Characterization of iris sphincter smooth muscle endothelin receptor subtypes which are coupled to cyclic AMP formation and polyphosphoinositide hydrolysis.

In the mammalian iris sphincter smooth muscle, endothelins (ET) activate both adenylate cyclase and the polyphosphoinositide cascade, and the levels of cyclic AMP (cAMP) and inositol 1,4,5-trisphosphate (IP3) produced are species specific. Radioligand binding studies, using [125I]ET-1 and [125I]ET-3 and determination of changes in cAMP, IP3 and contraction due to the peptides revealed the existence of ETA and ETB receptor subtypes in this tissue. In rabbit sphincter, ETA receptors constitute about 80% of total ET receptor population and these are coupled to IP3 production and contraction. In bovine sphincter, ETB receptors constitute about 72% of the total ET receptors and these are coupled to cAMP formation. Thus, in rabbit sphincter: 1) ET-1 and ET-2, two potent ETA receptor agonists, induced IP3 production and contraction at a much higher rate than ET-3, a weak ETA agonist. The EC50 for contraction by ET-1, ET-2 and ET-3 were 40, 45 and 300 nM, respectively. 2) Sarafotoxin-S6c (SRTX-c), a selective ETB receptor agonist, had no effect on IP3 and contraction in this tissue. 3) D-Asp-L-Pro-D-Val-L-Leu-D-Trp (BQ-123), a selective ETA receptor antagonist, inhibited the above responses to ET. 4) ET and SRTX-c induced cAMP formation at a much lower rate than that of IP3 and contraction. In contrast, in the bovine sphincter: 1) ET and SRTX-c induced cAMP formation in a dose-dependent manner, the order of potency being SRTX-c > ET-3 congruent to ET-2 congruent to ET-1.(ABSTRACT TRUNCATED AT 250 WORDS)