Journal of hypertension. Supplement : official journal of the International Society of Hypertension最新文献

Despite the apparent consensus on the existence of endothelial dysfunction in conduit and resistance arteries of spontaneously hypertensive rats (SHR), a commonly employed experimental model of hypertension, there are a number of reports showing that endothelium-dependent vasodilatory responses are similar, or even increased, in SHR compared with their normotensive counterparts. The present paper aims to discuss the rationale for these apparent discrepancies, including the effect of age, type of artery and methodological aspects. Data from the literature indicate that the age of the animal is a contributing factor and that endothelial dysfunction is likely to be a consequence of hypertension. In addition, the use of antioxidant additives, such as ascorbic acid or ethylene diaminetetraacetic acid, and differences in the level of initial arterial stretch, might also be of importance because they may modify the oxidative status of the artery and the levels of vasoactive factors released by the endothelium.

Objective: Melatonin was shown to reduce blood pressure, enhance nitric oxide availability and scavenge free radicals. There is, however, a shortage of data with respect to the effect of melatonin on pathological left ventricular remodelling associated with haemodynamic overload.

Design: We investigated whether melatonin was able to prevent left ventricular hypertrophy (LVH) and fibrosis associated with N(G)-nitro-L-arginine-methyl ester (L-NAME)-induced hypertension.

Methods: Four groups of male Wistar rats were investigated: control, L-NAME (50 mg/kg per day), melatonin (10 mg/kg per day) and L-NAME plus melatonin. Blood pressure was measured non-invasively each week. After 5 weeks of treatment the animals were killed and nitric oxide synthase (NOS) activity, endothelial and inducible NOS expression, the level of collagenous proteins, hydroxyproline and conjugated dienes in the left ventricle were determined.

Results: The administration of L-NAME inhibited NOS activity, increased conjugated dienes concentration, elevated blood pressure and induced LVH and fibrosis (indicated by increased collagenous proteins and hydroxyproline levels). The addition of melatonin to L-NAME treatment failed to prevent the attenuation of NOS activity and the development of LVH and prevented hypertension only partly. The administration of melatonin, however, completely prevented the increase in conjugated dienes concentration and the development of left ventricular fibrosis. NOS expression was not different among experimental groups.

Conclusion: Melatonin prevented the development of left ventricular fibrosis and the increase in oxidative load in rats with L-NAME-induced hypertension. The antifibrotic effect of melatonin seems to be independent of its effects on NOS activity and might be linked to its antioxidant properties.

Hypertension in association with oxidative stress belongs to the most discussed topics within the literature on cardiovascular diseases. It is generally believed that elevated production of reactive oxygen species (ROS) plays an important role in hypertension, but clinical studies on chronic antioxidant therapy of hypertension fail to confirm this hypothesis. This discrepancy may be partly determined by the different effects of short and long-lasting treatment with antioxidants or scavengers. Elevated ROS production in hypertension need not be only harmful. It may also stimulate the activity of the antioxidant defence system and improve the nitric oxide (NO)/cyclic 3', 5'-guanosine monophosphate pathway, resulting in the establishment of a new equilibrium between enhanced oxidative load and the stimulated NO pathway, thus maintaining sufficient NO bioavailability. It has been suggested that antioxidant treatment might be beneficial for a short time, until increased NO generation predominates over ROS production. Further weakening of ROS formation by antioxidants may attenuate nuclear factor kappa B activation resulting in decreased endothelial NO synthase expression and activity. Prolonged antioxidant therapy may thus attenuate the beneficial regulatory effect of ROS, leading to decreased NO generation and the re-establishment of the undesirable disproportion between deleterious and protective forces. As a consequence prolonged antioxidant treatment in human hypertension may fail to provide the expected clinical profit.

Objective: It has been shown that the renin-angiotensin system participates in the development of the metabolic syndrome. This study aimed to show whether the angiotensin II type 1 receptor blocker, irbesartan, exerts a protective effect against metabolic and cardiovascular abnormalities in rats fed a high fat diet (HFD).

