Shear stress modulates the vascular tone in perfused livers isolated from normal rats

Abstract

Fluid shear stress can be increased either by increasing the flow rate or perfusing increasing doses of norepinephrine (NE) at a constant flow rate. Concomitantly, increased fluid shear stress at the surface of endothelial cells releases nitric oxide (NO). To better understand the role of NO released by shear stress in regulating intrahepatic vascular resistances, we increased fluid shear stress either by changing the flow rate or by perfusing increasing doses of NE at a constant flow rate in perfused livers isolated from normal rats. When concentration-response curves to NE were studied at low, mild, and high flow rates, portal pressure increased during NE perfusion. The higher the flow rate, the lower the response to NE. NO synthase inhibition similarly increased the response to NE at each flow rate. Thus, NO was released by NE-induced increased shear stress, but other vasodilators are likely to be responsible for the flowinduced increased shear stress. In additional experiments, when flow rate was decreased while infusing increasing doses of NE to maintain the portal pressure constant, shear stress remained steady and NO was not released. Hepatic NO production in the different conditions of shear stress could not be detected. Our data are consistent with the fact that in the liver, NO released by shear stress decreases the vasoconstriction to NE and regulates the intrahepatic vascular resistances. (HEPATOLOGY 2000;32:786-791.)Forces generated by blood flow act on vessels either perpendicular to the wall to induce blood pressure or parallel to the wall to create a frictional force or shear stress. 1,2 Although the entire vessel wall is subject to stretch, the fluid shear stress predominates on endothelial cells. Increased fluid shear stress at the surface of endothelial cells is then responsible for the release of nitric oxide (NO), but the precise mechanism coupling the increased shear stress and the enhanced production and release of NO remains unknown. Moreover, evidence exists that fluid shear stress (and consequently, endothelial NO release) is greatly modulated by the vasomotor tone, blood flow rate, and pulsatility. Shear-stress-dependent NO release constitutes a local feed-back mechanism to counteract vasoconstriction.Few data are available on the role of NO released by shear stress in modulating the hepatic vascular tone. Using a perfusion circuit to regulate hepatic blood pressure and flow in anesthetized cats, Macedo and Lautt 3 demonstrated that increased shear stress releases NO in the hepatic artery and the portal vein. Additionally, Shah et al. 4 showed that the exposure of isolated sinusoidal endothelial cells to increasing levels of flow increased the release of NO. Moreover, Mittal et al. 5 demonstrated that NO modulates the hepatic circulation in livers isolated from normal rats and perfused with increasing doses of NE at a constant flow rate. However, whether hepatic NO originated from a baseline production or from the effect of shear stress on endothelial cells is unknown. Recently, Shah e...

Opposite regulation of endothelial NO synthase by HSP90 and caveolin in liver and lungs of rats with hepatopulmonary syndrome

“…The hepatic resistance during the perfusion of 10 Ϫ5 M NE was similar in the Nl-KHB group (median 100%), CBDL-KHB group (median 78%), and CBDL-L-NAME group (median 82%) but was significantly increased in the Nl-L-NAME group (median 200%) (P ϭ 0.03). As we previously showed (25), the perfusion of KHB ϩ L-NAME solution did not modify hepatic resistances in the absence of NE (data not shown).…”

“…We perfused livers from normal (Nl, n ϭ 14) and CBDL-30 rats (n ϭ 14) with norepinephrine (NE) and NE ϩ acetylcholine (ACh), as previously described (25), in the presence or the absence of the NO synthase inhibitor N -nitro-L-arginine methyl ester (L-NAME). Livers were perfused with a Krebs-Henseleit-bicarbonate (KHB) solution for 20 min, followed by KHB ϩ 10 Ϫ7 M NE, KHB ϩ 10 Ϫ6 M NE, KHB ϩ 10 Ϫ5 M NE, KHB ϩ 10 Ϫ5 M NE ϩ 10 Ϫ7 ACh, KHB ϩ 10 Ϫ5 M NE ϩ 10 Ϫ6 ACh, and KHB ϩ 10 Ϫ5 M NE ϩ 10 Ϫ5 M ACh (3 min for each perfusion).…”

NO counterbalances HO-1 overexpression-induced acceleration of hepatocyte proliferation in mice

“…43 In perfused livers isolated from normal rats, it has been shown that NO was released by norepinephrine-induced vasoconstriction at constant flow Vasoactive systems and liver regeneration H Schuett et al rate, while increasing flow rate did not release NO, implying the contribution of other vasodilators in maintenance of hepatic vascular resistance under high flow conditions. 44 In support of this, and as observed in the present study, shear stress did not stimulate NOS-2 protein expression however it was capable of inducing HO-1 protein expression. 11 Thus, it is reasonable to speculate that at least under normal and increased flow conditions in liver microcirculation, CO rather than NO serves as effective mediator of vasoregulation either via agonism for the sGC or cGMP-independent via activation of vascular smooth muscle Ca 2 þ -activated K þ channels.…”

Direct visualization of nitric oxide release by liver cells after the arrest of metastatic tumor cells in the hepatic microvasculature1

“…It has been demonstrated that shear stress can cause NO release by endothelial cells [26]. In the liver, NO released by shear stress cannot only modulate the vascular tone but also trigger the liver regeneration cascade [27][28][29]. In this study, we also found that NO release can be induced by changes in flow rate which effect changes in shear force (Fig.…”