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(Circulation. 2000;102:2402.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Oxidized LDL Increases the Sensitivity of the Contractile Apparatus in Isolated Resistance Arteries for Ca²⁺ via a Rho- and Rho Kinase–Dependent Mechanism

Steffen-Sebastian Bolz, MD; Jan Galle, MD, PhD; Roland Derwand; Cor de Wit, MD; Ulrich Pohl, MD, PhD

From the Physiologisches Institut, Ludwig Maximilians Universität, München, and the Department of Medicine, Division of Nephrology, University Hospital of Würzburg, Würzburg (J.G.), Germany.

Correspondence to Steffen-Sebastian Bolz, Physiologisches Institut der Ludwig Maximilians Universität, Pettenkoferstraße 12, D-80336 München, Germany. E-mail bolz{at}lrz.uni-muenchen.de

Background—Oxidized LDL reduces NO-mediated and endothelium-derived hyperpolarizing factor–mediated dilations. We studied, in hamster skeletal muscle resistance arteries (213±8 µm; n=51), whether an altered vascular smooth muscle (VSM) response, particularly sensitization of the VSM contractile apparatus to Ca²⁺, is involved in this oxLDL effect.

Methods and Results—VSM or endothelial [Ca²⁺]_i and vascular diameter were measured in response to norepinephrine (0.3 µmol/L), sodium nitroprusside (10 µmol/L), C-type natriuretic peptide (1 to 100 nmol/L), papaverine (0.1 to 10 µmol/L), or the endothelial agonist acetylcholine (ACh, 0.01 to 1 µmol/L). OxLDL significantly increased resting VSM [Ca²⁺]_i (11±3%), decreased diameter (8±2%), and enhanced norepinephrine-induced constrictions. Dilations to sodium nitroprusside and C-type natriuretic peptide were significantly reduced (by 10±2% and 35±6%), whereas dose-response curves for papaverine and ACh were shifted to the right, despite unchanged increases in endothelial Ca²⁺ after ACh. OxLDL significantly shifted the Ca²⁺-diameter relation to the left, as assessed by stepwise increasing extracellular Ca²⁺ (0 to 3 mmol/L) in depolarized skeletal muscle resistance arteries. This sensitization to Ca²⁺ by oxLDL was abolished after inhibition of Rho (C3 transferase) or Rho kinase (Y27632).

Conclusions—OxLDL reduces VSM responsiveness to vasodilators by increasing VSM Ca²⁺ but preferentially by sensitizing VSM to Ca²⁺ via a Rho- and Rho kinase–dependent pathway.

Key Words: muscle, smooth • endothelium • endothelium-derived factors • atherosclerosis

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