RESUMO
BACKGROUND: Our study aimed to investigate the roles of autophagy against high glucose induced response in retinal pigment epithelium (ARPE-19 cells). METHODS: The morphological changes and reactive oxygen species (ROS) generation in ARPE-19 cells under high glucose treatment were respectively detected using the transmission electron microscopy and flow cytometry. The expression levels of Parkin, PINK1, BNIP3L, LC3-I and LC3-II in ARPE-19 cells received high glucose treatment were measured by western blot after pretreatment of carbonyl cyanide m-chlorophenylhydrazone (CCCP), 3-methyladenine (3-MA), N-acetyl cysteine (NAC) or cyclosporin A (CsA) followed by high glucose treatment. RESULTS: ARPE-19 cells subjected to high glucose stress showed an obvious reduction in the LC3-I expression and significant increase in the number of autophagosomes, in the intracellular ROS level, and in the expression levels of Parkin, PINK1, BNIP3L and LC3-II (p < 0.05). Pretreatment with CCCP significantly reduced the LC3-I expression and increased the expression levels of Parkin, PINK1, BNIP3L and LC3-II (p < 0.05). ARPE-19 cells pretreated with CsA under high glucose stress showed markedly down-regulated expressions of Parkin, PINK1 and BNIP3L compared with the cells treated with high glucose (p < 0.05). Pretreatment of ARPE-19 cells with NAC or 3-MA under high glucose stress resulted in a marked reduction in the expression levels of PINK1, BNIP3L and LC3-II (p < 0.05). Meanwhile, the expression level of Parkin in the ARPE-19 cells pretreated with NAC under high glucose stress was comparable with that in the control cells. CONCLUSION: Autophagy might have protective roles against high glucose induced injury in ARPE19 cells via regulating PINK1/Parkin pathway and BNIP3L.
Assuntos
Autofagia/efeitos dos fármacos , Glucose/farmacologia , Proteínas de Membrana/efeitos dos fármacos , Proteínas Quinases/efeitos dos fármacos , Proteínas Proto-Oncogênicas/efeitos dos fármacos , Epitélio Pigmentado da Retina/efeitos dos fármacos , Proteínas Supressoras de Tumor/efeitos dos fármacos , Ubiquitina-Proteína Ligases/efeitos dos fármacos , Autofagia/fisiologia , Linhagem Celular , Citometria de Fluxo , Humanos , Proteínas de Membrana/metabolismo , Microscopia Eletrônica de Transmissão , Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Epitélio Pigmentado da Retina/citologia , Transdução de Sinais/fisiologia , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Schistosomiasis mansoni is involved in hepatic fibrogenesis and portal hypertension. Previous studies proved that blockade of some components of the renin-angiotensin system (RAS) reduce liver fibrogenesis. However, the effects of inhibition of early stages of RAS pathway in schistosomal fibrosis have not been studied yet. Thus, the aim of this study was to compare the role of different antihypertensive drugs on hepatic fibrosis in murine schistosomiasis. BALB/c mice (nâ¯=â¯50) weighing 20g were subjected to inoculation of 50 cercariae and submitted to different treatments: aliskiren, 50â¯mg/kg (nâ¯=â¯10); bradykinin, 2⯵g/kg (nâ¯=â¯5); losartan, 10â¯mg/kg (nâ¯=â¯10); lisinopril 10â¯mg/kg (nâ¯=â¯5) and control, proportional volume vehicle (nâ¯=â¯5); daily for 14 weeks. Six animals were not subjected to cercariae inoculation or any type of treatment. Ultrasound, histological, immunohistochemical and proteomic analyzes were performed to evaluate markers associated with hepatic fibrogenesis. The hepatic areas stained with Sirius red and thenumber of cells marked by α-SMA in animals treated with aliskiren, bradykinin, lisinopril and losartan were diminished when compared to control group, demonstrating reduced hepatic fibrosis after RAS blockade. These results were reinforced by ultrasonography analysis and protein expression of TGFß. These findings demonstrated the effect of RAS inhibition on hepatic fibrosis in murine schistosomiasis, with the most evident results being observed in the losartan and aliskiren treated groups. The main mechanisms underlying this process appear to involve anti-fibrogenic activity through the inhibition of collagen and TGFß synthesis.
