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The angiotensin II type 2 receptor (AT2R) has attracted much attention as a potential target for the relief of neuropathic pain, which represents an area of unmet clinical need. A series of 1,2,3,4-tetrahydroisoquinolines with a benzoxazole side-chain were discovered as potent AT2R antagonists. Rational optimization resulted in compound 15, which demonstrated both excellent antagonistic activity against AT2R in vitro and analgesic efficacy in a rat chronic constriction injury model. Its favorable physicochemical properties and oral bioavailability make it a promising therapeutic candidate for neuropathic pain.

Kidney infiltrating immune cells such as monocytes, neutrophils, and T cells play critical roles in renal ischemia-reperfusion (IR) injury and repair. Recently, the angiotensin II type 2 receptor (AT(2)R) has been implicated in protecting kidneys against injury and monocyte infiltration, particularly in chronic kidney disease. However, the role of AT(2)R in IR injury and repair phases and T cell modulation is unknown. To address this question, Sprague–Dawley rats were subjected to IR with or without AT(2)R agonist C21 treatment. IR caused early (2 h postreperfusion) renal functional injury (proteinuria, plasma urea, and creatinine) and enhanced immune cells (T cells and CD4 T cells) infiltration and levels of the proinflammatory cytokines monocyte chemoattractant protein-1, TNF-α, and IL-6. C21 treatment reversed these changes but increased the anti-inflammatory IL-10 level. On day 3, C21 treatment increased CD4(+)FoxP3(+) (regulatory T cells) and CD4(+)IL-10(+) cells and reduced kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin in the kidney compared with the IR control, suggesting the involvement of AT(2)R in kidney repair. These data indicate that AT(2)R activation protects the kidney against IR injury and immune cell infiltration in the early phase and modulates CD4 T cells toward the regulatory T cell phenotype, which may have long-term beneficial effects on kidney function. NEW & NOTEWORTHY The angiotensin II type 2 receptor agonist C21 has been known to have a renoprotective role in various kidney pathologies. C21 treatment (before renal ischemia) attenuated postischemic kidney injury, kidney dysfunction, and immune cell infiltration during the injury phase. Also, C21 treatment modulated the kidney microenvironment by enhancing anti-inflammatory responses mainly mediated by IL-10. During the repair phase, C21 treatment enhanced IL-10-secreting CD4 T cells and FoxP3-secreting regulatory T cells in Sprague–Dawley rats.

Background: COVID-19 morbidity and mortality remains high and the need for safe and effective drugs continues despite vaccines. Methods: Double-blind, placebo-controlled, multi-centre, randomised, parallel group phase 2 trial to evaluate safety and efficacy of oral angiotensin II type 2 receptor agonist C21 in hospitalized patients with COVID-19 and CRP ≥ 50-150 mg/L conducted at eight sites in India (NCT04452435). Patients were randomly assigned 100 mg C21 bid or placebo for 7 days in addition to standard of care. Primary endpoint: reduction in CRP. The study period was 21 July to 13 October 2020. Findings: 106 patients were randomised and included in the analysis (51 C21, 55 placebo). There was no significant group difference in reduction of CRP, 81% and 78% in the C21 and placebo groups, respectively, with a treatment effect ratio of 0.85 [90% CI 0.57, 1.26]. In a secondary analysis in patients requiring supplemental oxygen at randomisation, CRP was reduced in the C21 group compared to placebo. At the end of the 7-day treatment, 37 (72.5%) and 30 (54.5%) of the patients did not require supplemental oxygen in the C21 and placebo group, respectively (OR 2.20 [90% CI 1.12, 4.41]). A post hoc analysis showed that at day 14, the proportion of patients not requiring supplemental oxygen was 98% and 80% in the C21 group compared to placebo (OR 12.5 [90% CI 2.9, 126]). Fewer patients required mechanical ventilation (one C21 patient; four placebo patients), and C21 was associated with a numerical reduction in the mortality rate (one vs three in the C21 and placebo group, respectively). Treatment with C21 was safe and well tolerated. Interpretation: Among hospitalised patients with COVID-19 receiving C21 for 7 days there was no reduction in CRP compared to placebo. However, a post-hoc analysis indicated a marked reduction of requirement for oxygen at day 14. The day 14 results from this study justify further evaluation in a Phase 3 study and such a trial is currently underway. Funding: Vicore Pharma AB and LifeArc, UK.

