Rho kinase contributes to basal vascular tone in humans: role of endothelium-derived nitric oxide

• Published in: American journal of physiology. Heart and circulatory physiology 2007-07, Vol.293 (1), p.H541-H547
• Main Authors: Bussemaker, E, Pistrosch, Frank, Forster, Sarah, Herbrig, Kay, Gross, Peter, Passauer, Jens, Brandes, Ralf P
• Format: Article
• Language: English
• Subjects: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - administration & dosage; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - analogs & derivatives; Adult; Arms; Biochemistry; Blood Flow Velocity - drug effects; Blood Flow Velocity - physiology; Blood pressure; Dose-Response Relationship, Drug; Forearm - blood supply; Forearm - physiology; Humans; Kinases; Male; Nitric oxide; Nitric Oxide - metabolism; rho GTP-Binding Proteins - antagonists & inhibitors; rho GTP-Binding Proteins - metabolism; Vasoconstriction - drug effects; Vasoconstriction - physiology
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00770.2006

1 Medizinische Klinik III, Nephrologie, Universitätsklinikum Dresden, Dresden, Germany; and 2 Institut für Kardiovaskuläre Physiologie, J. W. Goethe Universität, Frankfurt, Germany Submitted 18 July 2006 ; accepted in final form 21 March 2007 Our objective was to determine the role of the Rho-associated kinase (ROK) for the regulation of FBF (FBF) and to unmask a potential role of ROK for the regulation of endothelium-derived nitric oxide (NO). Moreover, the effect of fasudil on the constrictor response to endothelin-1 was recorded. Regarding background, phosphorylation of the myosin light chain (MLC) determines the calcium sensitivity of the contractile apparatus. MLC phosphorylation depends on the activity of the MLC kinase and the MLC phosphatase. The latter enzyme is inhibited through phosphorylation by ROK. ROK has been suggested to inhibit NO generation, possibly via the inhibition of the Akt pathway. In this study, the effect of intra-arterial infusion of the ROK inhibitor fasudil on FBF in 12 healthy volunteers was examined by venous occlusion plethysmography. To unmask the role of NO, fasudil was infused during NO clamp. As a result, fasudil markedly increased FBF in a dose-dependent manner from 2.34 ± 0.21 to 6.96 ± 0.93 ml/100 ml forearm volume at 80 µg/min ( P < 0.001). At 1,600 µg/min, fasudil reduced systolic, diastolic, and mean arterial pressure while increasing heart rate. Fasudil abolished the vasoconstrictor effect of endothelin-1. The vascular response to fasudil (80 µmol/min) was blunted during NO clamp (104 ± 18% vs. 244 ± 48% for NO clamp + fasudil vs. fasudil alone; data as ratio between infused and noninfused arm with baseline = 0%, P < 0.05). In conclusion, 1 ) basal peripheral and systemic vascular tone depends on ROK; 2 ) a significant portion of fasudil-induced vasodilation is mediated by NO, suggesting that vascular bioavailable NO is negatively regulated by ROK; and 3 ) the constrictor response to endothelin involves the activation of ROK. forearm blood flow Address for reprint requests and other correspondence: E. Büssemaker, Univ. of Dresden, Medizinische Klinik III, Nephrologie, Fetscherstrasse 74, 01307 Dresden, Germany (e-mail: eckhart.buessemaker{at}ukmuenster.de )