Pioglitazone, a peroxisome proliferator-activated receptor-γ agonist, induces dilation of isolated porcine retinal arterioles: role of nitric oxide and potassium channels.

Purpose: Pioglitazone, a peroxisome proliferator-activated receptor (PPAR)-γ agonist, has anti-inflammatory and atheroprotective effects on vascular tissue and may reduce cardiovascular risk in patients with diabetes. The effect of pioglitazone on the retinal microvascular diameter was examined, and it was determined whether the effect depends on the endothelium and/or potassium channels in smooth muscle to reveal the signaling mechanisms involved in this vasomotor activity.

Methods: Porcine retinal arterioles were isolated, cannulated, and pressurized without flow in vitro. Video microscopic techniques recorded diametric responses to pioglitazone.

Results: The retinal arterioles dilated in a concentration-dependent (10 nM-10 μM) manner in response to pioglitazone and decreased by 60% after endothelium removal. The nitric oxide (NO) synthase inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME) inhibited pioglitazone-induced vasodilation comparable to denudation. Inhibition of soluble guanylyl cyclase (1H-1,2,4-oxadiazolo[4,3-a]quinoxalin-1-one), blockade of phosphatidylinositol (PI) 3-kinase (wortmannin), and pretreatment with compound C, an AMP-activated protein kinase (AMPK) inhibitor, were comparable to l-NAME. Pioglitazone-induced vasodilation also was inhibited by a nonselective K(+) channel blocker, tetraethylammonium, and a voltage-gated K(+) (Kv) inhibitor, 4-aminopyridine (4-AP). Treatment with intraluminal and extraluminal GW9662, a PPAR-γ antagonist, similarly inhibited pioglitazone-induced vasodilation. Co-administration of l-NAME and 4-AP almost eliminated pioglitazone-induced vasodilation.

Conclusions: Pioglitazone elicits endothelium-dependent and -independent dilation of retinal arterioles mediated by NO release and Kv channel activation, respectively. The NO-mediated dilation pathway probably occurs via activation of guanylyl cyclase, PI3-kinase/Akt, and AMPK signaling. Understanding the effect of pioglitazone on retinal vasculature may provide new insights into therapeutic advances for treating diabetic retinopathy.