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Jose M. La Fuente, Argentina Fernández, Esther García-Rojo, Borja García-Gómez, Esaú Fernández-Pascual, Raphael Curvo, Javier Romero-Otero, Juan I. Martínez-Salamanca, Javier Angulo, Transient Receptor Potential Channel 5 (TRPC5) Inhibitor, AC1903, Produces Relaxation and Improves Endothelial Function in Human and Rat Penile Vascular Tissues., The Journal of Sexual Medicine, Volume 19, Issue Supplement_4, November 2022, Pages S3–S4, https://doi.org/10.1016/j.jsxm.2022.08.083
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Objectives
Transient receptor potential channels (TRPC) have been proposed to play a role in vascular function and vascular pathophysiology by regulating calcium signaling. Our aim was to evaluate the impact of TRPC inhibition on cavernosal tone and endothelial function in aged rats and ED patients.
Methods
The effects of the inhibitors of TRPC3, Pyr3, TRPC4, ML204, and TRPC5, AC1903, were evaluated in precontracted strips of corpus cavernosum (RCC) from young (3-months-old, 3m) and aged (20-months-old, 20m) rats and in human corpus cavernosum (HCC) and penile resistance arteries (HPRA) from ED patients undergoing penile prosthesis insertion. Effects of AC1903 on endothelial relaxation were also determined. TRPC protein expression was determined in HCC from ED patients and organ donors (NoED).
Results
Pyr3, ML204, and AC1903 produced consistent relaxations of phenylephrine-contracted corpus cavernosum from old and young rats, being the TRPC5 inhibitor the most effective (EC50 8.5±1.4 µM; Emax 83.6±5.6% in 3m, n=9, and 5.9±1.2 µM; 92.0±4.1% in 20m, n=4). Interestingly, AC1903-induced relaxations were significantly reduced by NO synthase inhibition (Emax 56.6±6.6 %, n=4, p<0.05) and remained after contracting RCC with high K+. AC1903 was also effective in relaxing HCC (EC50 6.9±1.5 µM; Emax 77.9±9.8%, n=5) and HPRA (2.5±2.0 µM; 96.2±0.8%, n=4) from ED patients. Pretreatment with AC1903 (3 µM) was able to enhance endothelium-dependent acetylcholine-induced relaxations in RCC from 20m rats (55.7±5.2% vs. 70.0±6.9%, n=4, p<0.05) and HCC from ED patients (51.6±58.5% vs. 77.5±7.2%, n=4, p<0.05). TRPC1 and TRPC3-6 proteins were detected in HCC but TRPC4 and TRPC5 expressions were relatively weak. TRPC1 and TRPC3 were increased in ED patients (n=9) with respect to NoED (n=9).
