Oryeongsan (Wulingsan) ameliorates impaired ANP secretion of atria from spontaneously hypertensive rats.

Oryeongsan (ORS), a herbal medicine formula, has long been used for the treatment of impaired body water balance in Asian countries. Recently, it was shown that ORS administration modulates the renin-angiotensin system (RAS). Purpose of the present study was to determine characteristics of atrial ANP secretion and effects of ORS on the secretion in the atria from spontaneously hypertensive rats (SHR). Normotensive WKY groups (WKY-V, WKY-ORS, WKY-LOS) and hypertensive SHR groups (SHR-V, SHR-ORS, SHR-LOS) treated with vehicle, ORS, and losartan as a positive control group, respectively, were used. Experiments were performed in perfused beating atria (1.3 Hz) allowing atrial distension, acetylcholine (ACh) stimulation, and serial collection of atrial perfusates. The secreted ANP concentration was measured using radioimmunoassay. Interstitial fluid (ISF) translocation was measured using [3H]inulin clearance. Stepwise increase in atrial distension by 1.1, 2.0, and 2.7 cmH2O above basal distension further increased ANP secretion proportionally in the atria from WKY-V, but the response was significantly suppressed in the atria from SHR-V. Cardiomyocyte ANP release, the first step of atrial ANP secretion, was suppressed in the atria from SHR-V compared to those from WKY-V (-8.02 ±â€¯2.86, -15.86 ±â€¯2.27, and -20.09 ±â€¯3.62%; n = 8, for SHR-V vs. 8.59 ±â€¯2.81, 15.65 ±â€¯7.14, and 38.12 ±â€¯8.28%; n = 8, for WKY-V; p < 0.001 for all stepwise distension, respectively). Chronic treatment with ORS reversed the suppressed ANP release in atria from SHR-ORS group (6.76 ±â€¯3.92, 9.12 ±â€¯2.85, and 28.79 ±â€¯1.79% for SHR-ORS; n = 5 vs. SHR-V; n = 8; p = 0.01, p < 0.001, p < 0.001, respectively). The effects of ORS were comparable to those of losartan. Trans-endocardial translocation of ISF, the second step of atrial ANP secretion was similar in the atria from the hypertensive SHR-V and normotensive WKY-V. ACh-induced ANP secretion and cardiomyocyte ANP release were also suppressed in the atria from SHR-V compared to WKY-V and ORS reversed the suppression. These findings were accompanied with accentuation of the AT1 receptor expression and suppression of the AT2/Mas receptor, M2 mACh receptor and GIRK4, a molecular component of KACh channel, expression in the atria from SHR-V. Further, treatment with ORS or losartan reversed the expressions in the groups of SHR-ORS and SHR-LOS. These results show that ANP secretion is suppressed in the atria from SHR in association with accentuation of AT1 receptor and suppression of AT2/Mas receptor and KACh channel expression. Treatment with ORS ameliorates impaired ANP secretion through improving cardiomyocyte ANP release with modulation of the cardiac RAS and muscarinic signaling. These findings provide experimental evidence which supports the effect of ORS on the regulation of atrial ANP secretion in the atria from SHR.

Dietary peptides from the non-digestible fraction of Phaseolus vulgaris L. decrease angiotensin II-dependent proliferation in HCT116 human colorectal cancer cells through the blockade of the renin-angiotensin system.