Assuntos
Cirrose Hepática/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Esquistossomose mansoni/complicações , Amidas/farmacologia , Amidas/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Bradicinina/farmacologia , Bradicinina/uso terapêutico , Fumaratos/farmacologia , Fumaratos/uso terapêutico , Lisinopril/farmacologia , Lisinopril/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática/parasitologia , Losartan/farmacologia , Losartan/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico Sintase Tipo III/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/efeitos dos fármacos , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Renina/efeitos dos fármacos , Renina/genética , Renina/metabolismo , Esquistossomose mansoni/tratamento farmacológico , Esquistossomose mansoni/patologia , Inibidor Tecidual de Metaloproteinase-1/efeitos dos fármacos , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fator de Crescimento Transformador beta1/efeitos dos fármacos , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Vasodilatadores/farmacologia , Vasodilatadores/uso terapêutico , Proteínas Quinases p38 Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
BACKGROUND: Our study aimed to investigate the roles of autophagy against high glucose induced response in retinal pigment epithelium (ARPE-19 cells). METHODS: The morphological changes and reactive oxygen species (ROS) generation in ARPE-19 cells under high glucose treatment were respectively detected using the transmission electron microscopy and flow cytometry. The expression levels of Parkin, PINK1, BNIP3L, LC3-I and LC3-II in ARPE-19 cells received high glucose treatment were measured by western blot after pretreatment of carbonyl cyanide m-chlorophenylhydrazone (CCCP), 3-methyladenine (3-MA), N-acetyl cysteine (NAC) or cyclosporin A (CsA) followed by high glucose treatment. RESULTS: ARPE-19 cells subjected to high glucose stress showed an obvious reduction in the LC3-I expression and significant increase in the number of autophagosomes, in the intracellular ROS level, and in the expression levels of Parkin, PINK1, BNIP3L and LC3-II (p < 0.05). Pretreatment with CCCP significantly reduced the LC3-I expression and increased the expression levels of Parkin, PINK1, BNIP3L and LC3-II (p < 0.05). ARPE-19 cells pretreated with CsA under high glucose stress showed markedly down-regulated expressions of Parkin, PINK1 and BNIP3L compared with the cells treated with high glucose (p < 0.05). Pretreatment of ARPE-19 cells with NAC or 3-MA under high glucose stress resulted in a marked reduction in the expression levels of PINK1, BNIP3L and LC3-II (p < 0.05). Meanwhile, the expression level of Parkin in the ARPE-19 cells pretreated with NAC under high glucose stress was comparable with that in the control cells. CONCLUSION: Autophagy might have protective roles against high glucose induced injury in ARPE19 cells via regulating PINK1/Parkin pathway and BNIP3L.
Assuntos
Humanos , Proteínas Quinases/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proteínas Proto-Oncogênicas/efeitos dos fármacos , Proteínas Supressoras de Tumor/efeitos dos fármacos , Ubiquitina-Proteína Ligases/efeitos dos fármacos , Epitélio Pigmentado da Retina/efeitos dos fármacos , Glucose/farmacologia , Proteínas de Membrana/efeitos dos fármacos , Proteínas Quinases/metabolismo , Autofagia/fisiologia , Transdução de Sinais/fisiologia , Linhagem Celular , Proteínas Proto-Oncogênicas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Microscopia Eletrônica de Transmissão , Epitélio Pigmentado da Retina/citologia , Citometria de Fluxo , Proteínas de Membrana/metabolismoRESUMO
PURPOSE: To investigate whether allopurinol exerts a protective effect on kidneys by measuring new kidney injury biomarkers (NGALp, NGALu, KIM 1 and IL 18) and analysing the renal function and histology in uninephrectomised rats subjected to ischaemia-reperfusion injury. METHODS: Thirty two Wistar rats were randomly allocated to four groups: Sham (S): laparotomy; Control (C): laparotomy and ischaemia-reperfusion in the left kidney; Control Allopurinol (CA): laparotomy and allopurinol at a dose of 100mg·kg 1·d 1; and Allopurinol (A): laparotomy ischaemia-reperfusion in the left kidney and allopurinol at a dose of 100mg·kg 1·d 1. The NGALp, NGALu, KIM 1, IL 18 and creatinine levels and the kidney histology were analysed. The significance level was established as p<0.05. RESULTS: Creatinine level increased in all the groups, with A ≈ C > S ≈ CA. The NGALp, NGALu and IL 18 levels exhibited similar behaviour in all the groups. KIM 1 was higher in group A than C and showed intermediate values in groups S and CA. Severity of injury in the left kidney was greater in groups C and A compared to S and CA. CONCLUSION: Allopurinol did not exert protective or damaging effects on the kidneys of rats subjected to ischaemia-reperfusion injury.
