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Dysregulation of the endocannabinoid system in the visceral adipose tissue (VAT) is associated with metabolic and cardiovascular complications of obesity. We studied perirenal VAT CB1 receptor expression in relation to anthropometry, VAT area and endocannabinoid levels, kidney microvascular damage (MVDa), and the presence of the CB1 gene A3813G variant, the frequency of which was also evaluated in a large population of obese-hypertensive (OH) patients with or without the metabolic syndrome (MetS). Perirenal VAT and kidney samples were obtained from 30 patients undergoing renal surgery. Total and perirenal VAT areas were determined by computed tomography. CB1 messenger RNA expression and endocannabinoid levels in perirenal VAT were determined by quantitative reverse transcriptase polymerase chain reaction and liquid chromatography-mass spectrometry, respectively. The MVDa was evaluated in healthy portions of kidney cortex. The A3813G alleles were identified by genotyping in these patients and in 280 nondiabetic OH patients (age

Background Fatty acid amide hydrolase (FAAH) inhibitors, preventing endocannabinoid (EC) degradation, reduce blood pressure (BP) and heart rate in young male (YM) hypertensive rodents. The functional human FAAH 129T gene variant results in reduced protein level and enzymatic activity but its relationship with BP is unknown. This study investigates the relationship among FAAH P129T alleles and cardiovascular features in YMs at baseline and after 9-year follow-up, and in older male obese hypertensive (OH) patients, in whom the EC system (ECS) is overactive. Methods Genotype analysis was performed in 215 Caucasian male students (24 (0.2) years old) and in 185 older OH patients (50 (0.2) years old). YMs were also followed up for 9 years. Clinical and anthropometric variables, BP, cardiac and carotid artery echographic measurements were evaluated. Results YMs with the FAAH 129T allele had lower systolic (P = 0.042) and mean BP (P = 0.022), and a trend toward lower diastolic BP (P = 0.06). Such significant association was maintained at follow-up. In contrast, the same allele was not associated with BP in older OH. No association was found with other cardiac and vascular variables. Conclusion An FAAH defective gene variant results in lower BP in YMs, similar to the findings in young rodents. This effect is lost in older OH patients. Because cannabinoid CB1 receptor blockade is associated with BP reduction in OH patients, EC effects and the use of ECS-interfering drugs is likely to be age and clinical-condition dependent.

Cardiovascular peptides such as angiotensin II (Ang II) and atrial natriuretic peptide (ANP) have metabolic effects on adipose cells. These peptides might also regulate adipocyte proliferation and visceral adipose tissue (VAT) expansion. Well-differentiated and stabilized primary cultures of human visceral mature adipocytes (MA) and in vitro-differentiated preadipocytes (DPA) were used as a model to study regulation of VAT expansion.Adipocyte differentiation was evaluated by Oil Red O staining and antiperilipin antibodies. MA and DPA from intra- and retro-peritoneal depots were treated with increasing Ang II (with or without valsartan, a highly selective, competitive, 'surmountable' AT1 antagonist devoid of peroxisome proliferator-activated receptor gamma agonistic activity) or ANP concentrations. Cell counts and bromodeoxyuridine incorporation were used to evaluate proliferation. Apoptosis was evaluated by Hoechst 33342 staining. 8-Bromo cyclic guanosine monophosphate (8Br-cGMP) was used to investigate ANP effects, and real-time PCR to evaluate Ang II and ANP receptors' expression.Cell proliferation was progressively stimulated by increasing Ang II concentrations (starting at 10-11 M) and inhibited by ANP (already at 10-13 M) in both MA and DPA. Co-incubation with increasing Ang II concentrations and valsartan indicated that Ang II effects were AT1-mediated. Indeed, AT2 receptors were not expressed. Valsartan alone slightly inhibited basal proliferation indicating an autocrine/paracrine growth factor-like effect of endogenous, adipocyte-derived Ang II. 8Br-cGMP experiments indicated that the effects of ANP were mediated by the guanylyl cyclase type A receptor.A cell-culture model to study VAT growth showed stimulation by Ang II and inhibition by ANP at physiological concentrations. Because similar effects are likely to occur in vivo, Ang II and ANP might be important modulators of VAT expansion and associated metabolic and cardiovascular consequences.

The C(-344)T promoter polymorphism of the human aldosterone synthase (CYP11B2) gene has been associated with hypertension and cardiac hypertrophy, but there were contrasting data. We analysed the genotype/phenotype associations between this polymorphism and cardiovascular variables in a young adult population, where interactions among genes, gene-environment, and acquired ageing-related organ damage are reduced. Anthropometric measurements, blood pressure, heart rate, left ventricular variables (by echocardiography), and carotid artery wall intimal-media thickness (by high-resolution sonography and digitalized morphometry) were taken in 420 white Caucasian students (mean age 23.5 years, s.d. 2.5 years). CYP11B2 alleles were detected by genomic polymerase chain reaction followed by digestion. Taking into account the three possible models of inheritance, we found no differences in the considered variables, except for an independent effect of the C(-344) allele on SBP in males (TT 125.6 (1.6), TC 128.4 (1.2) and CC 130.5 (2.2), mmHg, media (ES), P=0.03), and on interventricular septum thickness in diastole in females (CC 6.98 (0.12) vs TT 6.87 (0.09) and TC 6.87 (0.07), mmHg, P

Somatic mutations of genes codifying for key regulatory proteins are the cause of different types of hormone-secreting adenomas. Natriuretic peptides (NP) are the strongest inhibitors of aldosterone secretion but aldosterone-secreting adenomas (aldosteronomas) are resistant to this inhibition and have reduced binding sites for NPs. The objective of this study was to sequence the entire coding region of the NP receptor type A (NPRA, codified by the Npr1 gene) to find loss-of-function somatic mutations. Total RNA was extracted from eight aldosteronomas and cDNA was synthesized. NPRA mRNA expression was evaluated by Northern blot analysis and compared with beta-actin mRNA as the housekeeping gene. Twelve primer couples were designed on the basis of the Npr1 gene organization to amplify, by PCR, all 22 coding exons of the gene. The two strands of amplified DNAs were purified and directly sequenced by automated capillary sequencer. NPRA mRNA expression did not differ among aldosteronomas. Npr1 open reading frame sequences obtained from eight aldosteronomas did not contain any mutation. The coding sequences of all 22 exons were identical in all samples and identical to published sequences. In the 3'-untranslated region (3'-UTR) a new length difference 3C/4C polymorphism was found at position 15 129 (three adenomas were 3C/4C and two were 3C/3C). Such a 3C/4C polymorphism was present in genomic DNA from 80 control subjects (25, 4C/4C; 40, 3C/4C; 15, 3C/3C). Mutations in the coding exons of the Npr1 gene do not appear to be a common cause of aldosteronomas. Moreover, the exons of Npr1 encoding for the translated portion of mRNA do not appear to be prone to polymorphisms. The polymorphism identified in the 3'-UTR might affect mRNA stability resulting in lower receptor synthesis, but it is not likely to confer a predisposition to the development of aldosteronomas.

