Opportunities to Target Specific Contractile Abnormalities with Smooth Muscle Protein Kinase Inhibitors 英文参考文献.docVIP

Pharmaceuticals 2010, 3, 1739-1760; doi:10.3390/ph3061739 OPEN ACCESS pharmaceuticals ISSN 1424-8247 /journal/pharmaceuticals Review Opportunities to Target Specific Contractile Abnormalities with Smooth Muscle Protein Kinase Inhibitors Annegret Ulke-Lemée and Justin A. MacDonald * Smooth Muscle Research Group and Department of Biochemistry Molecular Biology, University of Calgary, 3280 Hospital Drive NW, Calgary, Alberta, T2N 4Z6, Canada; E-Mail: aulke@ucalgary.ca (A.U-L) * Author to whom correspondence should be addressed; E-Mail: jmacdo@ucalgary.ca; Tel.: +1-403-210-8433; Fax: +1-403-270-2211. Received: 8 April 2010; in revised form: 26 April 2010 / Accepted: 24 May 2010 / Published: 26 May 2010 Abstract: Smooth muscle is a major component of most hollow organ systems (e.g., airways, vasculature, bladder and gut/gastrointestine); therefore, the coordinated regulation of contraction is a key property of smooth muscle. When smooth muscle functions normally, it contributes to general health and wellness, but its dysfunction is associated with morbidity and mortality. Rho-associated protein kinase (ROCK) is central to calcium-independent, actomyosin-mediated contractile force generation in the vasculature, thereby playing a role in smooth muscle contraction, cell motility and adhesion. Recent evidence supports an important role for ROCK in the increased vasoconstriction and remodeling observed in various models of hypertension. This review will provide a commentary on the development of specific ROCK inhibitors and their clinical application. Fasudil will be discussed as an example of bench-to-bedside development of a clinical therapeutic that is used to treat conditions of vascular hypercontractility. Due to the wide spectrum of biological processes regulated by ROCK, many additional clinical indications m