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Background. The prevalence and severity of hypertension, as well as the activity of the systemic and local renin angiotensin systems (RASs), are gender related, with more symptoms in males than in females. However, the underlying mechanisms are not well understood. In this study, we investigated sex differences in renal vascular responses to angiotensin II (Ang II) administration with and without Ang II type 1 and Mas receptor (AT1R and MasR) antagonists (losartan and A779) in the 2K1C rat model of renovascular hypertension. Methods. Male and female 2K1C rats were divided into 8 experimental groups (4 of each sex) treated with vehicle, losartan, A779, or A779+losartan. Responses of mean arterial pressure (MAP), renal blood flow (RBF), and renal vascular resistance (RVR) to Ang II were determined. Results. In both sexes, the basal MAP, RBF, and RVR were not significantly different between the four groups during the control period. The Ang II administration decreased RBF and increased RVR in a dose-related manner in both sexes pretreated with vehicle or A779 ( P dose < 0.0001 ), but in vehicle pretreated groups, RBF and RVR responses were different between male and female rats ( P group < 0.05 ). AT1R blockade increased RBF and decreased RVR responses to Ang II, and no difference between the sexes was detected. Coblockades of AT1R and MasR receptors increased RBF response to Ang II significantly in males alone but not in females ( P group = 0.04 ). Conclusion. The impact of Ang II on RBF and RVR responses seems to be gender related with a greater effect on males, and this sex difference abolishes by Mas receptor blockade. However, the paradoxical role of dual losartan and A779 may provide the different receptor interaction in RAS between male and female rats.

Introduction. The roles of genes in the renin-angiotensin-aldosterone system (RAAS) in hypertension, including angiotensin-converting enzyme (ACE), angiotensinogen (AGT), angiotensin II receptor type 1 (AGTR1), and aldosterone synthase (CYP11B2), have been widely studied across different ethnicities, but there has been no such investigation in Thai population.Materials and Methods. Using 4,150 Thais recorded in the Electricity Generating Authority of Thailand (EGAT) study, we examined the association of rs1799752, rs699, rs5186, and rs1799998 located in or nearACE,AGT,AGTR1, andCYP11B2genes in hypertension. We investigated their roles in hypertension using multivariate logistic regression and further examined their roles in blood pressure (BP) using quantile regression. Sex, age, and BMI were adjusted as potential confounders.Results. We did not observe associations between hypertension and rs1799752 (P=0.422), rs699 (P=0.36), rs5186 (P=0.49), and rs1799998 (P=0.71). No evidence of association between these SNPs and BP was found across an entire distribution. A nonlinear relationship between age and BP was observed.Conclusion. In Thai population, our study showed no evidence of association between RAAS-related genes and hypertension. While our study is the first and largest study to investigate the role of RAAS-related genes in hypertension in Thai population, restricted statistical power due to limited sample size is a limitation.

Aminopeptidase A (APA) cleaves angiotensin (Ang) II, kallidin, and other related peptides. In the brain, it activates the renin angiotensin system and causes hypertension. Limited data are available on the dipsogenic effect of APA and pressor effect of degraded peptides of APA such as bradykinin. Wistar-Kyoto rats received intracerebroventricular (icv) APA in a conscious, unrestrained state after pretreatment with (i) vehicle, (ii) 80 μg of telmisartan, an Ang II type-1 (AT1) receptor blocker, (iii) 800 nmol of amastatin, an aminopeptidase inhibitor, and (iv) 1 nmol of HOE-140, a bradykinin B2 receptor blocker. Icv administration of 400 and 800 ng of APA increased blood pressure by 12.6 ± 3.0 and 19.0 ± 3.1 mmHg, respectively. APA did not evoke drinking behavior. Pressor response to APA was attenuated on pretreatment with telmisartan (vehicle: 22.1 ± 2.2 mmHg versus telmisartan: 10.4 ± 3.2 mmHg). Pressor response to APA was also attenuated with amastatin and HOE-140 (vehicle: 26.5 ± 1.1 mmHg, amastatin: 14.4 ± 4.2 mmHg, HOE-140: 16.4 ± 2.2 mmHg). In conclusion, APA increase in the brain evokes a pressor response via enzymatic activity without dipsogenic effect. AT1 receptors and B2 receptors in the brain may contribute to the APA-induced pressor response.

The human renin gene has been widely known to be involved in essential hypertension (EH) pathogenesis. Genetic variant C-5434T ofRENenhancer contributed to renin gene transcription and serum renin regulation. However, the mechanism associated with the transcription level changes remains unknown, and only a few reports exist that discussed serum renin levels on C-5434T ofREN. Thus, this study aims to investigate the relationship between genetic variant C-5434T ofRENenhancer and serum renin levels in Indonesian hypertensive patients. SNP of C-5434T was genotyped in 56 hypertensive patients by using RFLP. The data showed that serum renin is slightly higher in hypertensive patients with the TT genotype (39 ± 10.3) than patients with the CC genotype (33 ± 10.6) but the difference was not statistically significant (p=0.35). Here, we also present a docking approach for predicting interaction between genetic variant -5434C/T and STAT3 (Signal Transducers and Activators Transcription 3), the predicted transcription factor that regulates renin gene enhancer. The results showed that STAT3-DNA allele T more favorably binds to DNA than STAT3-DNA allele C. These data suggest that the presence of genetic variant C-5434T has changed the binding pattern of STAT3 toRENenhancer. This is likely to influence STAT3 activity to stimulate the expression of renin gene in producing renin.

Mitochondrial dysfunction is implicated in many cardiovascular diseases, including hypertension, and may be associated with an overactive renin-angiotensin system (RAS). Angiotensin (Ang) II, a potent vasoconstrictor hormone of the RAS, also impairs baroreflex and mitochondrial function. Most deleterious cardiovascular actions of Ang II are thought to be mediated by NADPH-oxidase- (NOX-) derived reactive oxygen species (ROS) that may also stimulate mitochondrial oxidant release and alter redox-sensitive signaling pathways in the brain. Within the RAS, the actions of Ang II are counterbalanced by Ang-(1–7), a vasodilatory peptide known to mitigate against increased oxidant stress. A balance between Ang II and Ang-(1–7) within the brain dorsal medulla contributes to maintenance of normal blood pressure and proper functioning of the arterial baroreceptor reflex for control of heart rate. We propose that Ang-(1–7) may negatively regulate the redox signaling pathways activated by Ang II to maintain normal blood pressure, baroreflex, and mitochondrial function through attenuating ROS (NOX-generated and/or mitochondrial).

Renin-angiotensin system (RAS) is activated in metabolic syndrome (MetS), and RAS inhibitors are preferred for the treatments of hypertension with MetS. Although RAS activation is important for the therapeutic target, underlying sympathetic nervous system (SNS) activation is critically involved and should not be neglected in the pathogenesis of hypertension with MetS. In fact, previous studies have suggested that SNS activation has the interaction with RAS activation and/or insulin resistance. As a novel aspect connecting the importance of SNS and RAS activation, we and other investigators have recently demonstrated that angiotensin II type 1 receptor (AT1R) blockers (ARBs) improve SNS activation in patients with MetS. In the animal studies, SNS activation is regulated by the AT1R-induced oxidative stress in the brain. We have also demonstrated that orally administered ARBs cause sympathoinhibition independent of the depressor effects in dietary-induced hypertensive rats. Interestingly, these benefits on SNS activation of ARBs in clinical and animal studies are not class effects of ARBs. In conclusion, SNS activation associated with RAS activation in the brain should be the target of the treatment, and ARBs could have the potential benefit on SNS activation in patients with MetS.

Many Studies suggest that changes in sympathetic nerve activity in the central nervous system might have a crucial role in blood pressure control. The present paper discusses evidence in support of the concept that the brain renin-angiotensin system (RAS) might be linked to sympathetic nerve activity in hypertension. The amount of neurotransmitter release from sympathetic nerve endings can be regulated by presynaptic receptors located on nerve terminals. It has been proposed that alterations in sympathetic nervous activity in the central nervous system of hypertension might be partially due to abnormalities in presynaptic modulation of neurotransmitter release. Recent evidence indicates that all components of the RAS have been identified in the brain. It has been proposed that the brain RAS may actively participate in the modulation of neurotransmitter release and influence the central sympathetic outflow to the periphery. This paper summarizes the results of studies to evaluate the possible relationship between the brain RAS and sympathetic neurotransmitter release in the central nervous system of hypertension.

Cardiovascular disease is America's leading health problem and the leading cause of death. One person in three suffers from some form of cardiovascular disease. There is an urgent need to develop new therapeutic strategies to improve the cardiovascular diseases outcome [1]. Very recent studies have demonstrated that the heptapeptide angiotensin (Ang)-(1-7) holds important cardiovascular beneficial effects [2]. These actions are generally mediated by activation of the G protein-coupled receptor Mas [3]. As a result of these novel findings, Ang-(1-7), in combination with Mas and angiotensin-converting enzyme (ACE) 2 [4, 5], the main enzyme involved in its formation, is thought to compose a cardioprotective branch within the renin-angiotensin system (RAS), which balances the ACE/Ang II/AT1 receptor axis effects [6]. Consequently, new therapeutic approaches targeting the ACE2/Ang-(1-7)/Mas axis have been proposed. In view of these new and exciting findings, we proposed a special issue in the International Journal of Hypertension. Our main objective was to compile original research articles as well as review articles from outstanding investigators around the World contributing to the continued efforts to understand the role of this axis in the cardiovascular system. Particularly, our intention was to give some insights into the advances in therapeutic approaches based on the ACE2/Ang-(1-7)/Mas axis to treat cardiovascular diseases. This special issue is composed of 15 papers (original articles and reviews). Importantly, part of them was presented in the VIII Vasoactive Peptides Symposium which was held in Brazil in April, 2011. This meeting was a unique opportunity for clinicians and researchers to exchange their experience within the cardiovascular field focusing on the RAS. The paper provided by N. E. Clarke and J. Turner is an overview of the biological roles of ACE2. They focused on the entrance of recombinant human ACE2 (rhACE2) into clinical trials discussing the potential use of this enzyme as a therapeutic strategy. A. J. Ferreira et al. expand this view to the whole ACE2/Ang-(1-7)/Mas axis highlighting the initiatives to develop potential therapeutic approaches based on this axis. Other three papers are original articles evaluating examples of these strategies. M. Durik et al. investigated the effects of a stabilized, thioether-bridged analogue of Ang-(1-7) called cyclic Ang-(1-7) [cAng-(1-7)] in rat model of myocardial infarction (MI). They found that MI increased the heart weight and myocyte size which was restored by cAng-(1-7) to sham levels. In addition, cAng-(1-7) lowered left ventricular end-diastolic pressure and improved endothelial function. The second strategy discussed in this special issue was the Ang-(1-7) included in hydroxypropyl β-cyclodextrin (HPβCD). F. D. Marques et al. evaluated the chronic cardiac effects of this compound in infarcted rats. Once-a-day oral HPβCD/Ang-(1-7) administration improved the cardiac function and reduced the deleterious effects induced by MI on TGF-β and collagen type I expression. Finally, the antiproliferative effects of the nonpeptide AVE 0991, an agonist of Mas, were investigated by C. Sheng-Long et al. It was observed that AVE 0991 attenuates the Ang II-induced vascular smooth muscle cells proliferation in a dose-dependent fashion and that this effect is associated with the Mas/heme oxygenase-1/p38 MAPK signaling pathway. In this special issue, the role of the ACE2/Ang-(1-7)/Mas axis in the cardiovascular function was extensively discussed in review articles and new findings regarding this axis were presented. E. R. M. Gomes et al. revised the actual knowledge about Ang-(1-7)-mediated signaling in cardiac cells, as well as the discoveries made in cardiomyocyte physiology through the use of genetic approaches. Interestingly, M. Poglitsch et al. reported significant differences in the conversion rates of recombinant human and recombinant murine ACE2 (rhACE2 and rmACE2, resp.) for diverse natural peptide substrates in plasma samples. They found species-specific differences in substrate specificities, probably leading to functional differences in the alternative axis of the RAS. Specially, in contrast to rhACE2, rmACE2 is substantially less potent in transforming Ang-(1-10) to Ang-(1-9). Of note, this enzymatic pathway was reviewed by M. P. Ocaranza and J. E. Jalil. They presented current experimental evidence suggesting that activation of the ACE2/Ang-(1-9) pathway might protect the heart and vessels from adverse cardiovascular remodeling in hypertension and in heart failure. In addition to the cardiovascular system, some insights were given in the renal system in this special issue. S. V. B. Pinheiro and A. C. Simoes e Silva highlighted the current understanding of the ACE2/Ang-(1-7)/Mas axis in renal physiology and in the pathogenesis of primary hypertension and chronic kidney disease. Also, L. C. Barroso et al. presented some data demonstrating the renal effects of acute administration of AVE 0991 in a murine model of renal ischemia/reperfusion. Administration of AVE 0991 promoted renoprotective effects evidenced by improvement of renal function, decreased tissue injury, prevention of local and remote leukocyte infiltration, and release of the chemokine CXCL1. In the past few years, the understanding of the RAS has improved significantly. This is not only a consequence of the identification of novel members, but also due to advances in the knowledge concerning the role of these components in many tissues and cells [2, 6]. Here, M. A. F. Godoy et al. provided an overview of the functional role and the molecular pathways involved in the biosynthesis and activity of Ang-(1-7) in diverse systems, including its actions in gastrointestinal smooth muscles. Also, S. E. Thatcher et al. evaluated the effects of ACE2 deficiency in bone marrow-derived stem cells on adipose inflammation and glucose tolerance in mice fed a high-fat diet. They concluded that ACE2 deficiency in these cells promotes inflammation in adipose tissue and augments obesity-induced glucose intolerance. Interestingly, J. W. Prokop et al. demonstrated that many different genes participating in the RAS can be affected by testis determining protein (SRY), apparently in coordinated fashion, to produce more Ang II and less Ang-(1-7). In certain circumstances and in some tissues, AT2 receptors appear to be involved in the Ang-(1-7) effects [7]. Furthermore, physical interaction between Mas and AT2 in selected tissues such as heart has been suggested as a putative mechanism for Ang-(1-7) actions [8]. In this special issue, R. E. Widdop's group presents an original article demonstrating the relationship between Ang-(1-7) and AT2 receptors. S. Bosnyak et al. reported that the hypotensive effect of Ang-(1-7) was dependent on the background dose of candesartan and that this effect was reversed by AT2 receptor blockade. In aged rats, the depressor effect of Ang-(1-7) was evident but was inhibited by either AT2 or Mas receptors blockade. Furthermore, E. S. Jones et al. reported that AT2 receptor stimulation does not significantly influence the antihypertensive effect of chronic AT1 receptor blockade but plays a role in the regulation of vascular structure, as well as in cardiac perivascular fibrosis. Thus, we hope that this special issue is able to make a picture of the role of the ACE2/Ang-(1-7)/Mas axis and of the potential therapeutic of this concept for treating cardiovascular and related diseases. Our expectation is that this special issue might serve as an important reference to scientists and physicians to update their knowledge about this contemporary theme. Anderson J. Ferreira Robson A. S. Santos Mohan K. Raizada