Abnormalities in the natriuretic peptide system could play a key role in the genesis of hypertension. We evaluated the associations between a family history of hypertension, cardiovascular phenotype and allelic variants of Npr1 and Npr3, two candidate genes that codify for natriuretic peptide receptors.We genotyped 45 young normotensive subjects (19 males, 26.8 +/- 3.7 years) with accurately assessed family history of hypertension (FH+) and 52 (26 males, 26.1 +/- 3.1 years) without (FH-) for the known variants of Npr1 and Npr3 genes, and for a novel length difference (3C/4C) polymorphism at position 15129 in the 3'-untranslated region of the Npr1 gene. Blood pressure, echocardiography and plasma brain natriuretic peptide were assessed.Both the novel Npr1 3C allele (59 versus 33%, P0.001) and the 3C/3C genotype (31 versus 8%; P0.001) were significantly more frequent in FH+ than in FH-. The inverse distribution of the 4C/4C genotype suggested that a casual association was very unlikely. Moreover, the 3C/3C homozygous had significantly higher systolic blood pressure (121.1 +/- 6.3 versus 115.6 +/- 7.8 mmHg in 4C/4C; P0.05) and a longer left ventricular isovolumic relaxation time (67 +/- 10 versus 61 +/- 9 ms; P0.05). The Npr3 C(-55) allele variant was also more frequent in FH+ (88 versus 76%, P0.05), but was not associated with the cardiovascular phenotype.The novel Npr1 gene 3C variant and the Npr3 gene C(-55) allele are associated with hypertensive family history. Moreover, the functional Npr1 3C variant, when homozygous, is also associated with higher systolic blood pressure and prolonged ventricular relaxation.

Objective: Our aim was to compare the effect of lacidipine and chlorthalidone on cardiovascular outcome as a primary parameter and blood pressure as a secondary in elderly patients with isolated systolic hypertension in a prospective study with an open design. Methods: 1882 males and females outpatients greater than or equal to60 years were randomly assigned to the administration of chlorthalidone 12.5.mg o.d. or lacidipine 4 mg o.d. Patients were recruited if sitting systolic blood pressure was greater than or equal to160 mmHg with a diastolic blood pressure equal or lower than 95 mmHg. Primary endpoint was a composite of cardiovascular and cerebrovascular events. Results: At randomization mean systolic blood pressure was 178.1 mmHg in the lacidipine and 178.2 mmHg in the chlorthalidone group, the corresponding mean diastolic values being 86.9 and 86.8 mmHg. In both lacidipine and chlorthalidone groups treatment caused a significant (p

Abstract —The objectives of our study were to assess the reproducibility of the trough-to-peak ratio (T/P) and to see whether a high T/P is accompanied by more organ protection or vice versa. The study included 175 (mean±SD age, 51±9 years) subjects with mild-moderate essential hypertension who had echocardiographic evidence of left ventricular (LV) hypertrophy taken from the SAMPLE study (Study on Ambulatory Monitoring of Blood Pressure and Lisinopril Evaluation), an open-label multicenter study. The study included a 3-week washout pretreatment period, a 12-month treatment period with lisinopril (n=84) or lisinopril plus hydrochlorothiazide (n=91) once daily, and a 4-week placebo follow-up period. Results of 24-hour ambulatory blood pressure monitoring and echocardiographic determination of left ventricular mass index (LVMI) were obtained before and after 3 and 12 months of treatment. T/Ps were computed in each patient by dividing the systolic and diastolic blood pressure changes at trough (changes in the last 2 hours of the monitoring period) by those at peak (average of the 2 adjacent hours with the maximal blood pressure reduction between the 2nd and 8th hour from drug intake) after 3 and 12 months of treatment. Average 24-hour blood pressure was similarly reduced at 3 and 12 months. Trough blood pressure changes at 3 and 12 months were closely correlated, as were the corresponding peak blood pressure changes. However, the 3- and 12-month T/Ps correlated to a lesser degree ( r

Objective Human and rat adipose tissue contain very high levels of natriuretic peptides clearance receptor messenger (m)RNA, and fasting inhibits its gene expression in adipose tissue. In this study we evaluated plasma atrial natriuretic peptide (ANP) and gene expression of biologically active type A natriuretic peptide receptor (NPr-A) and clearance natriuretic peptide receptor (NPr-C) in adipose tissue of obese hypertensive and obese normotensive patients. Design and methods We studied 27 untreated obese hypertensives, 26 obese normotensives (body mass index ≥ 30 kg/m 2 ), 24 non-obese essential hypertensives and 23 lean healthy subjects (body mass index ≤ 25 kg/m 2 ). Blood samples were withdrawn for ANP, plasma renin activity and aldosterone radioimmunoassays. Subcutaneous peri-umbilical adipose tissue samples were obtained, by needle aspiration, in 13 obese hypertensives and in 12 obese normotensives and used for RNA extraction. Then, complementary synthesis and semiquantitative polymerase chain reaction (PCR) with primers complementary to sequences of different exons of the genes encoding for NPr-A, NPr-C and β-actin, were performed. 32 P-labeled PCR products were separated by electrophoresis, blotted onto nylon membranes, and the exposed autoradiographic films were analysed by densitometry. NPr signals were normalized by the β-actin expression level. Results Plasma ANP was lower in obese hypertensives than in obese normotensives (37.5 ± 7 versus 43.2 ± 6 pg/ml, P< 0.05), but was higher in non-obese hypertensives than in non-obese normotensives. In contrast, plasma renin activity and aldosterone were higher in the obese hypertensives. Although NPr-A and NPr-C expression were not statistically different between the two obese groups, the NPr-A: NPr-C mRNA ratios were significantly lower in obese hypertensives (P < 0.03). Conclusions Our data suggest that in obese hypertensives compared to obese normotensives, the lower NPr-A: NPr-C ratio might determine decreased biological activity and/or an increased clearance of natriuretic peptide in adipose tissue, suggesting that the natriuretic peptide and its receptor system may be important in obesity-related hypertension where ANP levels are lower.

Background: Left ventricular hypertrophy (LVH) and microalbuminuria are common in hypertensive patients and are often associated with metabolic syndrome (MetS). However, it is not clear whether MetS could modify the association between cardiac and renal damage. Objective: The aim of this study was to assess if the relationship of albumin/creatinine ratio (ACR) and left ventricular mass (LVM) could be independent from MetS in hypertensive overweight/obese patients. Methods: 180 essential hypertensive and overweight/obese (body mass index [BMI] ‡25 kg/m 2 ) patients referred to our Hypertension Centre from January 2006 to April 2009 because of blood pressure (BP) control-related problems were studied. Exclusion criteria were scarce adherence to antihypertensive drug therapy as investigated by the Morisky Medical Adherence Scale (MMAS), heart failure (New York Heart Association III or IV or left ventricular ejection fraction [LVEF]

BackgroundOverweight (Ow) and obesity (Ob) influence blood pressure (BP) and left ventricular hypertrophy (LVH). It is unclear whether the presence of metabolic syndrome (MetS) independently affects echocardiographic parameters in hypertension.Methods380 Ow/Ob essential hypertensive patients (age ≤ 65 years) presenting for referred BP control-related problems. MetS was defined according to NCEP III/ATP with AHA modifications and LVH as LVM/h(2.7) ≥ 49.2 g/m(2.7) in males and ≥ 46.7 g/m(2.7) in females. Treatment intensity score (TIS) was used to control for BP treatment as previously reported.ResultsHypertensive patients with MetS had significantly higher BMI, systolic and mean BP, interventricular septum and relative wall thickness and lower ejection fraction than those without MetS. LVM/h(2.7) was significantly higher in MetS patients (59.14 ± 14.97 vs. 55.33 ± 14.69 g/m(2.7); p = 0.022). Hypertensive patients with MetS had a 2.3-fold higher risk to have LVH/h(2.7) after adjustment for age, SBP and TIS (OR 2.34; 95%CI 1.40-3.92; p = 0.001), but MetS lost its independent relationship with LVH when BMI was included in the model.ConclusionsIn Ow/Ob hypertensive patients MetS maintains its role of risk factor for LVH independently of age, SBP, and TIS, resulting in a useful predictor of target organ damage in clinical practice. However, MetS loses its independent relationship when BMI is taken into account, suggesting that the effects on MetS on LV parameters are mainly driven by the degree of adiposity.

