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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

In overweight patients (OW), the increased peripheral activity of the endocannabinoid system in visceral adipose tissue (VAT) may be mediated by cannabinoid type 1 (CB1) receptor expression. We determined whether CB1 receptor splice variants and messenger RNA (mRNA) levels in perirenal and subcutaneous adipose tissues are associated with obesity and metabolic syndrome (MetS). Gene expression with multiple-primers real-time polymerase chain reaction (TaqMan; Applied Biosystem, Weiterstadt, Germany) was performed to study VAT and paired subcutaneous adipose tissue (SAT) mRNA from 36 consecutive patients undergoing nephrectomy. Cannabinoid type 1A and CB1E mRNAs variants with the longer version of exon 4 were expressed. The CB1 expression in perirenal VAT significantly correlated with body mass index (BMI). Paired subcutaneous/perirenal samples from normal-weight patients (BMI25 kg/m(2)) showed higher CB1 expression in SAT (P = .002), whereas in OW (BMIor = 25 kg/m(2)), the higher CB1 expression was in VAT (P = .038). In unpaired samples, SAT of normal-weight patients had significantly higher CB1 mRNA levels compared with SAT of OW, whereas higher CB1 expression (P = .009) was found in VAT of OW (n = 25). Overweight patients with increased visceral CB1 expression had higher waist circumference (P.01), insulin (P.01), and homeostasis model assessment index (P.01). In addition, patients with the MetS (n = 22) showed higher CB1 expression in perirenal adipose tissues (P = .007). Visceral adipose CB1 expression correlated with BMI. Overweight patients and those with MetS showed a CB1 expression pattern supporting a CB1-mediated overactivity of the endocannabinoid system in human VAT.

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.

OBJECTIVES: To update previous guidelines to score the Cumulative Illness Rating Scale (CIRS) and test their usefulness in hospitalized elderly patients. DESIGN: The CIRS was scored retrospectively in a cohort of elderly patients followed for 18 months. SETTING: An acute internal medicine ward in an academic tertiary care hospital. PARTICIPANTS: Three hundred eighty-seven patients aged 65 and older. MEASUREMENTS: 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. RESULTS: 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. CONCLUSION: 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.

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.

The obesity pandemic is closely related to hypertension and metabolic syndrome. Visceral adipose tissue plays a key role in the metabolic and cardiovascular complications of being overweight. The pathophysiological link between visceral adiposity and cardiometabolic complications focuses on insulin sensitivity, sympathetic nervous system, renin-angiotensin-aldosterone system (RAAS) and, only recently, on cardiac natriuretic peptide system (CNPS). RAAS and CNPS are endogenous antagonistic systems on sodium balance, cardiovascular system, and metabolism. The circulating RAAS is dysregulated in obese patients, and adipose tissue has a full local renin-angiotensin system that is active at local and systemic level. Adipocyte biology and metabolism are influenced by local renin-angiotensin system, with angiotensin II acting as a 'growth factor' for adipocytes. CNPS induces natriuresis and diuresis, reduces blood pressure, and, moreover, has powerful lipolytic and lipomobilizing activity in humans but not in rodents. In obesity, lower plasmatic natriuretic peptides levels with increasing BMI, waist circumference, and metabolic syndrome have been documented. Thus, reduced CNPS effects coupled with increased RAAS activity have a central role in obesity and its deadly complications. We propose herein an integrated view of the dysregulation of these two antagonistic systems in human obesity complicated with hypertension, metabolic syndrome, and increased cardiovascular risk.

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 renin-angiotensin-aldosterone system (RAAS) is considered to be the main mediator of the cardiovascular damage associated with high blood pressure. Recent guidelines recognised, both directly and indirectly, the central role of RAAS, reporting the ‘compelling indications’ for the use of drugs that antagonise this system. The results of many large trials with the angiotensin receptor blockers (ARBs) candesartan, losartan, irbesartan and valsartan have been published from the year 2000 to the end of 2003. These trials have been conducted to verify that, beyond blood pressure control, ARBs could offer better organ protection in many different clinical conditions. Despite the favourable premises, some ARB trials not only failed to show superiority, but even equivalence with lower-cost therapies of confirmed efficacy (e.g. captopril 50mg three times daily). On the contrary, other ARB trials (IDNT [Irbesartan Diabetic Nephropathy Trial], IRMA2 [Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria], RENAAL [Reduction of End points in NIDDM with the Angiotensin II Antagonist Losartan], and LIFE [Losartan Intervention for End Point Reduction in Hypertension]) have had such clear-cut outcomes that irbesartan (300mg) and losartan (100mg) are the drugs of choice in type 2 diabetes patients with proteinuria or in hypertensive patients with left ventricular hypertrophy. The key factor for ARBs to succeed in delivering superior organ protection appears to be the high dosages used, dosages uncommonly utilised, with some exceptions, to treat hypertension in clinical practice. The results of the published ARB trials are reviewed, focusing on the dose-efficacy of target-organ protection beyond blood pressure control.

