Cell-to-cell heterogeneity of EWSR1-FLI1 activity determines proliferation/migration choices in Ewing sarcoma cells.

Ewing sarcoma is characterized by the expression of the chimeric EWSR1-FLI1 transcription factor. Proteomic analyses indicate that the decrease of EWSR1-FLI1 expression leads to major changes in effectors of the dynamics of the actin cytoskeleton and the adhesion processes with a shift from cell-to-cell to cell-matrix adhesion. These changes are associated with a dramatic increase of in vivo cell migration and invasion potential. Importantly, EWSR1-FLI1 expression, evaluated by single-cell RT-ddPCR/immunofluorescence analyses, and activity, assessed by expression of EWSR1-FLI1 downstream targets, are heterogeneous in cell lines and in tumours and can fluctuate along time in a fully reversible process between EWSR1-FLI1high states, characterized by highly active cell proliferation, and EWSR1-FLI1low states where cells have a strong propensity to migrate, invade and metastasize. This new model of phenotypic plasticity proposes that the dynamic fluctuation of the expression level of a dominant oncogene is an intrinsic characteristic of its oncogenic potential.

[Cardiovascular risk factors in France. Prevalence and association]. / Facteurs de risque cardiovasculaire en France. Prévalence et association.

The object of this study was to assess the prevalence of modifiable cardiovascular risk factors and their association in 61,108 subjects over 15 years of age who volunteered for a systematic medical check-up, free of charge, and performed in a health centre in central France. The risk factors were defined as follows: hypertension, diabetes, hypercholesterolaemia, hypertriglyceridaemia: medical treatment or value above the upper limits of normal defined by national or international recommendations. obesity and android fat distribution as defined by the principal recommendations. The commonest risk factor was hypercholesterolaemia (60% of men and 64% of women) followed by android obesity. The prevalence of hypertension was greater in men than in women (44 vs 33%). Twenty eight per cent of men and 17% of women admitted to smoking. The percentage of smokers was higher in people under 30. Diabetes was observed in 3% of men and 2% of women. The association of risk factors was observed at an older age in women than in men. The association of 3 risk factors was four times greater in men than in women in the whole population. In conclusion, this study shows that cardiovascular risk factors are very common in persons undergoing a medical check-up and that these factors are often associated at an earlier age in men than in women.

High blood pressure and associated cardiovascular risk factors in France.

OBJECTIVE: To estimate, with respect to age and gender, the prevalence of high blood pressure (BP) in treated and non-treated subjects and its association with other cardiovascular risk factors. DESIGN: A cross-sectional study. SETTING: Healthcare centres in the centre of France. PARTICIPANTS: All subjects (n = 61,108) who had a free health check-up, between February 1995 and September 1996. MAIN OUTCOME MEASURES: High BP (systolic blood pressure (SBP) > 140 mmHg, diastolic blood pressure (DBP) > 90 mmHg or antihypertensive therapy); diabetes (fasting glucose plasma concentration > 1.26 g/l or antidiabetic therapy); hypercholesterolaemia (total cholesterol > 2 g/l or lipid-lowering therapy); hypertriglyceridaemia (fasting triglycerides plasma concentration > 2 g/l or triglyceridaemia-lowering therapy); overweight (body mass index >or= 25 kg/m2); abdominal fat distribution (waist to hip ratio > 0.9 in males and > 0.8 in females). RESULTS: Prevalence of high BP was 37.7% in males and 22.2% in females. BP was normalized in 29.7% of treated males and 44.1% of treated females. High BP was associated with at least another cardiovascular risk factor in 83.8% of the males and 76.7% of the females with high BP. Hypercholesterolaemia was the most frequently associated risk factor. Except smoking, the prevalence of each cardiovascular risk factor was shown to increase with the severity of hypertension. Two or more other cardiovascular risk factors were present in 22.9% of the males and 9.8% of the females with high BP. CONCLUSIONS: Rate of high BP, even in treated subjects, is high. More than three out of four subjects with high BP have at least one other cardiovascular risk factor.

Reference values for clinic pulse pressure in a nonselected population.