A case of renin-secreting juxtaglomerular cell tumour which presented with a severe hypertensive crisis and did not respond to angiotensin converting enzyme inhibitors but was promptly controlled by intravenous labetalol is reported. The diagnostic difficulties which can be encountered in such cases and the usefulness of the different diagnostic tests, including renal vein renin measurement, are discussed.

Human angiotensinogen (AGT) gene promoter polymorphisms (G-217A; A-20C; G-6A) influence AGT transcription in vitro and have been implicated in the genetics of essential hypertension. We analysed the association among AGT promoter variants and AGT mRNA levels in human kidney and visceral adipose tissue (VAT) in vivo. Samples of kidney and VAT were obtained from 35 consecutive patients undergoing renal surgery. The AGT gene promoter of each patient was sequenced to identify variants. AGT gene expression was studied by real-time PCR TaqMan assay. Clinical data obtained before surgery were also considered in the statistical analysis. Two new polymorphisms at -175 and at -163 were identified. Although AGT expression was significantly higher in VAT than in the kidney, when both variants were present together AGT expression in VAT was about fivefold lower (P=0.033) than in the wild haplotype. This lower AGT expression in VAT suggests that the proximity and linkage of -175A and -163A variants might destabilize the binding of specific transcription factors to an acute-phase responsive element 3. Among the known AGT promoter variants, only -20C SNP has an important effect on tissue-specific differential AGT expression in the human tissues studied, inducing a 3.8-fold increase in AGT mRNA localized only in the kidney medulla (P=0.038). The other known polymorphisms (G-6A; G-217A) were not associated with different levels of AGT expression. Our results support the hypothesis that some human AGT promoter variants influence transcriptional activity in a tissue-specific way in humans.

Rare (611C) and common (1062V) variants of the Low-Density Lipoprotein Receptor-Related Protein 6 (LRP6) display reduced activation of Wnt/ß-catenin signaling. The rare gene variant was associated with hypertension, metabolic abnormalities, and early coronary artery disease. We investigated whether the common 1062V LRP6 variant was related to carotid artery atherosclerosis (CAA) in hypertensive patients.Retrospective study of 334 hypertensive patients (65 years old) who underwent carotid artery ultrasonography. Hypertension, type 2 diabetes, dyslipidemia, glomerular filtration rate, and smoking habit were evaluated. CAA was defined by the presence of atherosclerotic plaques (focal intima-media thickness ≥ 1.3 mm). Logistic regression models were used to estimate the independent effect of 1062V allele. The relationship between LRP6 genotypes and LRP6 gene expression in carotid plaques was also investigated. No difference was observed between genotypes in clinical variables except for a slightly higher fasting glucose in 1062V carriers. The 1062V LRP6 variant was an independent risk factor for CAA in both unadjusted (OR 2.08, 95%CI 1.27-3.41, p=0.003) and adjusted models (OR 1.92, 95%CI 1.09-3.39, p=0.02). LRP6 was expressed in carotid atherosclerotic plaques at significantly lower levels (p=0.015) in 1062V carriers.Beside the role of established risk factors, 1062V variant of LRP6 and CAA are strongly associated in hypertensive patients, making LRP6 a novel relevant candidate gene for atherosclerosis in the presence of hypertension.

In recent times, increasing attention has been paid to the recovery phase after exercise in patients with stable angina pectoris. The relation between a prolonged postexercise ST-segment depression and the degree of impairment of exercise tolerance, extent and severity of coronary artery disease, presence of collateral circulation and degree of left ventricular dysfunction has been investigated.1–5 Little is known about the reproducibility of postexercise ST-segment changes, and few studies have investigated the possible determinants of recovery duration in individual patients; in addition most studies have focused on the possible role of body position during and after exercise6,7 or of exercise type.7 This study investigates the reproducibility of postexercise ST-segment changes and identifies which parameters are capable of influencing them in individual patients.

The current disease-oriented, episodic model of emergency care does not adequately address the complex needs of older adults presenting to emergency departments (EDs). Dedicated ED facilities with a specific organization (e.g., geriatric EDs (GEDs)) have been advocated. One of the few GED experiences in the world is described and its outcomes compared with those of a conventional ED (CED). In a secondary analysis of a prospective observational cohort of 200 acutely ill elderly patients presenting to two urban EDs in Ancona, Italy, identifiers and triage, clinical, and social data were collected and the following outcomes considered: early (30-day) and late (6-month) ED revisit, frequent ED return, hospital admission, and functional decline. Death, functional decline, any ED revisit and any hospital admission were also considered as a composite outcome. Odds ratios and 95% confidence intervals (CIs) were calculated. Overall, GED patients were older and frailer than CED patients. The two EDs did not differ in terms of early, late, or frequent ED return or in 6-month hospital admission or functional decline. The mortality rate was slightly but significantly lower in the GED patients (hazard ratio=0.47, 95% CI=0.22-0.99, P=.047). The data suggest noninferiority and, indirectly, a slight superiority for the GED system in the acute care of elderly people, supporting the hypothesis that ED facilities specially designed for older adults may provide better care.

To update previous guidelines to score the Cumulative Illness Rating Scale (CIRS) and test their usefulness in hospitalized elderly patients.The CIRS was scored retrospectively in a cohort of elderly patients followed for 18 months.An acute internal medicine ward in an academic tertiary care hospital.Three hundred eighty-seven patients aged 65 and older.The CIRS was retrospectively scored for the enrolled patients. Intrarater and interrater reliability were calculated. Two illness severity indices (total score (TSC) and severity (SV)) and one comorbidity index (CM) were obtained. Clinical features and comprehensive geriatric assessment (CGA) variables were also used. All patients underwent an 18-month follow-up for mortality and rehospitalization.Intrarater and interrater reliability of the CIRS scored following the guidelines was good (intraclass correlation coefficients of 0.83 and 0.81, respectively). The TSC, SV, and CM correlated with clinical features (laboratory values, medication usage, and length of in-hospital stay) and CGA variables (cognitive impairment, depression and disability). All three indices were able to predict 18-month mortality and rehospitalization rates.This study confirmed the validity of the CIRS as an indicator of health status and demonstrated its ability to predict 18-month mortality and rehospitalization in hospitalized elderly patients. The availability of detailed guidelines for scoring the CIRS can improve its usefulness and facilitate more-widespread use for research and clinical aims.

Obese hypertensive (OH) patients carrying TCF7L2 alleles predisposing to type 2 diabetes (T2D) may have a further increase in 'cardiometabolic' risk; therefore, we studied 204 OH patients (

To evaluate the antihypertensive efficacy and tolerability of a low-dose diuretic, indapamide, 2.5 mg once daily, was given to 248 patients with uncomplicated, mild to moderate hypertension for a period of 24 months. Blood pressure during sitting was 165 +/- 1/105 +/- 1 mmHg (mean +/- standard error of the mean) at the end of the placebo run-in period and 143 +/- 1/88 +/- 1 and 140 +/- 1/85 +/- 1 mmHg after 2 and 24 months, respectively; heart rate was clinically unmodified (from 77 +/- 1 to 75 +/- 1 beats/min). Total cholesterol, high-density cholesterol and serum triglycerides were unchanged, and uric acid increased significantly (from 292.0 +/- 6.5 to 377.7 +/- 56.5 mumols/liter). A mild reduction in serum potassium (-0.36 +/- 0.03 mmol/liter) was observed after 2 and 6 months of therapy; however, the degree of reduction appeared to be lower than that from reported studies with other thiazide diuretics. The incidence of hypokalemia (serum potassium less than 3.5 mmol/liter) was highest in northern Italy (17%), intermediate in the central region (14%) and lowest in southern Italy (2%), although the absolute reduction in serum potassium was similar in all the geographic areas. Blood glucose tolerance was unchanged despite the changes in serum potassium. The tolerability was good on the whole, with a tendency toward an improvement in the well-being of patients, most of whom were already asymptomatic before starting the study.

