Tardive dyskinesia associated with metoclopramide.
These findings demonstrate for the first time the contribution of AT1 receptor in HHcy-induced atherosclerotic diseases; Hcy-induced activation of AT1 receptor involves MMP-9 and collagen type-1 modulation using ERK-1/2 and STAT3 signaling cascades.
Adding a statin to the ARB was of some help in improving vascular dysfunction more effectively than ARB monotherapy in nondiabetic PD patients. However, whether such limited improvements can lead to better clinical outcomes requires further investigation.
The aim of this study was to investigate the relative role of the angiotensin type 1 (AT1) and type 2 (AT2) receptors in mediating angiotensin II-induced regulation of AT2 receptor in mesenteric artery.
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.
AVANT GARDE-TIMI 43 trial, a multinational, double-blind trial, randomized 1101 patients stabilized after ACS without clinical evidence of heart failure or left ventricular function <or=40% but with an increased level of NP 3-10 days after admission to aliskiren, valsartan, their combination, and placebo. The primary endpoint was the change in NT-proBNP from baseline to Week 8. NT-proBNP declined significantly in each treatment arm, including placebo, by Week 8, though there were no differences in the reduction between treatment strategies (42% in placebo, 44% in aliskiren, 39% in valsartan, and 36% in combination arm). Although several subgroups had higher baseline levels of NP and greater reductions over the study period, there were no differences among treatment groups in any subgroup. There were no differences in clinical outcomes but there were more adverse events, including serious events and adverse events leading to early study drug discontinuation, in patients treated with active therapy.
1. Transient and sustained calcium-independent outward K(+) currents (I(t) and I(SS)) as well as action potentials were recorded in cardiac ventricular myocytes isolated from two models of diabetes mellitus. 2. Rats injected (I.V.) with streptozotocin (STZ, 100 mg kg(-1)) 6-10 days before cell isolation developed insulin-dependent (type 1) diabetes. I(t) and I(SS) were attenuated and the action potential prolonged. Incubation of myocytes (6-9 h) with the angiotensin II (ATII) receptor blockers saralasin or valsartan (1 microM) significantly augmented these currents. Inclusion of valsartan (1 g l(-1)) in the drinking water for 5-10 days prior to and following STZ injection partially prevented current attenuation. 3. Incubation of myocytes from STZ-treated rats (6-9 h) with 1 microM quinapril, an angiotensin-converting enzyme (ACE) inhibitor, significantly augmented I(t) and I(SS) and shortened the ventricular action potential. I(t) augmentation was not due to changes in steady-state inactivation or in recovery from inactivation. No acute effects of quinapril were observed. 4. The effects of quinapril and valsartan were abolished by 2 microM cycloheximide. 5. Myocytes were isolated from the db/db mouse, a leptin receptor mutant that develops symptoms of non-insulin-dependent (type 2) diabetes. K+ currents in these cells were also attenuated, and the action potentials prolonged. Incubation of these cells (> 6 h) with valsartan (1 microM) significantly enhanced the transient and sustained outward currents. 6. These results confirm recent suggestions that cardiac myocytes contain a renin-angiotensin system, which is activated in diabetes. It is proposed that chronic release of ATII leads to changes in ionic currents and action potentials, which can be reversed by blocking the formation or action of ATII. This may underlie the proven benefits of ATII receptor blockade or ACE inhibition in diabetes, by providing protection against cardiac arrhythmias.