Effect of Avosentan (SSP-301) in Porcine Ciliary Arteries

Purpose: To investigate the vasoactive effect of ETA– endothelin receptor antagonist avosentan (SPP-301) and other ETA – endothelin receptor antagonist BQ-123 in isolated porcine ciliary arteries with and without endothelium. To investigate the effect of avosentan on the endothelin-1 induced contractions in comparison with BQ-123 and BQ-788 (ETB - endothelin receptor antagonist) in isolated porcine ciliary arteries with and without endothelium. Methods: Vessels were placed in a myograph system to measure isometric forces. In a first set of experiments quiescent vessels were exposed, cumulatively, to increasing concentrations of avosentan and BQ-123 (10-9M – 3x10-6M). In a second set of experiments quiescent vessels were first incubated with avosentan (10-6M and 10-8M), BQ-123 (10-6M) and BQ-788 (10-6M), respectively. Then the vessels were exposed, cumulatively, to increasing concentrations of endothelin-1 (10-12M – 3x10-8M). Each set of experiments was conducted in the vessels with and without endothelium. Results: Cumulative doses of avosentan and BQ-123 had no vasoactive effect in quiescent vessels. Avosentan had a strong inhibitory effect on the endothelin-1 induced contractions. The inhibitory effect of 10-6M avosentan was significantly stronger than the effect of 10-8M avosentan. The effect of avosentan (10-6M) tended to be stronger than the effect of BQ-123 (10-6M). To a lesser extent BQ- 788 also had inhibitory effect on the endothelin-1 induced contractions. Conclusions: Avosentan has a strong inhibitory effect on the endothelin-1 induced contractions. Blockade of ET receptors is an attractive target in many eye diseases including laucoma. Further studies are needed to evaluate the usefulness of endothelin blockers in ophthalmology