Background Idiopathic dilated cardiomyopathy (IDC) has multiple genetic and acquired causes. Apelin is an endogenous peptide that increases cardiac inotropism through his APJ receptor. No data are available concerning the APJ gene mutations responsible for IDC or on the role of APJ receptor gene variants in predicting heart failure (HF) progression. Methods and Results We prospectively evaluated 202 consecutive patients with IDC and 202 matched controls: 90 were screened for APJ gene mutations and all 202 were genotyped for G212A and A445C APJ receptor polymorphisms. No mutations were found within the coding or untranslated regions of the APJ receptor, and no differences in allelic or genotype frequencies were observed comparing patients with a healthy control population. The correlations between APJ receptor polymorphisms and HF progression were assessed. During a median follow-up of 37 months, 35 patients experienced HF progression. Univariate analysis showed that patients carrying at least 1 copy of 212A had a significantly lower risk for HF-related events than those who were homozygous for the G212 variant, and multivariate analysis confirmed that it was significantly related to a more favorable prognosis. Conclusions APJ is unlikely to be a gene causing IDC, but the independent correlation between the 212A allele and a better prognosis suggests that it might act as a modifier gene.

OBJECTIVE Aldosterone secreting adenomas (aldosteronomas) have an unknown molecular origin. Ion channel currents are involved in signal transduction leading to aldosterone synthesis and secretion. HERG (human-ether-a-go-go-related gene) encodes for a potassium channel responsible for the outward rectifying delayed current and it is mutation prone. When mutated it causes most of the familial forms of both long QT and short QT syndromes. Abnormal repolarization in glomerulosa cells might increase aldosterone secretion or induce a proliferative advantage. The aims of this study were to: (1) evaluate HERG expression in aldosteronomas; (2) search for HERG somatic mutations; and (3) determine whether there is any relationship between the common HERG functional variant (A2690C, leading from lysine 897 to threonine, K897T) and aldosteronoma. DESIGN AND METHODS Aldosteronoma and blood samples from 17 patients were studied to evaluate HERG expression, full-length HERG complementary DNA sequencing, and genotyping for K897T alleles. The prevalence of HERG 897 alleles was also tested in a control population and a population consisting entirely of hypertensive individuals. RESULTS HERG was expressed in all aldosteronomas analysed. HERG somatic mutations were not detected. The 897T variant of HERG was significantly more common among patients with aldosteronoma (897T allele 41%) than in patients with moderate-severe essential hypertension (897T allele 20%, P = 0.007) or in the control population (897T allele 12%, P < 0.0001). The 897T/T genotype was present in 24% of the aldosteronoma patients versus 7% (P = 0.040) and 3% (P = 0.001) in essential hypertension and in the control population, respectively. When the chi test was performed considering the three groups together, the significance was similar (for alleles P < 0.0001 and for genotypes P = 0.004). CONCLUSION The common functional HERG variant 897T may predispose to the development of aldosteronoma.

Objective: To test the association of the C(−55)A polymorphism of the natriuretic peptide clearance receptor (NPRC) with blood pressure (BP), overweight/obesity, and body fat distribution in a large male adult population. Research Methods and Procedures: The study population was from a cross-sectional and follow-up study of 787 untreated male participants in the 1994 to 1995 follow-up examination of the Olivetti Heart Study in Naples (356 of whom were examined previously in 1975). BP and anthropometric measures were taken, and biochemical assays were performed. The NPRC gene polymorphism C(−55)A was evaluated by polymerase chain reaction and HgaI digestion. Results: In the whole study population, there was no difference in BP, BMI, and biochemical tests among genotypes. Considering an A(−55) recessive model of inheritance, the AA subjects had lower BMI and waist circumference and lower prevalence of overweight, obesity, and abdominal adiposity as compared with the CC+CA subjects. On reviewing the characteristics of the subgroup previously examined in 1975, the AA subjects had already lower BMI, and their 20-year rate of overweight and obesity was lower than the CC+CA subjects; no difference was observed in the rate of hypertension. Discussion: Male subjects carrying the A(−55)A NPRC genotype had a significantly lower prevalence of overweight, obesity, and abdominal adiposity. They also had a lower 20-year rate of overweight compared with CC+CA individuals. These findings from a large unselected and untreated male population are in keeping with the recent evidence of a powerful lipolytic and lipomobilizing activity of natriuretic peptides.

Irrespective of their clinical relevance, side effects cannot be considered a negligible problem in antihypertensive therapy. The aim of this trial was to evaluate the tolerability profile of lercanidipine with that of two other calcium antagonists (amlodipine and lacidipine) in elderly hypertensives.In a multicenter, double-blind, parallel study 828 elderly (agedor =60 years) hypertensives were randomized to lercanidipine 10 mg/day (n = 420), amlodipine 5 mg/day (n = 200), or lacidipine 2 mg/day (n = 208) (ratio 2:1:1). If blood pressure (BP) control was unsatisfactory (systolic BP/diastolic BPor =140/90 mm Hg), the dose of the double-blind medication was doubled and, as a further step, enalapril or atenolol (plus diuretic, if needed) was added. Patients were treated for an average of 12 months.Amlodipine patients had significantly (P.001) higher rates of edema (19%) and of early study discontinuations due to edema (8.5%) compared with lercanidipine (9% and 2.1%) and lacidipine patients (4% and 1.4%). Similarly, edema-related symptoms (lower limb swelling and heaviness) occurred significantly (P.01) more often with amlodipine (50% and 45%, respectively) than with lercanidipine (35% and 33%) and lacidipine (34% and 31%). Most edema cases occurred in the first 6 months, a between-treatment difference being evident since beginning of treatment. Other drug-related adverse events did not differ between treatments. Blood pressure was equally and effectively reduced in the three groups.The two lipophilic dihydropyridine calcium antagonists, lercanidipine and lacidipine, have an antihypertensive effect comparable to that of amlodipine, but a better tolerability profile.

It is well known that in pre-menopausal women the incidence of cardiovascular events is lower than in men of the same age and that after the menopause cardiovascular morbidity and mortality in women become similar, if not higher, than that in men indicating that female sex hormones play a relevant protective role upon the vasculature. Among the cardiovascular risk factors, hypertension appears to be more prevalent in postmenopausal women than in men but the precise mechanism through which menopause favours the development of hypertension is still a matter of debate. The prevalence of obesity and being overweight is also higher in postmenopausal women than that in men of comparable age. The pathogenesis of obesity-related hypertension recognizes a multifactorial mechanism including overactivity of the sympathetic nervous system, insulin resistance, leptin resistance, overactivity of the renin-angiotensin-aldosterone system and, finally, a blunted biological activity of the natriuretic peptides. The latter mechanism has been investigated by our group in recent years. Adipose tissue has been shown to express large amounts of mRNA for the biologically inactive C-type natriuretic peptide receptor (NPr-C) and this expression is decreased by fasting. Accordingly, adipose tissue can participate in the development and maintenance of high blood pressure through a reduced bioavailability of circulating natriuretic peptides leading to sodium retention. Since being overweight and obesity are a common finding in postmenopausal women, the complex mechanism of obesity-related hypertension can play a relevant role in explaining the high prevalence of hypertension after the menopause.

