Increased expression of angiotensin converting enzyme 2 in conjunction with reduction of neointima by angiotensin II type 1 receptor blockade.

Angiotensin converting enzyme 2 (ACE2), a newly recognized homolog of ACE that converts angiotensin II (Ang II) to angiotensin-1-7 (Ang-(1-7)), is found in vascular smooth muscle cells. Expression of ACE2 may be a local determinant of vascular Ang-(1-7) production and, when increased, may augment the increasingly recognized protective effects of this peptide within injured tissues. We previously showed that treatment with the angiotensin II type 1 (AT1) receptor blocker (ARB) olmesartan increased aortic ACE2 and Ang-(1-7) in conjunction with improved vascular remodeling in spontaneously hypertensive rats (SHR). In the present study, we investigated balloon injury-related ACE2 in the vasculature by determining the effect of sustained AT1 blockade on ACE2 protein expression in the carotid arteries of 12-week-old male SHR treated with either vehicle (n=5) or 10 mg/kg olmesartan (n=5) in drinking water for 14 days. Olmesartan treatment caused a 61% reduction in the cross-sectional area of the neointima, from 0.27+/-0.01 mm2 in vehicle-treated rats to 0.11+/-0.01 mm2 in olmesartan-treated rats. In contrast, olmesartan treatment had no effect on the medial area of injured or uninjured carotid arteries compared to that in vehicle-treated rats. Quantitative analysis of ACE2 immunostaining intensity in the carotid artery of SHR was significantly greater (p<0.05) in the neointima of olmesartan-treated SHR compared to that in vehicle-treated animals. In contrast, ACE2 immunostaining intensity was not quantitatively different in uninjured carotid arteries of olmesartan and vehicle-treated animals. These studies suggest that changes in ACE2 within the vascular system of SHR are regulated by a factor other than arterial pressure.     

Changes in pain perception during treatment with angiotensin converting enzyme-inhibitors and angiotensin II type 1 receptor blockade

OBJECTIVES : Besides the well-known role of the angiotensin system in blood pressure control, an interaction of angiotensin and pain perception has been suggested. This study sought to investigate whether an angiotensin converting enzyme inhibitor, which facilitates bradykinins, algesic peptides, and/or an AT1 receptor antagonist may modify hypertension-related hypoalgesia in humans. The study was approved by the ethical committee of our Department. METHODS : A total of 22 hypertensive patients were submitted to dental pulp stimulation to obtain the dental pain threshold and tolerance, and to 24 h blood pressure monitoring together with a control group of 55 normotensives. Then the hypertensives were randomized to enalapril or losartan treatment and were re-evaluated (dental pain perception and ambulatory monitoring) after 8 weeks of the first treatment and after an additional 8 weeks of the second treatment. RESULTS : Untreated hypertensives showed a reduced perception to painful stimuli when compared with normotensives. A significant reduction of both pain threshold and tolerance was observed during the anti-hypertensive treatments (Friedman test: P = 0.007 and P = 0.006, respectively). Pain sensitivity was similar during the two treatments and it did not differ from pain sensitivity values of normotensive controls. ANCOVAs were computed to evaluate the relationship between anti-hypertensive agents and pain sensitivity, after controlling for blood pressure. A 24 h mean pressure served as covariate, removing any effect of blood pressure; a significant difference was observed entering both pain threshold and tolerance as dependent variables (F = 5.28, P = 0.0076; F = 8.16, P = 0.0007, respectively). CONCLUSIONS : Both the angiotensin converting enzyme inhibitor enalapril and the AT1 receptor blocking agent losartan acted similarly on pain threshold and tolerance, pain sensitivity being increased during the two anti-hypertensive treatments. The blood pressure reduction during drug assumption could not account for the pain sensitivity changes observed. The latter may be due to a specific pharmacodynamic mechanism mediated through angiotensin II AT1 receptors.     