Background The activation of AT2 (angiotensin II type 2 receptor ) and Mas receptor by angiotensin II and angiotensin‐(1‐7), respectively, is the primary process that counteracts activation of the canonical renin‐angiotensin system (RAS). Although inhibition of canonical RAS could delay the progression of physiological aging, we recently reported that deletion of Mas had no impact on the aging process in mice. Here, we used male mice with a deletion of only AT2 or a double deletion of AT2 and Mas to clarify whether these receptors contribute to the aging process in a complementary manner, primarily by focusing on aging‐related muscle weakness. Methods and Results Serial changes in grip strength of these mice up to 24 months of age showed that AT2/Mas knockout mice, but not AT2 knockout mice, had significantly weaker grip strength than wild‐type mice from the age of 18 months. AT2/Mas knockout mice exhibited larger sizes, but smaller numbers and increased frequency of central nucleation (a marker of aged muscle) of single skeletal muscle fibers than AT2 knockout mice. Canonical RAS‐associated genes, inflammation‐associated genes, and senescence‐associated genes were highly expressed in skeletal muscles of AT2/Mas knockout mice. Muscle angiotensin II content increased in AT2/Mas knockout mice. Conclusions Double deletion of AT2 and Mas in mice exaggerated aging‐associated muscle weakness, accompanied by signatures of activated RAS, inflammation, and aging in skeletal muscles. Because aging‐associated phenotypes were absent in single deletions of the receptors, AT2 and Mas could complement each other in preventing local activation of RAS during aging.

Neprilysin and coronavirus receptor angiotensin‐converting enzyme‐2 (ACE2) are peptidases critically involved in the breakdown of deleterious angiotensin‐II and the formation of protective angiotensin‐(1‐7). A disintegrin and metalloproteinase‐17 (ADAM17) is involved in the shedding of neprilysin and ACE2. We have reported the increase in renal angiotensin‐(1‐7) formation upon activation of angiotensin‐II type 2 receptor (AT2R). However, the modulation of expression and activity of these peptidases upon stimulation of AT2R in the kidney under the normal, obese, and high‐salt diet (HSD)‐fed condition is not known. Hence, we have treated, male, lean and obese Zucker rats (OZR) for 14 days without or with AT2R agonist C21 (1 mg/kg/day, via osmotic pumps) while fed HSD or normal diet. We have observed that the activity of neprilysin and ACE2 is decreased in the kidney of OZR fed either diet, however, only neprilysin activity has been found increased in the plasma (p

Background and Aims In clinical settings, diabetics remain on higher risk of ischemic renal injury (IRI) than nondiabetic patients. In addition, IRI predisposes distant organs to dysfunction such as neurological impairments via activation of the pressor arm of renin-angiotensin system (RAS). In contrast, the role of depressor arm of RAS on IRI-associated neurological sequalae remains elusive. Hence, this study explored the role of angiotensin II type 2 receptor (AT2R) and angiotensin-converting enzyme 2 (ACE2) in IRI-associated neurological dysfunctions under nondiabetic (ND) and diabetes mellitus (DM) condition. Method Type 1 diabetes was induced by injecting streptozotocin (55 mg/kg i.p.). ND and DM rats with bilateral IRI were treated with AT2R agonist-Compound 21 (C21) (0.3 mg/kg/day, i.p.) or ACE2 activator-Diminazene Aceturate (Dize), (5 mg/kg/day, p.o.) per se or in combination therapy. Behavioural, biochemical, and histopathological analysis were done to assess IRI-induced neurological impairment. Moreover, immunohistochemistry, ELISA and qRT-PCR experiments were conducted for molecular mechanism analysis. Result In ND and DM rats, IRI caused hippocampal complications as evidenced by increased MDA and nitrite levels, augmented inflammatory cytokines (granulocyte colony stimulating factor, glial fibrillary acidic protein), altered protein and mRNA expressions of Ang II, Ang-(1-7), AT1R, AT2R and MasR. In contrast, concomitant therapy of C21 and Dize effectively normalised aforementioned hippocampal alterations. The protective effect of combination therapy was exerted due to augmented protein and mRNA levels of depressor arm components. Conclusion The current study demonstrated the protective role of AT2R agonist and ACE2 activator in IRI-associated neurological dysfunction through preventing oxidative stress, inflammation and upregulating brain depressor arm of RAS under ND and DM conditions.

