The Presence of the Endothelial Layer Reduces Nitric Oxide–Induced Hyporesponsiveness to Phenylephrine in Rat Aorta

Terluk, Márcia R.; Silva, Emiliana Domingues Cunha da; Antunes, Tayze T.; Assreuy, Jamil

doi:10.1080/10623320490512228

Cited by 5 publications

(2 citation statements)

References 30 publications

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“…Lymph vessels appear to have greatly enhanced sensitivity to fluid flow/shear in terms of its production of NO as well as its contractile responses compared to blood vessels, given the very low levels of shear found in lymphatic vessels (Dixon et al 2006; Bohlen et al 2009, 2011). We used the sGC inhibitor (ODQ, 30 μ m ) (Godfrey et al 2007; Ying et al 2012) to test if it can alter TD contractility similar to NO synthase blockade and if it can prevent NO donor‐induced relaxation [ S ‐nitroso‐ N ‐acetylpenicillamine (SNAP), 100 μ m ] (Terluk et al 2004; Mochizuki et al 2005). Additionally we attempted to mimic the changes in TD contractility seen with extrinsic flow by the application of the cGMP analogue (8‐(4‐chlorophenylthio)‐guanosine 3′,5′‐cyclic monophosphate sodium salt (8pCPTcGMP), 1–100 μ m ) (Russo et al 2004; Williams et al 2006; Nimmegeers et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Cyclic guanosine monophosphate and the dependent protein kinase regulate lymphatic contractility in rat thoracic duct

Gasheva

Gashev

Zawieja

2013

The Journal of Physiology

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Key points• Nitric oxide plays a principal role in the lymphatic endothelium/shear-dependent regulation of contractility in rat thoracic duct.• In this study we tested the hypothesis that cyclic guanosine monophosphate (cGMP) and the dependent protein kinase (PKG) are central to the intrinsic and extrinsic flow-dependent modulation of lymphatic contractility.• Both PKG-Iα and -Iβ isoforms are found in the thoracic duct, with ∼10 times greater expression of the PKG-Iα protein compared with the aorta and vena cava.• Functional data demonstrate that cGMP is critical to the flow-dependent regulation of thoracic duct contractility.• These findings indicate an important role for PKG, especially PKG-Iα in these processes and identifies the PKG protein as a potential therapeutic target. AbstractWe have previously demonstrated a principal role for nitric oxide (NO) in the endothelium/shear-dependent regulation of contractility in rat thoracic duct (TD). In this study we tested the hypothesis that cyclic guanosine monophosphate (cGMP) and the dependent protein kinase (PKG) are central to the intrinsic and extrinsic flow-dependent modulation of lymphatic contractility. Lymphatic diameters and indices of pumping in isolated, cannulated and pressurized segments of rat TD were measured. The influences of increased transmural pressure (1-5 cmH 2 O) and imposed flow (1-5 cm H 2 O transaxial pressure gradients) on lymphatic function were studied before and after: (1) inhibition of guanylate cyclase (GC) with and without a NO donor; (2) application of stable cGMP analogue; and (3) inhibition of the cGMP activation of PKG. Additionally, Western blotting and immunofluorescent tissue staining were used to analyse the PKG isoforms expressed in TD. We found that the GC inhibitor ODQ induced changes in TD contractility similar to NO synthase blockade and that in the aorta. Immunofluorescent labelling of PKG-Iα protein in the wall of rat thoracic duct confirmed its localization inside TD muscle cells. These findings demonstrate that cGMP is critical to the flow-dependent regulation of TD contractility; they also indicate an important involvement of PKG, especially PKG-Iα in these processes and identifies PKG protein as a potential therapeutic target.

