Preretinal neovascularization associated with acetazolamide-induced systemic acidosis in the neonatal rat

PURPOSE. NH4Cl gavage in the neonatal rat produces a metabolic acidosis-ind uced retinopathy which serves as a model for retinopathy of prematurity (RO P). Acetazolamide induces a metabolic acidosis via an alternative biochemic al mechanism (bicarbonate loss versus hydrogen ion load). In the present st udy, the following hypothesis was tested: acetazolamide-induced acidosis is associated with preretinal neovascularization in the neonatal rat. METHODS. All studies used newborn Sprague-Dawley rats raised in expanded Li tters of 25. Arterial blood pH was measured to determine the level of acido sis induced by intraperitoneal (IP) acetazolamide (50 or 200 mg/kg) or sali ne In a separate retinopathy study, newborn rats (n = 75) were randomized t o either IP acetazolamide, 50 mg/kg (low-dose), or IP saline twice daily fr om days 2 to 7, After S days of recovery, retinal vasculature was assessed using ADPase staining and light microscopy. The presence and severity (cloc k hours) of neovascularization were assessed by three masked observers. In an additional retinopathy study, newborn rats (n = 100) were randomized to either IP acetazolamide, 200 mg/kg (high-dose), or IP saline twice daily fr om days 2 to 7. After 5 days of recovery, the retinas were similarly analyz ed. RESULTS. Neovascularization occurred in 59% of rats receiving high-dose ace tazolamide (200 mg/kg). High-dose acetazolamide produced a severe acidosis (pH 7.13 +/- 0.06) during drug delivery. Low-dose acetazolamide (50 mg/kg) produced a pH (7.22 +/- 0.07) that was intermediate between high-dose (200 mg/kg) acetazolamide (P < 0.001) and saline controls (7.42 <plus/minus> 0.0 6, P < 0.001); however, neither low-dose acetazolamide nor saline induced p reretinal neovascularization. CONCLUSIONS. Acidosis induced by high-dose acetazolamide, independent of hy peroxemia or hypoxemia, is associated with preretinal neovascularization in the neonatal rat. Induction of neovascularization appears to depend on a c ritical threshold of acidosis severity. This study further supports a propo sed independent role for acidosis in the pathogenesis of ROP.