This study aimed to determine the ability of peptides present in the non-digestible fraction (NDF) of common beans to decrease angiotensin II (AngII) through the blockade of RAS and its effect on the proliferation of HCT116 human colorectal cancer cells. Pure synthesized peptides GLTSK and GEGSGA and the peptide fractions (PF) of cultivars Azufrado Higuera and Bayo Madero were used. The cells were pretreated with pure peptides, PF or AGT at their IC50 or IC25 values, in comparison with the simultaneous treatment of peptides and AGT. For western blot and microscopy analysis, 100 µM and 0.5 mg mL(-1) were used for pure peptides and PF treatments, respectively. According to the ELISA tests, GLTSK and GEGSGA decreased (p < 0.05) the conversion rate of AGT to angiotensin I (AngI) by 38 and 28%, respectively. All the peptides tested reduced (p < 0.05) the conversion rate of AngI to AngII from 38 to 50%. When the cells were pretreated with both pure peptides and PF before exposure to AGT, the effectiveness inhibiting cell proliferation was higher than the simultaneous treatment suggesting their preventive effects. GLTSK and GEGSGA interacted with the catalytic site of renin, the angiotensin-I converting enzyme, and the AngII receptor, mainly through hydrogen bonds, polar, hydrophobic and cation-π interactions according to molecular docking. Through confocal microscopy, it was determined that GLTSK and GEGSGA caused the decrease (p < 0.05) of AngII-dependent STAT3 nuclear activation in HCT116 cells by 66 and 23%, respectively. The results suggest that peptides present in the common bean NDF could potentially ameliorate the effects of RAS overexpression in colorectal cancer.

Kinetics of the inhibition of renin and angiotensin i converting enzyme by polar and non-polar polyphenolic extracts of Vernonia amygdalina and Gongronema latifolium leaves.

The aim of this study was to determine the in vitro modulation of the renin-angiotensin system by polyphenolic extracts and fractions of two green leafy vegetables, Vernonia amygdalina (VA) and Gongronema latifolium (GL), that are used for food and medicinal purposes. An 80% acetone extract of each leaf was fractionated on silicic acid-packed column to give two main fractions: acetone eluate (flow-through) and ethanol eluate (column-bound), that consist mostly of chlorophyllic and non-chlorophyllic fractions, respectively. Column fractionation resulted in polyphenolic fractions that displayed higher potency against angiotensin converting enzyme (ACE) and renin than the crude acetone extracts; generally, the chlorophyllic fraction was more active than the non-chlorophyllic fraction. ACE-inhibitory activity was significantly higher (p < 0.05) for the chlorophyllic fraction of VA than GL, with IC(50) values of 0.207 and 0.413 mg/ml, respectively. Similarly, the chlorophyllic fraction of VA had significantly higher (p < 0.05) renin inhibition than GL, with IC(50) values of 0.172 and 0.513 mg/ml, respectively. Kinetics studies showed that the chlorophyllic fractions of VA and GL exhibited mostly mixed-type ACE and renin inhibitions. We concluded that the hydrophobic nature of the chlorophyllic fraction may have contributed to the increased interaction with enzyme protein and inhibition of activities of ACE and renin.

The improvement of luteal insufficiency in fecund women by tokishakuyakusan treatment.

The effect of tokishakuyakusan, a Chinese herbal medicine, was examined, in vivo, in women with luteal insufficiency and in women with normal menstrual cycles. Luteal insufficiency was determined by daily measurement of basal body temperature and plasma progesterone levels. Tokishakuyakusan improved luteal insufficiency. Furthermore, the effects of tokishakuyakusan on prolactin, gonadotropins, steroids, angiotensin II, ANP and renin levels in the blood of women with normal menstrual cycles were studied, as were the medicine's effects on estrogens, pregnenediol and LH in the urine of the same women. Tokishakuyakusan had no adverse effect on hormonal levels in either blood or urine. Furthermore, no clinical side effects were detected. These results suggest that tokishakuyakusan improves luteal insufficiency in women but does not affect the hormonal levels of women with normal menstrual cycles.

[Effect of coffee on blood pressure and activity renin-angiotensin- aldosterone system and catecholamines concentration in patients with essential hypertension]. / Wplyw kawy na cisnienie tetnicze i aktywnosc ukladu renina-angiotensyna-aldosteron oraz stezenie amin katecholowych w surowicy chorych na pierwotne nadcisnienie tetnicze.

