Alpha 1-adrenergic receptor induced subsensitivity and supersensitivity in rabbit iris-ciliary body. Effects on myo-inositol trisphosphate accumulation, arachidonate release, and prostaglandin synthesis.
Topical treatment of the rabbit eye with three successive doses of 2% epinephrine resulted in attenuation of the in vitro drug response of the alpha 1-adrenoceptor-mediated phosphoinositide hydrolysis system and of alpha 1-adrenergic receptor-mediated contraction in the iris. In contrast, sympathetic denervation of the eye resulted in potentiation of these responses. Desensitized tissues showed a significant decrease in epinephrine-induced myo-inositol trisphosphate (IP3) accumulation, 1,2-diacylglycerol (DG) formation, measured as phosphatidate, arachidonic acid (AA) liberation, measured by radiochromatography, prostaglandin (PG) E2 release, measured by radiochromatography and radioimmunoassay, and muscle contraction. Adrenergic desensitization of the eye resulted in attenuation of: The polyphosphoinositide response in the iris, measured both as loss of 32P-radioactivity from phosphatidylinositol 4,5-bisphosphate (PIP2) and as IP3 accumulation; the epinephrine-stimulated liberation of AA, from membrane phosphoinositides and other phospholipids, and PGE2 release in the iris; and the epinephrine-induced muscle contraction in the iris dilator. This adrenergic desensitization of the eye is reversible. Surgical sympathetic denervation, previously found to increase alpha 1-adrenoceptor mediated accumulation of IP3 and contraction, increased AA liberation. Dexamethasone blocked the epinephrine-induced liberation of AA and PG release, both in vivo and in vitro. These data support the hypothesis that changes in the activity of the alpha 1-adrenergic receptor-mediated phosphoinositide hydrolysis system and its derived second messengers may underlie the mechanism of adrenergic subsensitivity and supersensitivity in the iris-ciliary body. How much the desensitization of alpha 1-adrenergic receptor-mediated responses contribute to the therapeutic action of epinephrine in the eye remains to be determined.
D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D002924:Ciliary Body / Q000294:innervation* / Q000378:metabolism / Q000648:ultrastructure; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone; D004351:Drug Resistance; D004837:Epinephrine / Q000494:pharmacology; D005260:Female; D006868:Hydrolysis; D015544:Inositol 1,4,5-Trisphosphate; D007295:Inositol Phosphates / Q000378:metabolism*; D007498:Iris / Q000294:innervation* / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D011458:Prostaglandins E / Q000096:biosynthesis*; D011817:Rabbits; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D013403:Sugar Phosphates / Q000378:metabolism*; D013562:Sympathectomy
D001095:Arachidonic Acids; D007295:Inositol Phosphates; D010716:Phosphatidylinositols; D011458:Prostaglandins E; D011942:Receptors, Adrenergic, alpha; D013403:Sugar Phosphates; D016718:Arachidonic Acid; D003907:Dexamethasone; D015544:Inositol 1,4,5-Trisphosphate; D015232:Dinoprostone; D009638:Norepinephrine; D004837:Epinephrine