摘要:

ObjectiveTo seek the mechanism whereby agonists, competitive antagonists and insurmountable antagonists affect the receptor function differently, by reviewing recent mutagenesis studies of angiotensin II type 1 receptor (AT1) in which the binding of the agonist and antagonists and receptor signaling were affected.AT1 receptor structure and ligand binding sitesWe built a model of seven transmembrane spanning domains of the AT1receptors using bacteriorhodopsin as a template. The carboxy terminal of angiotensin II binds to Lys199in transmembrane domain 5, whereas the guanidinium group of Arg2binds to Asp281in transmembrane domain 7. Results of studies using mutagenesis supporting proposed ligand-docking models are discussed.Hypothesis for the ligand-induced receptor signaling mechanismWe submit a set of hypotheses for a mechanism whereby the ligand binding induces changes in the receptor conformation by the rotation of transmembrane helices as the initial event for the subsequent activation of a G protein. In this mechanism antagonists are not capable of rotating the helices but agonists are able to do so, which results in the formation of a hydrogen bond between Asp74in transmembrane domain 2 and Tyr292in transmembrane domain 7. This mechanism also provides plausible explanation for the activation of monoamine receptors.Competitive and insurmountable antagonistsCompetitive antagonists share the same binding sites with agonists, but insurmountable antagonists do not, and binding of the latter does not preclude agonist binding, for example, to Asp281.ConclusionThis hypothesis of the intrareceptor signaling mechanism and the receptor model indicate that some amino acid residues essential for the signaling play their roles in the intrareceptor activation mechanism, whereas others participate directly in ligand binding.

ISSN:0263-6352    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

ObjectiveTo test the hypothesis that theHpaII variant of the atrial natriuretic peptide gene (ANP), which has been reported to be more common among black hypertensives than it is among normotensive controls, is related to the response of blood pressure to salt intake in normotensive Caucasians.MethodsOne hundred and three young (aged 19–35 years) male volunteers were fed a low-salt diet (20 mmol NaCl/day) for 2 weeks and a supplement of either 200 mmol NaCl/day (slow sodium) or placebo for 1 week each in a randomized double-blind cross-over order. Salt sensitivity was defined as a significant (P< 0.05) decrease in resting mean arterial blood pressure by > 3 mmHg under the low-salt diet. The genotype was determined by amplification of genomic DNA extracted from peripheral leukocytes and subsequent digestion of the amplicon withHpaII restriction enzyme.ResultsAccording to the above definition, 27 subjects were salt sensitive. There were no significant differences in age, body-mass index and waist: hip ratio between the salt-sensitive and salt-resistant groups. Only salt-sensitive subjects displayed a significantly higher blood pressure under the high-salt diet (increase in mean arterial pressure 5.6 ± 2.4 mmHg,P< 0.001). The prevalence of theANP-HpaII wild-type (w) allele did not differ between the salt-sensitive (qw= 1.0, qm= 0) and the salt-resistant group (qw= 0.96, qm = 0.04). Furthermore, the salt-induced response of blood pressure did not differ between homozygotes (ww) and heterozygotes (wm).ConclusionsOur findings do not support the hypothesis that theANP-HpaII polymorphism is a marker for salt sensitivity in young Caucasian normotensives.

ISSN:0263-6352    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

ObjectiveTo characterize the effects of estrogen, estrogen combined with progestin, and no treatment in ovariectomized cynomolgus monkeys during long-term reproductive hormone replacement.MethodsForty-five surgically postmenopausal cynomolgus monkeys fed a lipid-lowering diet were administered a conjugated equine estrogen (Premarin, 7.2 μg/day for the first 8 months, then 166 μg/day for the remaining 22 months), alone or in combination with 650 μg/day medroxyprogesterone acetate (Cycrin) for 30 months, or left with no hormone replacement therapy. Animals were anesthetized with ketamine–pentobarbital, and samples were taken for measurements of plasma renin activity, angiotensin converting enzyme activity, and angiotensin peptides, angiotensin I (Ang I), angiotensin II (Ang II), and angiotensin-(1-7) [Ang-(l-7)].ResultsChronic replacement therapy with estrogen resulted in a significant elevation of the plasma renin activity [11.7 ± 2.0 ng/ml per h control versus 22.8 ± 4.6 ng/ml per h with estrogen (P< 0.05) versus 32.8 ± 4.9 ng/ml per h with combination therapy (P< 0.01)], whereas estrogen or combination therapy caused a significant reduction in angiotensin converting enzyme activity [229 ± 8 nmol/ml per min control versus 189 ± 10 nmol/ml per min with estrogen (P< 0.05) versus 196 ± 11 nmol/ml per min with combination therapy (P< 0.05)]. Both of these changes in angiotensin processing enzymes observed during replacement therapy resulted in significant increases in plasma Ang I levels [46.7 ± 12.5 pg/ml control versus 175.5 ± 65.9 pg/ml with estrogen (P< 0.05) and 561.7 ± 373.6 pg/ml with combination therapy (P< 0.05)]. Plasma Ang II and Ang-(1–7) levels were not significantly changed. The mean blood pressure did not change with either treatment.ConclusionThese studies reveal that, although chronic estrogen replacement activates renin activity and Ang I, it causes a shift in the processing of angiotensin peptides such that the concurrent reduction in angiotensin converting enzyme activity leads to unchanged plasma Ang II levels. Thus, the potentially harmful effects of estrogen-induced hyperreninemia are balanced by its actions interfering with the formation of the vasoactive product Ang II.