Effect of angiotensin II type 1 receptor blockade on experimental hepatic fibrogenesis

BACKGROUND/AIMS: The aim of this study was to investigate whether in the liver, as in other tissues, there is evidence that angiotensin II, acting via the angiotensin II type 1 receptor (AT1-R), plays a role in fibrogenesis. METHODS: Sprague-Dawley rats were divided into three groups; sham, bile duct ligated (BDL) and BDL + AT1-R antagonist, irbesartan. Real time RT-PCR was utilised to assess gene expression of the AT1 receptor, TGF-beta1 and alpha1 (I) collagen in the liver. TGF-beta1 and alpha1 (I) collagen mRNA expression and localisation were also assessed by in situ hybridisation. TGF-beta1 activity was assessed by using the TGF-beta inducible gene product betaig-h3. Fibrosis was assessed by the Knodell scoring system, tissue hydroxyproline content and picro-sirius red staining. RESULTS: Real time RT-PCR revealed that there was a 6-fold up-regulation in AT1 receptor expression in BDL animals compared with shams. This was associated with marked increases in TGF-beta1, betaig-h3 and alpha1 (I) collagen gene expression which were attenuated by AT1-RA treatment. However, AT1-RA therapy produced no significant change in liver histology or hydroxyproline content. CONCLUSIONS: These results suggest that in the liver angiotensin II may play an important role in the fibrogenic response to injury. However, whether treatment with an AT1-RA will be of therapeutic benefit remains to be determined.     

Increased inflammatory biomarkers in hypertensive type 2 diabetic patients: improvement after angiotensin II type 1 receptor blockade

Diabetes and hypertension increasingly are recognized as pro-inflammatory conditions. We tested the hypothesis that in patients with hypertension and type 2 diabetes, blood pressure (BP) reduction with an angiotensin receptor blocker (ARB), valsartan, or with a beta blocker, atenolol, is associated with a decreased inflammatory response. Normotensive subjects and hypertensive patients with type 2 diabetes (40 to 70 years of age) participated in the study. Patients (n = 28) were randomized to double-blind treatment for 1 year with valsartan (80–160 mg) or atenolol (50–100 mg) daily, added to previous therapy. Age-matched controls (n = 12) were also studied. Serum levels of cytokines (IL-6, IL-18), chemokines (MCP-1), and adhesion molecules (sICAM, sE-selectin) were measured by enzyme-linked immunosorbent assay (ELISA) as indices of systemic and vascular inflammation, before and 1 year after treatment. BP was similarly reduced by valsartan and atenolol. Glycemic control and lipid profiles were comparable in the two groups and did not change significantly with antihypertensive therapy. Serum levels of all inflammatory markers were increased in patients before treatment (by two- to four-fold vs. controls, P < .05). IL-6, IL-18, sICAM, and MCP-1 levels were reduced by valsartan (three-fold, P < .05). Only IL-18 was reduced by atenolol compared with pretreatment levels (P < .05). These data indicate that proinflammatory mediators are significantly increased in hypertensive type 2 diabetic patients and that despite similar BP lowering by valsartan and atenolol and similar glucose levels in both treated groups, global inflammatory status was improved only in the valsartan group. Our findings suggest that antihypertensive treatment, particularly with an ARB, ameliorates inflammatory processes in diabetic hypertensive patients. Such effects, which are independent of BP and glycemic control, may contribute to cardiovascular protection.     

Long-term angiotensin II type 1 receptor blockade with fonsartan doubles lifespan of hypertensive rats

In this study, we investigated the outcome of lifelong treatment with the angiotensin II type 1 receptor (AT(1)) blocker fonsartan (HR 720) in young stroke-prone spontaneously hypertensive rats (SHR-SP). In addition to the primary end point, lifespan, and to determine the mechanisms involved in the treatment-induced effects, parameters such as left ventricular hypertrophy, cardiac function/metabolism, endothelial function, and the expression/activity of endothelial nitric oxide synthase and of angiotensin-converting enzyme (ACE) were also investigated. Ninety 1-month-old SHR-SP were allotted to 2 groups and treated via drinking water with an antihypertensive dose of fonsartan (10 mg. kg(-1). d(-1)) or placebo. Fonsartan doubled the lifespan to 30 months in SHR-SP, which was comparable to the lifespan of normotensive Wistar-Kyoto rats. After 15 months, a time when approximately 80% of the placebo group had died, left ventricular hypertrophy was completely prevented in fonsartan-treated animals. Furthermore, cardiac function and metabolism as well as endothelial function were significantly improved. These effects were correlated with increased endothelial nitric oxide synthase expression in the heart and carotid artery and with markedly decreased tissue ACE expression/activities. Lifespan extension and cardiovascular protection by long-term AT(1) blockade with fonsartan led to similar beneficial effects, as observed with long-term ACE inhibition.     

