Browsing by Autor "Javier Angulo"

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Activation and potentiation of the NO/cGMP pathway by N<sup>G</sup>‐hydroxyl‐<scp>L</scp>‐arginine in rabbit corpus cavernosum under normoxic and hypoxic conditions and ageing
(Wiley, 2003) Javier Angulo; Pedro Cuevas; Argentina Fernández; Sonia Gabancho; A Allona; Antonio Martín‐Morales; Ignacio Moncada; Iñigo Sáenz de Tejada
1 When nitric oxide synthase (NOS) produces NO from N(G)-hydroxy-L-arginine (OH-arginine) instead of L-arginine, the total requirement of molecular oxygen and NADPH to form NO is reduced. The aim of this work was to evaluate the effects of OH-arginine on the contractility of rabbit corpus cavernosum (RCC) and to compare the capacities of L-arginine and OH-arginine to enhance NO-mediated responses under normoxic and hypoxic conditions and in ageing, as models of defective NO production. 2 OH-arginine, but not L-arginine, was able to relax phenylephrine-contracted rabbit trabecular smooth muscle. OH-arginine-induced relaxation was inhibited by the NOS-inhibitor, L-NNA (300 microM), and by the guanylyl cyclase inhibitor, ODQ (20 microM), while it was not affected by the cytochrome P450 oxygenase inhibitor, miconazole (0.1 mM). Administration of OH-arginine, but not L-arginine, produced a significant increment of cGMP accumulation in RCC tissue. 3 Relaxation elicited by OH-arginine (300 microM) was still observed at low oxygen tension. The increase of cGMP levels induced by ACh (30 microM) in RCC was significantly enhanced by addition of OH-arginine (300 microM) in normoxic conditions, as well as under hypoxia, while L-arginine did not alter the effects of ACh on cGMP accumulation. 4 Endothelium-dependent and nitrergic nerve-mediated relaxations were both significantly reduced in RCC from aged animals (>20-months-old) when compared with young adult rabbits (5-months-old). Treatment with OH-arginine (300 microM) significantly potentiated endothelium-dependent and neurogenic relaxation in corpus cavernosum from aged rabbits, while L-arginine (300 microM) did not have significant effects. 5 Results show that OH-arginine promotes NO-mediated relaxation of RCC and potentiates the NO-mediated responses induced by stimulation of endogenous NO generation in hypoxic and aged tissues. We propose that the use of OH-arginine could be of interest in the treatment of erectile dysfunction, at least in those secondary to defective NO production.
Asymmetric dimethylarginine (ADMA) elevation and arginase up‐regulation contribute to endothelial dysfunction related to insulin resistance in rats and morbidly obese humans
(Wiley, 2016) Mariam El Assar; Javier Angulo; M R Santos-Ruiz; Juan Carlos Ruíz de Adana; María Luz Pindado; Alberto Sánchez‐Ferrer; Alberto Quirantes Hernández; Leocadio Rodríguez‐Mañas
Key points The presence of insulin resistance (IR) is determinant for endothelial dysfunction associated with obesity. Although recent studies have implicated the involvement of mitochondrial superoxide and inflammation in the defective nitric oxide (NO)‐mediated responses and subsequent endothelial dysfunction in IR, other mechanisms could compromise this pathway. In the present study, we assessed the role of asymmetric dimethylarginine (ADMA) and arginase with respect to IR‐induced impairment of endothelium‐dependent vasodilatation in human morbid obesity and in a non‐obese rat model of IR. We show that both increased ADMA and up‐regulated arginase are determinant factors in the alteration of the l ‐arginine/NO pathway associated with IR in both models and also that acute treatment of arteries with arginase inhibitor or with l ‐arginine significantly alleviate endothelial dysfunction. These results help to expand our knowledge regarding the mechanisms of endothelial dysfunction that are related to obesity and IR and establish potential therapeutic targets for intervention. Abstract Insulin resistance (IR) is determinant for endothelial dysfunction in human obesity. Although we have previously reported the involvement of mitochondrial superoxide and inflammation, other mechanisms could compromise NO‐mediated responses in IR. We evaluated the role of