ISSN:0263-6352    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

ObjectiveTo evaluate autonomic nervous function by power-spectral analysis of heart-rate variability in salt-sensitive and non-salt-sensitive patients with essential hypertension under the conditions of low and high salt intakes.Design and methodsThe blood pressures, heart rates, and electrocardiogram R–R intervals of 20 hypertensive patients were measured at intervals of 30 min during a 24 h period using a portable recorder (TM-2425) on the last day of the high- (250 mmol NaCl/day) and low-salt (25 mmol NaCl/day) diet periods. The patients whose 24 h average mean blood pressures were increased by more than 10% by the high salt intake were defined as salt-sensitive (n = 10); the other patients were considered non-salt-sensitive (n = 10). Power-spectral analysis of R–R intervals was performed to obtain the low-frequency component (0.05–0.15 Hz) and the high-frequency component (0.15–0.40 Hz).ResultsThe average 24 h blood pressure in the salt-sensitive patients was increased by the high salt intake [by 19.1 ± 2.0/9.1 ± 0.8 mmHg (mean ± SEM)], whereas the heart rate did not change. In contrast, the increase in 24 h blood pressure in the non-salt-sensitive patients caused by the high salt intake was not significant and the heart rate was decreased significantly by the high salt intake (by 5.9 ± 1.4 beats/min). The high-salt diet increased significantly the high-frequency component and decreased the low-frequency: high-frequency component ratio both during the daytime and during the night-time for the non-salt-sensitive patients. In contrast, the high-frequency component and the night-time low-frequency: high-frequency component ratio of the salt-sensitive patients did not respond to dietary salt manoeuvres.ConclusionsResponses of the parasympathetic and sympathetic nervous systems to dietary salt manoeuvres were blunted in salt-sensitive patients. These altered modulations of the autonomic nervous system may contribute to the salt sensitivity of the blood pressure in patients with essential hypertension.

ISSN:0263-6352    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

ObjectiveTo determine the longitudinal relationship between clinic and ambulatory blood pressures and subsequent left ventricular and carotid artery structure.DesignA retrospective follow-up study.SettingA large district general hospital in Harrow, UK.PatientsOne hundred and forty patients who had been subjected to 24 h ambulatory intra-arterial blood pressure monitoring on the basis of their having an elevated clinic blood pressure were followed up randomly a mean of 9.4 ± 3.4 years later. The ambulatory blood pressure parameters measured were the mean systolic, mean diastolic and mean pulse pressures. Follow-up variables assessed included the clinic blood pressure, body mass index, total cholesterol, number of years of follow-up, left ventricular mass index, carotid intima–media thickness and carotid artery cross-sectional area.Main outcome measuresThe left ventricular mass index, carotid intima–media thickness and carotid artery cross-sectional area.ResultsThe mean pulse pressure and mean systolic blood pressure were correlated significantly with the left ventricular mass index (r = 0.46,P< 0.001 and r = 0.36,P< 0.001, respectively), carotid intima–media thickness (r = 0.45,P< 0.001 and r = 0.37,P< 0.001, respectively) and carotid artery cross-sectional area (r = 0.46,P< 0.001 and r = 0.41,P< 0.001, respectively). The mean pulse pressure was associated independently with all three outcome measures. In addition, the body mass index was an independent determinant of the left ventricular mass index, whereas the serum cholesterol level was associated independently with the carotid artery cross-sectional area; the number of years of follow-up was related independently to the left ventricular mass index and carotid intima–media thickness, but not to the cross-sectional area.ConclusionsThese findings suggest that ambulatory blood pressure monitoring can play a role in guiding the choice of doses in drug therapy to limit potential target organ damage.