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Section: Introductionmentioning

confidence: 99%

Cyclic guanosine monophosphate and the dependent protein kinase regulate lymphatic contractility in rat thoracic duct

Gasheva

Gashev

Zawieja

2013

The Journal of Physiology

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“…NO is a vasodilator and causes hyporesponsiveness to vasoconstrictors in vitro (28,29). It is also well known that patients with sepsis do not respond to vasoconstrictive drugs to the same extent as patients without sepsis in part because of an increased basal NO production (16,30). To investigate if the M1 proteinYinduced vascular NO production was sufficient to affect vascular smooth muscle contraction, we studied the contractile response to the selective !…”

Section: Discussionmentioning

confidence: 99%

M1 Protein From Streptococcus Pyogenes Induces Nitric Oxide-Mediated Vascular Hyporesponsiveness to Phenylephrine

Sigurðardóttir¹,

Björck²,

Herwald

et al. 2010

Shock

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Streptococcus pyogenes carrying M1 protein causes the severe and increasingly prevalent streptococcal toxic shock syndrome and necrotizing fasciitis. M1 protein is an important virulence factor of S. pyogenes and induces an inflammatory response in human monocytes. We wanted to investigate if purified M1 protein in solution could induce vascular NO production leading to vasopressor hyporesponsiveness. Rat aortic segments were incubated with M1 protein or LPS in vitro. M1 protein (10 microg mL) and LPS (1 ng mL) to a similar extent induced NO production and hyporesponsiveness to the vasoconstrictor phenylephrine. Immunogold electron microscopy demonstrated that M1 protein binds to Toll-like receptor 2 (TLR2) as well as TLR4 in mouse aorta but only to TLR2 in human omental artery. Incubation with M1 protein caused a reduction in the contractile response to phenylephrine in aortic segments from wild-type and TLR2-knockout but not from TLR4-knockout mice. In conclusion, M1 protein causes vascular NO production leading to hyporesponsiveness to vasopressors via a mechanism involving TLR, but the subtypes may be species dependent. M1 protein could contribute to the circulatory disturbances accompanying severe invasive streptococcal infections.

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The therapeutic value of protein (de)nitrosylation in experimental septic shock

Benedet¹,

Menegatti²,

Gonçalves³

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Cardiovascular dysfunction and organ damage are hallmarks of sepsis and septic shock. Protein S-nitrosylation by nitric oxide has been described as an important modifier of protein function. We studied whether protein nitrosylation/denitrosylation would impact positively in hemodynamic parameters of septic rats. Polymicrobial sepsis was induced by cecal ligation and puncture. Female Wistar rats were treated with increasing doses of DTNB [5,5'-dithio-bis-(2-nitrobenzoic acid)] 30min before or 4 or 12h after sepsis induction. Twenty-four hours after surgery the following data was obtained: aorta response to phenylephrine, mean arterial pressure, vascular reactivity to phenylephrine, biochemical markers of organ damage, survival and aorta protein nitrosylation profile. Sepsis substantially decreases blood pressure and the response of aorta rings and of blood pressure to phenylephrine, as well as increased plasma levels of organ damage markers, mortality of 60% and S-nitrosylation of aorta proteins increased during sepsis. Treatment with DTNB 12h after septic shock induction reversed the loss of response of aorta rings and blood pressure to vasoconstrictors, reduced organ damage and protein nitrosylation and increased survival to 80%. Increases in protein S-nitrosylation are related to cardiovascular dysfunction and multiple organ injury during sepsis. Treatment of rats with DTNB reduced the excessive protein S-nitrosylation, including that in calcium-dependent potassium channels (BK), reversed the cardiovascular dysfunction, improved markers of organ dysfunction and glycemic profile and substantially reduced mortality. Since all these beneficial consequences were attained even if DTNB was administered after septic shock onset, protein (de)nitrosylation may be a suitable target for sepsis treatment.

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The Presence of the Endothelial Layer Reduces Nitric Oxide–Induced Hyporesponsiveness to Phenylephrine in Rat Aorta

Cited by 5 publications

References 30 publications

Cyclic guanosine monophosphate and the dependent protein kinase regulate lymphatic contractility in rat thoracic duct

Cyclic guanosine monophosphate and the dependent protein kinase regulate lymphatic contractility in rat thoracic duct

M1 Protein From Streptococcus Pyogenes Induces Nitric Oxide-Mediated Vascular Hyporesponsiveness to Phenylephrine

The therapeutic value of protein (de)nitrosylation in experimental septic shock

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