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Potassium channel and NKCC cotransporter involvement in ocular refractive control mechanisms.

Crewther SG, Murphy MJ, Crewther DP - PLoS ONE (2008)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: School of Psychological Science, La Trobe University, Melbourne, Australia. s.crewther@latrobe.edu.au

ABSTRACT
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.

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The effect on refractive and growth compensation of blocking retinal and RPE potassium channels with intravitreal Ba2+ ion at an effective concentration of 5mM.A. Scatter plot of Refraction in dioptres versus Vitreous Chamber depth (mm). across all eyes measured. The applied defocus is indicated by the triangles or circle symbols, with green symbols indicating Ba2+ and blue symbols indicating saline injected eyes. B. Refractions of eyes injected with Ba2+ compared with those injected with similar volume of Saline. Compensation in Ba2+ eyes is suppressed for both positive and negative lens defocus. The same colour code applies as for A. C. Vitreous chamber depths of Ba2+ and SAL eyes. An inverse relationship between vitreous chamber depth and refraction is evident. The same colour code applies as for A. The effect of defocus on VC depth is much less for Ba2+ than for SAL eyes, however the mean VC depth for Ba2+ eyes averaged over all lens groups is very similar to that for SAL eyes. This indicates that Ba2+ does not inhibit eye growth per se, but suppresses compensation to defocus-related eye growth. Data presented as means±SE.
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pone-0002839-g001: The effect on refractive and growth compensation of blocking retinal and RPE potassium channels with intravitreal Ba2+ ion at an effective concentration of 5mM.A. Scatter plot of Refraction in dioptres versus Vitreous Chamber depth (mm). across all eyes measured. The applied defocus is indicated by the triangles or circle symbols, with green symbols indicating Ba2+ and blue symbols indicating saline injected eyes. B. Refractions of eyes injected with Ba2+ compared with those injected with similar volume of Saline. Compensation in Ba2+ eyes is suppressed for both positive and negative lens defocus. The same colour code applies as for A. C. Vitreous chamber depths of Ba2+ and SAL eyes. An inverse relationship between vitreous chamber depth and refraction is evident. The same colour code applies as for A. The effect of defocus on VC depth is much less for Ba2+ than for SAL eyes, however the mean VC depth for Ba2+ eyes averaged over all lens groups is very similar to that for SAL eyes. This indicates that Ba2+ does not inhibit eye growth per se, but suppresses compensation to defocus-related eye growth. Data presented as means±SE.

Mentions: Potassium channels were blocked via intravitreal injection of barium chloride to a vitreal concentration of approximately 5mM. Retinoscopy and ultrasonography demonstrated that while saline injected eyes showed about 85% refractive compensation to the applied defocus over the four days of rearing, barium suppressed refractive compensation to both positive and negative lenses, but did not significantly affect refractive state for the chicks reared with focused vision (0D group). A generally negative linear relationship between refraction and vitreous chamber depth is clearly evident in the data - across all lens groups and the two drug groups (Ba2+, SAL), the data fall along a main trend line (see Figure 1A). A between group Analysis of Variance (ANOVA) (for Lens Defocus (+10D, 0D, −10D) and Treatment (Ba2+, Saline)) demonstrated a significant main effect of Lens Defocus (F(2,59) = 61.1, p<.0001) but not of Treatment on ocular refraction (F(1,59) = 0.98, p = .32). A significant interaction between Lens Defocus and Treatment was also observed (F2,59 = 16.2, p<.0001), - see Fig 1B. Post-hoc tests showed the suppression of compensation to defocus by Ba2+, with significant refractive difference for both positive and negative lenses compared with saline injected eyes (Fisher's PLSD, p<.005) (see Table 1).


Potassium channel and NKCC cotransporter involvement in ocular refractive control mechanisms.

Crewther SG, Murphy MJ, Crewther DP - PLoS ONE (2008)

The effect on refractive and growth compensation of blocking retinal and RPE potassium channels with intravitreal Ba2+ ion at an effective concentration of 5mM.A. Scatter plot of Refraction in dioptres versus Vitreous Chamber depth (mm). across all eyes measured. The applied defocus is indicated by the triangles or circle symbols, with green symbols indicating Ba2+ and blue symbols indicating saline injected eyes. B. Refractions of eyes injected with Ba2+ compared with those injected with similar volume of Saline. Compensation in Ba2+ eyes is suppressed for both positive and negative lens defocus. The same colour code applies as for A. C. Vitreous chamber depths of Ba2+ and SAL eyes. An inverse relationship between vitreous chamber depth and refraction is evident. The same colour code applies as for A. The effect of defocus on VC depth is much less for Ba2+ than for SAL eyes, however the mean VC depth for Ba2+ eyes averaged over all lens groups is very similar to that for SAL eyes. This indicates that Ba2+ does not inhibit eye growth per se, but suppresses compensation to defocus-related eye growth. Data presented as means±SE.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2481396&req=5

pone-0002839-g001: The effect on refractive and growth compensation of blocking retinal and RPE potassium channels with intravitreal Ba2+ ion at an effective concentration of 5mM.A. Scatter plot of Refraction in dioptres versus Vitreous Chamber depth (mm). across all eyes measured. The applied defocus is indicated by the triangles or circle symbols, with green symbols indicating Ba2+ and blue symbols indicating saline injected eyes. B. Refractions of eyes injected with Ba2+ compared with those injected with similar volume of Saline. Compensation in Ba2+ eyes is suppressed for both positive and negative lens defocus. The same colour code applies as for A. C. Vitreous chamber depths of Ba2+ and SAL eyes. An inverse relationship between vitreous chamber depth and refraction is evident. The same colour code applies as for A. The effect of defocus on VC depth is much less for Ba2+ than for SAL eyes, however the mean VC depth for Ba2+ eyes averaged over all lens groups is very similar to that for SAL eyes. This indicates that Ba2+ does not inhibit eye growth per se, but suppresses compensation to defocus-related eye growth. Data presented as means±SE.
Mentions: Potassium channels were blocked via intravitreal injection of barium chloride to a vitreal concentration of approximately 5mM. Retinoscopy and ultrasonography demonstrated that while saline injected eyes showed about 85% refractive compensation to the applied defocus over the four days of rearing, barium suppressed refractive compensation to both positive and negative lenses, but did not significantly affect refractive state for the chicks reared with focused vision (0D group). A generally negative linear relationship between refraction and vitreous chamber depth is clearly evident in the data - across all lens groups and the two drug groups (Ba2+, SAL), the data fall along a main trend line (see Figure 1A). A between group Analysis of Variance (ANOVA) (for Lens Defocus (+10D, 0D, −10D) and Treatment (Ba2+, Saline)) demonstrated a significant main effect of Lens Defocus (F(2,59) = 61.1, p<.0001) but not of Treatment on ocular refraction (F(1,59) = 0.98, p = .32). A significant interaction between Lens Defocus and Treatment was also observed (F2,59 = 16.2, p<.0001), - see Fig 1B. Post-hoc tests showed the suppression of compensation to defocus by Ba2+, with significant refractive difference for both positive and negative lenses compared with saline injected eyes (Fisher's PLSD, p<.005) (see Table 1).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: School of Psychological Science, La Trobe University, Melbourne, Australia. s.crewther@latrobe.edu.au

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus