Human Penile Arteries Research Articles

Short-term pharmacological activation of Nrf2 ameliorates vascular dysfunction in aged rats and in pathological human vasculature. A potential target for therapeutic intervention

Oxidative stress contributes to endothelial dysfunction, a key step in cardiovascular disease development. Ageing-related vascular dysfunction involves defective antioxidant response. Nuclear factor erythroid 2-like-2 (Nrf2), orchestrates cellular response to oxidative stress. We evaluated the impact of Nrf2-activation on endothelium-dependent and H2O2-mediated vasodilations in: aorta (RA), mesenteric artery (RMA), coronary artery (RCA) and corpus cavernosum (RCC) from ageing rats and in human penile arteries (HPRA) and corpus cavernosum (HCC) from erectile dysfunction (ED) patients. Relaxant responses were evaluated in organ chambers and wire myographs. Nrf2 content and heme oxygenase-1 (HO-1) were determined by ELISA. Superoxide and Nrf2 were detected by immunofluorescence. Pharmacological activation of Nrf2 with sulforaphane (SFN) improved NO- and endothelium-derived hyperpolarizing factor-mediated endothelium-dependent vasodilation and H2O2-induced relaxation in vascular beds from aging rats. SFN-induced effects were associated with increased Nrf2 (RMA, RCA) and reduced superoxide detection in RCA. Improvement of vascular function was confirmed in HPRA and HCC from ED patients and mimicked by another Nrf2 activator, oltipraz. Nrf2 increase and superoxide reduction together with HO-1 increase by Nrf2 activation was evidenced in HCC from ED patients. PDE5 inhibitor-induced relaxations of HPRA and HCC from ED patients were enhanced by SFN. Nrf2 short-term pharmacological activation attenuates age-related impairment of endothelium-dependent and reactive oxygen species (ROS)-induced vasodilation in different rat and human vascular territories by upregulation of Nrf2-related signaling and decreased oxidative stress. In ED patients target tissues, Nrf2 potentiates the functional effect of ED conventional pharmacological therapy suggesting potential therapeutic implication.

MP47-14 PIOGLITAZONE IS PROTECTIVE AGAINST POST-PROSTATECTOMY ERECTILE DYSFUNCTION

INTRODUCTION AND OBJECTIVES: Penile smooth muscle tone is finely tuned by neurogenic stimuli. Alteration of neurogenic regulation could cause an imbalance in favour of contractile stimuli and compromise erection. We have previously observed that calcium-activated potassium channel (KCa) stimulation enhances vasodilatory capacity of PDE5 inhibitors in human penile arteries. The aim of this work was to evaluate the impact of KCa modulation on the neurogenic regulation of cavernosal smooth muscle tone in rats and humans. METHODS: Rat corpus cavernosum (RCC) was obtained from thirty 12-16 weeks old male Sprague-Dawley rats. Human corpus cavernosum (HCC) strips were obtained from 20 patients with erectile dysfunction (ED) who gave informed consent at the time of penile prosthesis implantation. RCC and HCC were mounted in organ chambers and responses to electrical field stimulation (EFS) were evaluated. RESULTS: EFS caused reproducible, frequency-dependent contractions in RCC. Blockade of KCa with tertaethylammonium (TEA) markedly potentiated neurogenic contractions (16Hz, 67.2 3.2% vs. 105.6 4.6% at 5mM, p<0.001) but did not modify norepinephrineinduced contractions. By using specific KCa subtype blockers, largeconductance KCa (BK) appeared as responsible for modulation of neurogenic contractions. Stimulation of BK with NS1619 significantly inhibited EFS-induced contractions in RCC (67.5 5.4% vs. 39.3 5.8%, p<0.01 at 30mM). BK stimulation also caused a significant potentiation of EFS-induced relaxations in phenylephrine-contracted RCC treated with guanethidine and atropine (2 Hz, 31.8 6.9% vs. 64.9 6.7%, p<0.01). Similar results were obtained in HCC where TEA caused concentration-dependent enhancement of EFS-induced contractions (35.3 3.4% vs. 118.5 32.0% at 5mM, p<0.01) while BK activation with NS1619 (30mM) inhibited neurogenic contractions and potentiated neurogenic relaxations. CONCLUSIONS: BK participates in regulation of neurogenic control of cavernosal smooth muscle tone. Pharmacological stimulation of these channel would favor relaxant responses over contractile input in rat and human cavernosal tissue. Thus, BK stimulation could be a reasonable strategy for treating ED mainly in situations involving imbalanced regulation of neurogenic control.

