Effects of protein kinase C modulators on Na+/K+ adenosine triphosphatase activity and phosphorylation in aortae from rats with cirrhosis

Lahaye, Philippe; Tazi, Khalid A.; Rona, Jean‐Pierre; Dellis, Olivier; Lebrec, Didier; Moreau, Richard

doi:10.1002/hep.510280310

Cited by 10 publications

(11 citation statements)

References 34 publications

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“…The modulation of Na + /K + pump activity is thought to be regulated by direct phosphorylation and dephosphorylation of Na + /K + pump isoforms by protein kinases and protein phosphatases (44,45). Specifically, PKC phosphorylation of the ␣ subunits of the Na + /K + pump was shown to affect the activation state of the Na + /K + pump in vitro and in vivo (19,(46)(47)(48). However, the functional significance of the PKC-mediated changes in the phosphorylation state of the Na Furthermore, as the majority of the studies used nonspecific pharmacological activators and inhibitors of PKC, a specific PKC isoform or a distinct function for PKC could not be identified.…”

Section: Discussionmentioning

confidence: 99%

PKCδ Activation

et al. 2001

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Insulin and insulin-like growth factor-1 (IGF-1) are members of the family of the insulin family of growth factors, which activate similar cellular downstream pathways. In this study, we analyzed the effects of insulin and IGF-1 on the proliferation of murine skin keratinocytes in an attempt to determine whether these hormones trigger the same signaling pathways. Increasing doses of insulin and IGF-1 promote keratinocyte proliferation in an additive manner. We identified downstream pathways specifically involved in insulin signaling that are known to play a role in skin physiology; these include activation of the Na + /K + pump and protein kinase C (PKC). Insulin, but not IGF-1, stimulated Na + /K + pump activity. Furthermore, ouabain, a specific Na + /K + pump inhibitor, abolished the proliferative effect of insulin but not that of IGF-1. Insulin and IGF-1 also differentially regulated PKC activation. Insulin, but not IGF-1, specifically activated and translocated the PKC␦ isoform to the membrane fraction. There was no effect on PKC isoforms ␣, , , and , which are expressed in skin. PKC␦ overexpression increased keratinocyte proliferation and Na + /K + pump activity to a degree similar to that induced by insulin but had no affect on IGF-1-induced proliferation. Furthermore, a dominant negative form of PKC␦ abolished the effects of insulin on both proliferation and Na + /K + pump activity but did not abrogate induction of keratinocyte proliferation induced by other growth factors. These data indicate that though insulin or IGF-1 stimulation induce keratinocyte proliferation, only insulin action is specifically mediated via PKC␦ and involves activation of the Na + /K + pump. Diabetes 50:255-264, 2001

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Section: Discussionmentioning

confidence: 99%

PKCδ Activation

et al. 2001

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“…The solution was bubbled continuously with a mixture of 95% O 2 :5% CO 2 and maintained at 37°C with an outer water jacket and a circulating heat pump. Contractions and relaxations were recorded with a multichannel polygraph (1302-06, Gould Electronics, Balainvilliers, France) and expressed in g. As previously described, 16,24,25 a baseline force of 1.5 grams was applied to rings. This tension has been shown to provide optimum vasoactive responses in preliminary studies.…”

Section: Aortic Reactivitymentioning

confidence: 99%

Terlipressin inhibitsin vivoaortic iNOS expression induced by lipopolysaccharide in rats with biliary cirrhosis

et al. 2002

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In cirrhosis, lipopolysaccharide (LPS, a product of Gram-negative bacteria) in the blood may cause septic shock. LPS-elicited induction of arterial inducible nitric oxide synthase (iNOS) results in nitric oxide (NO)-induced vasodilation, which causes arterial hypotension and hyporeactivity to ␣ 1 -adrenergic constrictors. In vitro studies have suggested that vasopressin inhibits iNOS expression in cultured vascular smooth muscle cells exposed to LPS. Thus, the aim of this study was to investigate the effects of terlipressin administration (a vasopressin analog) on in vivo LPS-induced aortic iNOS in rats with cirrhosis. LPS (1 mg/kg, intravenously) was administered followed by the intravenous administration of terlipressin (0.05 mg/kg, intravenously) or placebo 1 hour later. Arterial pressure was measured, and contractions to phenylephrine (an ␣ 1 -adrenoceptor agonist), iNOS activity, and iNOS expressions (mRNA and protein) were investigated in isolated aortas. LPS-induced arterial hypotension and aortic hyporeactivity to phenylephrine were abolished in rats that received terlipressin. LPS-induced aortic iNOS activity and expression were suppressed in terlipressin-treated rats. In conclusion, in LPS-challenged rats with cirrhosis, terlipressin administration inhibits in vivo LPS-induced aortic iNOS expression. Terlipressin administration may be a novel approach for the treatment of arterial hypotension and hyporeactivity to ␣ 1 -adrenergic constrictors in patients with cirrhosis and septic shock.