Methods: Wistar rats (n = 30) were divided into three groups: (1) rats fed a standard diet for 7 weeks were used as a control group; (2) rats fed a HFD (33.5% fat) for 7 weeks; and (3) rats fed a HFD (33.5% fat) treated with irbesartan (0.1 mg/kg per day) for 7 weeks. Body weight, white and brown adipose tissue weight, plasma concentrations and protein expression of leptin and adiponectin in white adipose tissue, and glucose metabolism were investigated. Vascular reactivity in aortic rings and heart function were also evaluated.

Results: HFD rats showed increased (P < 0.05) body, epididymal and lumbar adipose tissue weights, but did not experience a change in brown adipose tissue weight. Irbesartan attenuated (P < 0.05) all of these parameters, but increased brown adipose tissue weight. The leptin/adiponectin ratio of plasma concentrations and protein expression in lumbar adipose tissue increased (P < 0.05) in HFD rats, and were normalized by irbesartan. Along with these changes, irbesartan improved (P < 0.05) insulin sensitivity and exaggerated responses to angiotensin I and II in the aorta.

Conclusion: Irbesartan reduced body and white adipose tissue weights, improved glucose metabolism and vascular function in the aorta. The correction of leptin-adiponectin imbalance may be an important mechanism participating in the protective effect of irbesartan in HFD rats.

Objectives: The effects of indapamide, a thiazide-like diuretic, and captopril, an angiotensin-converting enzyme inhibitor, on spontaneous hypertension and the development of left ventricular hypertrophy (LVH), nitric oxide generation and oxidant status were investigated.

Methods: Six-week-old male spontaneously hypertensive rats (SHR) were treated with indapamide (1 mg/kg per day) or captopril (10 mg/kg per day) or a combination of indapamide plus captopril. After the 6-week treatment, nitric oxide synthase (NOS) activity, the expression of NOS isoform proteins, conjugated dienes concentration and relaxation responses of the femoral artery were analyzed.

Results: Indapamide and captopril partly prevented a blood pressure increase in young SHR. Captopril in contrast to indapamide reduced LVH. The effect of the combined indapamide and captopril treatment on the prevention of hypertension was additive. Combined indapamide and captopril treatment increased NOS activity and endothelial NOS protein expression in the aorta and decreased conjugated dienes concentration in the kidney compared with the indapamide monotherapy group. Indapamide and indapamide and captopril treatment increased acetylcholine-induced relaxation of the femoral artery.

Conclusion: Whereas captopril reduced LVH, indapamide enhanced NOS activity and decreased oxidative damage in the case of the combined treatment. It is concluded that the complex protective effects of the combined indapamide plus captopril treatment on hypertension may be exerted via its effects on blood pressure, hypertrophy and vasorelaxation.

In experimental rodents, surgical removal of the pineal gland, the major source of circulating melatonin, causes a gradual and sustained rise in blood pressure. Conversely, when melatonin is chronically administered to pinealectomized rodents the increment in blood pressure is ameliorated. In humans as well, the night time rise in endogenous circulating melatonin levels may be inversely related to the reduction in night time blood pressure. Among patients with hypertension, some exhibit a much greater reduction in blood pressure at night (the so-called 'extreme dippers' and 'dippers'), whereas others exhibit only a slight night time reduction in systolic and diastolic pressure ('non-dippers' and 'inverted dippers'). Longitudinal studies of these patients show that inverted dippers and non-dippers die at a faster rate than do dippers and extreme dippers. The chronic administration of melatonin to individuals with hypertension induces a measurable drop in night time systolic and diastolic blood pressure. Moreover, the higher the night time level of endogenous melatonin (estimated from urinary metabolite of melatonin, 6-hydroxymelatonin sulphate), the greater the reduction in arterial blood pressure at night. The implication of these findings is that melatonin may have utility as an antihypertensive agent.

Objective: Low birth weight contributes to the early onset of end-stage renal disease. Therefore, this study was undertaken to investigate early and late glomerular structural alterations in both sexes of Wistar rat offspring from dams submitted to severe low protein intake during gestation.

Methods: Offspring from dams fed normal protein (19% of protein) or low protein (5% of protein) were studied at days 0, 10, 90 and 180 of age.

