Biphasic vasodilator action of troglitazone on the renal microcirculation

Abstract

Recent studies have demonstrated that thiazolidinediones, novel antidiabetic compounds that improve the insulin sensitivity, lower BP and decrease urinary protein excretion. However, neither the target vasculature nor the underlying mechanism for their actions is well understood. In this study, the action of troglitazone (Tro), a thiazolidinedione compound, on the glomerular afferent (Af-Arts) and efferent (Ef-Arts) arterioles, crucial vascular segments to the control of glomerular hemodynamics, were directly examined. Rabbit Af-Arts or Ef-Arts were microdissected from the superficial cortex and perfused at constant pressure. Increasing doses of Tro (10-8 to 10-5 M) were added to both the bath and lumen of preconstricted arterioles. In Af-Arts, Tro caused dose-dependent and biphasic dilation. Tro at 10-5 M increased the diameter by 28 ± 6% (n = 8, P < 0.01) until 20 min, with the diameter remaining at this level for 60 min, and then Tro began to dilate Af-Arts again. At 120 min, Tro at 10-5 M further increased the diameter by 23 ± 4% (n = 6). Disrupting the endothelium had no effect on either dilation (n = 7 or n = 5). Pretreatment with SKF 96365 (50 μM), which inhibits both voltage- and receptor-operated calcium channels, abolished the early-phase dilation without affecting the late-phase dilation; 20 or 120 min after adding Tro at 10-5 M, the diameter increased by 4 ± 2% (n = 7) or 28 ± 3% (n = 6), respectively. In contrast to Af-Arts, Tro caused monophasic dilation in Ef-Arts; Tro at 10-5 M did not cause significant dilation until 80 min, and at 120 min the diameter increased by 37 ± 4% (n = 5). These results suggest that in the Af-Art Tro has biphasic endothelium-independent vasodilator action, which is partly mediated by an inhibition of calcium influx. This vasodilator action may play a role in the BP-lowering effect of Tro. In addition, by dilating the postglomerular Ef-Art, Tro may decrease the glomerular capillary pressure and hence the excretion of urinary protein.