Antagonizing penile smooth muscle contraction by inhibition of orai calcium channels. A potential therapeutic target in erectile dysfunction
Angulo, J1; El Assar, M2; Romero-Otero, J3; La Fuente, JM4; Fernández, A1; Sánchez-Ferrer, A2; Sevilleja-Ortiz, A1; García-Gómez, B3; Medina-Polo, J3; Rodríguez-Mañas, L5
1: Hospital Universitario Ramón y Cajal, Spain; 2: FIBio Hospital Universitario de Getafe, Spain; 3: Hospital Universitario Doce de Octubre, Spain; 4: Hospital Santo Antonio, Portugal; 5: Hospital Universitario de Getafe, Spain
Objective: Initially considered as irrelevant for vascular smooth muscle contraction, recent evidences propose store operated calcium entry (SOCE) and its key players, stromal interaction molecule (STIM) and Orai calcium channels as emergent therapeutic targets in cardiovascular pathophysiology. The aim was to evaluate the contribution of STIM/Orai in human penile tissue contraction and to analyze the influence of erectile dysfunction (ED) at functional and expression levels.
Methods: Human penile resistance arteries (HPRA) and corpus cavernosum (HCC) were dissected from cavernosal specimens from 15 organ donors (OD) without history of ED and from 20 ED patients undergoing penile prosthesis insertion and functionally evaluated in wire myographs and organ chambers, respectively. All ED patients presented cardiovascular risk factors. Expression of STIM-1, Orai1 and Orai3 in HCC was localized and quantified by immunofluorescence.
Results: Inhibition of Orai channels with YM-58483 (20 µM) significantly reduced norepinephrine (NE)-induced contractions in both HCC and HPRA from either OD or ED subjects but the effects were more marked in ED (19.1±9.1% vs.47.3±13.1% and 11.5±2.8% vs.28.7±2.7% reduction in Emax to NE in HCC and HPRA, respectively). Thromboxane- and KCl-induced contractions were also reduced by Orai inhibition. In fact, addition of YM-58483 concentration-dependently relaxed precontracted HPRA and HCC. These relaxations were significantly more pronounced in tissues from ED patients (EC50 7.5 vs. 1.3 µM and 10.5 vs. 1.3 µM, for HCC and HPRA, respectively). All analyzed HCC specimens displayed expression of STIM-1, Orai1 and Orai3. Increased expression of Orai1 (+47.5±10.1%) and Orai3 (+82.2±14.4%, p<0.05) but not STIM-1 was observed in ED patients.
Conclusions: Orai channels significantly contribute to human penile smooth muscle contraction. Orai contribution is enhanced in ED, suggesting Orai inhibition as a potential therapeutic strategy to reduce penile contractile tone in ED.
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