AT1 Receptor Blocker Valsartan Research Articles

Valsartan attenuates pulmonary hypertension via suppression of mitogen activated protein kinase signaling and matrix metalloproteinase expression in rodents.

It has previously been demonstrated that the renin-angiotensin system is involved in the pathogenesis and development of pulmonary hypertension (PH). However, the efficacy of angiotensin II type I (AT1) receptor blockers in the treatment of PH is variable. The present study examined the effects of the AT1 receptor blocker valsartan on monocrotaline (MCT)‑induced PH in rats and chronic hypoxia‑induced PH in mice. The results demonstrated that valsartan markedly attenuated development of PH in rats and mice, as indicated by reduced right ventricular systolic pressure, diminished lung vascular remodeling and decreased right ventricular hypertrophy, compared with vehicle treated animals. Immunohistochemical analyses of proliferating cell nuclear antigen expression revealed that valsartan suppressed smooth muscle cell proliferation. Western blot analysis demonstrated that valsartan limited activation of p38, c‑Jun N‑terminal kinase 1/2 and extracellular signal‑regulated kinase 1/2 signaling pathways and significantly reduced MCT‑induced upregulation of pulmonary matrix metalloproteinases‑2 and ‑9, and transforming growth factor‑β1 expression. The results suggested that valsartan attenuates development of PH in rodents by reducing expression of extracellular matrix remodeling factors and limiting smooth muscle cell proliferation to decrease pathological vascular remodeling. Therefore, valsartan may be a valuable future therapeutic approach for the treatment of PH.

Agonistic autoantibodies against the angiotensin AT1 receptor increase in unstable angina patients after stent implantation.

Agonistic AT1 receptor autoantibodies have been described in patients with hypertension and preeclampsia. These autoantibodies could stimulate proliferation of vascular smooth muscle cells (VSMCs), which are involved in angiotensin II-induced vascular injury in cardiovascular disease. Hence, in this study, we explored the existence of agonistic AT1 receptor autoantibodies in unstable angina (UA) patients and the possible effects of them on the in-stent restenosis of these patients. A total of 95 UA patients and 98 healthy volunteers were enrolled. The serum of each patient was analyzed for the presence of AT1 receptor autoantibodies by enzyme-linked immunosorbent assay. Their effects on VSMC proliferation and c-fos and c-jun expression were studied in vitro. AT1 receptor autoantibodies were detected in 34/95 patients with UA. The incidence was 10.2% in the control group and rose to 47.37% after stent implantation. In vitro, this autoantibody had agonist-like activity, shown as stimulation of VSMC proliferation and upregulation of c-fos and c-jun expression. These effects were similar to that of angiotensin II and could be weakened partly by the AT1-receptor blocker valsartan. Our findings show that the autoantibody from UA patients has similar agonistic activity to angiotensin II and might play a role in the pathogenesis of in-stent restenosis in these patients.

Autoantibodies targeting AT1 receptor from patients with acute coronary syndrome upregulate proinflammatory cytokines expression in endothelial cells involving NF-κB pathway.

Our study intended to prove whether agonistic autoantibodies to angiotensin II type 1 receptor (AT1-AAs) exist in patients with coronary heart disease (CHD) and affect the human endothelial cell (HEC) by upregulating proinflammatory cytokines expression involved in NF-κB pathway. Antibodies were determined by chronotropic responses of cultured neonatal rat cardiomyocytes coupled with receptor-specific antagonists (valsartan and AT1-EC2) as described previously. Interleukin-6 (IL-6), vascular cell adhesion molecule-1 (VCAM-1), and monocyte chemotactic protein-1 (MCP-1) expression were improved at both mRNA and protein levels in HEC, while NF-κB in the DNA level was improved detected by electrophoretic mobility shift assays (EMSA). These improvements could be inhibited by specific AT1 receptor blocker valsartan, NF-κB blocker pyrrolidine dithiocarbamate (PDTC), and specific short peptides from the second extracellular loop of AT1 receptor. These results suggested that AT1-AAs, via the AT1 receptor, induce expression of proinflammatory cytokines involved in the activation of NF-κB. AT1-AAs may play a great role in the pathogenesis of the acute coronary syndrome by mediating vascular inflammatory effects involved in the NF-κB pathway.