Effects of angiotensin II and angiotensin II type 1 receptor blockade on neointimal formation after stent implantation

The prevalence of chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF) increases substantially with age. The coexistence of COPD and CHF is common but often unrecognized in elderly patients. To avoid overlooking COPD in elderly patients with known CHF pulmonary function tests should be routinely obtained. Likewise, to avoid overlooking CHF in elderly patients with known COPD left ventricular (LV) function should be routinely assessed. Plasma brain natriuretic peptide levels are useful to differentiate COPD exacerbation from CHF decompensation in patients presenting with acute dyspnea. Aging exacerbates skeletal muscle alterations that occur in patients with CHF and COPD. Skeletal muscle metabolic alterations and atrophy and the resulting deterioration of functional capacity progress rapidly in elderly patients with COPD and CHF. Physical conditioning reverses rapidly progressing skeletal muscle metabolic alterations and atrophy and promotes independence and life quality in the elderly. Physical conditioning is clearly an essential component of the management of elderly patients with COPD and CHF. The pharmacological management of patients with coexistent COPD and CHF should focus on not depriving these patients from long-term beta adrenergic blockade. Long-term beta adrenergic blockade has been repeatedly shown to improve survival in elderly patients with CHF due to LV systolic dysfunction and, contrary to conventional belief, is well tolerated by patients with COPD.     

Genetic contribution to the acute effects of angiotensin II type 1 receptor blockade

OBJECTIVE: Clinical observations point towards heterogeneity in patients' responses to antihypertensive drugs. As our earlier work showed that angiotensin II (AngII) sensitivity is associated with the A1166C polymorphism of the AngII type 1 receptor (AT1R) gene, we conducted the present study in which the responses to acute AT1R blockade were evaluated. METHODS: After 7 days of low and high sodium diet, the hormonal as well as systemic and renal hemodynamic responses to acute AT1R blockade with EXP3174 (active metabolite of losartan) were studied in 15 AA and 14 CC essential hypertensive patients. By means of platelet-binding studies the baseline AT1R density (Bmax) and affinity (KD) was tested. RESULTS: During low and high salt diet, baseline Bmax and KD were comparable between both genotype groups. At baseline, during low salt diet, CC patients had significantly lower glomerular filtration rate and a trend towards lower effective renal plasma flow (ERPF) compared to AA patients. Blood pressure responses to EXP3174 during high salt were significantly blunted in CC patients compared to AA patients (mean arterial pressure: 1.8 versus 7.5%; P < 0.05). During low salt the increase in ERPF (12.9 versus 16.1%; P = 0.08), as well as the decrease in filtration fraction (9.0 versus 14.0%; P = 0.05) and renal vascular resistance (7.5 versus 15.1%; P = 0.06) were blunted in CC patients compared to AA patients. Humoral effects did not differ between the groups. CONCLUSION: This study shows that the systemic and renal hemodynamic responses to acute AT1R blockade are, at least in part, genetically determined.     

