Sc. Zhang et al., Preretinal neovascularization associated with acetazolamide-induced systemic acidosis in the neonatal rat, INV OPHTH V, 42(5), 2001, pp. 1066-1071
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.