Expression of NADPH oxidase and production of reactive oxygen species in aorta in an active immunization mouse model with AT1-EC2 peptide

The antibody against AT1-EC2 plays a role in some kinds of inflammatory vascular diseases including malignant hypertension, preeclampsia, and renal-allograft rejection, but the detailed mechanisms remain unclear. In order to investigate the changes of NADPH oxidase and reactive oxygen species in the aorta in a mouse model which can produce AT1-EC2 antibody by active immunization with AT1-EC2 peptide, 15 mice were divided into three groups: control group, AT1-EC2-immunized group, and AT1-EC2-immunized and valsartan-treated group. In AT1-EC2-immunized group and AT1-EC2-immunized and valsartan-treated group, the mice were immunized by 50 μg peptide subcutaneously at multiple points for 4 times: 0, 5, 10, and 15 days after the experiment. In AT1-EC2-immunized and valsartan-treated group, valsartan was given at a dose of 100 mg/kg every day for 20 days. After the experiment, the mice were sacrificed under anesthesia and the aortas were obtained and frozen in liquid nitrogen for the preparation of frozen section slides and other experiments. The titer of AT1-EC2 was assayed by using ELISA. The level of NOX1 mRNA in the aorta was determined by using RT-PCR. The expression of NOX1 was detected by using Western blotting. Confocal scanning microscopy was used to assay the α-actin and NOX1 expression in the aortic tissue. The O(2)∸ production was detected in situ after DHE staining. The mice produced high level antibody against AT1-EC2 in AT1-EC2-immunized group and AT1-EC2-immunized and valsartan-treated group, and the level of NOX1 mRNA in the aortic tissues was 1.6±0.4 times higher and the NOX1 protein expression was higher in AT1-EC2-immunized group than in control group. There were no significant differences in the level of NOX1 mRNA and protein expression between control group and AT1-EC2-immunized and valsartan-treated group. The expression and co-localization of α-actin and NOX1 in AT1-EC2-immunized group increased significantly as compared with those in control group, and the O(2)∸ production increased about 2.7 times as compared with control group. There were no significant differences between control group and AT1-EC2-immunized and valsartan-treated group. It is concluded that active immunization with AT1-EC2 can activate NOX1-ROS, and increase vascular inflammation, which can be inhibited by AT1 receptor blocker valsartan. This may partially explain the mechanism of the pathogenesis of inflammatory vascular diseases related to antibody against AT1-EC2.

Valsartan inhibited HIF-1α pathway and attenuated renal interstitial fibrosis in streptozotocin-diabetic rats

AimTo investigate the effect of angiotensin II AT1 receptor blocker valsartan on hypoxia-inducible factor (HIF)-1α-mediated gene activation and its association with renal interstitial fibrosis (RIF) in diabetic nephropathy rats. MethodsSprague-Dawley rats were randomly divided into 3 groups: control (C group), streptozocin-induced diabetic nephropathy (D group), and valsartan-treated D rats (T group). At end of the 4th, 8th and 12th week 6 rats from each group were sacrificed and blood, urine and kidneys were collected. Blood glucose, serum creatinine (Scr) and 24-h urinary protein were measured and kidneys were processed for Masson-stain as well as immunohistochemistry and real time-PCR analyses of the expressions of HIF-1α, and its target genes tissue inhibitor of metalloproteinase (TIMP)-1 and endothelin (ET)-1 in the kidney. Result(1) At the 4th, 8th and 12th week, the areas of RIF were significantly increased in D and T groups, which was accompanied by higher levels of 24-h urinary protein, Scr, HIF-1α, ET-1 and TIMP-1 compared with C group. (2) At the 8th and 12th week, the above changes were significantly attenuated in T group compared with D group. ConclusionsValsartan may reduce HIF-1α-mediated gene activation and consequently improve kidney damage in diabetic nephropathy rats.