Effects of selective angiotensin II type 1 receptor blockade with losartan on arterial compliance in patients with mild essential hypertension

It has been suggested that antihypertensive drugs should not only decrease blood pressure, but also improve large artery compliance. The aim of the present study was to examine the effect of losartan, a selective angiotensin II type 1 receptor antagonist, on parameters reflecting arterial compliance. In a randomized, double-blind cross-over study, 16 patients with mild essential hypertension were examined after 4 weeks of treatment with placebo/losartan. The effect on finger plethysmographic arterial pulse curves were quantified by computing the relative height of the dicrotic notch, and pulse wave velocity was estimated by measurements of the time delay from the start of the QRS-complex (electrocardiogram) to the foot of the plethysmographic pulse wave. Compared with placebo, losartan reduced the relative height of the dicrotic notch from 55% (SD 12) to 47% [14] (p < 0.01), and pulse wave velocity from 9.3 m/sec to 8.7 m/sec (p < 0.05). The supine blood pressure decreased from 146/89 mmHg to 134/82 mmHg (p < 0.01). There was no correlation between the effects on blood pressure and the effects on the arterial compliance parameters, suggesting that losartan exerted an effect on arterial compliance beyond its effect on blood pressure.     

The clinical course of mesangial proliferative glomerulonephritis.

Patients with a pure mesangial proliferative glomerulonephritis may present with either hematuria, asymptomatic proteinuria, or nephrotic syndrome. For patients with hematuria, the clinical course is self-limited, and spontaneous resolution of recurrent episodes of macroscopic hematuria occurred in many of these patients. For patients with asymptomatic proteinuria, a spontaneous decrease in proteinuria occurred and none of these patients developed a progressive course. The clinical course of patients with nephrotic syndrome was similar to that usually observed in children and adults with pure minimal change lesions. A complete remission of the nephrotic syndrome occurred in most of these patients during treatment with prednisone and cyclophosphamide. Overall, the prognosis for the patients reported in this series was quite good.     

Age-related changes in the kidney of patients with mild mesangial proliferative glomerulonephritis

In order to clarify age-related changes in kidneys, the renal function and histological changes were evaluated in 962 patients with mild mesangial proliferative glomerulonephritis (Mes PGN) whose ages ranged from 7 to 82 years. The glomerular filtration rate (GFR) (Ccr), renal plasma flow (RPF) (CPAH) and PSP excretion rate were significantly lower in nephritic patients than in normal subjects. Age-related decreases of GFR, RPF, PSP excretion rate and maximal urine specific gravity in Fishberg concentration test were found in both groups. Serum levels of creatinine, urea nitrogen and uric acid were significantly higher in nephritic patients than in the normal population. Age-related increases of those parameters were found in both groups. The incidence of sclerotic glomeruli was almost same as that of the normal population estimated by Kaplan et al. The incidence of arterio- and arteriolosclerosis was also higher than that of normal subjects estimated by Bell. Thus, arterio- and arteriolosclerosis seems to be more age-dependent than glomerulosclerosis in patients with mild Mes PGN. In conclusion, renal functions decrease and renal arteriolar lesions increase gradually in proportion to aging. Mes PGN, even mild, can accelerate the physiological age-related decrease of renal function.     

Platelet aggregability in patients with hypertension treated with angiotensin II type 1 receptor blockers

AIM: Cardiovascular events associated with hypertension often involve thrombosis. Increased platelet activity is one of the risk factors of cardiovascular diseases. Antithrombotic properties of antihypertensive agents are not fully characterized. Angiotensin II type 1 receptor blockers (ARBs) are widely used for the treatment of hypertension. Some ARBs can provoke antiaggregatory effects on platelets in vitro. Whether ARBs can inhibit platelet aggregation was tested in hypertensive patients in vivo. METHODS: Platelet aggregation was assessed by the highly sensitive particle counting method using laser-light scattering. RESULTS: Large platelet aggregation induced by adenosine diphosphate (ADP, 3 microM) was 2.6+/-0.4 (x10(7)) (SE) in hypertensive patients treated with losartan (72+/-3 years old, n=10) while it was 3.9+/-0.6 in hypertensive patients treated with candesartan (70+/-5 years old, n=6; p=0.056). Large platelet aggregation induced by thromboxane A2 receptor agonist, U46619 (10 microM), was 2.8+/-0.5 (x10(7)) in hypertensive patients treated with losartan while it was 5.1+/-0.9 in hypertensive patients treated with candesartan (p=0.033). Clinical characteristics including the control of blood pressure did not differ between the two groups (losartan 136+/-5/73+/-3 mmHg vs. candesartan 135+/-4/76+/-5). CONCLUSION: Thus, losartan may have the possibility to inhibit platelet activation in patients with hypertension independent of blood pressure reduction. Antiaggregatory properties may be independent of angiotensin II type 1 receptor or of antihypertensive actions. The favorable effects of losartan on reduction of adverse cardiovascular events among hypertensive patients may be at least partly mediated by inhibition of platelet activation.     