The purpose of this study was to investigate whether the renin-angiotensin-aldosterone system activity RAAA or plasma catecholamines concentrations and blood pressure are related to distinct patterns of drinking one cup of coffee in hypertensive patients with low or normal plasma renin activity. Plasma renin activity and enzyme converting angiotensin I to angiotensin II activity and serum concentration of aldosterone and catecholamines were measured by radioimmunoassay. Blood pressure was measured by ambulatory monitoring. Our data suggest that drinking one cup of coffee caused after 60 min, to 2 hours elevated systolic and after 60 min diastolic pressure, only in hypertensive patients, with low RAAA habitually drinking coffee. Hypertensive patients with normal RAAA, habitually drinking coffee, after drinking one cup of coffee had elevation only of diastolic blood pressure from 60 min to 120 min after drinking, but systolic blood pressure did not elevate. Plasma catecholamines and aldosterone concentrations, blood renin activity and enzyme converting angiotensin I to angiotensin II activity were not elevated in hypertensive patients with low or normal RAAA after drinking one cup of coffee.

Equivalent reduction of proteinuria in hypertensives by either nifedipine GITS or enalapril: disparate effects on neurohormones and ambulatory blood pressure and the influence of salt.

OBJECTIVE: We compared the efficacy of two classes of antihypertensive therapy on ambulatory blood pressure control and proteinuria in patients with hypertension. Furthermore, we determined the effects of the interaction of these therapies on neurohormonal activation and of the patients' ambient sodium intake on the outcomes. METHODS: Sustained-release nifedipine (nifedipine gastrointestinal therapeutic system, GITS) 30-120 mg/day was compared in a double-blind sequential randomized placebo-controlled trial with enalapril 5-30 mg/day regarding office and 24-hour blood pressure control, plasma renin activity, noradrenaline and adrenaline levels and 24-hour urinary protein and sodium in 46 elderly nondiabetic hypertensive patients in a 16- to 18-week trial. RESULTS: Both nifedipine GITS and enalapril controlled ambulatory blood pressure during the day and at peak effect. Nifedipine GITS controlled ambulatory blood pressure during the early morning surge and at night time as well. Nifedipine GITS increased plasma renin activity and noradrenaline by 50 and 20%, respectively, compared to the 150 and 0% change produced by enalapril. Both nifedipine GITS and enalapril reduced proteinuria by 37%. Patients had increasing levels or proteinuria proportional to higher ambient sodium intake (r = 0.48; p < 0.01). This effect was accentuated during nifedipine GITS therapy as compared to enalapril. CONCLUSION: Nifedipine GITS was superior to enalapril in controlling ambulatory blood pressure, but they were equivalent in reducing proteinuria (37%). They had disparate effects on neural activation and the duration of action. Raised protein excretion appears to be associated with raised sodium intake. This was apparent especially during nifedipine XL therapy.

Effects of estrogens and progestogens on the renin-aldosterone system and blood pressure.

Endogenous 17 beta-estradiol (E2) and low parenteral doses of exogenous E2 are vasodilators. High dose estrogens, especially ethinylestradiol (EE) and mestranol, stimulate the synthesis of hepatic proteins including coagulation factors, sex hormone binding globulin, and angiotensinogen (Aogen). In the steady state, high plasma levels of Aogen produce only a very small increase of angiotensin II (AII) and plasma renin activity, because AII inhibits the secretion of renin and lowers plasma renin concentration. However, the increase in AII is sufficient for a slight reduction in renal blood flow and a slight increase in exchangeable sodium and blood pressure; in susceptible women, blood pressure may rise considerably. Effects of estrogens on the brain may also be involved in blood pressure changes. Endogenous progesterone is a mineralocorticoid receptor antagonist. Endogenous or exogenous progesterone leads to sodium loss and a compensatory increase in renin secretion, plasma renin activity, AII, and plasma aldosterone, e.g. in the second half of the menstrual cycle. Synthetic progestogens are commonly devoid of the mineralocorticoid receptor antagonistic effect of progesterone, and some are weak estrogen receptor agonists. Combined use of EE and synthetic progestogens may therefore enhance estrogen effects on body sodium and blood pressure. A new progestogen (Drospirenone) with an antimineralocorticoid effect like that of progesterone is described that slightly lowers body weight and blood pressure in a contraceptive formulation together with EE. An almost ideal oral contraceptive would be progestogen like Drospirenone together with a low dose natural estrogen that does not stimulate Aogen synthesis. Since most oral formulations for postmenopausal estrogen replacement also stimulate hepatic protein synthesis (including Aogen) to some extent, the transdermal route of E2 application for contraceptive purposes should also be investigated, since it has reduced potential for undesirable side effects.