Objective and design The clearance receptor for natriuretic peptides (NPRC), a candidate gene for essential hypertension, is highly expressed in adipose tissue, where is nutritionally regulated. The objectives of the present study were to sequence the human 5'-flanking regulatory region of NPRC, to identify allelic variants and their frequencies, and to study the genotype/phenotype correlation in hypertensive patients. Methods and results Using polymerase chain reaction (PCR) and direct automated sequencing, a biallelic (A/C) polymorphism was detected at position -55 in a conserved promoter element named P1. The novel C(-55) variant makes the promoter sequence identical to the mouse gene and introduces a second Hgal site in the amplified DNA, allowing the genotyping of a large number of subjects. In a random sample of 232 white Caucasians the C(-55) allele was more commonly found (81.7% of all alleles) with 155 CC (66.8%), 69 AC (29.7%) and only eight AA (3.5%) genotypes. Atrial natriuretic peptide (ANP) levels were determined in 84 patients with essential hypertension. In the presence of obesity (body mass index (BMI) ≥ 30 kg/m 2 ) the homozygous CC hypertensives (n = 21) had significantly lower plasma ANP (33.6 ± 11.1 pg/ml) compared with the AC patients (n = 11; 46.8 ± 15.9 pg/ml; P = 0.01), whereas systolic blood pressure (SBP) and mean blood pressure (MBP) had the opposite association (SBP 163.9 ± 18.7 versus 150.9 ± 12.9 and MBP 123.3 ± 12 versus 114.5 ± 5.9 mmHg; P < 0.05). The difference in ANP levels were also present when overweight patients (BMI ≥ 27 kg/m 2 ) were considered. Conclusion A common 'ancestral' C(-55) variant of the NPRC P1 promoter is associated with lower ANP levels and higher SBP and MBP in obese hypertensives. The C(-55) variant, in the presence of increased adiposity, might reduce plasma ANP through increased NPRC-mediated ANP clearance, contributing to higher blood pressure.

Abstract —The expression of the natriuretic peptide clearance receptor is abundant in human and rat adipose tissue, where it is specifically inhibited by fasting. In obese hypertensives, plasma atrial natriuretic peptide (ANP) levels were found to be lower than in obese normotensives. Therefore, the increased adipose mass might influence ANP levels and/or its biological activity. The aim of the present study was to evaluate whether the humoral, hemodynamic, and renal effects of exogenous ANP in obese hypertensives might be enhanced by a very low calorie diet. Eight obese hypertensives received a bolus injection of ANP (0.6 mg/kg) after 2 weeks of a normal calorie/normal sodium diet, and blood pressure (BP), heart rate, ANP, cGMP, plasma renin activity, and aldosterone were evaluated for 2 hours before and after the injection. Diuresis and natriuresis were measured every 30 minutes. The patients then started a low calorie/normal sodium diet (510 kcal/150 mmol/d) for 4 days, and then the ANP injection protocol was repeated. The low calorie diet induced a slight weight loss (from 90.6±1.1 to 87.7±1.2 kg; P P P P P

Angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism has been shown to be an independent risk factor for myocardial infarction and other cardiovascular diseases. The aim of the study was to investigate the relationship between ACE genotype and carotid atherosclerosis evaluated by ultrasonography.ACE I/D polymorphism was determined in 240 low-risk patients (mean age 53.6 +/- 7 years) in relation to traditional risk factors and the degree of carotid atherosclerosis. Intimal-medial thickness was measured at the level of the common carotid artery, bifurcation and internal carotid on both sides. Patients were defined as normal (n = 47, intimal-medial thickness1.0 mm), thickened (n = 56, intimal-medial thicknessor = 1.0 andor = 1.3 mm in the thickest wall) or with an atherosclerotic plaque (n = 137, intimal-medial thickness1.3 mm for at least one level of examination). Age, sex, body mass index, blood pressure levels and prevalence of other risk factors were similar in the three groups. I/D polymorphism was determined by polymerase chain reaction using specific primers and genomic DNA from leukocytes as template. Plasma ACE levels, plasma renin activity and plasma aldosterone were evaluated in all patients by standard procedures.No significant differences were found in humoral parameters, ACE, genotype distribution and the corresponding allele frequency among the three groups of patients. Only ACE plasma levels were significantly higher in the DD and ID genotypes compared with the II genotype (DD 14.27 +/- 5.05 IU/ml, ID 12.70 +/- 4.31 IU/ml; II 8.04 +/- 3.45 IU/ml). The mean intimal-medial thickness was similar in all three genotypes.Although ACE genotype has been shown to be related to coronary atherosclerosis, the present data do not indicate that the DD genotype is associated with carotid atherosclerosis. However, further studies of larger populations are needed to clarify whether genetic ACE polymorphism is associated with carotid atherosclerosis.

The early phase of weight loss induced by fasting is associated with diuresis, natriuresis and reduction in blood pressure through unclear mechanisms. Atrial natriuretic peptide (ANP) is a cardiac hormone with potent natriuretic, diuretic and hypotensive effects mediated by 'biologically active' receptors (NPr-A). A second type of receptor mediates the clearance of ANP (the clearance receptor, NPr-C). Since NPr-C appears to be abundant in adipose tissue, we analysed NPr-C and NPr-A gene expression in white and brown adipose tissue (WAT and BAT) as well as in renal cortex of fasting rats. Plasma ANP, cyclic GMP and aldosterone were also measured.Twelve male Wistar rats were deprived of food for about 50 h, and 12 other rats were fed ad libitum. Periepididymal WAT, interscapular BAT and left renal cortex were used for RNA extraction and northern blot analysis with rat NPr-C and NPr-A complementary DNA probes labelled with 32P-dCTP. Densitometric analysis of hybridization signals was corrected by beta actin expression before statistical analysis. Blood was drawn for ANP, cyclic GMP (cGMP) and aldosterone radioimmunoassays, which were also measured in a group of six rats deprived of food for 25 h.A dramatic decrease in NPr-C steady-state messenger RNA levels was observed both in WAT (about 3.6-fold, P0.001) and in BAT (about threefold, P0.01), but fasting did not affect the expression of NPr-A in adipose tissues. In the renal cortex NPr-C and NPr-A messenger RNA levels were unaffected by fasting. ANP and aldosterone levels were reduced after fasting whereas cyclic GMP was increased at 25 h, but the differences did not reach statistical significance.Fasting exerts a tissue-specific and gene-specific suppression of NPr-C gene expression in adipose tissue that appears to be accompanied by an increased biological activity of ANP. The natriuresis and diuresis and reduction of blood pressure induced by fasting might result from a reduced expression of NPr-C in adipose fat pads.