Prevention of hypertension by irbesartan in Dahl S rats relates to central angiotensin II type 1 receptor blockade

Hypertension in Dahl S rats on high-salt intake is in general considered a model of "low-renin hypertension," unresponsive to treatment with blockers of the renin-angiotensin system. However, direct central administration of an angiotensin II type 1 (AT(1)) receptor blocker prevents both the sympathoexcitation and hypertension caused by high-salt intake in Dahl S rats. In the present study, we tested the hypothesis that chronic peripheral administration of an AT(1) receptor blocker inhibits the salt-induced hypertension relative to the extent of central AT(1) receptor blockade that is induced. Dahl S rats received a high-salt (1370 micromol Na(+)/g) or regular (101 micromol Na(+)/g) diet from 4 to 8 weeks of age. In 3 different sets of experiments, Dahl S on high salt were randomized to intracerebroventricular (ICV) treatment with control infusion versus irbesartan at 50 or 250 microg. kg(-1). d(-1), oral treatment with control versus irbesartan at 125 or 500 mg. kg(-1). d(-1) once daily by gavage, or subcutaneous treatment with control versus irbesartan at 50 or 150 mg. kg(-1). d(-1) by once daily injection. At 8 weeks of age, MAP was measured in conscious rats at rest and in response to angiotensin II ICV or IV. On high-salt intake, Dahl S developed the anticipated marked increase in MAP to approximately 160 mm Hg. Irbesartan ICV did not affect pressor responses to angiotensin II IV, but irbesartan administered subcutaneously or by gavage markedly inhibited these responses. Irbesartan ICV or by gavage partially inhibited pressor responses to angiotensin II ICV and the development of hypertension. Irbesartan subcutaneously at the higher dose more completely inhibited pressor responses to angiotensin II ICV and fully prevented the salt-induced hypertension. The degree of central but not peripheral AT(1) receptor blockade parallels the antihypertensive effect of irbesartan, indicating that inhibition of the brain renin-angiotensin system can contribute to a significant extent to the therapeutic effectiveness of AT(1) receptor blockers such as irbesartan when administered in sufficiently high doses to cause central AT(1) receptor blockade.     

Aldosterone breakthrough during angiotensin II receptor blockade in hypertensive patients with diabetes mellitus

BACKGROUND: Aldosterone is an important pathogenetic factor, independent of the renin-angiotensin system in cardiovascular and renal disease. Aldosterone breakthrough during angiotensin-converting enzyme (ACE) inhibitor therapy was reported in hypertension, diabetes mellitus, and chronic renal disease. It is unclear whether the angiotensin II receptor blocker (ARB) causes aldosterone breakthrough in patients with hypertension and diabetes mellitus, and whether aldosterone breakthrough contributes to renal injury in these patients. METHODS: We prospectively studied 95 hypertensive patients with diabetes mellitus. Patients were treated with candesartan (8 mg/day, n = 47) or valsartan (80 mg/day, n = 48) for 15 months. Blood pressure (BP), urinary albumin excretion (UAE), biochemical markers, plasma aldosterone concentration (PAC), and plasma renin activity (PRA) were measured before and at 3, 6, 12, and 15 months of treatment. Nine patients who exhibited aldosterone breakthrough after treatment with ARB were placed on spironolactone (25 mg/day) for 3 months, and BP, UAE, and biochemical markers were measured after treatment. RESULTS: Although the overall PAC was significantly decreased (P < .05) in each group, it eventually increased in 21 (candesartan, 11 patients; valsartan, 10 patients) of 95 patients (22%; aldosterone breakthrough). Blood pressure, PRA, and biomedical markers did not differ between the two groups during treatment. Although UAE was significantly decreased in patients with or without aldosterone breakthrough at 6 months, it was increased again at 15 months of treatment in patients with aldosterone breakthrough. Treatment with spironolactone markedly reduced UAE in these patients. CONCLUSIONS: Aldosterone breakthrough was seen to be equal in hypertensive patients with diabetes mellitus treated with candesartan or valsartan. Aldosterone blockade therapy may be effective in preventing renal injury in hypertensive patients with aldosterone breakthrough.     