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

Atrial natriuretic peptide (ANP) and B-type or brain natriuretic peptide (BNP) inhibit aldosterone secretion in humans both in vitro and in vivo. Unresponsiveness of aldosterone-secreting adenomas (aldosteronomas) to ANP in vitro and in vivo, might be due to reduced expression of the biologically-active natriuretic peptide receptor type A (NPr-A) and/or increased expression of the clearance receptor for natriuretic peptides (NPr-C). Therefore, we have analyzed NPr gene expression and ANP binding sites in human adrenals and aldosteronomas. Using reverse transcription and polymerase chain reaction, we cloned and characterized cDNAs for NPr-A, NPr-C, and the receptor (NPr-B) for the C-type natriuretic peptide (CNP). Total RNA from three normal human adrenals (obtained at surgery from patients with renal cancer) and five aldosteronomas were used for Northern analysis. NPr-A mRNA (approximately 4 kb) and NPr-B mRNA (approximately 4 kb) were expressed without significant differences in adrenals and in aldosteronomas except in an aldosteronomas that contained only very low amounts of NPr mRNAs. The gene expression of NPr-C was barely detectable both in adrenals and in aldosteronomas. ANP binding sites were analyzed by autoradiography with 125I-labeled ligand in other six aldosteronomas. Only one of the adenomas analyzed showed ANP binding sites with density of granules similar to nonadenomatous glomerulosa, whereas the others had significantly reduced densities. In summary, aldosteronomas express the genes encoding for NPr but mainly NPr-A, similarly to control adrenals. On the contrary, the binding sites for ANP are greatly reduced in most aldosteronomas. A somatic mutation or a post-transcriptional defect that reduces ANP binding sites might be present in some aldosteronomas.

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.

To characterize natriuretic peptide receptor (NPr) gene expression in human tissues, we cloned portions of the cDNAs codifying for NPr with guanylyl cyclase activity (NPr-A and NPr-B) and without guanylyl cyclase activity (NPr-C). Total RNA was extracted from samples taken at surgery from normal human tissues. NPr-A and NPr-B cDNAs obtained from lung as well as NPr-C cDNA obtained from renal cortex were cloned, characterized, and used for comparative Northern analysis. NPr-A mRNA (approximately 4 kb) was most abundant in adipose tissue (8 patients) independently on the site of sampling, whereas it was approximately 2.5-fold and 5-fold less abundant, respectively, in kidney (either renal cortex or papilla from 3 patients) and adrenal (4 patients), known target tissues of natriuretic peptides. NPr-C mRNAs (approximately 7.7 and 6.8 kb) had a similar tissue distribution but the highest levels were found in renal tissue and only very low expression levels were found in adrenals (approximately 20-fold lower than renal cortex). The ratio of NPrA versus NPr-C mRNA levels were highest in adrenal and lowest in renal tissue. NPr-B mRNA (approximately 4 kb), which encodes the receptor for the C-type natriuretic peptide, had a different and wide tissue distribution, including expression in ileum and liver, with the highest levels in venous and prostatic tissue. These results indicate that, in humans, different patterns of NPr expression with different NPr-A/NPr-C mRNA level ratios, are present in known target tissues of natriuretic peptides. "Non-classic" target tissues, such as the adipose one, maximally expressed NPr-A and also NPr-C, suggesting that natriuretic peptides may have wider functional activities than those previously demonstrated.

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]

This study investigated (1) the efficacy and safety of doxazosin versus enalapril when added to a diuretic regimen in essential hypertensive patients and (2) the effect of doxazosin alone or combined with chlorthalidone on postural hemodynamics, the renin-angiotensin-aldosterone system, renal function, and plasma catecholamines. Doxazosin reduced blood pressure comparably to enalapril; when added to chlorthalidone, doxazosin showed an additive effect, although to a lesser extent than that obtained when enalapril was added to chlorthalidone. One patient treated with doxazosin alone stopped therapy because of severe headache. The hemodynamic and humoral response to tilting was comparable for doxazosin and enalapril either alone or in combination with chlorthalidone. In particular, no patient experienced symptomatic orthostatic hypotension after the first dosing of doxazosin even when the diuretic regimen was initiated. These findings confirm the efficacy and safety of doxazosin alone or in combination with diuretics.