Background There are no reports about the association of angiotensin II type 2 receptor ( AT2R) gene polymorphisms and susceptibility to systemic lupus erythematosus (SLE) in children. Objective The objective of this research is to study AT2R gene polymorphisms in exon 3 (C1593A) and intron 1 (A1675G) in Egyptian children with SLE and its correlation with disease manifestations and serum angiotensin-converting enzyme (ACE) level. Methods Typing of AT2R gene polymorphisms was conducted in 123 children with SLE in comparison with 100 healthy controls using the restriction fragment length polymorphism method. Results Significant differences were found between SLE patients and controls for A-containing genotypes (CA + AA) and A-allele frequencies of AT2R in exon 3 (C1593A) ( p = 0.01, odds ratio (OR) = 2.5, 95% confidence interval (CI) = 1.3–5.05; p = 0.01, OR = 2.2, 95% CI = 1.2–4.1, respectively). G-containing genotypes (AG + GG) and G allele of AT2R in intron 1 (A1675G) were more frequent in SLE patients compared to controls ( p = 0.01, OR = 2.3, 95% CI = 1.2–4.5; p = 0.02, OR = 2.1, 95% CI = 1.2–3.7, respectively). Serum ACE level was significantly higher in SLE patients than in controls ( p < 0.001). There was no association between AT2R gene polymorphisms and ACE level in serum. Moreover, there was no association between AT2R gene polymorphisms and SLE clinical manifestations. Conclusion AT2R gene polymorphisms can be considered risk factors for SLE development in Egyptian children.

Our study aimed to determine the effects of losartan and PD123319 in ischemia–reperfusion (IR) injury in isolated perfused rat heart. The study used 40 male Wistar albino rats that were grouped as Control, IR, and IR treatment groups that received losartan (20 mg/kg), PD123319 (20 mg/kg), and losartan+PD123319. The hearts were attached to Langendorff isolated heart system by employing in situ cannulation method, and cardiodynamic parameters were recorded during the experiment. At the end of experiment, hearts were retained for biochemical analysis and all data were statistically evaluated. A partial recovery of cardiodynamic parameters was observed in all treatment groups. A significant increase in oxidative stress parameters were seen in the IR group, whereas all treatment groups exhibited lower increase. Furthermore, levels of all antioxidant parameters were significantly lower in the IR group, but higher in the treatment groups. Effects on all parameters were much more remarkable in the PD123319 group. Levels of angiotensin II and renin were increased (P < 0.001) with IR application and decreased (P < 0.001) with the treatment of both antagonists. In conclusion, treatment of losartan and PD123319 played a cardioprotective role against IR injury, PD123319 being more effective in this protection.

Obesity is the major risk factor for several cardiovascular and metabolic disorders. Previous studies reported that deletion of Angiotensin II type 2 receptor (AT2R) protects against metabolic dysfunctions induced by high fat (HF) diet. However, the role of AT2R in obesity-induced cardiac hypertrophy remains unclear. Male AT2R knockout (AT2RKO) and wild type (AT2RWT) mice were fed with control or HF diet for 10 weeks. HF diet increased cardiac expression of AT2R in obese mice. Deletion of AT2R did not affect body weight gain, glucose intolerance and fat mass gain induced by HF feeding. However, loss of AT2R prevented HF diet-induced hypercholesterolemia and cardiac remodeling. Mechanistically, we found that pharmacological inhibition or knockdown of AT2R prevented leptin-induced cardiomyocyte hypertrophy in vitro. Collectively, our results suggest that AT2R is involved in obesity-induced cardiac hypertrophy.

The angiotensin II type 2 receptor (AT2R) agonist, compound 21 (C21), has been shown to be neurovascularly protective after ischemic stroke in male rats. In the current study, we aim to study the impact of C21 treatment on female rats. Young female Wistar rats were subjected to different durations of middle cerebral artery occlusion (MCAO) (3 h, 2 h, and 1 h) using a silicone-coated monofilament, treated at reperfusion with 0.03 mg/kg ip of C21 and followed up for different times (1, 3, and 14 days) after stroke. Behavioral tests were performed (Bederson, paw grasp, beam walk, and rotarod), and animals were euthanized for infarct size analysis and Western blot analysis. In vitro, primary male and female brain microvascular endothelial cells (ECs) were grown in culture, and the expression of the AT2R was compared between males and females. At 1 day, C21 treatment resulted in an improvement in Bederson scores. However, at 3 days and 14 days, the impact of C21 on stroke outcomes was less robust. In vitro, the expression of the AT2R was significantly higher in female ECs compared with male ECs. In conclusion, C21 improves Bederson scores after stroke in female rats when administered early at reperfusion. The ability of C21 to exert its neuroprotective effects might be affected by fluctuating levels of female hormones.NEW & NOTEWORTHY The present study shows the neuroprotective impact of C21 on ischemic stroke in female rats and how the protective effects of C21 can be influenced by the hormonal status of female rodents.