It has recently been shown that ischemia in collateral-dependent myocardium may develop at a very variable threshold in anginal patients; accordingly, the aim of this study was to assess whether nifedipine and diltiazem can increase blood flow to collateralized myocardium in man. Nine patients with complete coronary occlusion filled by collaterals, with no other coronary stenosis, normal left ventricular function, and reproducibly positive exercise tests were studied. They underwent exercise tests off therapy and after acute randomized administration of nifedipine (10 mg sublingually), diltiazem (120 mg orally), and nitroglycerin (0.5 mg sublingually), the latter a drug known to increase blood flow to collateralized myocardium. Following nifedipine, time to 1 mm ST segment depression increased significantly (from 430 +/- 176 to 576 +/- 205 seconds, p0.01), while heart rate and rate-pressure product remained unchanged (115 +/- 16 vs 121 +/- 17 beats/min and 199 +/- 29 vs 204 +/- 44 beats/min.mm Hg.10(2), respectively, p = NS for both). Similarly, diltiazem significantly increased time to ischemic threshold from baseline to 638 +/- 125 seconds (p0.01), but did not change heart rate and rate-pressure product at 1 mm ST segment depression. Submaximal rate-pressure products were significantly lowered by both nifedipine and diltiazem. Nitroglycerin not only significantly improved time to ischemic threshold (from baseline to 666 +/- 76 seconds, p0.01), but also increased heart rate (from baseline to 137 +/- 16 beats/min, p0.01) and rate-pressure product (from baseline to 242 +/- 48 beats/min.mm Hg.10(2), p0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

OBJECTIVE: To investigate whether the hypotensive effects of angiotensin converting enzyme (ACE) inhibitors in comparison with those of calcium antagonist might be predicted by urinary kallikrein activity, a marker of the activity of the renal kallikrein-kinin system. DESIGN: Seventy-five essential hypertensive patients were randomly assigned to treatment with ACE inhibitors (enalapril or lisinopril 20 mg once a day) or with calcium antagonists (nifedipine 20 mg twice a day or lacidipine 4 mg once a day). Fifty-four had normal (NK) and 21 low (LK) kallikrein activity. Blood pressure was measured after 2 weeks, and 3 and 6 months. Patients whose diagnostic blood pressure, 2 weeks after the first dose, decreased by at least 15 mmHg or was < or = 90 mmHg were defined as responders. The others were defined as non-responders. In non-responders a second drug was added and the patients were not considered for further analysis. METHODS: Urinary kallikrein activity was determined by a spectrophotometric assay using a synthetic chromogenic substrate. RESULTS: After 2 weeks therapy with ACE inhibitors 88% of NK patients were responders, whereas in the LK subgroup 40% were responders, a significant difference between subgroups. For the patients treated with calcium antagonists, conversely, 59% of NK patients were responders in comparison with 82% of the LK subgroup, a significant difference between drug groups. After 3 and 6 months of treatment blood pressure was significantly lower in NK patients treated with ACE inhibitors and in LK patients treated with calcium antagonists. In the NK group on ACE inhibitors the mean arterial pressure after the first dose was significantly related to that observed after 6 months (n = 0.71, P < 0.01). CONCLUSIONS: Our data indicate that urinary kallikrein activity may represent an index to predict the chronic antihypertensive effect not only of ACE inhibition but also of calcium antagonism, and support the concept that the renal kallikrein-kinin system might play some contributory role in modulating the hypotensive action of ACE inhibitors.

OBJECTIVE To seek possible correlations between plasma atrial natriuretic factor (ANF) and left ventricular diastolic function (LVDF) in hypertensive patients. DESIGN Since LVDF abnormalities can be detected in patients with normal left ventricular mass, we studied a group of hypertensive patients without left ventricular hypertrophy. METHODS Untreated hypertensive patients (n = 23) and normotensive control subjects (n = 19) were studied. LVDF indices were obtained by M-mode and pulsed Doppler echocardiography. Blood samples for plasma ANF were taken in the recumbent position from subjects on normal-sodium intake. RESULTS Plasma ANF levels were significantly higher in hypertensive patients than in normotensive subjects. All indices for systolic function were normal in both normotensive subjects and hypertensive patients. Left atrial diameter was significantly higher for hypertensive patients than for normotensive subjects. Considering LVDF, all indices for ventricular filling were found to be altered, on average, in hypertensive patients, the only exception being peak early velocity. In addition, significant correlations were found between plasma ANF and the pulsed Doppler parameters of left ventricular filling, peak atrial velocity and the peak early:peak atrial velocity ratio. Overall correlations between plasma ANF and left atrial diameter, and between left atrial diameter and left ventricular mass index were also observed. CONCLUSIONS The high levels of plasma ANF observed in our hypertensive patients and their correlation with the LVDF indices (which mainly reflect the atrial contribution to ventricular filling) could be the result of an increased atrial stretch due to diastolic ventricular dysfunction. This may exist in hypertensive patients before the development of ventricular hypertrophy.

In order to seek possible relationships between renal kallikrein and atrial natriuretic factor (ANF), we measured urinary kallikrein (UK) and ANF in 84 normal subjects (NS) and in 104 uncomplicated essential hypertensives (HP). Atrial natriuretic factor was significantly higher in HP than in NS (38.5 +/- 1.3 vs 29.0 +/- 1.3 pg/mL, P less than .01), whereas UK was significantly lower in HP than in NS (11.1 +/- 0.9 v 15.3 +/- 0.6 nkatal/24 h, P less than .01). Calculating the 95% of the percentile distribution of the single values of UK in the group of NS we were able to show that 24 out of 104 HP had a UK which fell below the lowest limit (4.5 nkat/24 h) of the normal range. We therefore divided our HP into two subgroups: patients with normal kallikrein excretion (NK) (n = 80; mean UK 13.8 +/- 0.8 nkat/24 h) and patients with low kallikrein excretion (LK) (n = 24; mean UK 2.3 +/- 0.3 nkat/24 h). Normal kallikrein patients had a mean plasma ANF value of 31.9 +/- 1.2 pg/mL which was almost superimposable to that found in NS; on the contrary, the mean plasma level of ANF in LK patients (50.7 +/- 2.2 pg/mL) was significantly higher than that measured in NK patients and in NS (P less than .01 v NK patients and NS, respectively). Since a low urinary kallikrein excretion may represent a marker of an impaired production of renal kallikrein, the high levels of ANF found in the LK subgroup could be the result of a compensatory response of the atrium attempting to maintain sodium and volume homeostasis.

Heavy reversible proteinuria induced by antihypertensive treatment with low doses of captopril has recently been reported by our group in psoriatic patients. To ascertain whether an increased permeability of the glomerular basal membrane of psoriatics can lead to an enhanced urinary excretion of albumin independently from the presence or absence of coexisting diabetes or hypertension, the latter parameter was measured in 39 patients affected by diffuse psoriasis. A high prevalence of microalbuminuria was observed in diabetic and hypertensive psoriatics. Moreover, a direct correlation was found between the diastolic blood pressure (BP) values and the urinary excretion of albumin in the entire group of psoriatics, thus suggesting systemic hypertension as one of the factors responsible for proteinuria in these patients. However, more than 50% of normotensive psoriatics showed an enhanced excretion of albumin. Since microalbuminuria has been indicated as a reliable index to predict the development of renal impairment, the finding of an enhanced albumin loss in psoriatics represents a further risk factor in these patients, who are particularly susceptible to experience cardiovascular complications.

To investigate the role of Angiotensin II in the release of ACTH, the response of adrenocorticotrophic hormone to hypoglycaemia was studied before and during treatment with an angiotensin converting enzyme inhibitor, enalapril, in 15 male patients with essential hypertension. Plasma levels of ACTH were measured before and 60, 90 and 120 min after an i.v. bolus of normal saline, as placebo, and, 3 days later, after an i.v. bolus of regular insulin (0.15 U/Kg b.w.). Enalapril treatment was then started and both placebo and hypoglycaemic tests were repeated 15 days thereafter. No changes in ACTH plasma levels were observed after acute normal saline either before or during enalapril treatment. On the contrary, hypoglycaemia induced a sharp increase of ACTH before enalapril (from 19.5 +/- 4.1 to 74.4 +/- 13.0 pg/ml, p less than 0.01 60 min after insulin) but not during ACE inhibition (from 26.1 +/- 6.2 to 34.6 +/- 5.9 pg/ml, NS, at min 60 of the study). The present data confirm our previous observation on the reduction of the hypoglycaemic-induced ACTH release during ACE inhibition with captopril and support the hypothesis that circulating Ang II may exert a facilitating role on adrenocorticotrophic hormone release.

