Biomedical subjects

Javier Angulo

Publications and source records attributed to Javier Angulo.

12 recordsLinked to original sources

PubMed2006

Enhanced thromboxane receptor-mediated responses and impaired endothelium-dependent relaxation in human corpus cavernosum from diabetic impotent men: role of protein kinase C activity.

We have evaluated the influence of protein kinase C (PKC) activity on penile smooth muscle tone in tissues from diabetic and nondiabetic men with erectile dysfunction. Human corpus cavernosum (HCC) strips were obtained from impotent diabetic and nondiabetic men at the time of penile prosthesis implantation and studied in organ chambers. Contractility responses to a prostanoid precursor, to prostanoids, and to the endothelium-dependent vasodilator acetylcholine were studied. Arachidonic acid (AA; 100 microM) caused cyclooxygenase-dependent relaxation of HCC. This relaxation was impaired in diabetic tissues and normalized by blocking thromboxane (TP) receptors with 20 nM [1S-[1alpha,2alpha(Z),3alpha,4alpha]]-7-[3-[[2-[(phenylamino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (SQ29548). Diabetes did not affect prostaglandin (PG)E(1)-induced relaxation, but it reduced relaxation induced by the PGE(1) metabolite PGE(0). This effect was related to an interaction of PGE(0) with TP receptors. Diabetic tissues had reduced endothelium-dependent relaxation, which was partially improved by SQ29548 and completely normalized by the PKC inhibitor 3-[1-[3-(dimethylaminopropyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione monohydrochloride (GF109203X; 1 microM). In HCC from nondiabetic patients, treatment with the PKC activator phorbol-12,13-dibutyrate (0.3 microM) significantly attenuated endothelium-dependent relaxation, an effect prevented by coadministration of GF109203X. Tissues from diabetic patients had enhanced sensitivity to the contractile effects of the TP receptor agonist 9,11-dideoxy-9alpha,11alpha-epoxymethano PGF(2alpha) (U46619) (EC(50) = 0.65 +/- 0.42 and 6.01 +/- 2.28 nM in diabetic and nondiabetic patients, respectively). Inhibition of PKC with 1 microM GF109203X, prevented diabetes-induced hypersensitivity to U46619-induced contractions (EC(50) = 8.55 +/- 3.12 microM). Overactivity of PKC in diabetes is responsible for enhanced contraction and reduced endothelium-dependent relaxation of HCC smooth muscle. Such alterations can result in erectile dysfunction.

Alprostadil↗

PubMed2006

Extent of prostate-specific antigen contamination in the Spanish section of the European Randomized Study of Screening for Prostate Cancer (ERSPC).

OBJECTIVES: The performance of tests outside prostate cancer screening trials (PSA contamination) may affect their statistical power. The present study addressed the extent of PSA contamination in the Spanish section of the European Randomized Study of Screening for Prostate Cancer (ERSPC) and its impact on biopsy performance and prostate cancer detection. METHODS: Data linkage was performed to address screening-related interventions outside the study. Four databases were used: (1) Spanish ERSPC database (n=4278), (2) laboratory database with all PSA determinations (n=31,140), (3) database of 1608 prostate biopsies, and (4) records of all prostate cancers (n=819) diagnosed at our centre. PSA contamination, biopsy performance, and cancer detection rates were calculated. RESULTS: Median follow-up time was 6.6 yr. A total of 2201 PSA determinations were performed for 1253 men. Cumulative PSA contamination was 29.3% (17% in the control arm during the first 4 yr). A higher proportion of men undergoing biopsies was found in the screening arm (21.3% vs. 2.9% in the control arm, p<0.0001). Similarly, higher cancer detection rates were found in the screening (4.7% vs. 1.2% in the control arm, p<0.0001). CONCLUSIONS: In our experience, the PSA contamination rate has increased during the last years, but its impact on biopsy performance and cancer detection in the control arm of the trial is limited and not likely to compromise the statistical power of the ERSPC trial.

Aged↗

PubMed2006

Antidepressant-induced inhibition of genital vascular responses is reversed by vardenafil in female rabbits.