Intense efforts are being undertaken to understand the pathobiology of ischemia and to develop novel and effective treatments. Angiotensin II type 2 receptor (AT2R) is related with a beneficial role in neurodegenerative disorders, including ischemia. However, the underlying molecular mechanism remains elusive. In this study, we have established that AT2R stimulation by C21 compound, a specific AT2R agonist, caused a VEGF upregulation. Using mouse primary cortical neurons exposed to oxygen-glucose deprivation (OGD), we established that this effect was mediated by a mechanism dependent of mTORC1 signaling since mTOR inhibition abolished the C21-induced VEGF upregulation. Also, we have temporally characterized the changes on VEGF levels after ischemia induction in rats using two different approaches: transient and permanent middle cerebral artery occlusion (tMCAO and pMCAO). VEGF levels were permanently augmented after reperfusion (tMCAO) whereas lower levels of VEGF were found after pMCAO, remarkably at 21days. Therefore, C21 compound accelerated the recovery of the neurological status of pMCAO rats, reduced the ischemic damage area and abolished pMCAO-induced VEGF downregulation at 21days. This effect of C21 compound was mainly observed in neurons of the peri-infarct area. Our results suggest that a C21-induced VEGF upregulation may be crucial after an ischemic neuronal insult in both of our experimental approaches. This upregulation was mediated by a mechanism dependent of Akt/mTOR signaling pathway, since mTOR inhibition abolished the VEGF upregulation induced by C21. Considering that VEGF is involved in regenerative processes, we propose that AT2R activation could be used as a potential pharmacological strategy after ischemic stroke.

The renin–angiotensin system is one of the key long-term regulators of blood pressure and has been a mainstay for the treatment of cardiovascular and renal diseases for the last 30 years. In recent years, new components of the renin–angiotensin system have been discovered beyond the classical pathway that have led to the development of novel therapies targeting this system. Moreover, dual inhibitors which block the renin–angiotensin system and other systems involved in the regulation of blood pressure may provide superior treatment for cardiovascular and renal diseases.

We here report on our continued studies of ligands binding to the promising drug target angiotensin II type 2 receptor (AT2R). Two series of compounds were synthesized and investigated. The first series explored the effects of adding small substituents to the phenyl ring of the known selective nonpeptide AT2R antagonist C38, generating small but significant shifts in AT2R affinity. One compound in the first series was equipotent to C38 and showed similar kinetic solubility, and stability in both human and mouse liver microsomes. The second series was comprised of new bicyclic derivatives, amongst which one ligand exhibited a five‐fold improved affinity to AT2R as compared to C38. The majority of the compounds in the second series, including the most potent ligand, were inferior to C38 with regard to stability in both human and mouse microsomes. In contrast to our previously reported findings, ligands with shorter carbamate alkyl chains only demonstrated slightly improved stability in microsomes. Based on data presented herein, a more adequate, tentative model of the binding modes of ligand analogues to the prototype AT2R antagonist C38 is proposed, as deduced from docking redefined by molecular dynamic simulations.

Although surgical excision and intralesional collagenase injection are mainstays in Dupuytren disease treatment, no effective medical therapy exists for recurrent disease. Compound 21, a selective agonist of the angiotensin II type 2 receptor, has been shown to protect against fibrosis in models of myocardial infarction and stroke. The authors investigated the potential use of compound 21 in the treatment of Dupuytren disease.Human dermal fibroblasts were treated in vitro with compound 21 and assessed for viability using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, migration by means of scratch assay, and profibrotic gene transcription by means of quantitative reverse transcription polymerase chain reaction. Compound 21 effects in vivo were assessed using a xenograft model. Dupuytren disease cord specimens from patients undergoing open partial fasciectomy were divided into two segments. Segments were implanted under the dorsal skin of nude mouse pairs. Beginning on day 5, one mouse from each pair received daily intraperitoneal injections of compound 21 (10 μg/kg/day), and the other received vehicle. On day 10, segments were explanted and submitted for immunohistochemistry.Human dermal fibroblasts treated with compound 21 displayed decreased migration and decreased gene expression of connective tissue growth factor, fibroblast specific protein-1, transforming growth factor-β1, Smad3, and Smad4. Dupuytren disease segments from compound 21-treated mice demonstrated significantly reduced alpha-smooth muscle actin and Ki67 staining, with increased density of CD31 staining vessels.Compound 21 significantly decreases expression of profibrotic genes and decreases myofibroblast proliferation as indicated by reduced Ki67 and alpha-smooth muscle actin expression. These findings support compound 21 as a potential novel treatment modality for Dupuytren disease.