The aim of this study has been to see whether acute variations in the proportions of circulating active and inactive renin in normal subjects were related to concurrent changes in the excretion of urinary kallikrein. Hydrochlorothiazide (50 mg/day) was given to 6 normal volunteers for 6 days; another group of 6 normal subjects received spironolactone (300 mg/day) for 6 days whereas synthetic aldosterone (0.5 mg/day) was administered i.m. for three days to 3 normal subjects. Both diuretics induced a sharp rise in active and total renin and a significant transient decrease in inactive renin so that the active: total renin proportion significantly increased. Urinary kallikrein excretion did not significantly change in either group. Parenteral administration of aldosterone induced a striking fall in all renin components without changing the proportions of active and inactive renin whereas urinary kallikrein excretion increased. These results indicate that changes in active: total renin proportions can occur without parallel variations in urinary kallikrein excretion. The latter cannot be used, therefore, as a reliable index of the possible role of renal kallikrein as activator in-vivo of inactive renin in man.

A retrospective analysis of renal vein renin results has been done in 96 patients with renal artery stenosis and hypertension studied in two Italian centers (Sassari and Pisa) with respect to the outcome of either surgery or percutaneous transluminal angioplasty (PTA). In all patients the renal vein renin ratio and the V-A/A ratios for the affected and unaffected kidney were calculated. Each patient underwent surgery (75) of PTA (21): 71 subjects were cured, 17 improved whereas the arterial pressure did not vary after revascularisation procedure in 8 patients. In the Pisa series all 54 patients showed a lateralisation with contralateral renin suppression and 95% of them benefitted from surgery. In the Sassari series 42 patients were submitted to PTA or surgery, not only on the basis of a positive renal vein renin study but taking into account a complete clinical evaluation: 8 of them were cured or improved in spite of negative renal vein renin criteria. In the two series, the better predictive index appeared to be the suppression of the renin secretion from the contralateral kidney while the high/low renin ratio showed a consistent amount of false-positive and false-negative results. Our retrospective study demonstrates that the renal vein test in hypertensive patients with renal artery stenosis is highly predictive of the curability of the disease, particularly when contralateral suppression of renin secretion is present. On the other hand, since patients with negative renin indexes can also take benefit from surgery of PTA, the renin parameters cannot be adopted as the sole criterion in making the decision to operate.

Conflicting data concerning the presence of enhanced serum angiotensin-converting enzyme (SACE) activity in psoriasis are reported in the literature. In order to verify whether this abnormality is a typical pattern of psoriasis, SACE levels were determined in 27 psoriatics as well as in 18 healthy subjects and in 30 patients with essential hypertension. We found that SACE levels were normal in patients affected by psoriasis independently of the presence or the absence of abnormalities in carbohydrate metabolism. Furthermore, SACE levels were not related to the severity of the skin lesions. We conclude that an elevated SACE activity is not a typical pattern of psoriasis, whereas, when present in a psoriatic, it might suggest the possibility of a coexisting unknown systemic sarcoidosis.

Thirty-one essential hypertensives with normal or low PRA were evaluated before and after a single oral dose (50 mg) of captopril. A significant fall both in systolic and diastolic blood pressure (BP) was obtained in the subgroup of patients who were classified as "normal kallikrein hypertensives", while no significant change in BP was observed in "low kallikrein hypertensives". Furthermore the mean percentage fall in mean BP, throughout the 2 hours following captopril administration, was significantly related to the basal value of urinary kallikrein excretion (r = 0.47 p less than 0.05) in the entire group of patients. Our results suggest that a blunted activity of the kallikrein system might be responsible for failure of captopril in lowering BP in patients in whom the renin-angiotensin system is not pathogenetically implicated.

Despite their vasodilating action, calcium antagonists increase renal sodium excretion. To ascertain whether renal kallikrein plays a role in the renal effects of calcium antagonists, nifedipine (N) (10 mg orally) or placebo (P) was given to 17 male patients with mild to moderate essential hypertension during a 6-h infusion of either saline (S) or aprotinin (A) (2 X 10(6) KIU in 200 ml of saline). Blood pressure (BP) and heart rate (HR) were measured every 10 min, and blood samples were taken at -10, 0, 30, 60, 120, 240, 360 min for plasma renin activity (PRA), creatinine, and osmolarity determinations. Urinary kallikrein, aldosterone, creatinine, and electrolytes were measured in 6-h urine collections. The acute administration of N induced a significant systolic BP (SBP) and diastolic (DBP) fall and a transient PRA increase that peaked at 30 min and were not modified by A infusion. Urinary volume (+47%), Na+ (+54%) and Cl- (+58%) excretion were significantly enhanced by N. There were less pronounced and statistically not significant increases in urinary excretion of Ca2+ (+38%) and K+ (+29%). Infusion of A did not interfere with the natriuretic effect of N. Our data do not support the hypothesis that the kallikrein-kinin system plays an important role in mediating the renal effects of nifedipine in humans.

Relationships between renal kallikrein and plasma atrial natriuretic factor were investigated by measuring urinary kallikrein excretion (by spectrophotometric assay) and plasma atrial natriuretic factor (by radio-immunoassay after extraction from plasma) in 84 normal subjects and in 104 essential hypertensives with a normal renal function. The atrial natriuretic factor was significantly higher in the essential hypertensives than in the normal subjects (38.5 +/- 1.3 versus 29.0 +/- 1.3 pg/ml, P less than 0.01), whereas urinary kallikrein excretion was significantly lower in the hypertensives than in the normal subjects (11.1 +/- 0.9 versus 15.3 +/- 0.6 nkat/24 h, P less than 0.01). Taking the 95% confidence limits of urinary kallikrein excretion in the normal subjects (from 4.5 to 29.9 nkat/24 h), we divided our essential hypertensives into two subgroups, patients with a normal kallikrein excretion (n = 80; mean urinary kallikrein excretion 13.8 +/- 0.8 nkat/24 h) and patients with a low kallikrein excretion (n = 24; mean urinary kallikrein excretion 2.3 +/- 0.3 nkat/24 h) The patients with a normal kallikrein excretion had a mean plasma atrial natriuretic factor value of 31.9 +/- 1.2 pg/ml, which was similar to that found in normal subjects. In contrast, the mean plasma level of atrial natriuretic factor in the patients with a low kallikrein excretion (50.7 +/- 2.2 pg/ml) was significantly higher than that measured in the patients with a normal kallikrein excretion and in the normal subjects (P less than 0.01 versus patients with normal kallikrein excretion and normal subjects, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

1. Activation of inactive renin in rat plasma has been studied with different trypsin concentrations and incubation times at pH 6.2 and 4°C. 2. Trypsin concentrations below 2 mg/ml, lower than endogenous rat plasma anti-trypsin activity, do not activate inactive renin, whereas maximal activation is obtained with trypsin at 6 mg/ml for 1 min at 4°C, pH 6.2. 3. Under these conditions trypsin can cleave dialysable fragments from renin substrate. ANG I can be generated at 37°C with a pH optimum of 5.3. Nevertheless, the ANG I formation at pH 6.2 was totally unaffected. 4. Incubations longer than 2 min with trypsin at 6 mg/ml can induce a direct cleavage of dialysable ANG I-containing fragments strongly interfering with the measurements of renin activity at pH 6.2. 5. On average 40% of the total renin measured in plasma of normotensive WK rats is in the inactive form, although a wide range of variation is observed.