Assuntos
Proteínas de Fase Aguda/análise , Alopurinol/farmacologia , Antimetabólitos/farmacologia , Interleucina-18/análise , Isquemia/tratamento farmacológico , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Lipocalinas/análise , Proteínas Proto-Oncogênicas/análise , Proteínas de Fase Aguda/efeitos dos fármacos , Animais , Biomarcadores/sangue , Creatinina/sangue , Rim/patologia , Lipocalina-2 , Lipocalinas/efeitos dos fármacos , Masculino , Proteínas Proto-Oncogênicas/efeitos dos fármacos , Distribuição Aleatória , Ratos Wistar , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/patologiaRESUMO
PURPOSE: To investigate whether allopurinol exerts a protective effect on kidneys by measuring new kidney injury biomarkers (NGALp, NGALu, KIM 1 and IL 18) and analysing the renal function and histology in uninephrectomised rats subjected to ischaemia-reperfusion injury. METHODS: Thirty two Wistar rats were randomly allocated to four groups: Sham (S): laparotomy; Control (C): laparotomy and ischaemia-reperfusion in the left kidney; Control Allopurinol (CA): laparotomy and allopurinol at a dose of 100mg·kg 1·d 1; and Allopurinol (A): laparotomy ischaemia-reperfusion in the left kidney and allopurinol at a dose of 100mg·kg 1·d 1. The NGALp, NGALu, KIM 1, IL 18 and creatinine levels and the kidney histology were analysed. The significance level was established as p<0.05. RESULTS: Creatinine level increased in all the groups, with A ≈ C > S ≈ CA. The NGALp, NGALu and IL 18 levels exhibited similar behaviour in all the groups. KIM 1 was higher in group A than C and showed intermediate values in groups S and CA. Severity of injury in the left kidney was greater in groups C and A compared to S and CA. CONCLUSION: Allopurinol did not exert protective or damaging effects on the kidneys of rats subjected to ischaemia-reperfusion injury. .
Assuntos
Animais , Masculino , Proteínas de Fase Aguda/análise , Alopurinol/farmacologia , Antimetabólitos/farmacologia , /análise , Isquemia/tratamento farmacológico , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Lipocalinas/análise , Proteínas Proto-Oncogênicas/análise , Proteínas de Fase Aguda/efeitos dos fármacos , Biomarcadores/sangue , Creatinina/sangue , Rim/patologia , Lipocalinas/efeitos dos fármacos , Proteínas Proto-Oncogênicas/efeitos dos fármacos , Distribuição Aleatória , Ratos Wistar , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/patologiaRESUMO
The prevalence of Type 2 diabetes mellitus is predicted to increase dramatically over the coming years and the clinical implications and healthcare costs from this disease are overwhelming. In many cases, this pathological condition is linked to a cluster of metabolic disorders, such as obesity, systemic hypertension and dyslipidaemia, defined as the metabolic syndrome. Insulin resistance has been proposed as the key mediator of all of these features and contributes to the associated high cardiovascular morbidity and mortality. Although the molecular mechanisms behind insulin resistance are not completely understood, a negative cross-talk between AngII (angiotensin II) and the insulin signalling pathway has been the focus of great interest in the last decade. Indeed, substantial evidence has shown that anti-hypertensive drugs that block the RAS (renin-angiotensin system) may also act to prevent diabetes. Despite its long history, new components within the RAS continue to be discovered. Among them, Ang-(1-7) [angiotensin-(1-7)] has gained special attention as a counter-regulatory hormone opposing many of the AngII-related deleterious effects. Specifically, we and others have demonstrated that Ang-(1-7) improves the action of insulin and opposes the negative effect that AngII exerts at this level. In the present review, we provide evidence showing that insulin and Ang-(1-7) share a common intracellular signalling pathway. We also address the molecular mechanisms behind the beneficial effects of Ang-(1-7) on AngII-mediated insulin resistance. Finally, we discuss potential therapeutic approaches leading to modulation of the ACE2 (angiotensin-converting enzyme 2)/Ang-(1-7)/Mas receptor axis as a very attractive strategy in the therapy of the metabolic syndrome and diabetes-associated diseases.