In 2004, the first nonpeptide selective angiotensin II type 2 receptor (AT2R) agonist was reported. This nonpeptide (C21), which, exerts anti-inflammatory and antifibrotic actions in vivo, has been extensively explored and is currently in clinical trials. Subsequently, a large number of related drug-like AT2R agonists have been disclosed. Reviews that summarize known structure-activity relationships (SAR) of nonpeptide AT2R agonists have recently appeared in the literature; however, very few reviews discuss the role of angiotensin peptides as AT2R agonists. Furthermore, to date, there have been no reports focusing on the medicinal chemistry perspective of peptide AT2R agonists. In the present review, reports on linear and conformationally constrained Ang II analogues, with a focus on AT2R selective ligands that are proven to act as agonists at the AT2 receptor are summarized. The impact of truncations and macrocyclizations of Ang II analogues and of incorporation of scaffolds that mimic secondary structures into Ang II related peptides is highlighted. A survey of the efforts to transform the nonselective octapeptide Ang II to more drug-like selective AT2R agonists is presented. The relationship between the structures of the AT2R agonists and their affinity to the AT2R is briefly discussed and common pharmacophore elements of AT2R selective Ang II peptide analogues and selective nonpeptide AT2R agonists are compared.

The objective was to investigate the role of angiotensin II type 2 receptor during electrophysiological remodeling of left ventricular hypertrophic myocardium in spontaneously hypertensive rats (SHRs). A total of 36, aged 10 weeks, male SHRs were divided into three groups: control, valsartan, and valsartan + PD123319 groups (n = 12 in each). The systolic blood pressure, left ventricular mass index, ventricular effective refractory period, and ventricular fibrillation threshold (VFT) were also measured after 8 weeks. At the same time, I Na , I CaL , I to , and membrane capacitance were measured in left ventricular myocytes by whole-cell patch-clamp. The VFT of valsartan was higher than that of control (valsartan vs. control: 17.4 ± 0.6 mA vs. 15.8 ± 0.5 mA, P P to of valsartan was higher than that of control (valsartan vs. control: 14.7 ± 0.42 pA/pF vs. 11.2 ± 0.15 pA/pF, P to of valsartan was higher than that of valsartan + PD123319 (valsartan vs. valsartan + PD123319: 14.7 ± 0.42 pA/pF vs. 13.6 ± 0.30 pA/pF, P CaL of valsartan was lower than that of control (valsartan vs. control: −4.6 ± 0.2 pA/pF vs. −6.9 ± 0.1 pA/pF, P CaL of valsartan was lower than that of valsartan + PD123319 (valsartan vs. valsartan + PD123319: −4.6 ± 0.2 pA/pF vs. −5.4 ± 0.1 pA/pF, P

ObjectiveThere is an unmet clinical need for novel analgesics for neuropathic pain. This study was designed to elucidate the mechanism through which EMA300, a small molecule antagonist of the angiotensin II type 2 receptor (AT(2)R) with >1,000-fold selectivity over the angiotensin II type 1 receptor, produces analgesia in a rodent model of neuropathic pain.

It is now widely accepted that the renin-angiotensin system (RAS) not only contributes to pathological mechanisms involved, e.g. in hypertension or hypertensive and diabetic end-organ damage, but also harbors a "protective arm" represented mainly by two receptors, the AT2 (angiotensin type 2) receptor and the Mas receptor, both mediating tissue-protective and pro-regenerative actions. Several compounds are currently in preclinical and clinical development, which aim at targeting the "protective RAS" by agonism on the AT2 or the Mas receptor. In a recent issue of Expert Opinion on Investigational Drugs Koen Verdonk and co-authors review the physiology and patho-physiology of the AT2 receptor and discuss potential future clinical indications and putative adverse effects of AT2 receptor agonists. This article comments the review by Verdonk et al., suggests some additional possible indications, and particularly re-reviews whether there is preclinical in vivo evidence for adverse effects of AT2 receptor agonists.

All well-known deleterious effects of angiotensin (Ang) II, including vasoconstriction, inflammation, water and salt retention, and vascular remodeling, are mediated via its type 1 (AT(1)) receptor. This explains why AT(1) receptor blockers (ARBs) and inhibitors of Ang II synthesis, such as ACE inhibitors and renin inhibitors, are beneficial for cardiovascular disease. Yet, Ang II has a second receptor, the Ang II type 2 (AT(2)) receptor, the function of which, even after over 20 years of research, remains largely unknown. In this issue, Marion et al. provide a new chapter to the AT(2) receptor story.

Successful conditions for the transcarbamylation/transesterification reaction of sulfonylcarbamates with alcohols by microwave heating under continuous-flow conditions were developed. After optimization of the processes, two series of O-alkylsulfonylcarbamates were obtained in high yields and purities using microwave transparent borosilicate tube reactors. In order to also illustrate the usefulness of the protocol in a medicinal chemistry context, the methodology was used for the synthesis of three angiotensin II type 2 receptor ligands.

