Myopia affects well over 30% of adult humans globally. However, the underlying physiological mechanism is little understood. This study tested the hypothesis that ocular growth and refractive compensation to optical defocus can be controlled by manipulation of potassium and chloride ion-driven transretinal fluid movements to the choroid. Chicks were raised with +/-10D or zero power optical defocus rendering the focal plane of the eye in front of, behind, or at the level of the retinal photoreceptors respectively. Intravitreal injections of barium chloride, a non-specific inhibitor of potassium channels in the retina and RPE or bumetanide, a selective inhibitor of the sodium-potassium-chloride cotransporter were made, targeting fluid control mechanisms. Comparison of refractive compensation to 5 mM Ba(2+) and 10(-5) M bumetanide compared with control saline injected eyes shows significant change for both positive and negative lens defocus for Ba(2+) but significant change only for negative lens defocus with bumetanide (Rx(SAL)(-10D) = -8.6 +/- .9 D; Rx(Ba2+)(-10D) = -2.9 +/- .9 D; Rx(Bum)(-10D) = -2.9 +/- .9 D; Rx(SAL)(+10D) = +8.2 +/- .9 D; Rx(Ba2+)(+10D) = +2.8 +/- 1.3 D; Rx(Bum)(+10D) = +8.0 +/- .7 D). Vitreous chamber depths showed a main effect for drug conditions with less depth change in response to defocus shown for Ba(2+) relative to Saline, while bumetanide injected eyes showed a trend to increased depth without a significant interaction with applied defocus. The results indicate that both K channels and the NKCC cotransporter play a role in refractive compensation with NKCC blockade showing far more specificity for negative, compared with positive, lens defocus. Probable sites of action relevant to refractive control include the apical retinal pigment epithelium membrane and the photoreceptor/ON bipolar synapse. The similarities between the biometric effects of NKCC inhibition and biometric reports of the blockade of the retinal ON response, suggest a possible common mechanism. The selective inhibition of refractive compensation to negative lens in chick by loop diuretics such as bumetanide suggests that these drugs may be effective in the therapeutic management of human myopia.