INTRODUCTION: Administration of serotonin reuptake inhibitors (SRI) or serotonin and norepinephrine reuptake inhibitors (SNRI) relieves depressive symptoms but may cause sexual dysfunction in women and men. AIM: The aim of the present study was to evaluate the effects of the phosphodiesterase type 5 (PDE5) inhibitor, vardenafil, on inhibition of genital vascular responses (GVR) induced by SRI or SNRI administration in female rabbits. METHODS: Vaginal and clitoral vasodilatory responses to pelvic nerve electrical stimulation were measured by laser Doppler flow needle probes. RESULTS: GVR were significantly potentiated by vardenafil even at the low dose of 0.1 mg/kg, in clitoris and vagina (181 +/- 22% and 180 +/- 31% of control, in vagina and clitoris, respectively, at 8 Hz). The selective SRI, paroxetine (5 mg/kg), significantly inhibited GVR in female rabbits (54 +/- 5% and 48 +/- 6% of control). GVR were also significantly inhibited by the SNRIs, venlafaxine (5 mg/kg) (57 +/- 3% and 32 +/- 11%) and duloxetine (1 mg/kg) (40 +/- 7% and 28 +/- 5%). Treatment with vardenafil (0.1 and 0.3 mg/kg) completely reversed the inhibition of GVR induced by paroxetine, venlafaxine, or duloxetine. CONCLUSIONS: Potentiation of the nitric oxide (NO) pathway by vardenafil improves vascular sexual responses in female rabbits and overcomes the inhibitory effects of acutely administered antidepressants on GVR, irrespective of the underlying pathophysiologic mechanism, i.e., disruption of the NO pathway or enhancement of alpha-adrenergic mechanisms. PDE5 inhibition may represent a reasonable approach to treat SRI- or SRNI-induced female sexual dysfunction, in particular, arousal disorders.

Animals↗

PubMed2005

Pathophysiology of erectile dysfunction.

INTRODUCTION: Multiple regulatory systems are involved in normal erectile function. Disruption of psychological, neurological, hormonal, vascular, and cavernosal factors, individually, or in combination, can induced erectile dysfunction (ED). The contribution of neurogenic, vascular, and cavernosal factors was thoroughly reviewed by our committee, while psychological and hormonal factors contributing to ED were evaluated by other committees. AIM: To provide state of the art knowledge on the physiology of ED. METHODS: An international consultation in collaboration with the major urology and sexual medicine associations assembled over 200 multidisciplinary experts from 60 countries into 17 committees. Committee members established specific objectives and scopes for various male and female sexual medicine topics. The recommendations concerning state-of-the-art knowledge in the respective sexual medicine topic represent the opinion of experts from five different continents developed in a process over a 2-year period. Concerning the pathophysiology of ED committee, there were seven experts from five different countries. MAIN OUTCOME MEASURE: Expert opinion was based on the grading of evidence-based medical literature, widespread internal committee discussion, public presentation, and debate. RESULTS: The epidemiology and classification of neurogenic ED was reviewed. The evidence for the association between vascular ED and atherosclerosis/hypercholesterolemia, hypertension and diabetes was evaluated. In addition, the pathophysiological mechanisms implicated in vascular ED were defined, including: arterial remodeling, increased vasoconstriction, impaired neurogenic vasodilatation, and impaired endothelium-dependent vasodilatation. The possible mechanisms underlying the association between chronic renal failure and ED were also evaluated as well as the evidence supporting the association of ED with various classes of medications. CONCLUSIONS: A better understanding of how diseases interfere with the physiological mechanisms that regulate penile erection has been achieved over the last few years, which helps establish a strategy for the prevention and treatment of ED.

Cardiovascular Agents↗

PubMed2005

Enhancement of both EDHF and NO/cGMP pathways is necessary to reverse erectile dysfunction in diabetic rats.

AIMS AND METHODS: Phosphodiesterase 5 (PDE5) inhibitors are less effective in the treatment of erectile dysfunction (ED) in diabetic men than in nondiabetic patients. We have evaluated the effects of sildenafil, a PDE5 inhibitor that enhances the nitric oxide (NO)/cGMP pathway, calcium dobesilate (DOBE), which potentiates endothelium-derived hyperpolarizing factor (EDHF)-mediated responses and the combination of both on erectile responses elicited by cavernosal nerve electrical stimulation (CNES) in a rat model of ED after 8 weeks of streptozotocin-induced diabetes. RESULTS: After 8 weeks of diabetes, erectile responses to CNES were significantly decreased in diabetic animals compared with nondiabetic time controls. While intravenous administration of sildenafil (0.3 mg/kg) or DOBE (10 mg/kg), individually, enhanced erectile responses in nondiabetic rats (214.7 +/- 34.1% and 268.5 +/- 30.1% of control response at 1 Hz, respectively), each failed to significantly enhance erectile responses in diabetic rats. Only when administered in combination did DOBE and sildenafil markedly potentiate erectile responses in these animals (380.1 +/- 88.6% of control response at 1 Hz), completely restoring erectile function. CONCLUSIONS: These findings emphasize the importance of NO/cGMP and EDHF pathways for normal erectile function. They also give support to the in vitro observation that diabetes impairs NO and EDHF-dependent responses, precluding the complete recovery of erectile function with PDE5 inhibitors and explaining the relatively poor clinical response of diabetic men with ED to PDE5 inhibition. Finally, our study suggests that a pharmacological approach that combines enhancement of NO/cGMP and EDHF pathways could be necessary to treat ED in many diabetic men.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2004

Mechanisms for the inhibition of genital vascular responses by antidepressants in a female rabbit model.