Assuntos
Angiotensina I/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Resistência à Insulina , Insulina/metabolismo , Fragmentos de Peptídeos/metabolismo , Sistema Renina-Angiotensina , Transdução de Sinais , Angiotensina II/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Enzima de Conversão de Angiotensina 2 , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Hipoglicemiantes/uso terapêutico , Peptidil Dipeptidase A/metabolismo , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/efeitos dos fármacos , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Receptores Acoplados a Proteínas G/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND AND PURPOSE: AVE 0991 (AVE) is a non-peptide compound, mimic of the angiotensin (Ang)-(1-7) actions in many tissues and pathophysiological states. Here, we have investigated the effect of AVE on pulmonary remodelling in a murine model of ovalbumin (OVA)-induced chronic allergic lung inflammation. EXPERIMENTAL APPROACH: We used BALB/c mice (6-8 weeks old) and induced chronic allergic lung inflammation by OVA sensitization (20 µg·mouse(-1) , i.p., four times, 14 days apart) and OVA challenge (1%, nebulised during 30 min, three times per·week, for 4 weeks). Control and AVE groups were given saline i.p and challenged with saline. AVE treatment (1 mg·kg(-1) ·per day, s.c.) or saline (100 µL·kg(-1) ·per day, s.c.) was given during the challenge period. Mice were anaesthetized 72 h after the last challenge and blood and lungs collected. In some animals, primary bronchi were isolated to test contractile responses. Cytokines were evaluated in bronchoalveolar lavage (BAL) and lung homogenates. KEY RESULTS: Treatment with AVE of OVA sensitised and challenged mice attenuated the altered contractile response to carbachol in bronchial rings and reversed the increased airway wall and pulmonary vasculature thickness and right ventricular hypertrophy. Furthermore, AVE reduced IL-5 and increased IL-10 levels in the BAL, accompanied by decreased Ang II levels in lungs. CONCLUSIONS AND IMPLICATIONS: AVE treatment prevented pulmonary remodelling, inflammation and right ventricular hypertrophy in OVA mice, suggesting that Ang-(1-7) receptor agonists are a new possibility for the treatment of pulmonary remodelling induced by chronic asthma.
Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Angiotensina I/farmacologia , Antiasmáticos/farmacologia , Asma/tratamento farmacológico , Imidazóis/farmacologia , Pulmão/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Artéria Pulmonar/efeitos dos fármacos , Veias Pulmonares/efeitos dos fármacos , Angiotensina II/metabolismo , Animais , Asma/induzido quimicamente , Asma/imunologia , Asma/metabolismo , Asma/fisiopatologia , Líquido da Lavagem Broncoalveolar/imunologia , Broncoconstrição/efeitos dos fármacos , Doença Crônica , Citocinas/metabolismo , Modelos Animais de Doenças , Hipertrofia Ventricular Direita/metabolismo , Hipertrofia Ventricular Direita/prevenção & controle , Pulmão/irrigação sanguínea , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mimetismo Molecular , Ovalbumina , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/efeitos dos fármacos , Proteínas Proto-Oncogênicas/metabolismo , Artéria Pulmonar/imunologia , Artéria Pulmonar/metabolismo , Artéria Pulmonar/fisiopatologia , Veias Pulmonares/imunologia , Veias Pulmonares/metabolismo , Veias Pulmonares/fisiopatologia , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Receptores Acoplados a Proteínas G/metabolismo , Fatores de TempoRESUMO
The aim of the present study was to investigate the coronary effects of Ang-(1-7) [angiotensin-(1-7)] in hypertrophic rat hearts. Heart hypertrophy was induced by abdominal aorta CoA (coarctation). Ang-(1-7) and AVE 0991, a non-peptide Mas-receptor agonist, at picomolar concentration, induced a significant vasodilation in hearts from sham-operated rats. These effects were blocked by the Mas receptor antagonist A-779. Pre-treatment with L-NAME (N(G)-nitro-L-arginine methyl ester) or ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinozalin-1-one) [NOS (NO synthase) and soluble guanylate cyclase inhibitors respectively] also abolished the effect of Ang-(1-7) in control hearts. The coronary vasodilation produced by Ang-(1-7) and AVE 0991 was completely blunted in hypertrophic hearts. Chronic oral administration of losartan in CoA rats restored the coronary vasodilation effect of Ang-(1-7). This effect was blocked by A-779 and AT2 receptor (angiotensin II type 2 receptor) antagonist PD123319. Acute pre-incubation with losartan also restored the Ang-(1-7)-induced, but not BK (bradykinin)-induced, coronary vasodilation in hypertrophic hearts. This effect was inhibited by A-779, PD123319 and L-NAME. Chronic treatment with losartan did not change the protein expression of Mas and AT2 receptor and ACE (angiotensin-converting enzyme) and ACE2 in coronary arteries from CoA rats, but induced a slight increase in AT2 receptor in aorta of these animals. Ang-(1-7)-induced relaxation in aortas from sham-operated rats was absent in aortas from CoA rats. In vitro pre-treatment with losartan restored the Ang-(1-7)-induced relaxation in aortic rings of CoA rats, which was blocked by the Mas antagonist A-779 and L-NAME. These data demonstrate that Mas is strongly involved in coronary vasodilation and that AT1 receptor (angiotensin II type 1 receptor) blockade potentiates the vasodilatory effects of Ang-(1-7) in the coronary beds of pressure-overloaded rat hearts through NO-related AT2- and Mas-receptor-dependent mechanisms. These data suggest the association of Ang-(1-7) and AT1 receptor antagonists as a potential therapeutic avenue for coronary artery diseases.