A wide pulse pressure (PP) may constitute an independent predictor of cardiovascular morbidity and mortality. We assessed the reference values of brachial clinic PP, according to age and gender in a nonselected population (61,724 subjects) who were undergoing a routine systematic health examination. According to mean values, 50 mm Hg is likely the reference value for clinic PP in both men and women. Diagnostic thresholds for clinic PP (> or =65 mm Hg) determined either by adding 2 SD to the means or from the 95th percentiles are in close agreement with clinic PP values previously reported to be associated with increased cardiovascular morbidity and mortality.

Differential effects of tyrosine kinase inhibitors on contraction and relaxation of the aortas of normotensive and hypertensive rats.

The contribution of tyrosine kinase activity to vasoreactivity in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats was investigated on isolated aortic preparations by the use of two tyrosine kinase inhibitors: methyl-2,5-dihydroxycinnamate (30 microM) and genistein (30 microM). The pretreatment of endothelium denuded aorta with methyl-2,5-dihydroxycinnamate reduced the sensitivity of the rings to noradrenaline to a larger extent in SHR than in WKY. The relaxing effects evoked by methyl-2,5-dihydroxycinnamate and genistein on the sustained contraction induced by endothelin-1 were also more pronounced in SHR denuded rings. Furthermore, in presence of methyl-2,5-dihydroxycinnamate, the endothelium-independent contractile responses to equipotent doses of cyclopiazonic acid were more depressed in SHR than in WKY. In WKY and SHR endothelium-intact aortas contracted with either phenylephrine or endothelin-1, carbachol and cyclopiazonic acid evoked endothelium derived relaxing factor (EDRF)/nitric oxide (NO)-dependent relaxations which were reduced by pretreatment of the rings with methyl-2,5-dihydroxycinnamate or genistein. These inhibitory effects were larger in WKY rings and more important on the cyclopiazonic acid response. In addition, sodium orthovanadate (30 microM) potentiated the noradrenaline-mediated contractions of endothelium-denuded SHR rings and reduced the cyclopiazonic acid-induced relaxation of endothelium-intact WKY rings. The present study suggests a regulatory role for tyrosine kinase in the smooth muscle contraction and the endothelium-dependent relaxation in WKY and SHR aortas and demonstrates the existence of a different relationship in the effect of tyrosine kinase inhibitors on vasoreactivity between SHR and WKY. We propose that an increase in the tyrosine kinase activity in SHR could lead to an enhanced reactivity of Ca2+-linked contractile mechanisms. In addition, our results suggest a link between the loss of tyrosine kinase activity and the altered endothelium-dependent relaxation associated with hypertension.

[Comparison between the effects of angiotensin-converting enzyme inhibitors and angiotensin II antagonists]. / Comparaison des effets des inhibiteurs de l'enzyme de conversion et des antagonistes de l'angiotensine II.

The renin-angiotensin-aldosterone system (RAAS) plays an important role in blood pressure regulation and fluid and electrolyte homeostasis. Angiotensin converting enzyme inhibitors (ACEI) were the first of the RAAS blocking agents to be widely used in the treatment of hypertension and congestive heart failure. Angiotensin II receptor antagonists, another class of pharmacological blockers of the RAAS, have more recently been shown to be safe and useful in hypertension and perhaps also in heart failure. This review deals with the similarities and differences between these two classes of drugs with particular emphasis on the effects of the drugs on the heart, the blood vessels, the kidney (role of the drugs as nephroprotective), the brain, the hormonal profile and finally the potential adverse effects. The place of angiotensin II antagonists in congestive heart failure remains to be more precisely defined.

Assessment of the acute arterial effects of converting enzyme inhibition in essential hypertension: a double-blind, comparative and crossover study.

