Prazosin Prevents the Glucocorticoid‐Induced Capillary Rarefaction in Skeletal Muscle

Abstract

Prolonged exposure to elevated glucocorticoids (GC) results in skeletal muscle capillary rarefaction, which may promote insulin resistance and limb ischemia. Conversely, treatment with the a1‐adrenergic receptor inhibitor prazosin increases muscle blood flow and stimulates angiogenesis. We hypothesized that prazosin treatment would prevent GC‐induced capillary rarefaction and improve markers of insulin resistance. Corticosterone (Cort) or placebo (wax) pellets (400mg/rat) were implanted subcutaneously in young male Sprague‐Dawley rats. Two days after, prazosin was administered in the animal's drinking water (50mg/L). Plasma levels of Cort correlated significantly with fasting plasma insulin levels (r=0.76), suggesting that sustained elevations in Cort resulted in insulin resistance; this relationship was unaffected by prazosin (r=0.78). Skeletal muscle capillary‐to‐fiber ratio (C:F) correlated inversely with fasted plasma insulin levels (r=‐0.77) and with plasma Cort levels (r=‐0.62). In 16‐day Cort‐treated animals, prazosin significantly increased mRNA levels of pro‐angiogenic VEGF‐A but not levels of anti‐angiogenic thrombospondin‐1 (TSP1), thus resulting in an elevated ratio of VEGF‐A to TSP1. Most notably, the Cort‐induced capillary rarefaction (2.0+0.08 vs. 1.6+0.08) was prevented with prazosin treatment (1.6+0.08 vs. 2.0+0.11). Fasting plasma insulin increased dramatically with Cort (0.51+0.02 vs. 4.1+0.5ng/ml, P<0.05), and improved slightly with prazosin treatment (4.1+0.5 vs. 3.7+0.3ng/ml, P<0.05). This study demonstrates the potential benefits of prazosin in preventing the GC‐induced loss of capillaries and lowering fasting plasma insulin levels (Funding: NSERC and HSF Canada).