E0138 AT1 receptor blocker valsartan attenuates left ventricular remodelling and failure in a rat model of adriamycin-induced dilated cardiomyopathy by upregulating the expression of angiotensin-converting enzyme 2 and angiotensin-(1–7)

IntroductionAdriamycin (ADR) is an effective antineoplastic agent whose use has been limited by its cardiotoxic side effects. Angiotensin-converting enzyme 2 (ACE2) has emerged as a novel regulator of cardiac function...

Rapid electrical pacing of cardiomyocytes alters the behavior of cardiac fibroblasts: Implications for atrial fibrillations

Background: Atrial fibrillation (AF) produces atrial tachycardia-related changes in atrial electrophysiology, providing a possible explanation for the progressive nature of the arrhythmia. Structural remodeling results from ventricular dysfunction due to a rapid response to AF, but whether AF itself can cause atrial fibrosis remains unclear. This study investigated the hypothesis that rapid atrial cardiomyocyte activation produces factors that influence atrial fibroblast proliferation and secretory functions. 
 Methods: Cultured canine atrial fibroblasts were treated with medium from rapidly-paced atrial cardiomyocytes (group 5Hz), non-paced cardiomyocytes (group NP) and cardiomyocyte pacing medium alone (group Ø), and analyzed by [3H]thymidine incorporation, Western-blot and real-time RT-PCR. 
 Results: Rapidly-paced cardiomyocyte-conditioned medium had a potent anti-proliferative effect, reducing [3H]thymidine uptake compared to non-paced cardiomyocyte-conditioned medium and medium alone (2,143±1,490** vs. 15,870±3,343 and 16,440±4,193 respectively, **P < 0.01 vs. both NP and Ø). Conditioned medium from rapidly-paced cardiomyocytes increased αSMA protein reflecting an activated myofibroblast phenotype (1.62±0.20** vs. 1.08±0.26 and 1.01±0.24), collagen-1 (2.41±0.22* vs. 1.49±0.33 and 1.10±0.19, *P < 0.05 both NP and Ø) and fibronectin-1 (3.05±0.28* vs. 1.80±0.45 and 1.20±0.19) mRNA expression compared to control cells. Treatment of the conditioned medium with the AT1 receptor blocker valsartan, partially attenuated the pacing-induced αSMA increase but had no effect on fibroblast proliferation. Atrial tissue from 1-week atrial-tachypaced dogs with AV block/ventricular pacing to control ventricular rate similarly showed upregulation of collagen-1 (2.6±0.5 vs. 0.7±0.3, P < 0.01) and fibronectin-1 (4.9±0.6 vs. 1.1±0.4, P < 0.001) mRNA versus unpaced shams. Conclusion: Rapidly-paced cardiomyocytes release substances that profoundly alter cardiac fibroblast function and induce an activated myofibroblast phenotype that is reflected by altered ECM-gene expression in vivo. These findings are consistent with recent observations that AF per se causes ECM remodeling and may have important consequences for understanding and preventing the mechanisms underlying AF progression.

NO and cGMP mediate angiotensin AT2receptor-induced renal renin inhibition in young rats

We hypothesized that angiotensin subtype-2 receptor (AT(2)R) inhibits renal renin biosynthesis in young rats via nitric oxide (NO). We monitored changes in renal NO, cGMP, renal renin content (RRC), and ANG II in 4-wk-old rats in response to low sodium (LNa(+)) intake alone and combined with 8-h direct renal cortical administration of AT(1) receptor blocker valsartan (VAL), AT(2)R blocker PD123319 (PD), NO synthase inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME), NO donor S-nitroso-N-acetyl penicillamine (SNAP), or guanylyl cyclase inhibitor 1H-[1,2,4] oxadiazolo[4,2-alpha] quinoxaline-1-one (ODQ). In addition, we monitored renal endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS) in response to VAL or PD. LNa(+), VAL, PD, l-NAME, and ODQ increased RRC, ANG II, and renin mRNA. PD and l-NAME decreased NO and cGMP, while SNAP reduced RRC, ANG II, renin mRNA, and reversed the effects of PD. PD also reduced eNOS and nNOS protein and mRNA. Combined treatment with PD, l-NAME, or ODQ and VAL reversed the effects of VAL and caused further increase in RRC, ANG II, renin mRNA, and protein. ODQ reversed the effects of SNAP. These data demonstrate that the renal AT(2) receptor decreases renal renin biosynthesis and ANG II production in young rats. Reversal of the PD effects by SNAP and SNAP effects by ODQ confirms that NO and cGMP mediate the AT(2) receptor inhibition of renal renin production.