Vaginal and clitoral vasodilator responses (genital vascular responses; GVRs) to pelvic nerve electrical stimulation in female rabbits were measured by laser Doppler flow needle probes. The intravenous administration of various treatments was evaluated. GVRs were attenuated by a nitric-oxide synthase inhibitor (48.5 and 51.8% of control at 8 Hz in the vagina and clitoris, respectively) and norepinephrine (NE) (78.5 and 61.5%), whereas serotonin (5-HT) had no inhibitory effect. The selective 5-HT reuptake inhibitor (SSRI) escitalopram did not modify GVRs, whereas the SSRI paroxetine dose-dependently inhibited GVRs in female rabbits (43.3 and 53.1% at 5 mg/kg). GVRs were also significantly inhibited by the 5-HT and NE reuptake inhibitors venlafaxine (53.4 and 52.6% at 5 mg/kg) and duloxetine (40.9 and 37.4% at 1 mg/kg). L-arginine prevented the inhibitory effects of paroxetine (105.5 and 115.3%) and partially prevented duloxetine-induced reduction of GVRs but had no effect on the inhibition of GVRs induced by venlafaxine. Conversely, the alpha-adrenergic receptor blocker phentolamine had no effect on paroxetine-induced reduction of GVRs, partially prevented the inhibitory effects of duloxetine, and fully prevented the effects of venlafaxine (93.0 and 96.7%). Duloxetine-induced inhibition of GVRs was completely prevented by combined administration of L-arginine and phentolamine (123.5 and 103.6%). Although 5-HT or the highly selective SRI escitalopram did not inhibit GVRs, NE or inhibition of nitric oxide (NO) synthesis did. Inhibition of the NO pathway by paroxetine and duloxetine or activation of alpha-adrenergic mechanisms by venlafaxine and duloxetine lead to antidepressant-induced inhibition of GVRs in female rabbits.

Adrenergic Uptake Inhibitors↗

PubMed2004

Physiology of erectile function.

INTRODUCTION: There are numerous investigations concerning the balance and interactions between relaxant and contractile factors regulating penile smooth muscle (arterial and trabecular) tone, the determinant of penile flaccidity or erection. Enhanced knowledge of erectile physiology may improve management of men with erectile dysfunction. Aim. To provide state-of-the-art knowledge on the physiology of erectile function. METHODS: An international consultation in collaboration with the major urology and sexual medicine associations assembled over 200 multidisciplinary experts from 60 countries into 17 committees. Committee members established specific objectives and scopes for various male and female sexual medicine topics. The recommendations concerning state-of-the-art knowledge in the respective sexual medicine topic represent the opinion of experts from five continents developed in a process over a two-year period. Concerning the physiology of erectile function and pathophysiology of erectile dysfunction committee, there were seven experts from five countries. MAIN OUTCOME MEASURE: Expert opinion was based on the grading of evidence-based medical literature, widespread internal committee discussion, public presentation, and debate. RESULTS: Key roles in the mechanism determining the tone of penile smooth muscle are played by the rise of the intracellular concentration of free calcium and the sensitivity of the contractile machinery to calcium, endothelial health, endothelium-derived nitric oxide, endothelium-derived hyperpolarizing factor (EDHF), neuronal nitric oxide, cyclic guanosine monophosphate-dependent protein kinase and phosphodiesterase type 5. CONCLUSIONS: A number of new mechanisms have been identified for the local regulation of penile smooth muscle contractility and therefore penile erection. Molecules participating in these pathways can be considered targets for the development of new treatments to treat erectile dysfunction.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2003

Diabetes impairs endothelium-dependent relaxation of human penile vascular tissues mediated by NO and EDHF.