To compare the antihypertensive efficacy and safety of pinacidil in mild to moderate essential hypertension with that of captopril, 128 patients (63 men and 65 women), mean age 50.49 ± 0.71 years, were treated in a controlled study lasting 10 weeks. The initial dosage (pinacidil: 12.5 mg BID; captopril: 25 mg BID) could be doubled (25 mg BID and 50 mg BID, respectively) or combined with hydrochlorothiazide (12.5 mg BID) at fixed times during the study, whenever diastolic blood pressure remained >95 mmHg. Normalization of blood pressure was reported for 67.2% of patients treated with pinacidil and 68.7% of those treated with captopril. The captopril group required the diuretic combination more frequently. Heart rate, body weight, and laboratory parameters did not show clinically important changes during either treatment. No side effects were observed in 86% of patients treated with pinacidil and in 89% of those treated with captopril.

AIM To review the effects of calcium antagonists, and of the new dihydropyridine lacidipine in particular, on the glomerular filtration rate, renal plasma flow, and the sodium to water ratio in hypertensive patients. METHODS Review of published data. RESULTS Different studies have shown a wide range of responses to all three subgroups of calcium antagonists in glomerular filtration rates and in renal plasma flows. In some studies there was a reduction and in others a rise in these two renal parameters. The administration of lacidipine was associated with a significant rise in renal plasma flow which disappeared with chronic treatment and no change in the glomerular filtration rate. There are only a few studies on the long-term natriuretic and diuretic effects of calcium antagonists. In the short term, dihydropyridine calcium antagonists appear to produce diuretic and natriuretic effects, but these effects are not seen with verapamil. Lacidipine showed no trend towards sodium and water retention. CONCLUSIONS Reported differences between calcium antagonists in glomerular filtration and renal plasma flow probably reflect differences in the baseline tone of pre- and postglomerular arterioles. Calcium antagonists do not cause sodium and water retention during chronic therapy. The new dihydropyridine derivative lacidipine lowers blood pressure without reducing renal function or causing sodium and water retention.

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.

Degenerate oligonucleotide primers complementary to the highly conserved subdomains III and VIII of subclass III tyrosine kinase receptors (TKr-III) were utilized to amplify rat aortic cDNA by polymerase chain reaction. Most of the cloned DNA products were rat platelet-derived growth factor receptor beta and macrophage-colony stimulating growth factor receptor cDNAs. Screening of the clones with probes coding for the receptor-specific kinase insert domain allowed the identification of a novel putative TKr-III cDNA, which hybridized with a approximately 6.1 kb mRNA with a distinctive tissue distribution. In situ hybridization on rat tissues and Northern analysis of cultured cells indicate that endothelial cells express a novel putative TKr-III mRNA.

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: 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.

Natriuretic peptide system plays a well-defined role in the regulation of blood pressure and fluid volume. Although the effects of natriuretic peptides (atrial natriuretic peptide, brain natriuretic peptide and C-type natriuretic peptide) are mediated by specific biologic receptors, their plasma level is influenced by clearance receptors. It has been demonstrated that in hypertensive subjects plasma levels of natriuretic peptides are impaired; furthermore peptide receptor polymorphisms have been shown to be significantly associated with hypertension and cardiac hypertrophy. Studying normotensive subjects at high genetic risk of developing hypertension on the basis of family history makes it possible to investigate the role of natriuretic peptide system in the genesis of hypertension. It has been shown that plasma atrial and ventricular natriuretic peptide levels are significantly reduced in normotensive subjects with a family history of hypertension. Our study is the first one showing association among positive family history of essential hypertension and natriuretic peptide receptor polymorphisms. We identified a novel insertion/deletion polymorphism at position 15,129 in the 3'-untranslated region (3'-UTR) of NPRA receptor mRNA. The NPRA gene deletion variant is associated with hypertensive family history and higher systolic blood pressure. The "deletion 15129" variant might participate in the functional impairment of natriuretic peptide system defining an increased genetic susceptibility to hypertension.

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.

