(434) Photoresponsive sGC Activator, GSK-Rosa, Improves Erectile Function in Rats Without Lowering Blood Pressure

Introduction Impairment of endothelial function and nerve transmission in the corpus cavernosum reduces the release of nitric oxide (NO), leading to erectile dysfunction (ED). In these cases, the effectiveness of phosphodiesterase type 5 (PDE-5) inhibitors, the first-line treatment for ED, is limited. Therefore, it is important to investigate alternative approaches that directly activate the NO/soluble guanylate cyclase (sGC) pathway to effectively treat patients with refractory ED. In our previous studies, we found that GSK2181236A, a direct sGC activator, significantly enhanced erectile function in rats. However, it also caused a marked decrease in blood pressure. To overcome this, we developed GSK-Rosa, a photoresponsive sGC activator allowing spatial control of drug activity by green light. Objective In this study, we investigated the effects of GSK-Rosa and green light irradiation on erectile function and blood pressure in rats. Methods Eight 8-week-old male Sprague-Dawley rats were used. Blood pressure and intracavernosal pressure (ICP) were monitored under isoflurane anesthesia. The cavernous nerve was electrically stimulated (5.0 V, 2/4/8 Hz for 1 min) before the administration. Then, GSK-Rosa (1.0×10-4 M, 100 μl) was administered via the crus of the penis. The cavernous nerve was electrically stimulated under identical conditions, while green light (568 nm, 46 mW/cm2) was simultaneously irradiated onto the penis. Erectile function was assessed using the maximum ICP/mean arterial pressure (MAP) ratio. Blood pressure reduction was assessed by comparing MAP values before and after drug administration. Results The ICP/MAP ratio increased significantly under each stimulation (2Hz: pre- 0.29±0.08, post- 0.49±0.11, p<0.05; 4Hz: pre- 0.45±0.11, post- 0.62±0.10, p<0.05; 8Hz: pre- 0.52±0.14, post- 0.64±0.08, p<0.05). There was no difference in blood pressure reduction before and after GSK-Rosa administration and light exposure (2Hz: pre- 10%±3%, post- 13%±5%, n.s.; 4Hz: pre- 13%±5%, post- 12%±3%, n.s.; 8Hz: pre- 12%±4%, post- 14%±3%, n.s.). Conclusions GSK-Rosa and green light irradiation significantly enhanced erectile function in rats while minimizing adverse effects on blood pressure. This approach may offer a new treatment option for patients with refractory ED due to NO deficiency. Disclosure No