MP47-13 CALCIUM-ACTIVATED POTASSIUM CHANNEL (KCA) STIMULATION MODULATES NEUROGENIC CONTRACTION AND FAVOURS NEUROGENIC RELAXATION IN RAT AND HUMAN CORPUS CAVERNOSUM

You have accessJournal of UrologySexual Function/Dysfunction/Andrology: Basic Research II1 Apr 2014MP47-13 CALCIUM-ACTIVATED POTASSIUM CHANNEL (KCA) STIMULATION MODULATES NEUROGENIC CONTRACTION AND FAVOURS NEUROGENIC RELAXATION IN RAT AND HUMAN CORPUS CAVERNOSUM Juan I. Martínez-Salamanca, José M. La Fuente, Argentina Fernández, Eduardo Martínez-Salamanca, Joaquín Carballido, and Javier Angulo Juan I. Martínez-SalamancaJuan I. Martínez-Salamanca More articles by this author , José M. La FuenteJosé M. La Fuente More articles by this author , Argentina FernándezArgentina Fernández More articles by this author , Eduardo Martínez-SalamancaEduardo Martínez-Salamanca More articles by this author , Joaquín CarballidoJoaquín Carballido More articles by this author , and Javier AnguloJavier Angulo More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1466AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Introduction and Objectives Penile smooth muscle tone is finely tuned by neurogenic stimuli. Alteration of neurogenic regulation could cause an imbalance in favour of contractile stimuli and compromise erection. We have previously observed that calcium-activated potassium channel (KCa) stimulation enhances vasodilatory capacity of PDE5 inhibitors in human penile arteries. The aim of this work was to evaluate the impact of KCa modulation on the neurogenic regulation of cavernosal smooth muscle tone in rats and humans. Methods Rat corpus cavernosum (RCC) was obtained from thirty 12-16 weeks old male Sprague-Dawley rats. Human corpus cavernosum (HCC) strips were obtained from 20 patients with erectile dysfunction (ED) who gave informed consent at the time of penile prosthesis implantation. RCC and HCC were mounted in organ chambers and responses to electrical field stimulation (EFS) were evaluated. Results EFS caused reproducible, frequency-dependent contractions in RCC. Blockade of KCa with tertaethylammonium (TEA) markedly potentiated neurogenic contractions (16Hz, 67.2±3.2% vs. 105.6±4.6% at 5mM, p<0.001) but did not modify norepinephrine-induced contractions. By using specific KCa subtype blockers, large-conductance KCa (BK) appeared as responsible for modulation of neurogenic contractions. Stimulation of BK with NS1619 significantly inhibited EFS-induced contractions in RCC (67.5±5.4% vs. 39.3±5.8%, p<0.01 at 30μM). BK stimulation also caused a significant potentiation of EFS-induced relaxations in phenylephrine-contracted RCC treated with guanethidine and atropine (2 Hz, 31.8±6.9% vs. 64.9±6.7%, p<0.01). Similar results were obtained in HCC where TEA caused concentration-dependent enhancement of EFS-induced contractions (35.3±3.4% vs. 118.5±32.0% at 5mM, p<0.01) while BK activation with NS1619 (30μM) inhibited neurogenic contractions and potentiated neurogenic relaxations. Conclusions BK participates in regulation of neurogenic control of cavernosal smooth muscle tone. Pharmacological stimulation of these channel would favor relaxant responses over contractile input in rat and human cavernosal tissue. Thus, BK stimulation could be a reasonable strategy for treating ED mainly in situations involving imbalanced regulation of neurogenic control. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e523 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Juan I. Martínez-Salamanca More articles by this author José M. La Fuente More articles by this author Argentina Fernández More articles by this author Eduardo Martínez-Salamanca More articles by this author Joaquín Carballido More articles by this author Javier Angulo More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Ca2+ -activated K+ channel (KCa) stimulation improves relaxant capacity of PDE5 inhibitors in human penile arteries and recovers the reduced efficacy of PDE5 inhibition in diabetic erectile dysfunction.

We have evaluated the influence of calcium-activated potassium channels (KCa ) activation on cGMP-mediated relaxation in human penile tissues from non-diabetic and diabetic patients, and on the effects of PDE5 inhibitors on erectile responses in control and diabetic rats. Cavernosal tissues were collected from organ donors and from patients with erectile dysfunction (ED). Relaxations of corpus cavernosum strips (HCC) and penile resistance arteries (HPRA) obtained from these specimens were evaluated. Intracavernosal pressure (ICP) increases to cavernosal nerve electrical stimulation were determined in anaesthetized diabetic and non-diabetic rats. Concentration-dependent vasodilation to the PDE5 inhibitor, sildenafil, in HPRA was sensitive to endothelium removal, NO/cGMP pathway inhibition and KCa blockade. Accordingly, activation of KCa with NS-8 (10 μM) significantly potentiated sildenafil-induced relaxations in HPRA (EC50 0.49 ± 0.22 vs. 5.21 ± 0.63 μM). In HCC, sildenafil-induced relaxation was unaffected by KCa blockade or activation. Potentiating effects in HPRA were reproduced with an alternative PDE5 inhibitor (tadalafil) and KCa activator (NS1619) and prevented by removing the endothelium. Large-conductance KCa (BK) and intermediate-conductance KCa (IK) contribute to NS-8-induced effects and were immunodetected in human and rat penile arteries. NS-8 potentiated sildenafil-induced enhancement of erectile responses in rats. Activation of KCa recovered the impaired relaxation to sildenafil in diabetic HPRA while sildenafil completely reversed diabetes-induced ED in rats only when combined with KCa activation. Activation of KCa improves vasodilatory capacity of PDE5 inhibitors in diabetic and non-diabetic HPRA, resulting in the recovery of erectile function in diabetic rats. These results suggest a therapeutic potential for KCa activation in diabetic ED.