Rationale and design of the GISSI-Atrial Fibrillation trial: a randomized, prospective, multicentre study on the use of valsartan, an angiotensin II AT1-receptor blocker, in the prevention of atrial fibrillation recurrence

The possibility of preventing atrial fibrillation recurrence with anti-arrhythmic agents is very limited, given the discouraging results obtained with current drugs in many patients. Data from experimental studies suggest that angiotensin II AT1-receptor blockers can influence atrial remodelling, a key factor in atrial fibrillation initiation and maintenance. Moreover, some preliminary clinical data show that angiotensin II AT1 -receptor blockers can prevent atrial fibrillation episodes. The GISSI-Atrial Fibrillation (AF) trial is a randomized, prospective, parallel group, placebo-controlled, multicentre study designed to test whether angiotensin II AT1-receptor blockers can reduce atrial fibrillation recurrence. The primary objective of the study is to demonstrate that, in patients with a history of recent atrial fibrillation who are treated with the best recommended therapies, the addition of the angiotensin II AT1-receptor blocker valsartan (titrated up to 320 mg) is superior to placebo in reducing atrial fibrillation recurrence. A substudy will analyse the effect of valsartan on left atrial dimensions and on neurohormones. The study population consists of patients with symptomatic atrial fibrillation (at least two electrocardiogram documented atrial fibrillation episodes in the previous 6 months or successful cardioversion in the last 2 weeks) with underlying cardiovascular diseases or comorbidities. With approximately 100 centres participating in Italy, a total of 1402 patients are randomized in a 1 : 1 ratio to receive valsartan or placebo. The enrolment period will last 12 months and the patients will be followed for 12 months from study entry. The GISSI-AF is the largest trial aimed at assessing the role of angiotensin receptor blockade in reducing the recurrence of atrial fibrillation and its possible mechanisms of action in terms of its effects on atrium remodelling and neurohormones.

PPAR-γ inhibits ANG II-induced cell growth via SHIP2 and 4E-BP1

The present study evaluated the effects of peroxisome proliferator-activated receptor (PPAR)-γ activators on ANG II-induced signaling pathways and cell growth. Vascular smooth muscle cells (VSMC) derived from rat mesenteric arteries were treated with ANG II, with/without the AT1 receptor blocker valsartan or the AT2 receptor blocker PD-123319, after pretreatment for 24 h with the PPAR-γ activators 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) or rosiglitazone. Both 15d-PGJ2 and rosiglitazone decreased ANG II-induced DNA synthesis. Rosiglitazone treatment increased nuclear PPAR-γ expression and activity in VSMC. However, rosiglitazone did not alter expression of PPAR-α/β, ERK 1/2, Akt, or ANG II receptors. 15d-PGJ2 and rosiglitazone decreased ERK 1/2 and Akt peak activity, both of which were induced by ANG II via the AT1 receptor. Rosiglitazone inhibited ANG II-enhanced phosphorylation of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), as well as Src homology (SH) 2-containing inositol phosphatase 2 (SHIP2). PPAR-γ activation reduced ANG II-induced growth associated with inhibition of ERK 1/2, Akt, 4E-BP1, and SHIP2. Modulation of these pathways by PPAR-γ activators may contribute to regression of vascular remodeling in hypertension.

Sex Difference in Vascular Injury and the Vasoprotective Effect of Valsartan Are Related to Differential AT 2 Receptor Expression