OBJECTIVE: The angiotensin II type 2 receptor (AT2R) has been suggested to counterbalance the angiotensin II type 1 receptor (AT1R) in the central regulation of blood pressure and sympathetic tone. We previously reported the decrease in mean arterial pressure (MAP) to selective stimulation of central AT2R with Compound 21 (C21) in conscious spontaneous hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). Here we show the differences in day- and nighttime pressure. We also assess the impact on spontaneous baroreflex sensitivity (SBRS), norepinephrine (NE) plasma levels and autonomic function. DESIGN AND METHOD: Animals were implanted with a radio-telemetry device and an intracerebroventricular cannula connected to a miniosmotic pump delivering saline vehicle, AT2R-agonist C21 alone or in combination with AT2R-antagonist PD123319. MAP was assessed for 14-21 days: 7 days baseline (saline), 7-14 days treatment (e.g. C21) (n = 6-8/group). RESULTS: During daytime, 7-day C21-infusion decreased MAP similarly in the two strains (WKY -5.5 ± 0.6 mmHg, SHR -5.4 ± 1.5 mmHg). During nighttime, C21 reduced MAP significantly more in SHR (-12.6 ± 1.9 mmHg) than in WKY (-8.2 ± 0.8 mmHg;p

Background— The precise function of angiotensin II type 2 receptor (AT 2 -R) in the mammalian heart in vivo is unknown. Here, we investigated the role of AT 2 -R in cardiac pressure overload. Methods and Results— Rats were infused with vehicle, angiotensin II (Ang II), PD123319 (an AT 2 -R antagonist), or the combination of Ang II and PD123319 via subcutaneously implanted osmotic minipumps for 12 or 72 hours. Ang II–induced increases in mean arterial pressure, left ventricular weight/body weight ratio, and elevation of skeletal α-actin and β-myosin heavy chain mRNA levels were not altered by PD123319. In contrast, AT 2 -R blockade resulted in a marked increase in the gene expression of c-fos, endothelin-1, and insulin-like growth factor-1 in Ang II–induced hypertension. In parallel, Ang II–stimulated mRNA and protein expression of atrial natriuretic peptide were significantly augmented by AT 2 -R blockade. Moreover, PD123319 markedly increased the synthesis of B-type natriuretic peptide. Furthermore, the expression of vascular endothelial growth factor and fibroblast growth factor-1 was downregulated by Ang II only in the presence of AT 2 -R blockade. Conclusions— Our results provide evidence that AT 2 -R plays a functional role in the cardiac hypertrophic process in vivo by selectively regulating the expression of growth-promoting and growth-inhibiting factors.

It is widely accepted that the angiotensin II type 1 receptor (AT1R) accounts for the majority of cardiovascular effects evoked by angiotensin II (Ang II), such as contraction/pressor activity and growth-promoting effects leading to cardiac and vascular hypertrophy. However, there has been an increasing body of evidence that indicates that the angiotensin II type 2 receptor (AT2R) may exert pharmacological actions per se as well as play a role in pathophysiological processes. In particular, it has been suggested that the AT2R may exert beneficial vasodilator and antigrowth effects, as well as contribute to the efficacy of AT1R antagonists (see reviews by Matsubara, 1998; Horiuchi et al., 1999a; de Gasparo & Siragy, 1999; Unger, 1999; de Gasparo et al., 2000; Gallinat et al., 2000; Henrion et al., 2001). Therefore, for the purposes of the current review, we have updated the status of such work, particularly in light of some recent data suggesting that the AT2R, in fact, causes opposite effects, for example, cardiac growth-promoting effects (Senbonmatsu et al., 2000; Ichihara et al., 2001). In addition, we have critically reviewed whether or not experimental outcomes are consistent with the hypothesis that AT2R may contribute to the therapeutic effects of AT1R antagonists (de Gasparo et al., 2000; Carey et al., 2001a; Siragy, 2002).

