Oxidized LDL Increases the Sensitivity of the Contractile Apparatus in Isolated Resistance Arteries for Ca via a Rho- and Rho Kinase–Dependent Mechanism

Background—Oxidized LDL reduces NO-mediated and endothelium-derived hyperpolarizing factor–mediated dilations. We studied, in hamster skeletal muscle resistance arteries (21368 mm; n551), whether an altered vascular smooth muscle (VSM) response, particularly sensitization of the VSM contractile apparatus to Ca, is involved in this oxLDL effect. Methods and Results—VSM or endothelial [Ca]i and vascular diameter were measured in response to norepinephrine (0.3 mmol/L), sodium nitroprusside (10 mmol/L), C-type natriuretic peptide (1 to 100 nmol/L), papaverine (0.1 to 10 mmol/L), or the endothelial agonist acetylcholine (ACh, 0.01 to 1 mmol/L). OxLDL significantly increased resting VSM [Ca]i (1163%), decreased diameter (862%), and enhanced norepinephrine-induced constrictions. Dilations to sodium nitroprusside and C-type natriuretic peptide were significantly reduced (by 1062% and 3566%), whereas dose-response curves for papaverine and ACh were shifted to the right, despite unchanged increases in endothelial Ca after ACh. OxLDL significantly shifted the Ca-diameter relation to the left, as assessed by stepwise increasing extracellular Ca (0 to 3 mmol/L) in depolarized skeletal muscle resistance arteries. This sensitization to Ca by oxLDL was abolished after inhibition of Rho (C3 transferase) or Rho kinase (Y27632). Conclusions—OxLDL reduces VSM responsiveness to vasodilators by increasing VSM Ca but preferentially by sensitizing VSM to Ca via a Rhoand Rho kinase–dependent pathway. (Circulation. 2000;102:2402-2410.)