The angiotensin II type 2 (AT2) receptor is upregulated in pathological conditions such as vascular injury and exerts antagonistic effects against AT1 receptor-mediated actions. We examined the possibility that the sex difference in vascular remodeling is associated with altered AT2 receptor expression, which is located on the X chromosome. In this study, we examined this possibility by using AT2 receptor-null (Agtr2-) mice. Vascular injury was induced by polyethylene cuff placement around the femoral artery of wild-type (Agtr2+) and Agtr2- mice. In Agtr2+ mice, AT2 receptor expression in the injured artery was enhanced, and this increase was greater in female than in male mice, with no significant difference in AT1 receptor expression between male and female mice. Increases in neointimal formation, DNA synthesis, expression of monocyte chemoattractant protein-1, production of superoxide anion, and NADPH oxidase activity in the injured artery were attenuated in female compared with male mice. These parameters were augmented in Agtr2- mice, whereas the sex differences in these parameters were smaller in Agtr2- than in Agtr2+ mice. Treatment with a nonhypotensive dose of the AT1 receptor blocker valsartan decreased these parameters significantly in Agtr2+ mice, and these inhibitory effects of valsartan were greater in female mice. This sex difference in valsartan's inhibitory effect was less marked in Agtr2- mice. Our results suggest that the sex difference in response to vascular injury could be at least partially attributed to the exaggerated AT2 receptor expression in the injured vessel in female mice.

Local Renal Aldosterone System and Its Regulation by Salt, Diabetes, and Angiotensin II Type 1 Receptor

CYP11B2 is the enzyme responsible for aldosterone synthesis mainly in the adrenal gland. In this study, we hypothesized that CYP11B2 gene, protein, and aldosterone are produced locally in kidney and regulated by low salt intake, angiotensin II type 1 (AT1) receptor and insulin-deficient diabetes hyperglycemia. We used real-time RT-PCR, immunohistochemistry staining, and microdialysis techniques to monitor changes in renal CYP11B2 mRNA and protein and aldosterone production in normal, adrenalectomized, or streptozotocin-induced insulin-deficient diabetic hyperglycemic rats. In normal kidney, CYP11B2 mRNA and protein were localized mainly in the renal cortex and upregulated by angiotensin II and low salt intake. The angiotensin II effect was reversed by AT1 receptor blocker valsartan. Immunohistochemistry staining demonstrated presence of CYP11B2 in glomeruli. Although aldosterone was absent in plasma of adrenalectomized rats, it was present in renal interstitium and tissue. Diabetes increased renal cortical and total kidney CYP11B2 mRNA and protein. Lowering blood glucose with insulin decreased total renal CYP11B2 mRNA and protein. Despite lack of significant changes in blood glucose, valsartan treatment caused significant reduction in renal CYP11B2 mRNA and protein. In presence of diabetes, there was an increase in CYP11B2 immunostaining in glomeruli and proximal tubules. This expression was abrogated with insulin or valsartan treatment. These results demonstrate the presence of all components of local renal aldosterone system. This system is physiologically active because it is regulated by angiotensin II and low salt intake. In insulin-deficient diabetes hyperglycemia rat model, glucose, insulin, and AT1 receptor modulate CYP11B2 expression in the kidney.

Cardiovascular and Renal Regulation by the Angiotensin Type 2 Receptor

The renin-angiotensin system is a coordinated hormonal cascade of major importance in cardiovascular and renal regulation. The principle effector of this system is the octapeptide angiotensin II (Ang II), which acts at 2 cell membrane receptors, AT1 and AT2. The majority of the actions of Ang II have been demonstrated to be mediated by the AT1 receptor, including growth promotion, vasoconstriction, antinatriuresis, aldosterone secretion, salt appetite, thirst, sympathetic outflow and inhibition of renin biosynthesis, and secretion.1 The AT2 receptor has been less well understood. Past studies, however, clearly demonstrated that the AT2 receptor mediates cellular differentiation and growth, opposing the actions of Ang II through the AT1 receptor.2 Studies in the mid to late 1990s demonstrated that AT2 receptor stimulation engenders an autacoid vasodilator cascade composed of bradykinin (BK), nitric oxide (NO), and guanosine cyclic 3′, 5′-monophosphate (cGMP).3–5 This discovery turned attention to the possibility that the AT2 receptor may mediate vasodilation, opposing the vasoconstrictor actions of Ang II at the AT1 receptor.6 Parallel cell signaling studies indicated that the AT2 receptor is G-protein–coupled (through Giα) and that receptor stimulation is accompanied by an increase in phosphotyrosine phosphatase activity and an inhibition of MAP kinase enzymes (p42 and p44) composing the extracellular signal-related kinase (ERK1/2). AT2 receptor-mediated inhibition of the extracellular signal-regulated kinase pathway opposed the actions of Ang II, resulting in extracellular signal-regulated kinase phosphorylation via the AT1 receptor.1,2,6,7 Work during the late 1990s through 2002 suggested that the AT2 receptor might serve as a vasodilator counterforce to the AT1 receptor.2,6,7 However, vasorelaxation was difficult to elicit in some experimental models, attributed to the relatively low level of AT2 receptor vascular expression compared with that of the …

