change in seated trough SBP after 6 weeks compared with baseline was the primary end point. Secondary end points were the percentage achieving the target fall in SBP and the change from baseline in seated trough DBP. Incidence and severity of adverse events and physical examination and laboratory parameters were monitored for the safety evaluation. Baseline demographics in telmisartan 20 mg (n = 206), 40 mg (n = 210), 80 mg (n = 207), HCTZ 12.5 mg (n = 205) and placebo (n = 211) treatment groups were comparable: (mean +/- SD) age, 63.0 +/- 10.9 years; SBP, 162.9 +/- 8.1 mmHg; and DBP 83.4 +/- 5.0 mmHg. No previous antihypertensive therapy had been received by 66% of the patients. Mean reductions in seated trough SBP (adjusted for baseline and country) were: telmisartan 20 mg, 15.6 mmHg (n = 204); 40 mg, 17.9 mmHg (n = 209); and 80 mg, 16.9 mmHg (n = 205), compared with placebo, 11.4 mmHg (n = 208), and HCTZ 12.5 mg, 15.7 mmHg (n = 204). The target fall in seated trough SBP (< or =140 mmHg or reduction by > or =20 mmHg) was achieved in 46.6% (telmisartan 20 mg), 51.7% (telmisartan 40 mg), 53.9% (telmisartan 80 mg), 27.4% (placebo) and 42.7% (HCTZ 12.5 mg); the response rate was significantly higher for telmisartan 80 mg than for HCTZ 12.5 mg (P = 0.03). All-causality adverse events occurred in 19.9, 17.6 and 20.3% receiving telmisartan 20, 40 and 80 mg, respectively; 20.9% receiving placebo and 22.0% receiving HCTZ 12.5 mg. No drug-related serious adverse events occurred. All doses of telmisartan (20-80 mg) were significantly superior to placebo in reducing SBP in patients with ISH and clinically comparable to HCTZ 12.5 mg. Tolerability of telmisartan was similar to that of placebo.
 
Top-cited authors
Luis Ruilope
  • Hospital 12 de Octubre
Sverre Kjeldsen
  • University of Oslo
Eoin O'Brien
  • National University of Ireland, Dublin
Guido Grassi
  • Università degli Studi di Milano-Bicocca
Gianfranco Parati
  • Università degli Studi di Milano-Bicocca