Nebivolol Dilates Human Penile Arteries and Reverses Erectile Dysfunction in Diabetic Rats through Enhancement of Nitric Oxide Signaling

Traditional beta-blockers have sometimes been associated with erectile dysfunction (ED). Nebivolol is a cardioselective β(1)-adrenoceptor antagonist that promotes vasodilation through a nitric oxide (NO)-dependent mechanism. We evaluated the effects of nebivolol on the NO/cyclic guanosine monophosphate (cGMP) signaling pathway, on erectile function and dysfunction, and in human penile vascular tissues. Erectile response to cavernosal nerve electrical stimulation in control and diabetes-induced ED rats were evaluated, along with serum nitrite/nitrate (NOx) concentration and plasma/tissue cGMP levels. Endothelium-dependent and sildenafil-induced relaxation of isolated human corpus cavernosum (HCC) and human penile resistance arteries (HPRA) were also determined. The effects of nebivolol on erectile function and dysfunction and on NO/cGMP-mediated responses. Treatment with nebivolol significantly potentiated erectile response in control rats, regardless of its effects on blood pressure. Nebivolol increased NOx and plasma cGMP by 3-fold and 2.75-fold, respectively, and significantly augmented the elevation of plasma cGMP produced by sildenafil. Nebivolol enhanced endothelium-dependent and sildenafil-induced relaxations of HCC tissue, and produced endothelium-dependent vasodilation of HPRA. Nebivolol, but not atenolol, significantly improved erectile response in diabetic rats (51.6%, 53.2%, and 87.1% of response at 3 Hz in nondiabetic rats, for vehicle-treated, atenolol-treated, and nebivolol-treated diabetic rats, respectively); after sildenafil administration, ED was completely reversed in nebivolol-treated diabetic rats (69.6% and 112% for diabetic rats treated with sildenafil and nebivolol plus sildenafil, respectively). Accordingly, nebivolol restored systemic NOx levels and cGMP content in penile tissue from these animals. Nebivolol in vivo activated the NO/cGMP pathway, enhanced erectile response and reversed ED in diabetic rats. Moreover, nebivolol in vitro potentiated NO/cGMP-mediated relaxation of human erectile tissues. These effects may account for the low incidence of ED in nebivolol-treated hypertensive patients. Nebivolol therefore may have utility in the treatment of ED, particularly ED associated with diabetes.

Relaxation induced by milrinone and rolipram in human penile arteries and veins

We studied the relaxant effects of milrinone, an inhibitor of phosphodiesterase 3, and rolipram, an inhibitor of phosphodiesterase 4, on contracted human penile dorsal artery and deep dorsal vein. Vascular rings from 12 multi-organ donors were suspended in organ baths for isometric recording of tension. Both milrinone and rolipram inhibited (100%) the contraction induced by noradrenaline and shifted the relaxation–response curves to the cAMP forming agents prostaglandin E 1 and forskolin to the left. The findings indicate that the cAMP pathway appears to be a main determinant of relaxation in human penile vessels.

Effects of sildenafil on human penile blood vessels

Objectives. To investigate the effects of sildenafil on human penile blood vessels and evaluate the interaction of sildenafil with neurogenic-mediated responses. Sildenafil is currently used in the treatment of erectile dysfunction. Methods. Penile dorsal arteries and deep dorsal veins were obtained from 14 multiorgan donors. Vascular rings were suspended in organ bath chambers, and the isometric tension was recorded. We then studied the effects of sildenafil on precontracted vessels and the neurogenic (noradrenergic and nitrergic) responses. Results. Sildenafil (10 −9 to 3 × 10 −6 M) caused concentration-dependent relaxation and amplified the relaxation induced by sodium nitroprusside. Relaxation was unaffected by the inhibitor of nitric oxide synthase N G-monomethyl- l-arginine (10 −4 M). Compared with zaprinast, sildenafil was 8 to 10 times more potent in terms of the median effective concentration (EC 50) values. Electrical field stimulation of the vessels under resting tension caused frequency-dependent contractions that were attenuated in the presence of sildenafil. When penile vessels were contracted after blockade of norepinephrine release with guanethidine (10 −6 M), electrical stimulation induced frequency-dependent, nitric oxide-dependent relaxations that were enhanced by sildenafil. Conclusions. These results indicate that the relaxation of human penile arteries and veins induced by sildenafil involves inhibition of noradrenergic contraction, enhancement of neurogenic nitric oxide-mediated relaxation, and inhibition of smooth muscle contraction.