Alpha-2 adrenoceptor mediated changes in aqueous dynamics: effect of pertussis toxin.
Because alpha-2 (alpha 2) adrenoceptor-mediated inhibition of signal transduction mechanisms is regulated, in part, by inhibitory G (Gi) protein, we studied the effects of pertussis toxin (PTX) pretreatment on alpha 2 adrenergic agonist, UK 14,304-18 (UK; brimonidine)-induced: (1) changes in intraocular pressure (IOP) and aqueous flow rate of rabbits; (2) modulation of 3H-norepinephrine (NE) overflow of rabbit iris-ciliary bodies (ICBs) and (3) accumulation of cyclic AMP in rabbit ICBs and cultured non-pigmented ciliary epithelial (NPE) cells. Results showed that UK (50 micrograms) lowered the IOP of normal rabbits by 8 +/- 1 mmHg (n = 8) at 3 hr when treated topically and that the reduction of IOP was accompanied by a decrease in aqueous humor inflow (35%, n = 5). Therefore, it was postulated that these UK-induced effects involve activation of a Gi protein linked to alpha 2 adrenoceptors. In PTX-pretreated (2.5 micrograms kg-1, i.a.) rabbits, hypotensive responses to UK were reduced by 50% and 70% (n = 8) at days 4 and 7 post PTX treatment, respectively. The suppression of aqueous humor inflow induced by UK was also prevented by the PTX treatment. In isolated, perfused rabbit ICBs, UK (1 microM) caused 50% inhibition of 3H-NE overflow from electrical field stimulation. Pretreatment with PTX (150 ng ml-1, 4 hr) partially prevented UK-induced inhibition of NE overflow. In in vitro assays of postjunctional alpha 2 adrenoceptor activity, UK (1 microM) inhibited isoproterenol (ISO, 1 microM)-stimulated cAMP accumulation by 45% and 48% in ICBs and NPE cells, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Ogidigben
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M
Department of Pharmacology and Toxicology, Morehouse School of Medicine, Atlanta, GA 30310.
Chu
T C
TC
Potter
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D000316:Adrenergic alpha-Agonists / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D001082:Aqueous Humor / Q000187:drug effects* / Q000502:physiology; D000068438:Brimonidine Tartrate; D000242:Cyclic AMP / Q000378:metabolism; D007429:Intraocular Pressure / Q000187:drug effects; D007700:Kinetics; D009638:Norepinephrine / Q000378:metabolism; D037342:Pertussis Toxin; D011810:Quinoxalines / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D011817:Rabbits; D014602:Uvea / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D000316:Adrenergic alpha-Agonists; D000959:Antihypertensive Agents; D011810:Quinoxalines; D010566:Virulence Factors, Bordetella; D000068438:Brimonidine Tartrate; D000242:Cyclic AMP; D037342:Pertussis Toxin; D009638:Norepinephrine