Document Type
Article
Publication Date
3-9-2009
Abstract
RhoA-activated kinase (ROK) is involved in the disorders of smooth muscle contraction found in hypertension model animals and patients. We examined whether the alpha1-adrenergic receptor agonist-induced ROK signal is perturbed in resistance small mesentery artery (SMA) of Lyon genetically hypertensive (LH) rats, using a ROK antagonist, Y27632. Smooth muscle strips of SMA and aorta were isolated from LH and Lyon normotensive (LN) rats. After Ca(2+)-depletion and pre-treatment with phenylephrine (PE), smooth muscle contraction was induced by serial additions of CaCl(2). In LH SMA Ca(2+) permeated cells to a lesser extent as compared with LN SMA, while CaCl(2)-induced contraction of LH SMA was greater than that of LN SMA, indicating a higher ratio of force to Ca(2+) in LH SMA contraction (Ca(2+) sensitization). No hyper-contraction was observed in LH aorta tissues. Treatment of LH SMA with Y27632 restored both Ca(2+) permeability and Ca(2+)-force relationship to levels seen for LN SMA. In response to PE stimulation, phosphorylation of CPI-17, a phosphorylation-dependent myosin phosphatase inhibitor protein, and MYPT1 at Thr853, the inhibitory phosphorylation site of the myosin phosphatase regulatory subunit, was increased in LN SMA, but remained unchanged in LH SMA. These results suggest that the disorder in ROK-dependent Ca(2+) permeability and Ca(2+)-force relationship is responsible for LH SMA hyper-contraction. Unlike other hypertensive models, the ROK-induced hyper-contractility of LH SMA is independent of MYPT1 and CPI-17 phosphorylation, which suggests that ROK-mediated inhibition of myosin phosphatase does not affect SMA hyper-contractility in LH SMA cells.
Recommended Citation
Freitas, Maria Regina; Eto, Masumi; Kirkbride, Jason A; Schott, Christa; Sassard, Jean; and Stoclet, Jean-Claude, "Y27632, a Rho-activated kinase inhibitor, normalizes dysregulation in alpha1-adrenergic receptor-induced contraction of Lyon hypertensive rat artery smooth muscle." (2009). Department of Molecular Physiology and Biophysics Faculty Papers. Paper 9.
https://jdc.jefferson.edu/physfp/9
PubMed ID
19298234
Included in
Biochemistry Commons, Cellular and Molecular Physiology Commons, Medical Biochemistry Commons, Medical Biophysics Commons, Oncology Commons
Comments
This article has been peer reviewed. It is the authors' final version prior to publication in Fundamental & Clinical Pharmacology. 2009 Apr;23(2):169-78. The published version is available at DOI: 10.1111/j.1472-8206.2008.00658.x. Copyright © John Wiley & Sons, Inc.