ISSN:0263-6352    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

ObjectiveTo examine the relation of insulin action and left ventricular diastolic function in uncomplicated essential hypertension.MethodsDoppler echocardiography and glucose clamping combined with indirect calorimetry were performed in 29, newly diagnosed, hypertensive men, free from cardiac and metabolic drugs. They were divided into two groups according to the clamp-derived whole-body glucose disposal level: 20 with insulin resistance (whole-body glucose disposal < 33 μmol/kg per min) and nine with normal insulin sensitivity.ResultsThe two groups were comparable in age, body mass index, heart rate and blood pressure. No difference in diastolic function was found except for the isovolumic relaxation time, which was prolonged for patients with insulin resistance (P= 0.02). For the population as a whole, the relaxation time had univariate relations with the left ventricular mass index (r = 0.57,P< 0.001), whole-body glucose disposal (r = −0.56,P< 0.001) and non-oxidative glucose metabolism (r = −0.54,P= 0.002). In a multivariate model including age, body mass index, heart rate, diastolic blood pressure, left ventricular mass index and whole-body glucose disposal as potential determinants, only the left ventricular mass index (β = 0.39,P= 0.02) and whole-body glucose disposal (β = −0.38,P= 0.03) were independent predictors of the relaxation time (R2= 0.43,P< 0.001).ConclusionsIn uncomplicated essential hypertension the insulin resistance is a determinant of abnormalities in isovolumic relaxation, independently from the influence exerted by increased blood pressure levels, being overweight and left ventricular hypertrophy.

ISSN:0263-6352    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

ObjectiveTo determine whether 12 days' treatment withNG-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, in spite of the increased arterial load, resulted in a growth-inhibitory response in the heart, aorta and skeletal muscle vascular bed, and whether the presence of L-NAME affected the expression of insulinlike growth factor-I and its receptor messenger RNA (mRNA).MethodsWistar rats were treated orally either with 100 mg/kg L-NAME or with tap water. On days 2, 4, 7 and 12 after initiation of treatment, the systolic blood pressure/mean arterial blood pressure and heart rate were measured, rats were killed and their heart and aorta were excised. Insulin-like growth factor-I and its receptor mRNA were quantitated by solution hybridization assay. On day 12 resistance properties in the skeletal muscle vascular bed were measured by using an in-vivo constant-flow preparation.ResultsThe blood pressure in L-NAME-treated rats was increased immediately after initiation of treatment and it continued to increase throughout the experimental period. No hypertrophy was noted in the heart. Moreover, a 21% (P< 0.05) decrease in the right: left ventricular weight ratio indicated that attenuation of growth of the right ventricle had occurred. Increased expression of insulin-like growth factor-I and its receptor mRNA was observed neither in the heart nor in the aorta. The skeletal muscle vascular bed showed a 26% increased resistance at maximal vasodilatation (P< 0.05), which was indicative of a reduced average lumen size. A lower than expected perfusion pressure at maximal vasoconstriction was observed (17% above control,P< 0.05), implicating only modest medial thickening.ConclusionL-NAME hypertension caused a prompt increase in blood pressure, which led neither to left ventricular hypertrophy nor to the expected overexpression of left ventricular/aortic insulin-like growth factor-I mRNA and only to partial structural adaptation in the skeletal muscle vasculature. These findings suggest that augmented expression of insulinlike growth factor-I and its receptor could be mandatory for conveying an appropriate adaptive hypertrophic response, at least in the heart.

