Urocortin Induces Endothelium-Dependent Vasodilatation and Hyperpolarization of Rat Mesenteric Arteries by Activating Ca2+-Activated K+ Channels

Seçilmiş, Mehmet Ata; Özü, Özlem Yorulmaz; Emre, Mustafa; Büyükafşar, Kansu; Kiroglu, Olcay Erhgürhan; Ertuğ, Peyman U.; Karataş, Yusuf; Önder, Serpil; Şingirik, Ergin

doi:10.1620/tjem.213.89

Cited by 10 publications

(4 citation statements)

References 37 publications

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“…In addition, the involvement of BKCa channels is in agreement with previous findings showing that the hyperpolarization and relaxation caused by urocortin have been found to be inhibited by BKCa channels inhibitors [24,25]. The results obtained in the present study about the role of K ATP channels in the effects of ucn II on Ca 2+ movements are totally new and are not in agreement with previous reports showing that the K ATP channels blocker, glybenclamide did not affect hyperpolarization and relaxation of rat mesenteric arteries induced by urocortin [24]. The fact that our findings have been obtained in endothelial cells and not in isolated vessels could explain this discrepancy.…”

Section: Discussionsupporting

confidence: 92%

“…Such coupling has been demonstrated in response to receptor-mediated stimuli [12][13][14][15] and receptor-independent emptying of intracellular stores by agents such as thapsigargin, ionomycin and cyclovirobuxine D [12][13][14][15][16] transients could be involved in NO production through changes of membrane potential [19] caused by large-conductance Ca 2+ -activated potassium (BKCa) channels opening which are widely expressed in endothelial cells [20][21][22] and participate in the regulation of vascular tone [23]. Indeed, members of CRF family peptides have been shown to cause endothelium-dependent and independent relaxation and hyperpolarization of rat mesenteric and coronary arteries, through the activation of BKCa channels [24,25].…”

Section: Introductionmentioning

confidence: 99%

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Modulation of Calcium Movements by Urocortin II in Endothelial Cells

Grossini¹,

Caimmi²,

Molinari³

et al. 2010

Cell Physiol Biochem

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Background: In endothelial cells urocortin II has recently been found to activate nitric oxide synthase through cAMP-dependent and Ca²⁺-related pathway. Aim: The present study was therefore planned to determine the mechanisms of urocortin II effect on Ca²⁺ movements. Methods. In Fura-2 loaded porcine aortic endothelial cells (PAE), the effects of urocortin II on [Ca²⁺]c were analyzed and compared with those of various K⁺ channels agonists/antagonists. Results: In Fura-2 loaded PAE, urocortin II promoted a transient increase of [Ca²⁺]c mainly originating from an intracellular pool sensitive to thapsigargin and slightly from the extracellular space. In addition, urocortin II caused the hyperpolarization of plasma membrane through the opening of K⁺ channels, which contributed to the increased [Ca²⁺]c. These effects were abolished by the corticotropin releasing factor receptors (CRFR2) blocker, the adenylyl cyclase and Ca²⁺-calmodulin-kinase (CaMKII) inhibitors and by blockers of K⁺ channels. In addition, in PAE cultured in Na⁺-free medium or loaded with the plasma-membrane Ca²⁺ pump inhibitor the urocortin II-evoked Ca²⁺ transient was slower. Conclusion: The results obtained show that urocortin II affects intracellular Ca²⁺ homeostasis in PAE by both promoting a discharge of intracellular pool and by interfering with the operation of store-dependent channels through CRFR2-cAMP-CaMKII related signalling and K⁺ channels opening.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Modulation of Calcium Movements by Urocortin II in Endothelial Cells

Grossini¹,

Caimmi²,

Molinari³

et al. 2010

Cell Physiol Biochem

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“…32,34 Moreover, vasodilatory effects via p38 mitogen-activated protein kinase and the protein kinase A pathway may contribute to the vasodilatory effect of Ucn2. 22 In addition, potent diuretic effects of Ucn2 have been described at least in an animal model of CHF 35 that might contribute to the BP-lowering effects of Ucn2 beyond direct vascular effects.…”