Angiotensin (1-7) (Ang (1-7)) causes vasodilator effects in Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs) via angiotensin type 2 receptors (AT2R). However, the role of vascular AT2R in aging is not known. Therefore, we examined the effect of aging on Ang (1-7)-mediated vasodepressor effects and vascular angiotensin receptor localization in aging. Blood pressure was measured in conscious adult (~17 weeks) and aged (~19 months) normotensive rats that received drug combinations in a randomised fashion over a 4-day protocol: (i) Ang (1-7) alone, (ii) AT1R antagonist, candesartan, alone, (iii) Ang (1-7) and candesartan, or (iv) Ang-(1-7), candesartan, and the AT2R antagonist, PD123319. In a separate group of animals, the specificMasR antagonist, A779, was administered in place of PD123319. Receptor localisation was also assessed in aortic sections from adult and aged WKY rats by immunofluorescence. Ang (1-7) reduced blood pressure (~15 mmHg) in adult normotensive rats although this effect was dependant on the background dose of candesartan. This depressor effect was reversed by AT2R blockade. In aged rats, the depressor effect of Ang (1-7) was evident but was now inhibited by either AT2R blockade orMasR blockade. At the same time, AT2R,MasR, and ACE2 immunoreactivity was markedly elevated in aortic sections from aged animals. These results indicate that the Ang (1-7)-mediated depressor effect was preserved in aged animals. Whereas Ang (1-7) effects were mediated exclusively via stimulation of AT2R in adult WKY, with aging the vasodepressor effect of Ang (1-7) involved both AT2R andMasR.