In subjects with essential hypertension, angiotensin-converting enzyme (ACE) inhibition increases arterial diameter, compliance and distensibility of peripheral muscular arteries in association with blood pressure reduction. Whether pulse pressure amplification is modified by ACE inhibition and whether changes in compliance and distensibility are due to a drug effect on the arterial wall, to the blood pressure reduction or to a combination of both factors, is largely ignored. In a randomised, double-blind crossover trial, we used the ACE inhibitor quinapril as a marker to evaluate the changes in: pulse pressure amplification (applanation tonometry), carotid compliance and distensibility (echo-tracking technique), and aortic distensibility (measured from pulse wave velocity). Quinapril decreased in the same extent carotid and brachial pulse pressure, thus causing a resetting of pulse pressure amplification toward normal values. Carotid compliance and distensibility as well as aortic distensibility increased significantly. Based on three-way analysis of variance, it was shown that, whereas the changes in carotid stiffness were exclusively due to blood pressure reduction and not to a drug-induced relaxation of the arterial wall, the changes in aortic distensibility were due to the combination of both factors. Thus, using an atraumatic non-invasive procedure, it was possible to show that: (i) ACE inhibition is able to maintain pulse pressure amplification, an important factor contributing to reduce the afterload of the heart; and (ii) ACE inhibition alters the hypertensive arterial wall in a very heterogeneous manner, with a maximal drug effect on muscular large arteries like the abdominal aorta, and not on elastic arteries like the carotid artery and the thoracic aorta.

Role of endothelium in the endothelin-1-mediated potentiation of the norepinephrine response in the aorta of hypertensive rats.

OBJECTIVE: To investigate the role of the endothelium in the functional interaction between endothelin-1 and norepinephrine in the contractile response of aortas from Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). METHODS: Thoracic aorta rings with and without endothelium from SHR and from WKY rats were suspended in an organ bath to record the isometric tension. After an equilibration period of 120 min, the preparations with and without endothelin-1 were subjected to single and cumulative additions of norepinephrine in different experiments. To characterize the mechanisms involved in the interaction between endothelin-1 and norepinephrine, the aortic rings were pretreated with a cyclooxygenase pathway inhibitor (piroxicam, SO29548), an inhibitor of NO synthase [NG-nitro-L-arginine (NLA)], or selective endothelin receptor blockers (BQ-123 or BQ-788). In some experiments we examined the contractile responses to norepinephrine in aortas pretreated either with angiotensin II (AII) or with U46619, an agonist of prostaglandin H2-thromboxane A2 receptors. Finally, we examined the effect of the combination of calcium-entry blockade by administration of nifedipine and treatment with either endothelin-1 or U46619 on the norepinephrine reactivity. RESULTS: Administration of 3 x 10(-10) mol/l endothelin-1 potentiated the contractile response to norepinephrine in SHR aortas with endothelium, irrespective of whether they had been treated with NLA. No endothelin-1-mediated enhancement of the response to norepinephrine was observed in SHR denuded rings and in untreated and NLA-treated WKY rat aortas. All did not affect the response to norepinephrine in SHR rings with endothelium. The amplification by endothelin-1 of the response to (1-100) x 10(-9) mol/l norepinephrine was abolished by blockade of the cyclooxygenase pathway with piroxicam or SO29548. In WKY rat and SHR denuded aortas, 10(-8) mol/l U46619 potentiated the contractile responses to norepinephrine. Administration of 3 x 10(-6) mol/l BQ-123 abolished the increase in reactivity to norepinephrine evoked by endothelin-1 in intact SHR aorta, whereas 3 x 10(-6) mol/l BQ-788 failed to modify this potentiating effect. Administration of 10(-8) mol/l nifedipine inhibited the potentiation of the norepinephrine-induced contractions evoked both by endothelin-1 in SHR aortic rings with endothelium and by U46619 in SHR denuded rings. CONCLUSION: Our results show that a low concentration of endothelin-1 induced potentiation of the contractile response to norepinephrine in SHR aortas but not in WKY rat aortas. This response was endothelium-dependent. Furthermore, our study affords functional arguments that both endothelial and smooth muscle pathways are involved in the potentiating interaction. We propose that endothelin-1 stimulates the production of endothelium- and cyclooxygenase-generated vasoconstrictor factors, which in turn may serve directly as priming stimuli at the vascular smooth muscle level, to activate the Ca(2+)-signal pathway and consequently to increase locally the vascular sensitivity to norepinephrine.

Influence of gender on the level of pulse pressure: the role of large conduit arteries.

