Role of rho-kinase in the regulation of vascular tone in hypertensive renal transplant recipients.
Activation of rho-kinase (ROK) is involved in the development of hypertension as it is a potent regulator of vascular smooth muscle cell (VSMC) contractility. Here we evaluated whether activation of ROK is present in hypertensive kidney transplant recipients (NTX). We tested the effect of the ROK-inhibitor fasudil on the regulation of forearm blood flow (FBF) in NTX and in healthy control subjects (CTL). In addition potential modulating effects of ROK-inhibition on local vascular nitric oxide (NO) release were studied. The effect of intra-arterial infusion of fasudil on FBF was studied by venous-occlusion plethysmography in NTX and CTL. To unmask the role of NO fasudil was infused with/without clamping of vascular NO in NTX and CTL. To unravel the basal NO-mediated tone the NO-synthase inhibitor l-NMMA was infused. Fasudil markedly but comparably increased FBF in NTX and CTL. The vascular response to fasudil was blunted during NO-clamp in CTL (104+/-18% vs. 244+/-48% for NO-clamp+fasudil vs. fasudil alone; baseline=0%, P<0.05) but not in NTX. The l-NMMA-induced vasoconstriction was impaired in NTX compared to CTL. In NTX and CTL basal vascular tone equally depends on ROK. Fasudil-induced vasodilatation is partly mediated by vascular NO in CTL but not in NTX. The greater NO-insensitive fasudil-induced increase in FBF in NTX suggests an increased ROK-mediated VSMC constrictor tone in these patients. Basal NO-mediated tone is attenuated in hypertensive NTX.
Büssemaker
E
E
Medizinische Klinik und Poliklinik D, Universitätsklinikum Münster, Münster, Germany. buessema@hotmail.com
Herbrig
K
K
Pistrosch
F
F
Palm
C
C
Passauer
J
J
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D016022:Case-Control Studies; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005542:Forearm / Q000098:blood supply*; D006801:Humans; D006973:Hypertension / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology; D007261:Infusions, Intra-Arterial; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009599:Nitroprusside / Q000008:administration & dosage; D009638:Norepinephrine / Q000008:administration & dosage; D010991:Plethysmography; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D012039:Regional Blood Flow; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000008:administration & dosage; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage; D019323:omega-N-Methylarginine / Q000008:administration & dosage; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D047428:Protein Kinase Inhibitors; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009599:Nitroprusside; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D019001:Nitric Oxide Synthase; D054460:rho-Associated Kinases; C049347:fasudil; D009638:Norepinephrine