Mechanism of butyrate‐induced vasorelaxation of rat mesenteric resistance artery

Aaronson, Philip I.; McKinnon, William; Poston, Lucilla

doi:10.1111/j.1476-5381.1996.tb15200.x

Cited by 23 publications

(25 citation statements)

References 31 publications

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“…Moreover, butyric acid suppressed eNOS protein and mRNA levels in HUVECs. 43,44 5-azacytidine, an inhibitor of DNA methyltransferase activity, increased eNOS mRNA levels in nonendothelial cell lines (human aortic vascular smooth muscle cells and several human carcinoma cell lines). In contrast, the expression of eNOS mRNA levels in HUVECs was not increased by treatment with 5-azacytidine.…”

Section: Discussionmentioning

confidence: 99%

Hydroxyurea induces the eNOS-cGMP pathway in endothelial cells

Čokić¹,

Beleslin-Čokić²,

Tomić³

et al. 2006

Blood

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Hydroxyurea is a cell-cycle-specific drug that has been used to treat myeloproliferative diseases and sickle cell anemia. We have recently shown that hydroxyurea, like nitric oxide (NO)-donor compounds, increased cGMP levels in human erythroid cells. We show now that hydroxyurea increases endothelial-cell production of NO; this induction of NO in human umbilical vein endothelial cells (HUVECs) and human bone marrow endothelial cell line (TrHBMEC) is blocked by competitive inhibitors of NO synthase (NOS), such as N G -nitro-L-arginine-methyl ester (L-NAME) and N G -nitro-L-arginine. It is dependent on cAMP-dependent protein kinase (PKA) and protein kinase B (PKB/Akt) activity. We found that hydroxyurea dose-and time-dependently induced rapid and transient phosphorylation of eNOS at Ser1177 in a PKA-dependent manner; inhibitors of PKB/Akt could partially abrogate this effect. In addition, hydroxyurea induced cAMP and cGMP levels in a dose-dependent manner, as well as levels of intracellular calcium in HUVECs. These studies established an additional mechanism by which rapid and sustained effects of hydroxyurea may affect cellular NO levels and perhaps enhance the effect of NO in myeloproliferative diseases. IntroductionHydroxyurea is a cytostatic agent (S-phase inhibitor) that has been used to treat erythrocytosis and thrombocytosis in polycythemia vera and other myeloproliferative diseases. 1 More recently, hydroxyurea demonstrated therapeutic benefit for sickle cell anemia by increasing fetal hemoglobin (HbF). 2 In addition to the known inhibition of ribonucleotide reductase, hydroxyurea can be oxidized by heme groups to produce nitric oxide (NO) in vivo (in rats) and in humans. 3,4 Hydroxyurea reacts with oxyHb and deoxyHb to form metHb, which then reacts with another hydroxyurea to form iron nitrosyl hemoglobin (HbNO). 5 The formation of HbNO involves the specific transfer of NO from the -NHOH group of hydroxyurea by a series of intermediate reactions. 3 Additionally, in vivo production of NO may result from the hydrolysis of hydroxyurea to hydroxylamine, followed by the rapid reactions of hydroxylamine with Hb. 6 It has been reported that hydroxyurea administration significantly increased NO x (NO metabolites nitrite and nitrate) and cGMP levels in plasma of sickle cell patients. 7 We have recently shown that hydroxyurea, like NO-donor compounds, increased cGMP levels contributing to gamma-globin gene expression in human erythroid cells. 8 Hydroxyurea is completely absorbed and elimination is through both renal and nonrenal mechanisms. 9 The metabolism of hydroxyurea to NO most likely occurs in the liver. 3 Chemical oxidation of hydroxyurea with a variety of oxidants, including copper(II) ions, produces NO. 9,10 Hydroxyurea-treated vascular endothelial cells showed significant morphologic changes such as an increase in apparent cell size, accompanied by an increase in cell Na and K contents. 11 During hydroxyurea treatment, cells accumulate in the late G1 to early S phase of the cell cycle. 12 Also, the level...

