Metabolic acidosis-induced retinopathy in the neonatal rat

PURPOSE. Carbon dioxide (CO₂)-induced retinopathy (CDIR) in the neonatal rat, analogous to human retinopathy of prematurity (ROP), was previously described by our group. In this model, it is possible that CO₂- associated acidosis provides a biochemical mechanism for CDIR. Therefore, the effect of pure metabolic acidosis on the developing retinal vasculature of the neonatal rat was investigated. METHODS. A preliminary study of arterial blood pH was performed to confirm acidosis in our model. In neonatal rats with preplaced left carotid artery catheters, acute blood gas samples were taken 1 to 24 hours after garage with either NH₄Cl 1 millimole/100 g body weight or saline. In the subsequent formal retinopathy study, 150 newborn Sprague-Dawley rats were raised in litters of 25 and randomly assigned to be gavaged twice daily with either NH₄Cl 1 millimole/100 g body weight (n = 75) or saline (n = 75) from day 2 to day 7. After 5 days of recovery, rats were killed, and retinal vasculature was assessed using fluorescein perfusion and ADPase staining techniques. RESULTS. In the preliminary pH study, the minimum pH after NH₄Cl garage was 7.10 ± 0.10 at 3 hours (versus 7.37 ± 0.03 in controls, mean ± SD, P < 0.01). In the formal retinopathy study, preretinal neovascularization occurred in 36% of acidotic rats versus 5% of controls (P < 0.001). Acidotic rats showed growth retardation (final weight 16.5 ± 3.0 g versus 20.2 ± 2.6 g, P < 0.001). The ratio of vascularized to total retinal area was smaller in acidotic rats (94% ± 4% versus 96% ± 2%, P < 0.001). CONCLUSIONS. Metabolic acidosis alone induces neovascularization similar to ROP in the neonatal rat. This suggests a possible biochemical mechanism by which high levels of CO₂ induce neovascularization and supports the suggestion that acidosis may be an independent risk factor for ROP.