Angiotensin II is an effector peptide of the renin angiotensin system. Angiotensin II which regulates cellular growth in response to developmental, physiological, and pathological processes has two main receptor subtypes which are the AT1 and AT2 receptor. It is well established that angiotensin II has an important role in regulating cardiovascular hemodynamics and structure. Most of the known effects of angiotensin II in cardiovascular system are attributable to the AT1 receptor, and it has been a drug target in cardiovascular disease for many years. On the other hand, less was known about the AT2 receptor and it remained only an academic interest. This circumstance has changed with the synthesis of a first non-peptide AT2 receptor agonist, compound 21. The studies using compound 21 indicated tissue protective effects and functional improvement after myocardial infarction. Then, the research has continued to reveal AT2 receptor mediated effects in cardiovascular system. Herein, we will discuss the role of the peptide (CGP42112A, novokinin) and the non-peptide (compound 21) AT2 receptor agonists in the cardiovascular system. Key words: Angiotensin II; AT2 Agonist; Cardiovascular System., Anjiyotensin II renin anjiyotensin sisteminin etkili bir peptididir. Gelişimsel, fizyolojik ve patolojik süreçler içerisinde hücresel büyümeyi düzenleyen Anjiotensin II' nin AT1 ve AT2 olmak üzere başlıca iki reseptör alt tipi vardır. Kardiyovasküler hemodinami ve yapının düzenlemesinde Anjiotensin II' nin önemli bir role sahip olduğu iyi bir şekilde ortaya konulmuştur. Anjiotensin II, kardiyovasküler sistem üzerindeki pek çok etkisini AT1 reseptörü üzerinden gerçekleştirmekte olup, bu özelliği ile kardiyovasküler hastalıklarda yıllardır bir ilaç hedefi olarak kullanılmaktadır. Buna karşılık, AT2 reseptörünün katkısı ise çok fazla bilinmemekte ve sadece akademik bir ilgi alanı olarak kalmaktaydı. İlk non-peptid AT2 reseptör agonisti compound 21' in sentezlenmesi ile bu durum değişti. Compound 21 kullanılarak yapılan çalışmalar miyokard infarktüsü sonrasında doku koruyucu ve fonksiyonel iyileştirici etkilerini ortaya çıkardı. Daha sonra kardiyovasküler sistemde AT2 reseptör aracılı etkilerin ortaya çıkarılması için çalışmalar yapılmaya devam edildi. Biz bu derlemede peptid (CGP42112A, novokinin) ve non-peptid (compound 21) AT2 reseptör agonistlerinin kardiyovasküler sistem üzerindeki etkilerini tartışacağız. Anahtar kelimeler: Anjiyotensin II; AT2 Agonist; Kardiyovasküler Sistem.

Animal models with a genetic alteration of angiotensin II type 2 receptor (AT 2 receptor) expression have contributed to elucidation of the functional and pathophysiological roles of the AT 2 receptor. Mainly, deletion models have been well investigated to examine AT 2 receptor function. Overexpression models sometimes demonstrate functional discrepancies in the AT 2 receptor because its expression level is very low physiologically. Therefore, conditional models are used for analyzing the effect of AT 2 receptor overexpression. Moreover, double or multiple genetic alteration models have been generated to examine the interaction between the AT 2 receptor and other receptors or signaling pathways involving renin–angiotensin system components. Genetic alteration models have also contributed to in vitro analysis of primary cultures prepared from these animals to study the detailed signaling pathways of the AT 2 receptor.

Angiotensin II (Ang II) regulates a broad spectrum of cardiovascular and renal processes ranging from vasoconstriction to inflammatory processes, including atherosclerosis and vascular ageing. Ang II determines most of its effects via activation of 2 G-protein–coupled receptors with opposite effects: the type 1 (AT1R) and the type 2 receptors (AT2R). The relationships and interactions between AT1R and AT2R signals, their roles in the control of vascular tone and cardiovascular remodeling, and the underlying mechanisms are complex and remain to be defined fully. Kemp et al1 have added another relevant piece of evidence in this field through an elegant study in an animal model of AT2R stimulation recently published in the journal. These authors have, in fact, demonstrated that AT2R stimulation via the specific nonpeptide AT2R agonist compound-21 (C-21) increased the urinary sodium excretion without affecting the mean arterial blood pressure and the renal hemodynamics. This effect has been shown to be dependent on a bradykinin-nitric oxide-cyclic guanosine monophosphate pathway. Finally, the authors demonstrated that in a rat model of Ang …

Background: Angiotensin type 1 receptor (AT1R) blockers provide vascular protection and improve stroke outcomes in young otherwise healthy animals. These effects are believed to be mediated by the indirect stimulation of AT2R signaling. The AT2R agonist, compound 21 (C21), improves endothelial function in peripheral vascular beds but its effect on cerebral endothelial function remains unknown. It is important to determine the vascular effects of C21 in diabetes, a comorbid condition which is known to worsen stroke outcomes. Methods: Endothelium-dependent relaxation was assessed in male Wistar and Type 2 diabetic Goto-Kakizaki (GK) rats (n=3-6) by measuring acetylcholine (ACh, 1 nM - 5 μm) induced dilatory response in basilar arteries. In a subset of experiments C21 dose response curves were generated (0.1 nM - 1 μM) or vessels were pre-incubated with 100 nM C21 ± 1 μM PD123319 (AT2R blocker) for 30 min prior to Ach dose response curves. Area under the curve (AUC) and half maximal effective concentration (EC50 nM) were calculated as indices of total relaxation and receptor sensitivity, respectively. Angiotensin receptors expression was measured by immunoblotting of brain homogenates. Results: AT2R agonist C21 dose response curves showed no basilar reactivity in either control or diabetic animals. Pre-incubation with C21 enhanced relaxation to Ach in control animals (vehicle 146.7 ± 3.9 vs C21 pretreatment 229.6 ± 11.6), which was abolished by the blockade of AT2R (176.9 ± 25.5, p=0.007). Similarly, C21 improved sensitivity in control animals (vehicle 110.5 ± 32 vs C21 pretreatment 11.9 ± 2) which was abolished in the presence of PD123319 (93.8 ± 31, p=0.04). Basilar artery relaxation (AUC) was impaired in diabetic GK rats (93.9 ± 1.8%) as compared to controls (146.7 ± 3.9%) and C21 had no effect (98 ± 8.9%) indicating a disease and treatment interaction (p Conclusion: C21 improves vascular relaxation in control but not in diabetic rats in an AT2R-dependent manner. Underlying mechanisms blunting response to C21 need to be further investigated and may impact the subsequent development of C21 as a treatment for stroke.

