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.

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

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 mug/min (P < 0.001). At 1,600 mug/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 mumol/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.

Hyperthyroidism enhances endothelium-dependent relaxation in the rat renal artery.

OBJECTIVE: Hyperthyroidism has pronounced effects on vascular function and endothelium-dependent relaxation. The aim of the present study was to identify mechanisms underlying hyperthyroidism-induced alterations in endothelial function in rats. METHODS: Animals were subjected to either a single injection (36 h) or 8 weeks treatment with the thyroid hormone triiodothyronine (T3, i.p.). Vascular reactivity and agonist-induced hyperpolarization were studied in isolated renal arteries. Endothelial nitric oxide (NO) synthase expression and cyclic AMP accumulation were determined in aortic segments. RESULTS: Endothelium-dependent relaxations to acetylcholine (ACh) were enhanced by T3 36 h after injection and after treatment for 8 weeks. Thirty-six hours after T3 application, relaxation mediated by the endothelium-derived hyperpolarizing factor (EDHF) and by endothelium-derived NO were significantly enhanced. After 8 weeks treatment with T3, however, EDHF-mediated relaxation was impaired, whereas NO-mediated relaxation remained enhanced. KCl- and ACh-induced hyperpolarizations were more pronounced in arteries from rats treated with T3 for 36 h compared to control, whereas in arteries from rats treated with T3 for 8 weeks both responses were attenuated. In rats treated for 36 h, vascular cyclic AMP levels were enhanced in the aorta and inhibition of protein kinase A attenuated EDHF-mediated relaxations of the renal artery without affecting responses in arteries from the control group. In the aorta from rats treated with T3 for 8 weeks, the expression of the endothelial NO synthase was markedly up-regulated (463+/-68%). CONCLUSIONS: These data indicate that short-term treatment with T3 increases endothelium-dependent relaxation, most probably by increasing vascular cyclic AMP content. Following treatment with T3 for 8 weeks, expression of the endothelial NO synthase was enhanced. During this phase, NO appears to be the predominant endothelium-derived vasodilator.

Hyponatremia: pathophysiology, differential diagnosis and new aspects of treatment.

Hyponatremia is the most frequent electrolyte disorder in clinical medicine. It is usually attributable to primary vasopressin excess, causing the syndrome of inappropriate antidiuresis (SIAD), or to secondary vasopressin stimulation, involving a baroreceptor mechanism. The latter is regularly found in the hyponatremia of liver cirrhosis, cardiac failure and volume contraction. In the first kind of setting the concentrations of creatinine, urea and urate in plasma will be low because of the associated volume expanded state. In the second type of setting they will be elevated because of the circulatory compromise of these patients. The hyponatremia of SIAD may be treated by water restriction, furosemide and substitution of the inadvertent sodium losses by giving 3% NaCl. Baroreceptor hyponatremia is best treated by fluid restriction together with judiciously administered saline. In correcting severe chronic hyponatremia, the rate of correction should not exceed 1 mM/l/h and the corrected serum sodium concentration should not be higher than 130 mM/l. In the foreseeable future oral non-peptide oral vasopressin antagonists will become available. They are expected to become new tools for the treatment of hyponatremia.