Systemic propranolol reduces b-wave amplitude in the ERG and increases IGF-1 receptor phosphorylation in rat retina

Abstract

Purpose: To determine whether systemic application of propranolol, a nonselective beta-adrenergic receptor antagonist, with an osmotic pump will decrease the b-wave amplitude of the electroretinogram (ERG) and increase insulin-like growth factor (IGF)-1 receptor signaling.

Methods: Young rats at 8 weeks of age were treated with saline, phentolamine, a nonselective alpha-adrenergic receptor antagonist, or propranolol, a nonselective beta-adrenergic receptor antagonist, delivered by osmotic pumps for 21 days. On the 21st day, all rats underwent electroretinographic analyses followed by collection of the retinas for protein assessment using Western blot analysis for IGF binding protein 3 (IGFBP3), IGF-1 receptor (IGF-1R), Akt, extracellular signal-related kinases 1 and 2 (ERK1/2), and vascular endothelial cell growth factor (VEGF).

Results: Data indicate that 21 days of propranolol significantly decreased the b-wave amplitude of the ERG. The decrease in the b-wave amplitude occurred concurrently with a decrease in IGFBP3 levels and an increase in tyrosine phosphorylation of IGF-1 receptor on 1135/1136. This phosphorylation of IGF-1 receptor led to increased phosphorylation of Akt and ERK1/2. VEGF protein levels were also increased.

Conclusions: Overall, beta-adrenergic receptor antagonism produced a dysfunctional ERG, which occurred with an increase in IGF-1R phosphorylation and activation of VEGF. Systemic application of beta-adrenergic receptor antagonists may have detrimental effects on the retina.

Figure 1.

Top: electroretinographic recordings from a rat treated with saline (left), propranolol (middle), and phentolamine (right) for 21 days. Bottom: line graph of the mean of five animals from each treatment group for 21 days. Error bars represent mean ± SD for the b-wave amplitude of each treatment group at the 21-day point.

Figure 2.

Top: representative blot and bar graph of IGFBP3 protein levels in the retina of saline-, propranolol-, and phentolamine-treated rats at 21 days of treatment. *P < 0.05 versus saline (n = 4). Bottom: representative blots and bar graph of the ratio of phosphorylated IGF-1R to total IGF-1R on tyrosine 1135/1136 in the retinas of saline-, propranolol-, and phentolamine-treated rats after 21 days of treatment. *P < 0.05 versus saline (n = 4).

Figure 3.

Representative blot and bar graph of phosphorylated Akt (Ser473) to total Akt in the retinas of treated rats. *P < 0.05 versus saline (n = 4).

Figure 4.

Blots and bar graph of phosphorylated ERK1/2 to total ERK1/2 in the retinas of saline-, propranolol-, and phentolamine-treated rats. ERK1/2 was increased after both α-adrenergic receptor and β-adrenergic receptor blockade. *P < 0.05 versus saline (n = 4).

Figure 5.

Protein levels of VEGF in saline-, propranolol-, and phentolamine-treated rat retinas after 21 days of treatment. *P < 0.05 versus saline (n = 4).