The blood pressure curve may be divided into two components: a steady component represented by the mean arterial pressure, and a pulsatile component represented by the purse pressure. Whether the contribution of either these two components may be different in men and women was not yet investigated. The present study used 24 hours ambulatory brachial blood pressure monitoring and determination of casual carotid and radial pulse pressure by applanation tonometry to investigate 320 subjects (199 men and 121 women) with normal or elevated blood pressure. With ambulatory blood pressure monitoring, there was no gender influence on the mean values of mean and diastolic blood pressure, but men were characterized by a significantly higher systolic and pulse pressure (P < 0.001). In women, pulse pressure was strongly and positively correlated with systolic (and not diastolic) blood pressure. In men, pulse pressure was positively correlated with systolic blood pressure and negatively with diastolic blood pressure (P < 0.001). In the overall population (men plus women), brachial ambulatory pulse pressure was positively correlated with body height and mean arterial pressure (P < 0.001) but the latter correlation was stronger in women. Applanation tonometry indicated that, whereas carotid pulse pressure was identical in men and women, men had a significantly higher radial systolic blood pressure, indicating a gender difference in pressure wave transmission. The study provides evidence that men and women did not differ in terms of mean arterial pressure, but rather in terms of pulse pressure and pressure wave transmission, indicating that large (and not only small) arteries modulate the gender difference in the level of blood pressure. This finding may have important implications for the diagnosis and the clinical management of subjects with hypertension.

[Family physicians and scientific information. Survey on hypertension and diuretics]. / Médecin généraliste et information scientifique. Enquête sur l'hypertension artérielle et les diurétiques.

In order to analyse the quality of scientific communication in the field of hypertension, we have conducted a survey among French physicians. The topics of the questions were partly related to hypertension and partly to diuretics; 3,600 questions forms have been mailed: 610 answers were returned (17%). The results show that most of physicians are unsufficiently informed about primary prevention therapeutical trials and recommendations. Moreover, whereas all physicians questionned (97%) consider that diuretics constitute a current therapeutic approach, this class remains largely unknown concerning its mechanisms, efficacy and tolerance dose relationships. As 80% of general practitioners having participated to this survey wish to be more informed on recent data in this field, these results emphasize the necessity of adapting information to the need of practitioners, raise questions concerning the information supports, the role of scientific committees in the medical information and the necessity to complete clinical research by studies which results may be rapidly applicable in clinical practice.

Assessment of arterial distensibility by automatic pulse wave velocity measurement. Validation and clinical application studies.

Pulse wave velocity is widely used as an index of arterial distensibility. The aim of this study was to evaluate the accuracy of a new automatic device to measure it and then to analyze the major determinants of pulse wave velocity by application of this device in a large population. We evaluated the accuracy of on-line and computerized measurement of pulse wave velocity using an algorithm based on the time-shifted and repeated linear correlation calculation between the initial rise in pressure waveforms compared with the reference method (manual calculation) in 56 subjects. The results, analyzed according to the recommendations of Bland and Altman, showed a mean difference of -0.20 +/- 0.45 m/s for the mean carotid-femoral pulse wave velocity values (reference method, 11.05 +/- 2.58 m/s; automatic device, 10.85 +/- 2.44 m/s). The interreproducibility and intrareproducibility of measurements by each method were analyzed with the use of the repeatability coefficient according to the British Standards Institution. The interobserver repeatability coefficient was 0.947 for the manual method and 0.890 for the automatic, and intraobserver repeatability coefficients were 0.938 and 0.935, respectively. We evaluated the major determinants of the carotid-femoral pulse wave velocity measured by the automatic method in a separate study performed in 418 subjects of both sexes without any cardiovascular treatment or complication (18 to 77 years of age; 98 to 222 mm Hg systolic and 62 to 130 mm Hg diastolic pressure).(ABSTRACT TRUNCATED AT 250 WORDS)

Early disturbance of baroreflex control of heart rate after tail suspension in conscious rats.