the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) and arginase with respect to IR‐induced impairment of l ‐arginine/NO‐mediated vasodilatation in human morbid obesity and in a non‐obese rat model of IR. Bradykinin‐induced vasodilatation was evaluated in microarteries derived from insulin‐resistant morbidly obese (IR‐MO) and non‐insulin‐resistant MO (NIR‐MO) subjects. Defective endothelial vasodilatation in IR‐MO was improved by l ‐arginine supplementation. Increased levels of ADMA were detected in serum and adipose tissue from IR‐MO. Serum ADMA positively correlated with IR score and negatively with pD 2 for bradykinin. Gene expression determination by RT‐PCR revealed not only the decreased expression of ADMA degrading enzyme dimethylarginine dimethylaminohydrolase (DDAH)1/2 in IR‐MO microarteries, but also increased expression of arginase‐2. Arginase inhibition improved endothelial vasodilatation in IR‐MO. Analysis of endothelial vasodilatation in a non‐obese IR model (fructose‐fed rat) confirmed an elevation of circulating and aortic ADMA concentrations, as well as reduced DDAH aortic content and increased aortic arginase activity in IR. Improvement of endothelial vasodilatation in IR rats by l ‐arginine supplementation and arginase inhibition provided functional corroboration. These results demonstrate that increased ADMA and up‐regulated arginase contribute to endothelial dysfunction as determined by the presence of IR in human obesity, most probably by compromising arginine availability. The results provide novel insights regarding the mechanisms of endothelial dysfunction related to obesity and IR and establish potential therapeutic targets for intervention.
Calcium dobesilate potentiates endothelium‐derived hyperpolarizing factor‐mediated relaxation of human penile resistance arteries
(Wiley, 2003) Javier Angulo; Pedro Cuevas; Argentina Fernández; Sonia Gabancho; Sebastián Videla; Iñigo Sáenz de Tejada
1 We have evaluated the participation of endothelium-derived hyperpolarizing factor (EDHF) in the endothelium-dependent relaxation of isolated human penile resistance arteries (HPRA) and human corpus cavernosum (HCC) strips. In addition, the effect of the angioprotective agent, calcium dobesilate (DOBE), on the endothelium-dependent relaxation of these tissues was investigated. 2 Combined inhibition of nitric oxide synthase (NOS) and cyclooxygenase (COX) nearly abolished the endothelium-dependent relaxation to acetylcholine (ACh) in HCC, while 60% relaxation of HPRA was observed under these conditions. Endothelium-dependent relaxation of HPRA resistant to NOS and COX inhibition was prevented by raising the extracellular concentration of K(+) (35 mM) or by blocking Ca(2)(+)-activated K(+) channels, with apamin (APA; 100 nM) and charybdotoxin (CTX; 100 nM), suggesting the involvement of EDHF in these responses. 3 Endothelium-dependent relaxation to ACh was markedly enhanced by DOBE (10 micro M) in HPRA but not in HCC. The potentiating effects of DOBE on ACh-induced responses in HPRA, remained after NOS and COX inhibition, were reduced by inhibition of cytochrome P450 oxygenase with miconazole (0.3 mM) and were abolished by high K(+) or a combination of APA and CTX. 4 In vivo, DOBE (10 mg kg(-1) i.v.) significantly potentiated the erectile responses to cavernosal nerve stimulation in male rats. 5 EDHF plays an important role in the endothelium-dependent relaxation of HPRA but not in HCC. DOBE significantly improves endothelium-dependent relaxation of HPRA mediated by EDHF and potentiates erectile responses in vivo. Thus, EDHF becomes a new therapeutic target for the treatment of erectile dysfunction (ED) and DOBE could be considered a candidate for oral therapy for ED.
The phosphodiesterase inhibitory selectivity and the in vitro and in vivo potency of the new PDE5 inhibitor vardenafil
(Springer Nature, 2001) I Sáenz de Tejada; Javier Angulo; Pedro Cuevas; Aranzazu Fernández-Martínez; Ignacio Moncada; A Allona; Eva M Peñas- LLedó; HG Körschen; Ulrich Niewöhner; Helmut Haning
Vardenafil enhances clitoral and vaginal blood flow responses to pelvic nerve stimulation in female dogs
(Springer Nature, 2003) Javier Angulo; Pedro Cuevas; B. Cuevas; Erwin Bischoff; I Sáenz de Tejada