Section: Effects Of Ucn2 On Bpmentioning

confidence: 99%

Immediate and Sustained Blood Pressure Lowering by Urocortin 2

Dieterle

Meili-Butz²,

Bühler³

et al. 2009

Hypertension

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Abstract-Recently, novel corticotropin-releasing factor-related peptides, named urocortin 1, 2, and 3, and a distinct cardiac and peripheral vascular receptor (corticotropin-releasing factor receptor 2) were described being part of a peripheral corticotropin-releasing factor system modulating cardiovascular function in response to stress. Vasorelaxation and blood pressure lowering have been reported after acute administration of these peptides. No data are available on the acute and chronic effects of urocortin 2 on blood pressure in models of arterial hypertension. To test these effects, hypertensive salt-sensitive and normotensive salt-resistant Dahl rats were randomly assigned to twice-daily applications of urocortin 2 or vehicle for 5 weeks. Blood pressure, heart rate, and left ventricular dimension and function were recorded at baseline, after initial application, and, together with cardiac and aortic expression of urocortin 2 and its receptor, after 5 weeks of treatment. Urocortin 2 significantly reduced blood pressure in hypertensive rats without affecting heart rate. Long-term urocortin 2 treatment in hypertensive rats induced sustained blood pressure reduction and diminished the development of hypertension-induced left ventricular hypertrophy and the deterioration of left ventricular contractile function. Corticotropin-releasing factor receptor 2 expression was preserved despite chronic stimulation by urocortin 2. In conclusion, our study shows that, in an animal model of arterial hypertension, urocortin 2 has immediate and sustained blood pressure-lowering effects. Beneficial effects on blood pressure, left ventricular dimension, and function, together with preserved receptor expression, suggest that corticotropin-releasing factor receptor 2 stimulation by urocortin 2 may represent a novel approach to the treatment of arterial hypertension. A rterial hypertension remains the major risk factor for cardiovascular and related diseases. In its most recent report, the World Health Organization lists high blood pressure (BP) as the leading cause of death worldwide.

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“…The techniques for endothelium denudation have been previously described. 26 In brief, the mesenteric vascular bed was continuously perfused with saponin at a concentration of 50 mg/L for 10 min. Thereafter, the vascular bed was immediately perfused with fresh Krebs solution without saponin for 1 h before the acetylcholine test.…”

Section: Methodsmentioning

confidence: 99%

The production of vasoconstriction-induced residual NO modulates perfusion pressure in rat mesenteric vascular bed

et al. 2014

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In the presence of nitric oxide synthase (NOS) inhibitors, the contribution of residual NO to endothelium-dependent relaxation induced by chemical agonists acetylcholine and bradykinin has been documented in resistance vessels. However, the contribution of residual NO to the vasodilatation in response to pressure and fluid shear stress is not well understood. In this study, to demonstrate the activity of residual NO, we applied a NO scavenger, hydroxocobalamin (HCX), on the phenylephrine-induced increase in perfusion pressure in the presence of NOS inhibitors, Nω-nitro-L-arginine (L-NA) or Nω-nitro-L-arginine methyl ester (L-NAME) in the rat perfused mesenteric bed. The perfusion pressure was increased by phenylephrine (1-2 µM), an α1-adrenoceptor agonist. This increase was augmented by the addition of L-NA or L-NAME. In the presence of any NOS inhibitors, the application of hydroxocobalamin (100 µM) further increased the perfusion pressure. The removal of endothelium by saponin (50 mg/L) and the use of a non-selective protein kinase inhibitor, staurosporine (5 nM), and a tyrosine kinase inhibitor, erbstatin A (30 µM), but not a calmodulin inhibitor, calmidazolium (0.5 µM), inhibited the additional pressor responses induced by L-NA or L-NAME and a combination of either of them with hydroxocobalamine. These findings show that there could be a NOS inhibitor-resistant residual NO production in response to pressure in the rat mesenteric vascular bed. This residual NO production may be associated with the activation of tyrosine kinase and protein kinases, but not calmodulin. Finally, this pressure-induced residual NO exerts a modulatory role against vasoconstriction induced by phenylephrine.

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Urocortin Induces Endothelium-Dependent Vasodilatation and Hyperpolarization of Rat Mesenteric Arteries by Activating Ca2+-Activated K+ Channels

Cited by 10 publications

References 37 publications

Modulation of Calcium Movements by Urocortin II in Endothelial Cells

Modulation of Calcium Movements by Urocortin II in Endothelial Cells

Immediate and Sustained Blood Pressure Lowering by Urocortin 2

The production of vasoconstriction-induced residual NO modulates perfusion pressure in rat mesenteric vascular bed

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