Potential sites of action of TNPA: a dopamine-2 receptor agonist.
The purpose of this study was to correlate potential mechanisms with site(s) of action for TNPA-induced ocular hypotension. In response to R(-)-2, 10, 11-trihydroxy-N-propyl-noraporphine hydrobromide (TNPA, 75 microg), a D2 dopamine receptor agonist, the intraocular pressure decreased by 4.5 and 8 mm Hg at 1 and 2 hr, respectively, as measured by pneumatonometry. The levels of norepinephrine in aqueous humor, as determined by high performance liquid chromatography with electrochemical detection, were reduced by 38% and 79% at 1 and 2 hr, respectively, following topical application of TNPA (75 microg). Following pretreatment with raclopride (750 microg), a D2 receptor antagonist, and a subsequent challenge with TNPA (75 microg), the depression of intraocular pressure and levels of norepinephrine induced by TNPA (75 microg, 2 hr) were antagonized. In order to examine sites of action, immunohistochemistry of D2 dopamine receptors was performed in the ciliary body of normal and sympathetically denervated rabbits utilizing a goat polyclonal D2 receptor IgG and anti-goat IgG-FITC. Results from immunolocalization experiments demonstrated that D2 receptors are present on postganglionic sympathetic nerves in the ciliary body of normal rabbits but minimally detectable in that of sympathectomized rabbits. It is concluded that immunohistochemical identification of D2 receptors in the ciliary body associated with the suppression of aqueous norepinephrine levels by topical application of the D2 receptor agonist, TNPA, provide strong evidence of prejunctional (neuronal) site of action of TNPA. Antagonism of TNPA-induced ocular hypotension by raclopride coupled with the immunohistochemical and norepinephrine data suggest that D2 dopamine receptors are located on postganglionic sympathetic neurons in the ciliary body.
Chu
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Department of Pharmacology and Toxicology, Morehouse School of Medicine, Atlanta, Georgia 30310-1495, USA.
Chu
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Potter
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D000287:Administration, Topical; D000704:Analysis of Variance; D000818:Animals; D001060:Aporphines / Q000008:administration & dosage* / Q000494:pharmacology; D001082:Aqueous Humor / Q000737:chemistry / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002924:Ciliary Body / Q000378:metabolism; D003864:Depression, Chemical; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D007150:Immunohistochemistry; D007429:Intraocular Pressure / Q000187:drug effects*; D009638:Norepinephrine / Q000032:analysis / Q000378:metabolism; D011817:Rabbits; D020891:Raclopride / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D013562:Sympathectomy
D001060:Aporphines; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D017448:Receptors, Dopamine D2; D020891:Raclopride; C031796:2,10,11-trihydroxy-N-n-propylnoraporphine; D009638:Norepinephrine