ISSN:0263-6352    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

ObjectiveTo investigate the possible role played by endogenous dopamine as a modulator of renal sodium (Na+) reabsorption after a combined Na+and volume load.DesignA randomized placebo-controlled study.MethodsTen healthy volunteers and four hypertensive patients were subjected to intravenous infusions of 2 l 0.9% saline (308 mmol Na+) administered from 1000 to 1300 h after oral administration of placebo or of carbidopa, a dopamine decarboxylase inhibitor.ResultsStudies on control subjects after placebo showed that natriuresis occurred during the 6 h after commencement of the saline infusion, with falls in plasma albumin concentration, plasma renin activity and plasma aldosterone concentration; in comparison with results of mock infusion (6 mmol Na+) there was no change in the urinary excretion of dopamine and noradrenaline (in their free or conjugated forms). There was, however, a marked surge in excretion of urinary conjugated dopamine and in the dopamine: noradrenaline ratio from 1300 to 1600 h, after either type of infusion. Administration of carbidopa before the saline infusion resulted in a marked decrease in excretion of urinary free dopamine, but had no effect on the surge in excretion of urinary conjugated dopamine. Saline infusion decreased proximal fractional Na+reabsorption. Administration of carbidopa delayed but did not prevent this decrease. The effects of saline infusion and of carbidopa on the urinary excretion of dopamine and noradrenaline from hypertensive patients were similar to those observed with the healthy volunteers.ConclusionsThese findings indicate that volume expansion by intravenous saline infusion has no appreciable effect on the urinary free dopamine excretion from normal or hypertensive humans; with any apparent increase, it is important to exclude the possibility of conversion of conjugates to free dopaminein vitro. Furthermore, that carbidopa administration did not inhibit the afternoon surge of conjugated dopamine suggests that administration of carbidopa is deficient as a tool to investigate the functional role of the renal dopamine system.

ISSN:0263-6352    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

BackgroundDiabetes and hypertension are both associated with an increased risk of renal disease. The combination of these diseases produces marked acceleration of the problems.ObjectiveTo examine the reactivity in the renal vasculature of diabetic hypertensive rats.MethodsWe investigated the reactivity towards 5-hydroxytryptamine (5-HT) in Krebs solution-perfused kidneys of diabetic normotensive Wistar–Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). In addition, the interaction between the thromboxane A2mimetic U46619 and 5-HT was examined.ResultsDiscrete dose–response curves were obtained for the response to 5-HT (0.1–30 μg/g kidney) in Krebs solution-perfused kidneys of control and diabetic WKY rats and SHR. The following order of reactivity was determined: control SHR > diabetic SHR > control WKY rats = diabetic WKY rats. The thromboxane A2mimetic U46619 (10 ng/ml) potentiated responses to 5-HT significantly in kidneys of diabetic WKY rats and control SHR, but not in kidneys from control WKY rats and diabetic SHR.ConclusionsThe differential affected reactivity towards 5-HT in kidneys from diabetic and hypertensive rats might be due to previously documented differences in receptor number. The marked effect of U46619 on the reactivity towards 5-HT in kidneys of diabetic and control rats indicates that this interaction might be important given the increased levels of thromboxane A2reported to occur in these diseases. The reason for the lack of effect of thromboxane/prostaglandin receptor stimulation on responses to 5-HT in the combined model (i.e. diabetic hypertensive rats) needs to be determined.

ISSN:0263-6352    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

BackgroundThat non-natriuretic doses of loop diuretics exert an antihypertensive action has been suggested, but not confirmed, by simultaneous measurements of the arterial pressure and sodium balance during therapy.ObjectiveTo examine the relationship between changes in arterial pressure and changes in sodium balance during furosemide treatment.DesignTwenty hypertensive Dahl salt-sensitive rats fed a 4% NaCl diet were allocated to four groups and administered the following treatments: placebo once a day intraperitoneally, continuous infusion of 4 mg/day furosemide intraperitoneally, 4 mg furosemide once a day intraperitoneally and 12 mg furosemide once every third day intraperitoneally.MethodsThe mean arterial pressure (MAP) was measured continuously with radiotelemetry and the sodium balance was measured with the rats in metabolic cages.ResultsAdministration of furosemide as a bolus injection once a day (P< 0.01) or once every third day (P< 0.05) lowered the MAP significantly compared with placebo, whereas continuous infusion of furosemide had no significant effect on the MAP (P< 0.07). Fast Fourier transformation analysis detected an acute antihypertensive action related to the temporary diuretic and natriuretic responses during the period 0–6 h after intraperitoneal bolus injections of 4 and 12 mg furosemide. None of the treatment regimens produced 24 h sodium or potassium losses. At the end of the study, the total body water, extracellular fluid volume, total body sodium and potassium were similar for rats in all groups.ConclusionsFurosemide has an acute antihypertensive action in Dahl salt-sensitive rats fed a 4% NaCl diet that is related to renal sodium and volume losses whereas the long-term antihypertensive effect is independent of changes in extracellular fluid volume, total body water, sodium and potassium.

ISSN:0263-6352    

出版商:OVID    

年代:1997

数据来源: OVID