STIM/Orai Inhibition as a Strategy for Alleviating Diabetic Erectile Dysfunction Through Modulation of Rat and Human Penile Tissue Contractility and in vivo Potentiation of Erectile Responses

Stromal interaction molecule (STIM)/Orai calcium entry system appears to have a role in erectile dysfunction (ED) pathophysiology but its specific contribution to diabetic ED was not elucidated. To evaluate STIM/Orai inhibition on functional alterations associated with diabetic ED in rat and human p...

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Published in:Journal of sexual medicine 2022-12, Vol.19 (12), p.1733-1749
Main Authors: Sevilleja-Ortiz, Alejandro, El Assar, Mariam, García-Gómez, Borja, La Fuente, José M., Alonso-Isa, Manuel, Romero-Otero, Javier, Martínez-Salamanca, Juan I., Fernández, Argentina, Rodríguez-Mañas, Leocadio, Angulo, Javier
Format: Article
Language:English
Subjects:
Adrenergic Agents - metabolism
Adrenergic Agents - pharmacology
Adrenergic Agents - therapeutic use
Animals
Diabetes
Diabetes Mellitus, Experimental - complications
Diabetes Mellitus, Type 2 - complications
Erectile Dysfunction
Erectile Dysfunction - drug therapy
Erectile Dysfunction - etiology
Human Corpus Cavernosum
Human Penile Arteries
Humans
Male
Orai Channels
Penile Erection
Penis - blood supply
Phosphodiesterase 5 Inhibitors - therapeutic use
Rat Corpus Cavernosum
Rats
Stromal Interaction Molecules - metabolism
Thromboxanes - metabolism
Thromboxanes - pharmacology
Thromboxanes - therapeutic use
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Summary:Stromal interaction molecule (STIM)/Orai calcium entry system appears to have a role in erectile dysfunction (ED) pathophysiology but its specific contribution to diabetic ED was not elucidated. To evaluate STIM/Orai inhibition on functional alterations associated with diabetic ED in rat and human penile tissues and on in vivo erectile responses in diabetic rats. Rat corpus cavernosum (RCC) strips from nondiabetic (No DM) and streptozotocin-induced diabetic (DM) rats and human penile resistance arteries (HPRA) and corpus cavernosum (HCC) from ED patients undergoing penile prosthesis insertion were functionally evaluated in organ chambers and wire myographs. Erectile function in vivo in rats was assessed by intracavernosal pressure (ICP) responses to cavernous nerve electrical stimulation (CNES). Expression of STIM/Orai elements in HCC was determined by immunofluorescence and immunoblot. Functional responses in RCC, HCC and HPRA and STIM/Orai protein expression in HCC. In vivo erectile responses to CNES. Inhibition of Orai channels with YM-58483 (20 µM) significantly reduced adrenergic contractions in RCC but more effectively in DM. Thromboxane-induced and neurogenic contractions were reduced by STIM/Orai inhibition while defective endothelial, neurogenic and PDE5 inhibitor-induced relaxations were enhanced by YM-58483 (10 µM) in RCC from DM rats. In vivo, YM-58483 caused erections and attenuated diabetes-related impairment of erectile responses. YM-58483 potentiated the effects of PDE5 inhibition. In human tissues, STIM/Orai inhibition depressed adrenergic and thromboxane-induced contractions in ED patients more effectively in those with type 2 diabetes. Diabetes was associated with increased expression of Orai1 and Orai3 in ED patients. Targeting STIM/Orai to alleviate diabetes-related functional alterations of penile vascular tissue could improve erectile function and potentiate therapeutic effects of PDE5 inhibitors in diabetic ED. Improving effects of STIM/Orai inhibition on diabetes-related functional impairment was evidenced in vitro and in vivo in an animal model and validated in human tissues from ED patients. Functional findings were complemented with expression results. Main limitation was low numbers of human experiments due to limited human tissue availability. STIM/Orai inhibition alleviated alterations of functional responses in vitro and improved erectile responses in vivo in diabetic rats, potentiating the effects of PDE5 inhibition. STIM/O
ISSN:1743-6095
1743-6109
DOI:10.1016/j.jsxm.2022.08.200