Aliskiren, a novel, orally effective renin inhibitor, lowers blood pressure in marmosets and spontaneously hypertensive rats

Aliskiren is a new renin inhibitor of a novel structural class that has recently been shown to be efficacious in hypertensive patients after once-daily oral dosing. We report the results of animal experiments performed in marmosets and rats in order to characterize aliskiren before its recent investigation in humans. The effects of aliskiren were investigated in sodium-depleted marmosets (oral dosing) and in spontaneously hypertensive rats (dosing via subcutaneous osmotic minipumps). Blood pressure (BP) and heart rate were measured by radiotelemetry. In sodium-depleted marmosets, single oral doses of aliskiren (1-30 mg/kg) dose-dependently lowered BP. At a dose of 3 mg/kg, peak effects were observed 1 h after dosing (-30 +/- 4 mmHg, n = 6) and the response persisted for more than 12 h. A single oral dose of 3 mg/kg aliskiren was more effective than the same dose of either remikiren or zankiren, two orally active renin inhibitors previously tested in humans. Aliskiren (10 mg/kg) was at least as effective as equal doses of the AT1-receptor blocker valsartan or the angiotensin-converting enzyme inhibitor benazepril. In spontaneously hypertensive rats, aliskiren dose-dependently (10-100 mg/kg per day) decreased BP. Aliskiren also potentiated the antihypertensive effects of low doses of valsartan or benazeprilat (1 or 3 mg/kg per day). Aliskiren is an orally effective, long-lasting renin inhibitor that shows antihypertensive efficacy in animals superior to previous renin inhibitors and at least equivalent to angiotensin-converting enzyme inhibitors and AT1-receptor blockers. Aliskiren may therefore represent an effective, novel approach to the treatment of hypertension and related disorders, alone or in combination with other antihypertensive agents.

Angiotensin Subtype-2 Receptors Inhibit Renin Biosynthesis and Angiotensin II Formation

Renin is regulated by angiotensin subtype 1 (AT1) receptor, but it is unknown whether angiotensin subtype 2 (AT2) receptor contributes to this regulation. We hypothesized that AT2 receptors inhibit angiotensin II (Ang II) through inhibition of renin biosynthesis. We monitored changes in renal Ang II, renin mRNA and protein expression, and plasma renin concentration (PRC) in response to renal cortical administration of the AT1 receptor blocker valsartan or the AT2 receptor blocker PD 123319 (PD) in conscious rats administered low sodium intake (LS). Renal interstitial Ang II increased by 47-fold in response to LS and increased further in response to valsartan or PD by 67-fold and 61-fold from normal sodium diet (NS) and by 41% and 29% from LS, respectively. Renin mRNA increased 63% during LS, and either valsartan or PD increased it further by 600% and 250% from NS and 538% and 187% from LS, respectively. Similarly, renal renin content and PRC increased in response to LS and increased further in response to combined LS and valsartan or PD administration. Immunostaining for renal renin protein demonstrated an increase in its expression in juxtaglomular and tubular cells during LS and increased further during AT1 or AT2 receptor blockade. These data demonstrate for the first time to our knowledge that AT2 receptors regulate the renin-angiotensin system activity via inhibition of renin synthesis.