OBJECTIVES AND DESIGN Angiotensinogen (AGT) gene variants influence angiotensinogen plasma levels in children and young adults. The angiotensinogen promoter (-6)A variant facilitates gene transcription in human tissues and it has been associated with high blood pressure in older adults. A young adult population can be used as a model to study genotype/phenotype associations between AGT (-6) variants and cardiovascular variables. METHODS AND RESULTS Anthropometric measurements, blood pressure and heart rate were taken in 422 white Caucasian students (mean age 23.5 years, SD 2.5 years). Family history for hypertension, physical activity and smoking history were evaluated. Left ventricular variables were measured by echocardiography. Carotid artery wall intimal-media thickness (IMT) was measured by high resolution sonography and digitalized morphometry. The AGT G(-6)A alleles were evaluated by mutagenically separated polymerase chain reaction controlled by direct sequencing. No significant associations were found between angiotensinogen genotype and blood pressure, cardiac variables [except for deceleration time in females which increased with the number of (-6)A alleles] and IMT. Allele frequencies were similar between the first and third tertile of blood pressure and left ventricular mass, and were also similar between negative or positive family history for hypertension (the last group having significantly higher systolic blood pressure in males, P = 0.04 and diastolic blood pressure in females, P < 0.01). Moreover, no relevant interaction on the cardiovascular variables was found between AGT genotype and body mass index. CONCLUSIONS The angiotensinogen G(-6)A variants do not affect cardiovascular parameters in young adults, but an effect of this polymorphism on cardiovascular phenotype (and hypertension) in older adults cannot be excluded. Additional factors, associated with ageing, should be present to unleash the supposed unfavourable potential of the (-6)A angiotensinogen variant.

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.

In this review we have analyzed the present knowledge about the differentiation and growth processes in vascular smooth muscle cells (SMC) in hypertension. The study of smooth muscle (SM) and nonmuscle (NM) myosin isoform expression has permitted us to identify a three-stage specific maturational pathway, namely, fetal, postnatal, and adult. In the renovascular (rabbit) and genetic (rat) models of hypertension, adaptive changes occurring in hypertensive vessels make SMC resemble those found in the early stages of development (smooth muscle plasticity). In fact, based on SM- and NM-myosin isoform distribution, postnatal-type SMC predominate in the arterial media during the early remodeling of the arterial wall that occurs in hypertension, whereas postnatal- and fetal-type SMC predominate in the intimal thickening. Locally produced or activated autocrine/paracrine factors, such as growth factors or cytokines, along with circulating hormones, seem to be involved in the growth response or changes in the differentiation pattern of SMC. Thus, these factors not only play a specific role in the regulation of blood pressure, but also are likely to be responsible for the remodeling of the arterial wall in hypertension.

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: Angiotensinogen (AGT)-derived peptides, as angiotensin II, regulate renal biology and physiology. Two novel AGT gene promoter variants (G-175A and G-163A) influence AGT gene expression in adipocytes as recently published. Moreover, obesity has been consistently linked to renal cell cancer. In a small population of kidney cancer patients studied mainly to obtain visceral adipose tissue samples, we have found a very high prevalence of -175A and -163A AGT gene variants.The aim of the present study was to compare the frequencies of these alleles in populations with or without kidney cancer. Design and Method: Three populations differing in size and gender were studied: 1075 healthy men of the Olivetti Heart Study (OHS) from southern Italy, 91 obese females, and 35 consecutive patients (both males and females) with kidney cancer from center Italy. The allele frequencies of G-175A and G-163A were evaluated. The known -20A/C SNP was used as control AGT promoter SNP. Results: AGT -163A and -175A variants were significantly more common with a striking 8-fold (for tha -163A) to 26-fold (for the -175A) difference in kidney cancer patients than in OHS males (P = 0.001) or obese female subjects (P = 0.001). Indeed, comparing allele frequencies we found that the -163A allele was 2.9% in OHS, 3.3% in obese females and 24.3% in kidney cancer patients (P = 0.001). The frequency of -175A allele was 1.8% in OHS, 1.1% in obese female but a striking 37.1% in kidney cancer patients (P = 0.001). No differences were found comparing -163A and -175A frequencies of OHS and obese females despite the differences in gender and size of populations. In kidney cancer patients no allele frequencies differences were found comparing males (n = 26) and females (n = 9). No differences in A-20C allele frequencies were found among the three different populations. Conclusions: Two novel AGT gene promoter functional variants are dramatically more frequent among kidney cancer patients suggesting a link between these genetic markers and renal cancer maybe through altered AGT expression in adipose tissue.