Sildenafil Improves Functional and Structural Outcome of Retinal Injury Following Term Neonatal Hypoxia-Ischemia

Abstract

PURPOSE. The purpose of this study was to investigate the effects of sildenafil on retinal injury following neonatal hypoxia-ischemia (HI) at term-equivalent age in rat pups.METHODS. Hypoxia-ischemia was induced in male Long-Evans rat pups at postnatal day 10 (P10) by a left common carotid ligation followed by a 2-hour exposure to 8% oxygen. Shamoperated rats served as the control group. Both groups were administered vehicle or 2, 10, or 50 mg/kg sildenafil, twice daily for 7 consecutive days. Retinal function was assessed by flash electroretinograms (ERGs) at P29, and retinal structure was assessed by retinal histology at P30.RESULTS. Hypoxia-ischemia caused significant functional (i.e., attenuation of the ERG a-wave and b-wave amplitudes and photopic negative response) and structural (i.e., thinning of the total retina, especially the inner retinal layers) retinal damage in the left eyes (i.e., ipsilateral to the carotid ligation). Treatment with the different doses of sildenafil led to a dose-dependent increase in the amplitudes of the ERG a-and b-waves and of the photopic negative response in HI animals, with higher doses associated with greater effect sizes. Similarly, a dose response was observed in terms of improvements in the retinal layer thicknesses.CONCLUSIONS. Hypoxia-ischemia at term-equivalent age induced functional and structural damage mainly to the inner retina. Treatment with sildenafil provided a dose-dependent recovery of retinal function and structure.

Clinical Pharmacology of Sildenafil in Infants and Children

“…Sildenafil is well tolerated in children with idiopathic pulmonary arterial hypertension [11]. The effects of sildenafil have reported in infants and children [12][13][14][15][16][17][18]. Sildenafil increases foetal body-weight at birth [12] and intravenous sildenafil improves oxygenation in infants [13].…”

“…Sildenafil increases foetal body-weight at birth [12] and intravenous sildenafil improves oxygenation in infants [13]. Treatment with sildenafil recovers neonatal retinal function and structure and these effects are dose dependent [14]. Oral sildenafil improves oxygenation index in infants with severe persistent pulmonary hypertension [15].…”

“…Treatment of newborn infants with intravenous sildenafil, during the first day of life, is associated with acute improvement in oxygenation in more than 40% of infants [13]. Treatment with sildenafil provides a dosedependent recovery of neonatal retinal function and structure [14]. Oral sildenafil is administered easily and tolerated as well as placebo and improves oxygenation index in infants with severe persistent pulmonary hypertension [15].…”

Quantify retinal structure in high-altitude residents with and without high altitude polycythemia

“…Hypoxia and hypobaric nature in high-altitude (HA) area could cause pathologic changes in cardiovascular system, respiratory system and nervous system [1]. The retina is one of the most active tissues, hence pathological level of hypoxia may firstly cause functional and structural changes in retina [2][3][4][5][6][7][8]. Hemorrhages, cotton wool spots, and papilledema that occurred during acute exposure to HA environment are known as high-altitude retinopathy (HAR) [9][10][11].…”

Cardiopulmonary Impact of Hypoxic Ischemic Encephalopathy in Newborn Infants. The Emerging Role of Early Hemodynamic Assessment in Determining Adverse Neurological Outcomes

“…This study is timely, as the ability of a cardiac dysfunction to predict the impact of hypoxic insults on neurological outcomes has been elusive, and these results may pave the way for new strategies to address the contribution of RV dysfunction to neurological injury and/or recovery. Recent studies have shown that agents that address RV function may be associated with brain recovery in animal models of HIE (5, 6). So far, two mechanisms of cardiac dysfunction have been described in neonates with a perinatal hypoxic insult: 1 ) depressed LV function from the initial insult that is further exacerbated by reactive oxygen species (from the reperfusion injury), leading to reduced normalQ. and pulmonary venous hypertension; and 2 ) hypoxia vasoconstriction of the pulmonary vascular bed, leading to elevated pulmonary vascular resistance and acute pulmonary hypertension physiology (3).…”