Direct comparison of the effects of valsartan and amlodipine on renal hemodynamics in human essential hypertension

Background To elucidate the renoprotective mechanism of AT 1-receptor blockers, we compared the effects of the AT 1-receptor blocker valsartan with those of the calcium channel blocker amlodipine on renal hemodynamics and microcirculation. Methods A total of 58 patients (50.2 ± 9.0 years) with mild to moderate essential hypertension were included in a randomized, double-blind study to receive either valsartan (80 to 160 mg) or amlodipine (5 to 10 mg). Renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured before and after 8 weeks of treatment. Glomerular hydrostatic pressure (P Glo) and resistances of the afferent (R A) and efferent (R E) arterioles were calculated according to the Gomez formulas. Results Blood pressure control was similar in both groups. RPF did not change with either treatment. In contrast, GFR increased with amlodipine (+8 ± 14 mL/min; P < .01) but was preserved with valsartan. Amlodipine caused a more marked increase in the R E/R A ratio than valsartan (+0.26 ± 0.26 v +0.13 ± 0.24, P < .05), which was paralleled by an increase in P Glo in patients treated with amlodipine (+1.9 ± 4.3 mm Hg; P < .05) but not in those treated with valsartan. Conclusions At similar blood pressure control, valsartan maintained GFR and P Glo, whereas amlodipine led to glomerular hyperfiltration and an increase in P Glo. The results might explain the favorable renal outcome with AT 1-receptor blocker therapy.

Role of AT2 receptor in the brain in regulation of blood pressure and water intake.

The effects of intracerebroventricular (ICV) injection of angiotensin II (ANG II) on blood pressure and water intake were examined with the use of ANG II receptor-deficient mice. ICV injection of ANG II increased systolic blood pressure in a dose-dependent manner in wild-type (WT) mice and ANG type 2 AT(2) receptor null (knockout) (AT(2)KO) mice; however, this increase was significantly greater in AT(2)KO mice than in WT mice. The pressor response to a central injection of ANG II in WT mice was inhibited by ICV preinjection of the selective AT(1) receptor blocker valsartan but exaggerated by the AT(2) receptor blocker PD-123319. ICV injection of ANG II also increased water intake. It was partly but significantly suppressed both in AT(2)KO and AT(1)aKO mice. Water intake in AT(2)/AT(1)aKO mice did not respond to ICV injection of ANG II. Both valsartan and PD-123319 partly inhibited water intake in WT mice. These results indicate an antagonistic action between central AT(1)a and AT(2) receptors in the regulation of blood pressure, but they act synergistically in the regulation of water intake induced by ANG II.

Predictors of one year blood pressure control and treatment resistance in the value trial

The Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) Trial is testing the hypothesis that for the same level of BP control, the AT1-receptor blocker valsartan reduces serious cardiac events by 15% compared to the CCB amlodipine. VALUE is a double-blind, randomized, in 31 countries, prospective trial of 15314 previously treated (92%) or untreated hypertensives, 42.4% women, mean age 67.2 yrs, BMI 28.6 kg/m2, coronary heart disease (CHD) in 45.8%, high cholesterol in 32.9%, type-2 diabetes mellitus (DM) in 31.7% and 24.0% smokers. The primary endpoint is expected in 1450 pts. in 2-3 yrs. The aim of this analysis is to identify predictors of 1-year BP control and resistance to treatment in the VALUE population. BP decreased from 154.7/87.6 at randomization to 141.3/80.9 mmHg at 12 months and control rate <140/90 mmHg improved from 21.4 to 54.6%. Responsive (n=4328) achieved goal BP on monotherapy and resistant (n=1091) remained >160 and/or >100 mmHg at the highest drug titration step (step 5). Characteristics are shown in the accompanying table. The odds of being controlled were up 23% in pts. with controlled SBP at baseline, decreased by 3% per mmHg rise in baseline pulse pressure (PP) and 2% per year of age, were 23% less in DM, 25% higher in USA, 85% higher in Asians, 25% higher in CHD and 34% higher in smokers. In the “best” model, pts. not in USA (RR 1.58, p<0.0001), Oriental (RR 0.49, p<0.0004) and PP (3% per mmHg rise, RR 1.03, p<0.0001) predicted resistance. Thus, overall the 1-year blood pressure control in VALUE is comparable to the best previously reported in large hypertension outcome trials. Geographical origin and pulse pressure at baseline most strongly predicted resistance to drug therapy.

Effect of valsartan and captopril in rabbit carotid injury. Possible involvement of bradykinin in the antiproliferative action of the renin-angiotensin blockade.