Effect of sodium chloride, enalapril, and losartan on the development of polycystic kidney disease in Han:SPRD rats.

We found that the administration of an angiotensin I-converting enzyme inhibitor and sodium chloride loading lessen the development of renal cystic disease induced by 2-amino-4-5-diphenylthiazole in rats. To determine whether similar effects could be observed in an autosomal dominant model of polycystic kidney disease, heterozygous cystic (Cy/+) and homozygous normal (+/+) Han:SPRD rats were divided into experimental groups at 3 weeks of age. The first study included four groups receiving enalapril (50 mg/L), losartan (400 mg/L), hydralazine (80 mg/L), or no drug in their drinking water. The second study included four groups fed a sodium-deficient diet or the same diet supplemented with 0.25%, 0.6%, or 3.3% sodium chloride. The Cy/+ rats receiving enalapril had lower kidney weights and histologic scores than those in the control group, and lower kidney weights, plasma creatinines, and histologic scores than those in the hydralazine group. The Cy/+ rats receiving losartan had lower plasma creatinines and histologic scores than those in the control and hydralazine treatment groups. A sodium-deficient diet markedly blunted the growth of the animals and the development of cystic disease. Increases in the sodium content of the diet in the other three groups were accompanied by higher relative kidney weights and histology scores, while the levels of plasma creatinine were not significantly different. Regression of the cystic disease was observed between 3 and 4 months of age. These results indicate that the development of autosomal dominant polycystic kidney disease in the rat can be modulated by pharmacologic and nutritional factors.(ABSTRACT TRUNCATED AT 250 WORDS)

[Changes in the humoral systems in juvenile arterial hypertension and their correction by using nifedipine and anaprilin]. / Zmina deiakykh humoral'nykh system pry iuvenil'nii arterial'nii hipertenziï i ïï korektsiia z dopomohoiu nifedypinu i anaprylinu.

Examined were 140 adolescents with juvenile arterial hypertension (JAH) and 54 healthy adolescents (age: 15-19 years). Niphedipine was used in 36, anaprilin in 40; 60--did not receive these drugs (control group). The treatment lasted 6 months. It was found that before treatment adolescents with JAH showed a clear increase of the angiotensin, testosterone and plasma renin activity (PRA). Niphedipine treatment resulted in normalization of the angiotensin level, while anaprilin treatment resulted in normalization of PRA and testosterone. The two drugs reduced equally the level of arterial pressure.

[The specificity of the hypotensive effect of calcium antagonists in hypertension]. / Spetsifichnost' gipotenzivnogo éffekta antagonistov kal'tsiia pri gipertonicheskoi bolezni.

The purpose of the study was to define prognostic criteria that determine individual sensitivity to the hypotensive effect of slow calcium channel blockers. After two weeks of placebo therapy 45 patients suffering from essential hypertension underwent an acute pharmacological test (APT) with nifedipine in a dose of 30 mg. Then the patients received monotherapy with nitrendipine in the increasing doses for 12 weeks. The drug effect on the renin-angiotensin-aldosterone system and the level of ionized calcium in the blood serum was estimated. In 17 patients who responded to the APT by a decrease of the mean arterial pressure (MAP) by not less than 20%, arterial pressure was corrected with nitrendipine administered in a dose not exceeding 20 mg. 28 patients whose MAP dropped by 10 to 20% in response to the APT required higher drug doses (40 mg). 7 patients in whom the MAP dropped less than 10% were practically refractory to the monotherapy with nitrendipine. A close negative correlation was found between the degree of the MAP lowering in response to the APT during nitrendipine monotherapy and plasma renin activity as well as the concentration of ionized calcium in the blood serum. The low content (less than 1.0 mmol/l) of ionized calcium in the blood serum of patients suffering from essential hypertension appeared the most valuable predictor for the hypotensive effect of the slow calcium channel blockers.