Differential effect of acute angiotensin II type 1 receptor blockade on the vascular and adrenal response to exogenous angiotensin II in humans

BACKGROUND: Aldosterone stimulation by angiotensin II may not exclusively be mediated by the angiotensin II type 1 (AT(1)) receptor. We have, therefore, investigated the vascular and adrenal response to angiotensin II infusion without and with pretreatment with the AT(1) receptor antagonist valsartan (160 mg). METHODS: In nine healthy human volunteers, angiotensin II was administered intravenously at doses of 1, 3, and 10 ng/kg/min, each over 45 min. Arterial blood pressure (BP) was measured oscillometrically at 5-min intervals. Blood for the determination of plasma renin activity and aldosterone was taken before the start of the infusion, at the end of each infusion period, and 1 h after the infusion was stopped. RESULTS: Angiotensin II increased systolic and diastolic BP from 121 +/- 3/70 +/- 2 mm Hg to a maximum of 146 +/- 2/97 +/- 1 mm Hg (P <.001) and plasma aldosterone from 39.2 +/- 9.8 to 290.7 +/- 48.3 (P <.001). The increase in BP after exogenous angiotensin II was completely abolished in volunteers pretreated with valsartan, averaging 118 +/- 3/72 +/- 1 mm Hg by the end of the maximum angiotensin infusion dose. In contrast, plasma aldosterone stimulation by angiotensin II was only partially blunted by concomitant AT(1) receptor blockade (98.9 +/- 16.3 pg/mL after the maximal dose of angiotensin II). CONCLUSIONS: These results indicate that although the vascular response to exogenous angiotensin II is exclusively mediated by the AT(1) receptor, the effects of angiotensin II on adrenal aldosterone release may involve other pathways.     

Gap junction remodeling in hypertrophied left ventricles of aortic-banded rats: prevention by angiotensin II type 1 receptor blockade

Remodeling of gap-junctional organization in hypertrophied left ventricle (LV) in response to pressure overload in rats induced by abdominal aorta banding was investigated by immunoconfocal and electron microscopy. Eight to 12 weeks after banding, rats developed significant LV hypertrophy. In contrast to control LV myocytes, which showed connexin43 (Cx43) labeling largely confined to the intercalated disks, LV myocytes from aortic-banded rats showed dispersion of punctate Cx43 labeling over the entire cell surface. In LV tissues sectioned longitudinally, the proportion of Cx43 label at the intercalated disk decreased significantly (control, 0.87 v aortic-banded, 0.62). En-face views of intercalated disks of hypertrophied myocardium revealed a reduction of Cx43 gap junctions in the disk center, giving rise to a significant decrease in the proportion of the disk occupied by gap-junctional membrane (control, 0.32 v aortic-banded, 0.24). Electron microscopy of hypertrophied LV tissue revealed that Cx43-containing gap junctions were frequently displaced from their usual locations to form side-to-side contacts distant from the disk, and also appeared as annular profiles. In aortic-banded rats treated with the angiotensin II (AII) type 1 receptor (AT1) antagonist, losartan (10 mg/kg/day, 11 weeks) not only LV hypertrophy, but also the gap junction disorganization was markedly reduced. These results suggest that LV hypertrophy induced by pressure overload is associated with Cx43 gap junction disorganization and that AII may play an important role either directly or indirectly in gap-junctional remodeling.