Endothelium-Dependent Hyperpolarization: The Evolution of Myoendothelial Microdomains

Garland, Christopher; Dora, K A

doi:10.1097/fjc.0000000000001087

Cited by 14 publications

(19 citation statements)

References 110 publications

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“…Endothelial dysfunction contributes to the pathogenesis of microvascular diabetic complications. Thus, considering that (a) endothelial relaxation depends on several agents such as NO [ 44 ], prostacyclin [ 45 ], and/or endothelium-derived hyperpolarizing factor (EDHF) [ 46 ], (b) endothelial-dependent vasorelaxation is altered in diabetes [ 47 ], and (c) the NO synthesis was involved in 5-HT 1D renal sympatho-inhibitory effect in normoglycaemic rats [ 18 ], we determined the possible role of these vasodilator agents in the serotonergic inhibitory action in diabetic rats using ODQ (a guanylyl cyclase inhibitor), indomethacin (a COX 1/2 inhibitor), or glibenclamide (an ATP-sensitive K + channels blocker) [ 48 , 49 , 50 ]. As was observed in normoglycaemic animals, only the NO pathway is involved in the 5-HT 1D renal sympatholytic action in diabetes, which is also in agreement with previous results by us in the diabetic pithed rat model [ 22 , 51 ].…”

Section: Discussionmentioning

confidence: 99%

Renal Sympathetic Hyperactivity in Diabetes Is Modulated by 5-HT1D Receptor Activation via NO Pathway

Fernández-González

García-Pedraza

Ordóñez

et al. 2023

IJMS

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Renal vasculature, which is highly innervated by sympathetic fibers, contributes to cardiovascular homeostasis. This renal sympathetic outflow is inhibited by 5-HT in normoglycaemic rats. Considering that diabetes induces cardiovascular complications, we aimed to determine whether diabetic state modifies noradrenergic input at renal level and its serotonergic modulation in rats. Alloxan diabetic rats were anaesthetized (pentobarbital; 60 mg/kg i.p.) and prepared for in situ autoperfusion of the left kidney to continuously measure systemic blood pressure (SBP), heart rate (HR), and renal perfusion pressure (RPP). Electrical stimulation of renal sympathetic outflow induces frequency-dependent increases (Δ) in RPP (23.9 ± 2.1, 59.5 ± 1.9, and 80.5 ± 3.5 mm Hg at 2, 4, and 6 Hz, respectively), which were higher than in normoglycaemic rats, without modifying HR or SBP. Intraarterial bolus of 5-HT and 5-CT (5-HT1/5/7 agonist) reduced electrically induced ΔRPP. Only L-694,247 (5-HT1D agonist) reproduced 5-CT inhibition on sympathetic-induced vasoconstrictions, whereas it did not modify exogenous noradrenaline-induced ΔRPP. 5-CT inhibition was exclusively abolished by i.v. bolus of LY310762 (5-HT1D antagonist). An inhibitor of guanylyl cyclase, ODQ (i.v.), completely reversed the L-694,247 inhibitory effect. In conclusion, diabetes induces an enhancement in sympathetic-induced vasopressor responses at the renal level. Prejunctional 5-HT1D receptors, via the nitric oxide pathway, inhibit noradrenergic-induced vasoconstrictions in diabetic rats.

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Section: Discussionmentioning

confidence: 99%

Renal Sympathetic Hyperactivity in Diabetes Is Modulated by 5-HT1D Receptor Activation via NO Pathway

Fernández-González

García-Pedraza

Ordóñez

et al. 2023

IJMS

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“…Opening endothelial SK Ca and IK Ca channels induces hyperpolarization, which could be transmitted to adjacent VSMCs via MEGJ, leading to hyperpolarization of VSMCs, closure of the Ca V 1.2 channel, and subsequent vasodilation ( Figure 2 ) [ 2 , 146 , 147 , 148 ]. In addition, K + ion accumulated in the extracellular space between ECs and VSMCs due to activation of endothelial SK Ca and IK Ca channels is proposed to cause hyperpolarization and relaxation of the VSMCs through activating the inwardly-rectifying K + (K ir ) channel and/or the Na + -K + -ATPase [ 149 , 150 ].…”

Section: K Ca Channels and Vascular Functionmentioning

confidence: 99%

“…EDHF plays an important role in regulating uterine vascular contractility during pregnancy [ 220 , 275 ]. Endothelial SK Ca 2.3 and IK Ca channels mediate endothelial membrane hyperpolarization and participate in EDHF-mediated vasodilator response [ 148 , 276 ]. Pregnancy significantly potentiates EDHF-mediated vasodilation of uterine arteries [ 204 , 277 ].…”

