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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.

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.

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

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]

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.

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.

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.

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.

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: 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.

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.

We studied two groups of hypertensive patients in order to ascertain whether the acute natriuretic effect of nifedipine is mediated by humoral factors such as renal kallikrein or atrial natriuretic factor (ANF). First, 17 patients with mild to moderate essential hypertension maintained on a 130-mmol/day diet, received either nifedipine (10 mg orally) or placebo during a 6-h infusion of the kallikrein inhibitor aprotinin (2 x 10(6) KIU) or saline as control. Aprotinin, while significantly reducing urinary kallikrein activity, did not interfere with the acute effects of nifedipine on blood pressure, heart rate, urinary volume, urinary Na+ and creatinine clearance. In another group of eight patients on a constant daily Na+ intake of 130 mmol and in the supine position, placebo or nifedipine (10 mg sublingually) were administered, and blood pressure, heart rate, plasma renin activity, plasma aldosterone and plasma ANF, urinary Na+, urine volume and creatinine clearance, were monitored for 2 h. While placebo did not induce changes in any of the above parameters, nifedipine administration induced a significant decrease in blood pressure and increase in urinary Na+, urine volume and creatinine clearance, and a significant rise in ANF levels, from 19.4 +/- 2.8 pg/ml to a maximum of 23.9 +/- 2.5 and 24.1 +/- 2.2 pg/ml (P less than 0.05) at 60 and 90 min, respectively. In conclusion, our data do not support a role for renal kallikrein as a humoral mediator of the natriuretic effect of calcium antagonists, but do not exclude the possibility that ANF might participate in the nifedipine-induced increase in sodium and water excretion.

Intracellular Ca2+ influx is an essential step in insulin (I) release. Calcium antagonists are reported to reduce I release in vitro and in patients with impaired glucose tolerance (IGT) during acute administration. Their effects during long-term therapy are still controversial. To evaluate the effects of chronic verapamil (V) and nifedipine (N) on carbohydrate metabolism, 12 hypertensive patients (WHO II; aged 37-64 years) with IGT underwent intravenous glucose tolerance tests (IVGTT) (0.33 g/kg body weight in 3 min), arginine (A) infusion (30 g/30 min), and hypoglycemic stress (regular insulin 0.15 U/kg body weight) during which blood levels of glucose (G), I, growth hormone (GH), glucagon (IRG), and cortisol (C) were measured. The patients were then randomized to V (120 mg b.i.d.) or N (20 mg b.i.d.) treatment and, 1 month later, both IVGTT and A infusion were repeated. Hormone determinations were performed by the radioimmunoassay (RIA) and G by the enzymatic method. The patients were maintained on their usual diet for the duration of the study. The rate of decline of G during IVGTT was expressed as Conard's K coefficient (K; normal values greater than 1.3). I and GH during IVGTT were evaluated as the differences between basal and peak values. I, IRG, and GH during A infusion were analyzed as incremental areas. Our results show that neither V nor N impaired carbohydrate metabolism in hypertensive patients with IGT.

To see whether the acute natriuretic effect of nifedipine is accompanied by changes in atrial natriuretic peptide levels, a group of eight hypertensive patients were studied. After at least a week of constant sodium intake, placebo or nifedipine (10 mg s.I.) were administered and blood pressure, heart rate, plasma renin activity, plasma aldosterone and atrial natriuretic peptide plasma levels, urinary sodium, urinary volume and creatinine clearance were monitored for 2 hours. While placebo did not induce changes in any of the above parameters, nifedipine administration was followed by a significant decrease in blood pressure and an increase in urinary sodium, urinary volume and creatinine clearance; these changes were accompanied by a significant rise in atrial natriuretic peptide levels from 19.4 +/- 2.8 pg/ml to a maximum of 23.9 +/- 2.5 pg/ml and 24.1 +/- 2.2 pg/ml (P less than 0.05) at 60 and 90 minutes, respectively. In conclusion, our data do not rule out the possibility that atrial natriuretic peptide participates in the nifedipine-induced increase in sodium and water excretion.

In 25 hypertensive patients (15 with renal artery stenosis and 10 with essential hypertension), captopril, in a single 12.5 mg dose, caused a prompt decrease in arterial pressure without changing the heart rate. Plasma active and trypsin-activated renin significantly increases, whereas inactive renin and plasma aldosterone decreased. The plasma active/inactive renin ratio was also increased, suggesting that captopril, together with a release of active renin, may induce an in vivo activation of inactive renin. No correlations were found between blood pressure changes and both pretreatment and captopril-induced variations of active, inactive and trypsin-activated renin or the active/inactive ratio. However, the percent decrease in mean arterial pressure was significantly related to the increase in the active/inactive renin ratio in a group of patients whose blood pressure was brought to normal (r = -0.78; p less than 0.001). This finding suggests the possibility that vasodilating substances, in addition to inhibiting angiotensin II formation, might play some role both in exerting a full effect of captopril on blood pressure and in triggering the in vivo mechanisms of inactive renin activation.

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)

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.