The effects of the specific angiotensin II (Ang II) AT1-receptor blocker valsartan on events related to restenosis were investigated in rabbits after common carotid balloon injury. Six animals were given valsartan from two days prior to injury until 14 days post-injury. Three control groups (n=6 in each group) were either sham-operated, untreated or treated with the angiotensin-converting enzyme (ACE) inhibitor,captopril. Both ACE inhibition and AT,-receptor blockade had marked effects on plasma levels of endothelin ET1, thromboxane TXB2 and 6-keto-PGF1-alpha. The most dramatic effects on ET, levels were seen in rabbits treated with valsartan, where levels were reduced to values close to those for sham-operated animals (96.85 vs. 86.45 pg/ml). Captopril treatment led to a statistically significant (p<0.01) reduction in ET1 levels compared with untreated animals, but the reduction was only about half that seen with AT1-receptor blockade. TXB2 levels doubled (202.58 vs.413.28 pg/ml) upon arterial injury in control animals but rose by only 20-35% in rabbits treated with captopril (246.45 pg/ml) or valsartan (268.13). In untreated animals, 6-keto-PGF1-alpha levels decreased slightly after injury, but for both the captopril and valsartan groups, there were significant increases in levels of this prostaglandin derivative, effects attributed to the action of bradykinins. Levels were highest in the captopril-treated animals. Valsartan and captopril treatment led to a significant reduction in neointimal thickness and the extent of lumen stenosis compared with untreated animals. Both treatments were effective in reducing neointimal area and significantly (p<0.05)reduced cell proliferation. The differences between treatments can be attributed to the different actions of the agents, as valsartan leaves the AT2-receptor unblocked, while captopril, through inhibition of Ang II synthesis, prevents stimulation of both receptors.A combination of both treatments may be a possible way forward in the clinical prevention of restenosis.

Cardiac Protective Effect of Aldosterone Blockade Is Mediated Through Ap-1 and Nf-κB Suppression in Angiotensin Ii-Induced Cardiac Damage

77 Aldosterone is a multifunctional mineralocorticoid affecting homeostasis of water and electrolytes, sympathetic activity, and tissue fibrosis. Aldosterone synthesis is induced by activation of the renin-angiotensin system. We tested whether or not the inhibition of aldosterone signaling can prevent fibrotic tissue remodeling in vivo. In a transgenic rat model overexpressing the human renin and angiotensinogen gens (dTGR), we investigated the effect of spironolactone (SPIRO 20 mg/kg/d) and the AT1 receptor blocker valsartan (VAL; 10 mg/kg/d) on growth factors and transcription factors leading chronic inflammation and tissue fibrosis. Untreated dTGR develop severe hypertension, cardiac hypertrophy, vasculopathy, and perivascular fibrosis. The hearts also show chronic inflammation and the animals have a 50% mortality at 7 weeks. VAL completely reversed these pathological features. SPIRO and VAL both prevented mortality, while only VAL normalized systolic blood pressure (VAL 121±9, SPIRO 161±11, dTGR 182±8, SD 109±2 mm Hg). Both reduced cardiac hypertrophy (SPIRO 4.2±0.1, VAL 3.6±0.1, dTGR 5.7±0.2, SD 3.6±0.1 mg/g) and reduced vasculopathy. Quantitative bFGF RT-PCR showed a complete mRNA reduction in the left ventricle in both treatment groups (SPIRO 11±4, VAL 5±1 dTGR 43±4, SD 4±1 arbitrary units). In contrast, RT-PCR of TGF beta and PDGF showed no upregulation in dTGR compared to non-transgenic hearts. Gel shift assay of the heart demonstrated a suppression of AP-1 and NF-κB DNA binding activity after SPIRO and VAL treatment. Immunohistology revealed reduced bFGF expression and less collagen I, fibronectin, and laminin in the interstitium of SPIRO and VAL-treated rats. These findings show that aldosterone promotes hypertrophy, cardiac remodeling, and fibrosis. In dTGR hearts this effect is at least partly mediated through the transcription factors AP-1 and NF-κB as well as bFGF. Blocking the aldosterone receptor downregulates these effector molecules and reduces angiotensin II-induced cardiac damage.