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“…Studies were performed in freshly isolated arteries as previously described. 28,32 Microelectrode preparation. Microelectrodes used for electrophysiologic studies were obtained from borosilicate capillary glass (Clark GC 150F; Clark Electromedical, Pangbourne Reading, United Kingdom) pulled with a Narishige PA81 microelectrode puller (Narishige Scientific Instrument Laboratory, Tokyo, Japan).…”

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“…Criteria for successful impalement were as follows 28,32 : (1) an abrupt drop in voltage as the electrode entered the cell, (2) a stable membrane potential for at least 2 minutes, (3) at the end of impalement, a sharp return to 0 mV, with resistance of the microelectrode tip unchanged, and (4) a tip potential less than 2 mV. Experiments were performed at 36°C.…”

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Evidence for an Endothelium-Derived Hyperpolarizing Factor in the Superior Mesenteric Artery From Rats With Cirrhosis

Barrière

Tazi

Rona³

et al. 2000

Hepatology

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In cirrhosis, in splanchnic arteries, endothelium-dependent relaxation may persist even if overactive nitric oxide synthase (NOS) and cyclooxygenase (COX) are inhibited. In normal arteries, a significant endothelium-dependent relaxation to acetylcholine persists after NOS/COX inhibition. This relaxation is caused by smooth muscle cell (SMC) membrane hyperpolarization, which is sensitive to a combination of the potassium channel blockers apamin and charybdotoxin, and is mediated by an endothelium-derived hyperpolarizing factor (EDHF). The aim of this study was to detect EDHF and evaluate its pathophysiologic role in isolated superior mesenteric arteries from cirrhotic rats. Arterial rings were obtained and exposed to N w -nitro-L-arginine (L-NNA, a NOS inhibitor) and indomethacin (a COX inhibitor). Acetylcholine-induced membrane potential responses and concentration-response curves to the relaxant of acetylcholine were obtained with and without apamin plus charybdotoxin. Acetylcholine-induced responses were measured in certain rings from endothelium-denuded arteries. Contractions caused by the ␣ 1 -adrenoceptor agonist phenylephrine were obtained in cirrhotic and normal rings with and without apamin and charybdotoxin. Significant acetylcholine-induced, endothelium-dependent, apamin-and charybdotoxin-sensitive, SMC membrane hyperpolarization and relaxation were found. An apamin-and charybdotoxinsensitive hyporesponsiveness to the contractile action of phenylephrine was found in cirrhotic rings. In conclusion, in cirrhotic rats, in the superior mesenteric artery exposed to NOS/COX-inhibitors, an EDHF exists that may replace NOS/COX products to induce endothelium-dependent arterial relaxation. (HEPATOLOGY 2000;32:935-941.)In portal hypertension, in splanchnic and systemic arteries, certain mechanisms induce endothelium-dependent smooth muscle cell (SMC) relaxation and hyporeactivity to vasoconstrictors by activating endothelial nitric oxide synthase (NOS) and cyclooxygenase (COX) to produce nitric oxide (NO) and prostacyclin (PGI 2 ). 1-12 However, it has been shown that, in portal hypertensive rats, NOS inhibition, alone or combined with COX inhibition, did not suppress arterial SMC relaxation and hyporeactivity to vasoconstrictors. 3,4,6,8 These findings show that a NOS/COX-inhibitor-insensitive SMC relaxation may be involved in arterial alterations associated with portal hypertension. It should be kept in mind that, in normal arteries, a significant endothelium-dependent arterial SMC relaxation (caused by shear stress or acetylcholine) persists even after NOS/COX inhibition. [13][14][15][16][17] This NOS/COX-inhibitor-insensitive relaxation is caused by SMC membrane hyperpolarization caused by endothelium-derived hyperpolarizing factors (EDHFs). 15,[17][18][19][20] In normal splanchnic arteries, a combination of the K ϩ channel blockers, apamin and charybdotoxin, 21 is known to inhibit EDHF-induced SMC hyperpolarization and relaxation. [22][23][24][25][26] In addition, a combination of barium (a K ϩ channel block...

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Effects of protein kinase C modulators on Na+/K+ adenosine triphosphatase activity and phosphorylation in aortae from rats with cirrhosis

Cited by 10 publications

References 34 publications

PKCδ Activation

PKCδ Activation

Terlipressin inhibitsin vivoaortic iNOS expression induced by lipopolysaccharide in rats with biliary cirrhosis

Evidence for an Endothelium-Derived Hyperpolarizing Factor in the Superior Mesenteric Artery From Rats With Cirrhosis

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