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Preretinal Neovascularization Associated with Acetazolamide-Induced Systemic Acidosis in the Neonatal Rat

¹ From the Departments of Ophthalmology and ² Anesthesiology, Mayo Clinic, Rochester, Minnesota; and ³ Department of Anatomy/Cell Biology/Ophthalmology, Wayne State University, Detroit, Michigan.

PURPOSE. NH₄Cl gavage in the neonatal rat produces a metabolic acidosis-induced retinopathy which serves as a model for retinopathy of prematurity (ROP). Acetazolamide induces a metabolic acidosis via an alternative biochemical mechanism (bicarbonate loss versus hydrogen ion load). In the present study, 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 litters of 25. Arterial blood pH was measured to determine the level of acidosis induced by intraperitoneal (IP) acetazolamide (50 or 200 mg/kg) or saline. In a separate retinopathy study, newborn rats (n = 75) were randomized to either IP acetazolamide, 50 mg/kg (low-dose), or IP saline twice daily from days 2 to 7. After 5 days of recovery, retinal vasculature was assessed using ADPase staining and light microscopy. The presence and severity (clock 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 from days 2 to 7. After 5 days of recovery, the retinas were similarly analyzed.

RESULTS. Neovascularization occurred in 59% of rats receiving high-dose acetazolamide (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 ± 0.06, P < 0.001); however, neither low-dose acetazolamide nor saline induced preretinal neovascularization.

CONCLUSIONS. Acidosis induced by high-dose acetazolamide, independent of hyperoxemia or hypoxemia, is associated with preretinal neovascularization in the neonatal rat. Induction of neovascularization appears to depend on a critical threshold of acidosis severity. This study further supports a proposed independent role for acidosis in the pathogenesis of ROP.

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