Clofibrate Acutely Reverses Saline-Induced Endothelial Dysfunction: Role of Calcium-Activated Potassium Channels

Background Endothelium-dependent vascular relaxation is impaired in various disease states including hypertension. Methods We investigated whether a single bolus dose of clofibrate could rapidly reverse saline-induced endothelial dysfunction, in vivo, in salt-loaded Sprague-Dawley (S-D) rats. S-D rats, 5 weeks of age, were divided into two groups. One group served as a control (Con) and was given tap water; the other group (Sal) was given normal saline (0.9% NaCl) ad libitum for 3 weeks. Results Mean arterial pressure (MAP) was significantly higher (138 ± 2 v 112 ± 2 mm Hg, P< .001), whereas the total plasma nitrite/nitrate levels were lower (1.7 ± 0.3 v 2.8 ± 0.2 μmol/L, P< .05) in Sal. At this time, endothelial function was assessed in vivo. Sal rats had decreased hypotensive responses to acetylcholine (ACh) but maintained normal responses to sodium nitroprusside. The ACh-induced hypotensive response was significantly inhibited by the nitric oxide synthase inhibitor, NG-nitro-l-arginine methyl ester (L-NAME, 100 mg kg−1 intraperitoneally [ip]) only in Con rats. Clofibrate (Clof, 200 mg kg−1 ip) did not change blood pressure but increased ACh-induced hypotensive responses only in Sal, an effect that was abolished by subsequent administration of apamin (Apa, 50 μg kg−1 iv) and charybdotoxin (ChTx, 50 μg kg−1 iv). Apa+ChTx blocked responses to ACh in Con and Sal, as expected. A single dose of clofibrate (200 mg kg−1 ip), given subsequently to Apa+ChTx, restored responses to ACh in both the Con and Sal groups, again without affecting baseline MAP. Conclusion Clofibrate has an acute salutary effect on endothelium-dependent vasodilation in saline-treated rats, probably mediated through vascular calcium-activated potassium channels and independent of an antihypertensive effect.