gms | German Medical Science

Phosphorylation of myosin light chain (MLC) is an important step for vascular smooth muscle contraction, regulated by the MLC kinase and the MLC phosphatase (MLCPh). Inhibition of the MLCPh results in Ca2+ sensitization. The small GTPase Rho activates the Rho-associated kinase (Rho-kinase) which then phosphorylates and thereby inhibits the MLCPh. Increased activity of Rho-kinase has been shown in models of hypertension. Its role in the regulation of vascular tone remained unclear.

Here we tested the role of Rho-kinase for the regulation of the peripheral vascular tone in healthy, normotensive volunteers. We infused the selective Rho-kinase inhibitor fasudil in locally active doses into the forearm circulation of 8 young healthy volunteers, each dose (10, 20, 40, 80 µg/min) for 10 minutes. Foreram blood flow (FBF) was measured after each dose of infusion. Values are given as flow in ml/100 ml forearm volume. At the highest dose of fasudil the nitric-oxide inhibitor l-NMMA was coinfused (16µmol/min). Subjects were normotensive and the systemic blood pressure did not change throughout the study. Infusion of fasudil markedly increased forearm blood flow in a dose-dependent manner indicating that activation of Rho-kinase contributes to maintenance of basal peripheral vascular tone in healthy volunteers (2,22±0,33, 2,50±0,50, 3,00±1,50, 4,65±1,83, 6,63±1,91 for baseline and fasudil 10-80 µg/min respectively, P<0,001). L-NMMA slightly, but significantly decreased forearm blood flow (6,83±1,91 at fasudil 80 µg/min vs. 5,25±1,77 after coadministration of l-NMMA, P<0,01).

We show for the first time that peripheral vascular tone in healthy volunteers is mediated by the activation of Rho-kinase. This effect appears to be mainly independent of endothelial-derived nitric oxide. Future studies should address the role of Rho-kinase under pathologic conditions with increased vascular tone. Therapeutic strategies that inhibit Rho-kinase activity should be implemented.