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Introduction: Angiotensin (Ang) A was first identified in human plasma and it differs from Ang II in Ala(1) instead of Asp(1). Here, we hypothesized that the actions of this peptide might explain, at least partially, the limited effects of AT1R antagonists in certain cardiovascular diseases., Materials and Methods: The effects of Ang A and Ang II on blood pressure (BP) and heart function were compared. Importantly, participation of AT1R in these effects was evaluated. Furthermore, the effects of these two peptides on ischemia/reperfusion arrhythmias and involvement of calcium in these effects were investigated., Results: Administration of increasing doses of these peptides caused elevations in BP at comparable magnitude. AT1R blockade completely abolished these effects. The actions of these peptides in cardiac function were quite similar although the effects of Ang A were only partially blocked by losartan. Interestingly, Ang II elicited an increase in the duration of ischemia/reperfusion arrhythmias while Ang A had no effect on cardiac rhythm during reperfusion. In accordance, differently to Ang II, Ang A did not induce any significant effect on calcium transient during baseline and ischemic stress conditions., Conclusions: These data suggest that the existence of alternative peptides of the renin-angiotensin system (RAS) might contribute to the limited effects of angiotensin receptor blockers (ARBs) in certain pathophysiological circumstances., (© The Author(s) 2013.)

Growing evidence has highlighted that angiotensin-converting enzyme (ACE)-inhibitors (ACEi)/AT1 receptor blockers (ARBs) may influence the complex interplay between dopamine and the renin-angiotensin system in the nigrostriatal pathway, thus affecting the development of levodopa-induced dyskinesia in Parkinson's disease (PD). In the present study, we analyzed whether the use of this class of medication was associated with a reduced occurrence of levodopa-induced dyskinesia, using electronically-stored information of idiopathic PD patients enrolled at Novara University Hospital “Maggiore della Carità". We conducted a retrospective case-control study identifying PD patients with dyskinesias (PwD; n = 47) as cases. For each PwD we selected a non-dyskinetic control (NoD), nearly perfectly matched according to sex, Unified Parkinson's Disease Rating Scale (UPDRS) part III score, and duration of antiparkinsonian treatment. Binary logistic regression was used to evaluate whether dyskinesias were associated with ACEi/ARBs use. Ninety-four PD patients were included, aged 72.18 ± 9 years, with an average disease duration of 10.20 ± 4.8 years and 9.04 ± 4.9 years of antiparkinsonian treatment. The mean UPDRS part III score was 18.87 ± 7.6 and the median HY stage was 2. In the NoD group, 25 (53.2%) were users and 22 (46.8%) non-users of ACEi/ARBs. Conversely, in the PwD group, 11 (23.4%) were users and 36 non-users (76.6%) of this drug class (Pearson chi-square = 8.824, P = 0.003). Concerning general medication, there were no other statistically significant differences between groups. After controlling for tremor dominant phenotype, levodopa equivalent daily dose, HY 3-4, and disease duration, ACEi/ARBs use was a significant predictor of a lower occurrence of dyskinesia (OR = 0.226, 95% CI: 0.080-0.636, P = 0.005). Therefore, our study suggests that ACEi/ARBs may reduce levodopa-induced dyskinesia occurrence and, thanks to good tolerability and easy management, represent a feasible choice when dealing with the treatment of hypertension in PD patients. The study was approved by the Ethics Committee of Novara University Hospital “Maggiore della Carità” (CE 65/16) on July 27, 2016.

Background. The mechanisms of uraemia-induced atherosclerosis have not been fully delineated. The aims of this study were (i) to investigate the extent and the phenotype of atherosclerosis, including the activation of local renin–angiotensin system (RAS), in a mouse model of mild uraemia and (ii) to determine the effects of angiotensin II type1 (AT1) receptor blockade on the uraemic atherosclerosis, clarifying the mechanisms of its action.Methods. Mild uraemia was induced by 5/6 nephrectomy in 8-week-old apo E-deficient mice (apoE-KO). After nephrectomy, the animals received either treatment with candesartan or no treatment for 12-weeks. Sham-operated apoE-KO mice were used as controls.Results. Uraemia led to a two-fold increase in aortic plaque area. This was associated with a significant upregulation of aortic angiotensin-converting enzyme (ACE), AT1 receptor, connective tissue growth factor (CTGF), monocyte chemoattractant protein (MCP)-1 and vascular cell adhesion molecule (VCAM)-1. Candesartan significantly reduced aortic atherosclerosis, prevented the upregulation of the uraemia-induced genes and led to changes predicting greater stability of the plaques, without influencing blood pressure or serum lipids.Conclusions. This study indicates that uraemia leads to an acceleration of aortic atherosclerosis. The upregulation of aortic RAS and the reduced atherosclerosis following AT1 receptor blocker treatment highlights the pivotal role of the local RAS in the development and acceleration of atherosclerosis in uraemia. [ABSTRACT FROM AUTHOR]

The angiotensin II (type 1) (AT1) receptor mediates many biological effects of the renin–angiotensin system (RAS), leading to remodelling of cardiac tissue. The present study was designed to analyse changes in the function and expression of the AT1 receptor as principal effector of the RAS in myocardium from type 2 diabetic patients compared with non-diabetic myocardium as control. In addition, we determined the effect of treatment with ACE inhibitors or AT1 receptor blockers on expression levels of the receptor in diabetic patients. Gene expression of the AT1 receptor was analysed by quantitative RT-PCR and protein expression was determined by immunoblot analysis in human right atrial myocardium. We investigated functional coupling of the receptors by measuring contractility in isolated trabeculae stimulated with increasing concentrations of angiotensin II. Diabetic myocardium showed a significant increase in protein expression (170 ± 16% of control) and median mRNA expression (186% of control) of the AT1 receptor. The additional receptors were functionally coupled, resulting in a stronger inotropic response upon stimulation with angiotensin II (89 ± 5.5% vs 29 ± 1.6% in controls), whereas receptor affinity was similar in both groups. However, myocardium from diabetic patients treated with ACE inhibitors or AT1 receptor blockers showed no increase in AT1 receptor expression. AT1 receptor expression in myocardium of type 2 diabetic patients is dynamic, depending on the level of glycaemic control and the activity of the RAS. These findings could at least in part explain the strong therapeutic benefit of RAS inhibition in diabetic patients. [ABSTRACT FROM AUTHOR]

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