BACKGROUND/OBJECTIVES: Recent studies have reported an association of the angiotensin II type 2 receptor (AT2R) 3123Cytosine/Adenine (3123C/A) polymorphism with essential hypertension and cardiovascular diseases. The purpose of the study was to investigate whether the AT2R 3123C/A polymorphism affects blood pressure for free-living hypertensive men during a 5-month intervention period. SUBJECTS/METHODS: The subjects were free-living hypertensive Japanese men aged 40 to 75 years who agreed to intervention in the period from 2004 to 2011. Detection of the AT2R 3123C/A polymorphism was determined by polymerase chain reaction. The dietary intervention was designed to decrease salt level and to increase potassium level through cooking instructions and self-monitoring of the diet. The exercise session consisted of activities such as stretching, resistance training, and walking. Blood pressure, urinary sodium and potassium excretion, dietary and lifestyle data, and non-fasting venous blood sample were collected at baseline and after the intervention period. RESULTS: Thirty nine subjects were eligible for participation and the follow-up rate was 97.4%. The C allele proportion was 57.9%. AT2R 3123C/A polymorphism was X-chromosome-linked, therefore we analyzed the C and A genotypes. At baseline, no significant differences were observed between the genotype groups. After the intervention, there were no significant differences in lifestyle habit between the groups. Nevertheless, the estimated salt excretion (g/day) was significantly decreased only in the C genotype (13.0-10.3, P = 0.031). No significant change was observed in systolic blood pressure (SBP) (mmHg) in the A genotype, but a significant decrease was observed in the C genotype (150.0-141.5, P = 0.024). CONCLUSTIONS: In the C genotype, it might be easy to improve SBP through lifestyle intervention in free-living hypertensive Japanese men, however generalization could not be achieved by the small sample size.

Patients with advanced congestive heart failure (CHF) or chronic kidney disease (CKD) often have increased angiotensin II (Ang II) levels and cachexia. Ang II infusion in rodents causes sustained s...

OBJECTIVESOur study goal was to analyze whether gene variants of angiotensin II type 2-receptor (AT2-R) modulate the effects of angiotensin II on the left ventricle (LV).BACKGROUNDExperimental data suggest that angiotensin II modifies ventricular growth responses via angiotensin II type 1-receptors (AT1-R) and AT2-R.METHODSIn 120 white, young male subjects with normal or mildly elevated blood pressure, we assessed plasma angiotensin II and aldosterone concentrations (RIA), 24-h urinary sodium excretion, 24-h ambulatory blood pressure and LV structure (two-dimensional guided M-mode echocardiography). The intronic +1675 G/A polymorphism of the X-chromosomal located AT2-R gene was investigated by single-strand conformational polymorphism analysis and DNA-sequencing.RESULTSHypertensive subjects with the A-allele had a greater LV posterior (11.0 ± 1.3 vs. 9.9 ± 1.3 mm, p < 0.001), septal (11.8 ± 1.4 vs. 10.1 ± 1.2 mm, p < 0.001) and relative wall thickness (0.44 ± 0.06 vs. 0.39 ± 0.06, p < 0.01) as well as LV mass index (138 ± 23 vs. 120 ± 13 g/m2, p < 0.001) than those with the G-allele. Confounding factors (i.e., body mass index and surface area, plasma angiotensin II, sodium excretion, systolic and diastolic ambulatory blood pressure) were similar between the two genotypes. In normotensive subjects, relative wall thickness (0.36 ± 0.05 vs. 0.35 ± 0.05) and LV mass index (115 ± 21 vs. 112 ± 17 g/m2) were nearly identical across the two genotypes, with similar confounding variables.CONCLUSIONSOur data indicate that the X-chromosomal located +1675 G/A-polymorphism of the AT2-R gene is associated with LV structure in young male humans with early structural changes of the heart due to arterial hypertension.