Is Blue Light the Next Little Blue Pill?: Effects of Light‐Stimulation on Erectile Dynamics

Abstract

INTRODUCTIONMany major risk factors for erectile dysfunction (ED) are associated with depressed nitric oxide (NO) availability. Phosphodiesterase type 5 inhibitors are the current first line therapy for ED and are ineffective in 30–50% of patients, largely due to impaired NO production. New therapeutic approaches for ED are needed under such conditions. The phenomenon of light‐stimulated vasodilation has recently been described in aortic tissue, which is enhanced by G‐protein coupled receptor kinase 2 (GRK2) inhibition and particular for blue light. The objective of this project was to determine if this GRK2 sensitive photorelaxation response is active in erectile tissue and the contribution of the NO signaling pathway to the response.METHODSYoung male mice (n = 4–8 / experiment) were sacrificed and erectile tissue was harvested from the shaft of the penis. Ex vivo constriction and relaxation responses were assessed in a muscle strip myograph. The GRK2‐sensitive photorelaxation response was assessed ± 1 μM GRK2 inhibitor using nine different wavelengths (365–700 nm) of light at constant intensity (100 Lux), and then at nine different light intensities (1–1000 Lux) at 455 nm. The contribution of the NO signaling pathway to the GRK2‐sensitive response was tested with stimulations of 20 and 100 Lux at 455 nm with 1 μM GRK2 inhibitor ± the NO synthase inhibitor L‐NAME, the soluble guanylate cyclase (sGC) inhibitor ODQ, the protein kinase G (PKG) inhibitor Rp‐8‐Br‐cGMPS, or the NO scavenger cPTIO, as well as in tissue from mice with a deletion of endothelial + neuronal NO synthase. Differences in responses were determined by two‐way repeated measures ANOVA followed by Sidak’s post hoc test where appropriate.RESULTSMaximal relaxation responses at 455 nm increased with increasing light intensity in the absence (2–10%) and presence (57–103%) of the GRK2 inhibitor, demonstrating a stark increase in photorelaxation under GRK2 inhibition. However, this response waned more rapidly at intensities > 100 Lux. Significant GRK2‐sensitive responses were observed at 365, 395, 430, and 455 nm at 100 Lux intensity, with no significant responses observed in the 490–700 nm range. Both L‐NAME and deletion of endothelial/neuronal NO synthase increased the magnitude of relaxation at all time‐points at 20 Lux, and prolonged maximal relaxation at 100 Lux. CPTIO prolonged the relaxation response at both intensities. ODQ drastically blunted the photorelaxation response at all time points and intensities. Rp‐8‐Br‐cGMPS had no effect on photorelaxation.CONCLUSIONSGRK2‐sensitive photorelaxation was determined to be optimal in the 430–455 nm (violet‐blue) range at ~100 Lux. Depletion of NO by scavenging, enzyme inhibition or genetic deletion enhanced the response, which is sGC‐dependent but PKG‐independent. These findings have implications for treatment of ED due to low NO availability if the GRK2‐sensitive photorelaxation pathway can be harnessed therapeutically.