Nitric oxide synthase inhibitors prevent the growth-inhibiting effects of quinpirole.
OBJECTIVE
Both dopamine and nitric oxide (NO) have been implicated in the signal cascade mediating ocular growth inhibition. If both are part of the same pathway, which precedes the other? We tested the hypothesis that dopamine acts upstream of NO, by using two NOS inhibitors in combination with the dopamine agonist quinpirole, and measured the effects on ocular growth rate.


METHODS
Chicks wore -10 D lenses or diffusers (FD) for 4 days starting at age 13 days. Experimental eyes received daily 20 μL injections of the following: quinpirole-lens: n = 12, FD: n = 20; n-ω-propyl-L-arginine (NPA)-lens: n = 6, FD: n = 4; quinpirole + NPA-lens: n = 17, FD: n = 19; and quinpirole + L-NIO-lens: n = 12, FD: n = 12. Saline injections were done as controls. High-frequency ultrasonography was done at the start, and on day 5, prior to injections and 3 hours later. Refractions were measured on day 5.


RESULTS
As expected, quinpirole prevented the development of axial myopia in both paradigms. When quinpirole was combined with either NOS inhibitor, however, eyes became myopic compared to quinpirole (FD: NPA: -5.9 D vs. -3.4 D; L-NIO: -5.8 D vs. -3.4 D; lens: NPA: -3.5 D vs. -0.4 D; p < 0.05 for all; L-NIO was not significant). This was the result of a disinhibition of vitreous chamber growth versus quinpirole (FD: NPA: 401 vs. 275 μm/4 d; L-NIO: 440 vs. 275 μm/4 d; LENS: NPA: 407 vs. 253µm/4 d; L-NIO: 403 vs. 253 μm/4 d; p < 0.05). Only NPA prevented the quinpirole-induced choroidal thickening in lens-wearing eyes (0 vs. 31 μm/3 h; p < 0.05). Choroidal thickening was not inhibited by either drug in FD eyes.


CONCLUSIONS
Dopamine acts upstream of NO and the choroidal response in the signal cascade mediating ocular growth inhibition in both form deprivation and negative lens wear. That neither NOS inhibitor inhibits choroidal thickening in FD eyes suggests that the choroidal mechanisms differ in the two paradigms.
*PhD †BA ‡MS Department of Biosciences and Disease, The New England College of Optometry, Boston, Massachusetts.
Debora L
DL
Nickla
Laimeng
L
Lee
Kristen
K
Totonelly
D000818:Animals; D000831:Animals, Newborn; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002645:Chickens; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology*; D004338:Drug Combinations; D005123:Eye / Q000000981:diagnostic imaging / Q000201:enzymology / Q000254:growth & development*; D056965:Injections, Intraocular; D009216:Myopia / Q000000981:diagnostic imaging / Q000473:pathology* / Q000517:prevention & control; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009952:Ornithine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019257:Quinpirole / Q000494:pharmacology*; D012029:Refraction, Ocular; D012683:Sensory Deprivation; D014463:Ultrasonography
D018491:Dopamine Agonists; D004338:Drug Combinations; C109599:N(omega)-propylarginine; D019257:Quinpirole; C065027:N(G)-iminoethylornithine; D001120:Arginine; D009952:Ornithine; D019001:Nitric Oxide Synthase