Results: Inner cortical structure showed immature (comma-shaped and S-shaped forms) and mature corpuscles in different proportions in low protein offspring (less maturity) and normal protein offspring (more maturity). At day 10 (end of the nephrogenesis period), immature corpuscles were observed only in low protein offspring. In adulthood, low protein offspring had higher blood pressure, and showed thicker glomerular basement membrane (GBM) with effacement of the pedicles, and slit diaphragm absent with some podocytes directly adhering to the basal membrane with pedicles absent. The number of renal corpuscles was lower in low protein offspring than in normal protein offspring of the same sex, all age groups (P < 0.001). No interaction was observed between sex and maternal nutrition for the same sex and all age groups.

Conclusion: Gestational low protein leads to glomerulogenesis retardation and consequently a lower nephron number with thick GBM and structural alterations in the pedicles of podocytes.

Several newer areas of hypertension research are presented in this supplement. First, the benefits of melatonin in the treatment of experimental hypertension including its cardioprotective effects are introduced. Second, the possible role of melatonin in the non-dipping blood pressure pattern is described. Third, two hypotheses discuss the potential reasons for the ineffectivness of antioxidants in hypertension treatment, and difficulties associated with interpretations of experimental findings in the model of the spontaneously hypertensive rat (SHR). Finally, interactions of indapamide with the nitric oxide system in SHR, the protective effect of angiotensin II type 1 receptor blockade against alterations in insulin-resistant rats, and the deleterious effect of a low protein diet on kidney maturation with the development of hypertension are presented.

Objective: Melatonin was shown to reduce blood pressure, oxidative load and to increase nitric oxide bioavailability predisposing melatonin to have antiremodelling potential.

Design: The aim of this study was to show whether melatonin can reverse left ventricular remodelling in spontaneously hypertensive rats (SHR) and to compare this potential protective effect with captopril, spironolactone, or simvastatin.

Methods: Six groups of 3-month old rats (eight per group) were treated for 5 weeks: control untreated Wistar rats, control SHR, SHR plus melatonin (10 mg/kg per 24 h), SHR plus captopril (100 mg/kg per 24 h), SHR plus spironolactone (200 mg/kg per 24 h) and SHR plus simvastatin (10 mg/kg per 24 h). Their systolic blood pressure (SBP) was measured by the tail-cuff method. The relative weights of the left ventricle, nitric oxide synthase (NOS) activity, endothelial NOS and nuclear factor kappa B (NF-kappaB) protein expression, conjugated dienes concentration, level of collagenous proteins and hydroxyproline were measured.

Results: SBP was reduced by all drugs investigated but most prominently by captopril in SHR. The activity of NOS and endothelial NOS expression increased in the left ventricles of SHR compared with controls. Melatonin and spironolactone further increased NOS expression. Left ventricular oxidative load, estimated by NF-kappaB expression and conjugated dienes concentration, increased in SHR. Only melatonin reduced NF-kappaB expression and decreased conjugated diens concentration. Only captopril reduced left ventricular hypertrophy in SHR, whereas melatonin reduced collagenous protein concentration and hydroxyproline content in the left ventricle.

Conclusion: It is concluded that although melatonin, in comparison with captopril, did not reverse left ventricle hypertrophy, it reversed left ventricular fibrosis. This protection by melatonin may be caused by its prominent antioxidative effect.

Objectives: Plasma melatonin concentrations in non-dipping patients show a blunted daily rhythm. Melatonin has a capacity to improve disturbances in biological rhythms. Hypertensive TGR(mRen2)27 (TGR) rats with an upregulated renin-angiotensin system and inverted blood pressure profile were used to elucidate whether melatonin is able to influence the control of blood pressure.

Design: Melatonin was administered in drinking water to normotensive Sprague-Dawley (SD) and hypertensive TGR rats during the dark phase of the light: dark cycle 12: 12 for 4 weeks.

Methods: The effect of melatonin on blood pressure was monitored, and the expression of clock genes per2 and bmal1 and melatonin receptor MT1 in the suprachiasmatic nucleus (SCN) and the heart was measured by real time polymerase chain reaction during a 24-h cycle.

Results and conclusion: The administration of melatonin did not influence clock gene expression in the SCN but its effect on clock gene expression in the heart was phase dependent in both SD and TGR rats. Melatonin administration did not decrease the expression of melatonin receptors in the SCN and the heart. Melatonin did not decrease blood pressure in TGR rats but influenced the peripheral oscillator in the heart independently of the SCN. A modified function of molecular circadian oscillators in the heart can interfere with anticipation and disturb the adaptation of this organ to pressure overload.