Experiments were performed on conscious chronically instrumented rats maintained on tail suspension to determine the time course of changes in baroreceptor control of heart rate produced by this procedure. Pressor responses were elicited by bolus injections of graded doses of phenylephrine and sodium nitroprusside, permitting evaluation of the totality of the sigmoidal curve relating mean arterial pressure to heart rate. Compared with control rats maintained at 0 degrees, rats maintained at 20 degrees using tail suspension for 24 h showed a significant reduction in reflex gain (-3.9 +/- 0.1 vs. -5.8 +/- 0.3 beats/min; P < 0.001) together with a reduction in the upper (472 +/- 11 vs. 512 +/- 5 beats/min; P < 0.01) and lower (270 +/- 3 vs. 284 +/- 2 beats/min; P < 0.01) plateaus of the sigmoidal curve. In three groups of rats, the sigmoidal curve was studied successively after returning for 1, 24, and 48 h at 0 degrees. The observed change in the gain of the reflex returned toward control values after 48 h, whereas the other parameters characterizing the sigmoidal curve did not change significantly. Transient but significant modifications of heart rate (tachycardic response) after the immediate return to the horizontal position were observed. The study provides evidence that 1) a significant change of the totality of the sigmoidal curve characterizing baroreceptor control of heart rate occurs very early after tail suspension in rats and 2) the gain of the reflex is restored during the 48 h after release of tail suspension, whereas the other parameters characterizing the curve, particularly the plateaus, remain altered.

The nicardipine-isoprenaline interaction in human and guinea-pig isolated airways.

The effects of the dihydropyridine calcium antagonist nicardipine on the concentration-response curves of relaxant compounds acting through the adenylate-cyclase/cAMP system (isoprenaline, forskolin, adenosine and theophylline) or by the cGMP pathway (sodium nitroprusside) were studied on human isolated bronchus and guinea-pig isolated trachea. These effects were compared with those of nifedipine (a dihydropyridine derivative) and theophylline (a non-selective phosphodiesterase inhibitor). Nicardipine, in the range of 0.01 to 1 microM, significantly potentiated the relaxant effects of isoprenaline, forskolin, adenosine and theophylline, whereas the effects of sodium nitroprusside were significantly potentiated at 10 microM only. These results suggest that nicardipine behaves as an inhibitor of phosphodiesterases III and IV. One such effect may be involved in the potentiation of the isoprenaline relaxation of human and guinea-pig isolated airways.

Role of adrenergic tone in mechanical and functional properties of carotid artery during aging.

The present study was designed to assess the role of the adrenergic tone in the regulation of carotid arterial compliance during aging. An experimental model of in situ isolated carotid arteries has been used to evaluate the elastic properties of the arterial wall in young (3-mo-old) and older (18-mo-old) Wistar rats. Binding experiments were performed in the same strain of rats to evaluate alpha 1- and beta-adrenoceptor affinity and density. In a third set of experiments, structural parameter of the carotid artery in younger and older rats was evaluated. Arterial distensibility (compliance per unit of volume) was significantly lower in older rats. This was associated with a significant thickness of the media (45.6 +/- 2.8 vs. 57.5 +/- 5.7 microns, P < 0.01) and increased collagen content in older rats (4,420 +/- 310 vs. 7,320 +/- 850 microns 2/mm, P < 0.001). However, carotid arterial compliance was not altered in older rats because of the significant increase in cross-sectional area with aging. Aging did not affect alpha 1-adrenoceptor affinity and density, whereas it decreased beta-density without changing their affinity. Pharmacological stimulation of alpha 1-adrenoceptor with phenylephrine (10(-5) M) decreased compliance in older but not in younger animals. Blockade of these receptors with prazosin or labetalol increased compliance in younger and had no effect on older rats. beta-receptor stimulation with isoproterenol or blockade with propranolol had no effect in any of the studied groups. We suggest that with aging there is an increased vasoconstricting effect of alpha-agonists and a decreased vasodilatative action of alpha-blockade.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuronal metabolism of catecholamines: plasma DHPG, DOMA and DOPAC.

Pre-synaptic endings of the sympathetic nervous fibers control the metabolism of catecholamines, particularly inactivating norepinephrine after its neuronal recapture. The present study was carried out to investigate this segment of the metabolism of catecholamines through measurements of DHPG, DOMA and DOPAC concentrations in plasma. A sensitive and specific radio-enzymatic assay was developed of which the major characteristic is to include the plasma sample in the incubation mixture without initial extraction of the deaminated metabolites. In the rat, there was a statistically significant correlation between norepinephrine and DHPG in both anesthetized and conscious conditions and after clonidine or guanethidine induced reduction of sympathetic activity; thus it can be suggested that plasma DHPG is a good index of neuronal metabolism of norepinephrine in this animal. In humans, our data indicate an interesting correlation between norepinephrine and DOMA concentrations in plasma in resting conditions and within three hours after clonidine. Further studies need to be carried out to establish whether DOMA is a better index of neuronal metabolism of norepinephrine than DHPG.

