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

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

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

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

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

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

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.

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

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.

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.

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 (

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

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

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

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

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

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

Plasma renin activity (PRA) of patients with Parkinson's disease was measured in recumbency, upright position, and after frusemide administration. The results show that the renin responses to both stimuli are significantly reduced as compared with those obtained in a group of normal subjects, while recumbent PRA levels of Parkinsonism patients are not significantly lower than those found in recumbent normal subjects. Levodopa treatment, alone or in combination with two different dopa-decarboxylase inhibitors, benserazide and carbidopa, does not modify the renin response to posture or to frusemide. Although the reduced activity of the renin-angiotensin system can play some role in the genesis of orthostatic hypotensive episodes encountered in patients with Parkinsonism, the greater incidence of orthostatis hypotension in patients treated with levodopa seems to be unrelated to any effect of this drug on the renin release.

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.

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

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

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

The local renin-angiotensin system may regulate adrenal cell growth and function. Angiotensinogen, renin, and angiotensin converting enzyme gene expression were studied in four normal adrenal glands (removed from patients with renal carcinomas) and five aldosterone-secreting adenomas. Northern blot analysis showed expression of angiotensinogen messenger RNA (mRNA) in normal adrenals at levels approximately 35-fold lower than liver and sixfold lower than kidney. Similar angiotensinogen mRNA levels were present in two aldosteronomas, whereas a third had levels approximately 50% of those found in kidney. Renin mRNA was detectable in most normal adrenals and in three adenomas, one of which had relatively high renin mRNA levels. Angiotensin converting enzyme gene was expressed in adrenal tissue and in three adenomas. Portions from these normal adrenals and two of these aldosteronomas, as well as samples from two other adrenals and three aldosteronomas, were also studied in an in vitro superfusion system coupled with active renin radioimmunometric assay, angiotensin II/III, and aldosterone radioimmunoassay. Total amounts of active renin and angiotensin II/III released from normal adrenals during 270 minutes of superfusion were higher than the amounts released from aldosteronomas (312 +/- 35 versus 187 +/- 43 and 823 +/- 100 versus 436 +/- 55 pg/100 mg tissue, respectively; mean +/- SEM, p less than 0.05), whereas aldosterone release from the adenomatous tissue was approximately threefold higher (320 +/- 21 versus 115 +/- 18 ng/100 mg tissue; mean +/- SEM, p less than 0.01). Total amounts of active renin and angiotensin II/III released by normal or adenomatous adrenal samples exceeded threefold to fourfold the amounts extracted from similar samples of the same surgical specimen.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of aprotinin on renin release and renal function were evaluated in 24 male essential hypertensive patients, on unrestricted (n = 17) and on chronic low as well as on high sodium intake. Aprotinin (1 X 10(6) kallikrein inhibitor units) or saline (200 ml) were infused in all patients for 6 h. Blood samples were taken for plasma renin activity (PRA) and 6-h urine collections were obtained for active and inactive kallikrein, sodium and potassium excretion measurement. In patients on unrestricted sodium diet, aprotinin had no effect on blood pressure (BP), glomerular filtration rate, renal plasma flow, urinary sodium and potassium excretion. However, an inverse relationship was found between pretreatment urinary sodium excretion and the per cent reduction of the latter after aprotinin. A significant reduction in urinary sodium excretion was induced by aprotinin in patients on high sodium intake, whereas no change was observed in the same patients when on a low sodium diet. Aprotinin reduced the urinary excretion of active kallikrein by 81% and the active to total kallikrein ratio from 24 to 6%. Infusion of aprotinin induced a significant decline in active renin but did not modify inactive renin levels in patients on unrestricted sodium diet as well as in patients on low or high sodium intake. Our data suggest that the inhibition of kallikrein and/or other serine proteases by aprotinin can interfere with renal release of active renin and also support the hypothesis that the renal kallikrein system exerts a regulatory control on sodium excretion in salt replete hypertensives.