Standard treatments for erectile dysfunction (ED) (i.e., PDE5 inhibitors) are less effective in diabetic patients for unknown reasons. Endothelium-dependent relaxation (EDR) of human corpus cavernosum (HCC) depends on nitric oxide (NO), while in human penile resistance arteries (HPRA) endothelium-derived hyperpolarizing factor (EDHF) and NO participate. Here we show that diabetes significantly reduced EDR induced by acetylcholine (ACh) in HCC and HPRA. Relaxation attributed to EDHF was also impaired in HPRA from diabetic patients. The PDE5 inhibitor, sildenafil (10nM), reversed diabetes-induced endothelial dysfunction in HCC, but not in HPRA. Calcium dobesilate (DOBE; 10 microM) fully reversed diabetes-induced endothelial dysfunction in HPRA by specifically potentiating the EDHF-mediated component of EDR. Impairment by diabetes of NO and EDHF-dependent responses precluded the complete recovery of endothelial function in HPRA by sildenafil. This could explain the poor clinical response to PDE5 inhibitors of diabetic men with ED and suggests that a pharmacological approach that combines enhancement of NO/cGMP and EDHF pathways could be necessary to treat ED in many diabetic men.

Acetylcholine↗

PubMed2003

Activation and potentiation of the NO/cGMP pathway by NG-hydroxyl-L-arginine in rabbit corpus cavernosum under normoxic and hypoxic conditions and ageing.

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.

Aging↗

PubMed2003

Calcium dobesilate potentiates endothelium-derived hyperpolarizing factor-mediated relaxation of human penile resistance arteries.

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.

Animals↗

PubMed2002

Regulation of human penile smooth muscle tone by prostanoid receptors.

We have characterized the prostanoid receptors involved in the regulation of human penile arterial and trabecular smooth muscle tone. Arachidonic acid induced relaxation of human corpus cavernosum strips (HCCS) that was blocked by the cyclo-oxygenase inhibitor, indomethacin, and augmented by the thromboxane receptor (TP) antagonist, SQ29548, suggesting that endogenous production of prostanoids regulates penile smooth muscle tone. TP-receptors mediate contraction of HCCS and penile resistance arteries (HPRA), since the agonist of these receptors, U46619, potently contracted HCCS (EC50 8.3+/-2.8 nM) and HPRA (EC50 6.2+/-2.2 nM), and the contractions produced by prostaglandin F(2alpha) at high concentrations (EC50 6460+/-3220 nM in HCCS and 8900+/-6700 nM in HPRA) were inhibited by the selective TP-receptor antagonist, SQ29548 (0.02 microM). EP-receptors are responsible for prostanoid-induced relaxant effects in HCCS because only prostaglandin E1 (PGE1), prostaglandin E2 and the EP2/EP4-receptor agonist, butaprost, produced consistent relaxation of this tissue (EC50 93.8+/-31.5, 16.3+/-3.8 and 1820+/-1284 nM, respectively). In HPRA, both prostacyclin and PGE1 (EC50 60.1+/-18.4 and 109.0+/-30.9 nM, respectively) as well as the selective IP receptor agonist, cicaprost, and butaprost (EC50 25.2+/-15.2 and 7050+/-6020 nM, respectively) caused relaxation, suggesting co-existence of IP- and EP-receptors (EP2 and/or EP4). In summary, endogenous production of prostanoids may regulate penile smooth muscle contractility by way of specific receptors. TP-receptors mediate contraction in HCCS and HPRA, while the relaxant effects of prostanoids are mediated by EP2- and/or EP4-receptors in HCCS and by EP- and IP-receptors in HPRA.

Alprostadil↗

PubMed2002

Autocrine regulation of human prostate carcinoma cell proliferation by somatostatin through the modulation of the SH2 domain containing protein tyrosine phosphatase (SHP)-1.

The present study was intended to gain additional information on the growth regulation of prostate by somatostatin (SRIF) and the intracellular events involved. The human prostate adenocarcinoma cell lines PC-3 and LNCaP produce SRIF and express subtypes 2 and 5 of SRIF receptors. The secretion of SRIF is related to the proliferative status of these cells; an inverse relationship exists between cell proliferation and the amount of secreted SRIF. Moreover, the growth of PC-3 cells is inhibited by SRIF overexpression and increased by blockage of endogenous SRIF. Coincident with the increase in SRIF secretion, the activity and levels of the SH2 domain containing protein tyrosine phosphatase (SHP)-1, present in PC-3 cells are augmented, but the effect can be partially prevented by neutralization of secreted endogenously SRIF. The activity of SHP-1 is also stimulated by the SRIF analog RC160. Overexpression of SHP-1 induces inhibition of PC-3 cell growth. SHP-1 is also present in normal prostate, benign prostatic hyperplasia, prostatic intraepithelial neoplasia, and well differentiated adenocarcinoma. In contrast, no signal is detected in poorly differentiated prostate cancer. These findings demonstrate that SRIF inhibits PC-3 and LNCaP cell proliferation through an autocrine/paracrine SRIF loop. This effect could be mediated by activation of the tyrosine phosphatase SHP-1 detected in these cells as well as in human prostate and prostate cancer.

Autocrine Communication↗