Endothelin modulates dihydropyridine receptor decreased binding in hippocampal slices from normotensive and spontaneously hypertensive rats.

Previous studies in rats have demonstrated both the link between voltage-operated calcium channels and endothelin and their cerebral involvement in the pathophysiology of spontaneous hypertension. In the present study, the interaction of endothelin with specific dihydropyridine (DHP) binding sites was investigated using the brain slices model. In rat hippocampal slices, pre-incubation with Bay K 8644 decreased [3H] (+) PN 200-110 binding. There was no difference in agonist-induced decrease of DHP binding in normotensive and spontaneously hypertensive (SH) rats. The effect of Bay K 8644 was partially inhibited by endothelin but not by angiotensin in both normotensive and hypertensive rats. These data compared to those of other studies suggest that DHP binding sites which are regulated by endothelin are post-synaptic. We conclude that brain slices provide a good in vitro model to study DHP receptor regulation and to explore endothelin interactions with DHP-sensitive Ca2+ channels.

Absence of a direct coupling of a G protein to dihydropyridine binding sites in rat heart.

In rat heart membranes, the addition of guanine 5'-O-(3-thiotriphosphate) (GTP-gamma-S), a stable GTP analogue, did not significantly modify the displacement of [3H]PN 200-110 binding by the 1,4-dihydropyridine (DHP) agonist Bay K 8644 and antagonists, nifedipine and nicardipine. These results are in agreement with some previously reported electrophysiological and pharmacological data, and they suggest that there is no direct involvement of a G protein in the modulation of DHP sensitive Ca channels in cardiac cells.

Central hypotensive effects of nicardipine in conscious freely moving spontaneously hypertensive rat.

The central cardiovascular effects of the calcium channel blocker nicardipine was studied in conscious freely moving normotensive Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Nicardipine was administered in a 1.5 microliters volume into the lateral ventricle of the brain (i.c.v.) or intravenously (i.v.). The injection of vehicle alone did not significantly change mean arterial pressure (MAP) or heart rate (HR). Nicardipine (10, 30, 100 and 300 micrograms/kg) intravenously administered, dose-dependently decreased MAP and increased HR in WKY and SHR. However, when administered i.c.v., nicardipine (10 micrograms/kg) increased MAP and HR in WKY and decreased MAP without any significant change in HR in SHR. These results are consistent with previous work reporting an exaggerated hypotensive response to i.c.v. administration of dihydropyridine calcium channel blockers in anesthetized SHR as compared to WKY. They suggest that a 1,4-dihydropyridine-sensitive pressor system is present in the SHR but not in the WKY.

Central 5HT1A-receptor binding in normotensive and spontaneously hypertensive rats.

Central 5HT1A-receptors have been found with a high density in brainstem and are involved in cardiovascular control. The high-affinity binding of [3H]-8-OH-DPAT, a specific 5HT1A-receptor ligand, was measured in medulla oblongata of normotensive and spontaneously hypertensive rats (SHR). The maximal number of [3H]-8-OH-DPAT binding site (Bmax) was significantly increased in SHR when compared to normotensive rats. Whether central 5HT1A-receptors are involved in the etiology of hypertension or are influenced by other neurochemical events remains to be investigated.

Pressor responses to endothelin-1 in normotensive and spontaneously hypertensive rats.

In freely moving rats, endothelin-1 (0.0135-4.5 nmol/kg) administered as an intravenous bolus injection, produced an immediate, short-lasting, dose-related fall in blood pressure followed by a long-lasting, dose-related increase in blood pressure. There was a higher sensitivity in the pressor responses to endothelin-1, in spontaneously hypertensive (SH) rats (ED(50) = 0.11 +/- 0.02 and 0.28 +/- 0.02 nmol/kg, in SH and normotensive rats, respectively), but no change in the maximal pressor effect of endothelin-1 in SH rats. In rat isolated aorta, endothelin-1 induced a greater vasocontractile effect in SH rats than in normotensive rats. In both rat strains, removal of the endothelium did not change the concentration-effect curves obtained in endothelium-intact preparations. These data add further support to the hypothesis that endothelin-1 could play a role in genetic hypertension, at least in the maintenance of high blood pressure.