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Section: Discussionmentioning

confidence: 99%

Hydroxyurea induces the eNOS-cGMP pathway in endothelial cells

Čokić¹,

Beleslin-Čokić²,

Tomić³

et al. 2006

Blood

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“…In addition, uncharged forms of acid-base pairs or related species (e.g. monocarboxylic acids, CO 2 or NH 3 ; see also ‘Effects of pH i on Small Artery Function’) move rapidly across cell membranes by passive diffusion through the lipid bilayer or through gas channels [66,67,68,69,70,71], whereas charged species such as metabolic monocarboxylates can move via specific transporters expressed in the VSMC plasma membrane [72]. Furthermore, it is well established that the Na + /H + exchangers are inhibited by extracellular acidosis [73,74], which will further contribute to the intracellular buildup of protons.…”

Section: Effects Of Pho On Phimentioning

confidence: 99%

Intracellular pH in the Resistance Vasculature: Regulation and Functional Implications

Boedtkjer

Aalkjær

2012

J Vasc Res

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Net acid extrusion from vascular smooth muscle (VSMCs) and endothelial cells (ECs) in the wall of resistance arteries is mediated by the Na⁺,HCO₃^– cotransporter NBCn1 (SLC4A7) and the Na⁺/H⁺ exchanger NHE1 (SLC9A1) and is essential for intracellular pH (pH_i) control. Experimental evidence suggests that the pH_i of VSMCs and ECs modulates both vasocontractile and vasodilatory functions in resistance arteries with implications for blood pressure regulation. The connection between disturbed pH_i and altered cardiovascular function has been substantiated by a genome-wide association study showing a link between NBCn1 and human hypertension. On this basis, we here review the current evidence regarding (a) molecular mechanisms involved in pH_i control in VSMCs and ECs of resistance arteries at rest and during contractions, (b) implications of disturbed pH_i for resistance artery function, and (c) involvement of disturbed pH_i in the pathogenesis of vascular disease. The current evidence clearly implies that pH_i of VSMCs and ECs modulates vascular function and suggests that disturbed pH_i either consequent to disturbed regulation or due to metabolic challenges needs to be taken into consideration as a mechanistic component of artery dysfunction and disturbed blood pressure regulation.

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“…Likewise, the vasodilatory effect and an increase in blood flow after the treatment with SCFA was shown in the coronary circulation; however, long-chain and medium-chain fatty acids were found to be more potent vasodilators than SCFA [34]. The vasodilatory effect of SCFA was also demonstrated in rat caudal artery [35] and rat mesenteric resistance artery [36].…”

Section: Short-chain Fatty Acidsmentioning

confidence: 76%

“…Vasorelaxation and improvement of colonic microcirculation [33] Dilatation of coronary and resistance arteries [34][35][36] Hypotensive potential and inhibition of angiotensin II effect [37,38] Anti-hypertensive action [10] ACS -acute coronary syndrome; CAD -coronary artery disease; CKD -chronic kidney disease; CV -cardiovascular; MACE -major adverse cardiovascular events there is still no evidence to support the use of H 2 S donors in clinical practice. Clinical research on H 2 S is thwarted by the lack of a reliable slow-releasing H 2 S-donor.…”

Section: Gut Bacteria Metabolites Biological/cardiovascular Actions Pmentioning

confidence: 99%

Gut bacteria-derived molecules as mediators and markers in cardiovascular diseases. The role of the gut-blood barrier

Nowiński

Ufnal

2018

Kardiol Pol

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Mechanism of butyrate‐induced vasorelaxation of rat mesenteric resistance artery

Cited by 23 publications

References 31 publications

Hydroxyurea induces the eNOS-cGMP pathway in endothelial cells

Hydroxyurea induces the eNOS-cGMP pathway in endothelial cells

Intracellular pH in the Resistance Vasculature: Regulation and Functional Implications

Gut bacteria-derived molecules as mediators and markers in cardiovascular diseases. The role of the gut-blood barrier

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