Assuntos
Angiotensina I/farmacologia , Cardiomegalia/tratamento farmacológico , Losartan/farmacologia , Fragmentos de Peptídeos/farmacologia , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Animais , Imidazóis/farmacologia , Técnicas In Vitro , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/agonistas , Proteínas Proto-Oncogênicas/efeitos dos fármacos , Piridinas/farmacologia , Ratos , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Vasodilatação/efeitos dos fármacosRESUMO
It is well known that the renin-angiotensin system (RAS) plays a pivotal role in the pathophysiology of cardiovascular diseases. This is well illustrated by the great success of ACE inhibitors and angiotensin (Ang) II AT(1) blockers in the treatment of hypertension and its complications. In the past decade, the classical concept of RAS orchestrated by a series of enzymatic reactions culminating in the linear generation and action of Ang II has expanded and become more complex. From the discoveries of new components such as the angiotensin converting enzyme 2 and the receptor Mas emerged a novel concept of dual opposite branches of the RAS: one vasoconstrictor and pro-hypertensive composed of ACE/Ang II/AT1; and other vasodilator and anti-hypertensive composed of ACE2/Ang-(1-7)/Mas. In this review we will discuss recent findings concerning the biological role of the ACE2/Ang-(1-7)/Mas arm in the cardiovascular system and highlight the initiatives to develop potential therapeutic strategies based on this axis for treating hypertension.
Assuntos
Angiotensina I/efeitos dos fármacos , Anti-Hipertensivos/farmacologia , Hipertensão/fisiopatologia , Fragmentos de Peptídeos/efeitos dos fármacos , Peptidil Dipeptidase A/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Receptores Acoplados a Proteínas G/fisiologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Angiotensina I/fisiologia , Enzima de Conversão de Angiotensina 2 , Humanos , Hipertensão/tratamento farmacológico , Fragmentos de Peptídeos/fisiologia , Proteínas Tirosina Quinases/efeitos dos fármacos , Proteínas Tirosina Quinases/fisiologia , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/efeitos dos fármacos , Receptores de Angiotensina/efeitos dos fármacos , Receptores de Angiotensina/fisiologia , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologiaRESUMO
The renin-angiotensin system plays a crucial role in erectile function. It has been shown that elevated levels of angiotensin II contribute to the development of erectile dysfunction both in humans and in aminals. On the contrary, the heptapeptide angiotensin-(1-7) appears to mediate penile erection by activation of the Mas receptor. Recently, we have shown that the erectile function of Mas gene-deleted mice was substantially reduced, which was associated with a marked increase in fibrous tissue in the corpus cavernosum. We have hypothesized that the synthetic non-peptide Mas agonist, AVE 0991, would potentiate penile erectile function. We showed that intracavernosal injection of AVE 0991 potentiated the erectile response of anaesthetized Wistar rats, measured as the ratio between corpus cavernosum pressure and mean arterial pressure, upon electrical stimulation of the major pelvic ganglion. The facilitatory effect of AVE 0991 on erectile function was dose dependent and completely blunted by the nitric oxide synthesis inhibitor, l-NAME. Importantly, concomitant intracavernosal infusion of the specific Mas receptor blocker, A-779, abolished the effect of AVE 0991. We demonstrated that AVE 0991 potentiates the penile erectile response through Mas in an NO-dependent manner. Importantly, these results suggest that Mas agonists, such as AVE 0991, might have significant therapeutic benefits for the treatment of erectile dysfunction.