Abstract
Purpose: :
Sildenafil (Viagra), a selective inhibitor of phosphodiesterase type–5 (PDE5) widely used for the treatment of erectile dysfunction, produces smooth muscle relaxation and vasodilation by inhibiting cyclic GMP (cGMP) degradation. Although sildenafil has been shown to increase retinal blood flow, whether it exhibits vasodilatory action in retinal arterial vasculature is controversial. In addition to the inhibition of PDE5, sildenafil has been suggested to activate mitogen–activated protein kinases (MAPK) and protein kinase C (PKC) in some tissues. However, whether these signaling molecules are involved in vasomotor action of sildenafil remain unclear. Herein, we directly examined the response of small retinal arterioles to sildenafil and identified the signaling pathways involved in this vasomotor activity.
Methods: :
Small second–order retinal arterioles from porcine eye were isolated, cannulated, and pressurized to 55 cm H2O lumenal pressure without flow for functional study. Diameter changes in response to sildenafil were recorded by using videomicroscopic techniques. Pharmacological tools were employed to probe signaling pathways.
Results: :
Retinal arterioles developed basal tone (68±4 µm; 70±7 % of maximal internal diameter) and dilated dose–dependently to sildenafil (10 ng/mL to 1 µg/mL) with 26% maximal dilation at the highest concentration. Administration of a soluble guanylyl cyclase inhibitor 1H–[1,2,4]oxadiazolo[4,3–a]quinoxalin–1–one (0.1 µM) did not alter basal diameter of retinal arterioles but abolished vasodilation to sildenafil. Inhibition of nitric oxide synthase (NOS) by L–NAME (10 µM) or blockade of MAPK signaling by PD98059 (0.3 µM) also abolished vasodilation to sildenafil. However, treating the vessels with a non–selective PKC inhibitor chelerythrine (0.1 µM) did not affect the vasodilation.
Conclusions: :
Sildenafil elicits a significant dilation of porcine retinal arterioles. NOS activation, possibly through MAPK signaling, and the subsequent NO production for guanylyl cyclase activation is involved in the sildenafil–induced vasodilation. It appears that the elevated level of cGMP as a result of NOS activation and PDE5 inhibition leads to the dilation of retinal arterioles in response to sildenafil.
Keywords: retina • nitric oxide • pharmacology