Section: K Ca Channels and The Uteroplacental Circ...mentioning

confidence: 99%

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Ca2+-Activated K+ Channels and the Regulation of the Uteroplacental Circulation

Zhang

2023

IJMS

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Adequate uteroplacental blood supply is essential for the development and growth of the placenta and fetus during pregnancy. Aberrant uteroplacental perfusion is associated with pregnancy complications such as preeclampsia, fetal growth restriction (FGR), and gestational diabetes. The regulation of uteroplacental blood flow is thus vital to the well-being of the mother and fetus. Ca2+-activated K+ (KCa) channels of small, intermediate, and large conductance participate in setting and regulating the resting membrane potential of vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) and play a critical role in controlling vascular tone and blood pressure. KCa channels are important mediators of estrogen/pregnancy-induced adaptive changes in the uteroplacental circulation. Activation of the channels hyperpolarizes uteroplacental VSMCs/ECs, leading to attenuated vascular tone, blunted vasopressor responses, and increased uteroplacental blood flow. However, the regulation of uteroplacental vascular function by KCa channels is compromised in pregnancy complications. This review intends to provide a comprehensive overview of roles of KCa channels in the regulation of the uteroplacental circulation under physiological and pathophysiological conditions.

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“…In order to perform such diverse functions, endothelial cells produce a range of important biomolecules, such as endothelium-derived hyperpolarizing factor (EDHF), nitric oxide (NO) and prostacyclin (PGI2), which present vasodilator and antiproliferative effects on vascular smooth muscle cells ( Garland and Dora, 2021 ). On the other hand, endothelial cells also generate endothelin-1 (ET-1), angiotensin II (AT-II) and reactive oxygen species (ROS), which present vasoconstrictor effects and promote the proliferation of vascular smooth muscle cells ( Sena et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Endothelial dysfunction due to the inhibition of the synthesis of nitric oxide: Proposal and characterization of an in vitro cellular model

et al. 2022

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The vascular endothelium plays a pivotal role in the maintenance of vascular homeostasis, mediated by vasoactive molecules produced by endothelial cells. The balance between vasoconstrictor and vasodilator biomolecules is what guarantees this equilibrium. Therefore, an increase in the bioavailability of vasoconstrictors along with a reduction in vasodilators may indicate a condition known as endothelial dysfunction. Endothelial dysfunction is marked by an inflammatory process and reduced activity of vasoprotective enzymes, being characterized by some factors like the reduction of the bioavailability of nitric oxide (NO) and increase in the production of reactive oxygen species (ROS), pro-inflammatory and vasoconstrictor molecules. This condition is a predictive marker of several cardiovascular diseases (e.g., atherosclerosis, hypertension, and diabetes). Research is affected by the scarcity of suitable in vitro models that simulate endothelial dysfunction. The goal of this study was to induce an in vitro condition to mimic endothelial dysfunction by inhibiting NO synthesis in cells. Thymus-derived endothelial cells (tEnd.1) were treated with different concentrations of L-NAME (from 1 to 1,000 μM) for different times (12, 24, 48, 72, 96, and 120 h without and with retreatment every 24 h). Cell viability, nitrite concentration, p22phox, NOX2, NOX4, IL-6, and ACE genes expression and lipid peroxidation were evaluated. The results indicate that the treatment with 100 μM L-NAME for 72 h without retreatment reduced NO concentration and NOX4 gene expression while increasing ACE expression, thus mimicking reduced vascular protection and possibly increased vasoconstriction. On the other hand, treatment with 100 μM L-NAME for 96 h with retreatment reduced the concentration of NO and the expression of the p22phox gene while increasing the expression of the IL-6 and ACE genes, mimicking the increase in inflammation and vasoconstriction parameters. Based on these results, we thus propose that both 100 μM L-NAME for 72 h without retreatment and 100 μM L-NAME for 96 h with retreatment may be used as models for in vitro endothelial dysfunction according to the purpose of the study to be conducted.

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Endothelium-Dependent Hyperpolarization: The Evolution of Myoendothelial Microdomains

Cited by 14 publications

References 110 publications

Renal Sympathetic Hyperactivity in Diabetes Is Modulated by 5-HT1D Receptor Activation via NO Pathway

Renal Sympathetic Hyperactivity in Diabetes Is Modulated by 5-HT1D Receptor Activation via NO Pathway

Ca2+-Activated K+ Channels and the Regulation of the Uteroplacental Circulation

Endothelial dysfunction due to the inhibition of the synthesis of nitric oxide: Proposal and characterization of an in vitro cellular model

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