We have previously reported on a high prevalence of high renin essential hypertension in psoriasis. Since angiotensin-converting enzyme (ACE) was also reported to be increased in some psoriatics, we found it rational to treat 10 patients with hypertension and diffuse psoriasis with captopril at a dose of 25 mg t.i.d. Five patients had high PRA levels and in 1 of them serum ACE was also increased. Serum creatinine, BUN and urinalysis were normal in all of them. SPB fell from 163 +/- 3 to 138 +/- 3 and DBP from 107 +/- 3 to 86 +/- 2 mm Hg after 1 month of captopril treatment. A surprising clinical improvement of the cutaneous lesions occurred in 3 patients previously resistant to every local or systemic treatment. Unfortunately, however, 3 patients developed heavy proteinuria (greater than 2 g/day) which disappeared after captopril discontinuation. The unexpected incidence of reversible proteinuria induced by low doses of captopril in our patients recommends a careful monitoring of the renal function every time this drug is employed in the treatment of hypertension in a psoriatic.

The Authors investigated anterior pituitary function in hypertensive patients in basal conditions and following a 15-day course of treatment with Captopril, a drug which blocks the generation of Angiotensin II (Angio II). No differences were observed for any of the pituitary hormones except ACTH, whose response to hypoglycemia was significantly blunted by the pharmacological treatment. A possible role of Angio. II in modulating some aspects of pituitary function is proposed.

The use of sublingual captopril has been recently suggested in hypertensive crisis on the assumption of a faster absorption and thus a more rapid effect on blood pressure than with the oral route. To verify this hypothesis we have compared the hypotensive effect of oral and sublingual captopril in 40 essential hypertensives who were randomly allocated to either route of administration. Captopril was administered orally dissolved in water or allowed to dissolve under the tongue. After 5, 10, 20, 30, 40, 60 and 90 minutes blood pressure, Plasma Renin Activity (PRA) and Angiotensin Converting Enzyme (ACE) were measured. No significant differences were found between the two groups in the time course of blood pressure decrease, PRA increase and ACE inhibition. The changes of the parameters studied was superimposable irrespective of the route of administration thus not supporting the hypothesis that sublingual captopril might be absorbed more rapidly.

The role of the kidney as a possible source or as activator of inactive renin was studied in 22 patients with Essential Hypertension (EH) and in 20 patients with Unilateral Renal Artery Stenosis (RAS). Active and inactive renin (trypsin activation) were measured in blood samples taken simultaneously from both renal veins and from a peripheral artery during acute diuretic stimulation induced by furosemide 40 mg i.v. In EH pts active and trypsin-activated renin were significantly higher in both renal veins than in arterial blood (P less than 0.001 and P less than 0.02 respectively) whereas no difference was seen as far as inactive renin is concerned. In unilateral RAS trypsin-activated and active renin from the ischemic kidney were significantly higher (P less than 0.01 and P less than 0.005 respectively) while inactive renin was significantly lower (P less than 0.005) than in arterial blood. No significant difference was seen between arterial and renal venous blood from the contralateral kidney as far as active and inactive renin are concerned. When comparing the V-A differences for active renin to the corresponding V-A differences for inactive renin from the ischemic kidney a significant negative correlation appeared (r = -0.49 p less than 0.05) whereas no correlation was found from the contralateral kidney (r = -0.26 n.s.). These data demonstrate that the ischemic kidney, in addition to its ability to release active renin, can also activate circulating inactive renin.

To test the hypothesis that acute angiotensin-converting enzyme (ACE) inhibition might predict the postoperative blood pressure outcome, a single oral dose of captopril ranging from 12.5 to 100 mg, was given to 26 patients with renovascular disease and its hypotensive effect was compared with that of surgery (21 patients) or of percutaneous transluminal angioplasty (PTA) (5 patients). Both systolic and diastolic blood pressure fell significantly (p less than 0.001) from 179.9 +/- 5.4/114.1 +/- 2.1 to 148.4 +/- 3.8/94.1 +/- 1.9 after captopril and to 141.1 +/- 3.7/88.9 +/- 2.0 at least 3 months after operation. Postoperative pressure values were directly related to those after captopril (SBP: r = 0.65, p less than 0.001; DBP: r = 0.45, p less than 0.05) as were their absolute decrements (SBP: r = 0.70, p less than 0.001; DBP: r = 0.64, p less than 0.001). However, after captopril, individual pressure tended to be higher (and their decrements to be lower) than after operation. 12 out of 19 patients cured by surgery were considered cured by captopril, while 5 out of the remaining 7 were improved and 2 not cured. The 6 patients improved by surgery or PTA were also improved by captopril and the only patient not cured by surgery was not cured by captopril. Therefore, if we consider both cure and improvement as a positive result, the captopril test gave 23 true-positive, 1 true-negative and 2 false-negative responses. Taken together, these data suggest that acute ACE inhibition may be an useful tool in predicting postoperative blood pressure of patients with renovascular disease.

The antihypertensive efficacy of angiotensin converting enzyme (ACE) inhibitors may result from the blockade of angiotensin II formation but also, theoretically, from the inhibition of kinin breakdown. To test whether a blunted activity of the kallikrein-kinin system might account for the failure of ACE inhibitors in lowering blood pressure (BP) in patients in whom the renin-angiotensin system (RAS) is not enhanced, 31 essential hypertensives with normal or low plasma renin activity (PRA) were evaluated before and after a single oral dose (50 mg) of captopril. A significant fall, in both systolic and diastolic BP, was obtained in the subgroup of patients who were classified as 'normal-kallikrein hypertensives' according to whether their pretreatment urinary kallikrein excretion was within the normal range, while no significant change in BP was observed in 'low-kallikrein hypertensives'. Furthermore, the mean percentage fall in mean BP, throughout the 2 h following captopril administration, was significantly related to the basal value of urinary kallikrein excretion (r = 0.47, P less than 0.05) in all the patients. Our results suggest that blunted activity of the kallikrein system might be responsible for failure of captopril to lower BP in some hypertensive patients.

Increased aldosterone secretion has been found in a mouse lacking the KCNE1 gene which codes for a regulatory protein of the KCNQ1 gene product, forming the channel for the outward rectifying delayed K+ current. Abnormalities in proteins regulating the K+ fluxes across membranes may be responsible for aldosterone-secreting adenomas (aldosteronomas) also because K+ channels are involved in cell growth. Normal and adenomatous adrenal samples and NCI-H295 cell line were used to: a) evaluate KCNE1 and KCNQ1 gene expression, b) sequence the full length cDNAs of KCNE1 and both KCNQ1 isoforms. These differently spliced KCNE1 and KCNQ1 mRNAs were expressed in adrenal tissue. In contrast, KCNQ1 isoform 2 mRNA was not expressed in kidney control tissues and NCl-H295 cell line. NCI-H295 cell line also had a significantly lower expression of KCNQ1 isoform 1 mRNA than normal adrenals and aldosteronomas. We did not find any somatic mutations in the coding sequences of both genes. This different expression pattern of KCNQ1 isoforms in NCI-H295 cell line with the lack of the mRNA for the dominant-negative KCNQ1 isoform 2 supports the involvement of voltage-gated K+ channel in cell proliferation.