Levcromakalim causes indirect endothelial hyperpolarization <i>via</i> a myo‐endothelial pathway

Murai, Takeshi; Muraki, Katsuhiko; Imaizumi, Yuji; Watanabe, Minoru

doi:10.1038/sj.bjp.0702956

Cited by 29 publications

(23 citation statements)

References 33 publications

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“…1). In the converse sense, smooth muscle hyperpolarization induced by K ATP channel openers has been shown to conduct to the endothelium via myoendothelial gap junctions in the rabbit mesenteric artery [131]. Direct communication between the endothelium and subjacent smooth muscle cells can also be visualized by perfusing isolated arterial segments with the cell-permeant agent calcein AM.…”

Section: Myoendothelial Gap Junctions Allow Transfer Of Charge and Smmentioning

confidence: 98%

“…Thus, electrophysiological measurements obtained during intravital microscopy have demonstrated differences in the resting membrane potential of endothelial and smooth muscle cells of the order of 10 mV in murine skeletal muscle arterioles [171]. Additionally, BK Ca blockade with iberiotoxin inhibits ACh-induced smooth muscle hyperpolarization in such vessels without affecting endothelial hyperpolarization [171], and adenosine induces dilation by activating smooth muscle K ATP channels but does not affect endothelial cell membrane potential [33], thus contrasting with isolated conduit arteries in which K ATP mediated hyperpolarization is transmitted to the endothelium via gap junctions [131]. In hamster cheek pouch arterioles also, smooth muscle depolarizations fail to affect endothelial membrane potential in vivo, hyperpolarizations initiated by ACh differ between endothelial and smooth muscle cells [196], and endothelial and smooth muscle hyperpolarization exhibit differential sensitivity to 17-octadecynoic acid, a putative inhibitor of cytochrome P-450 [197].…”

Section: Myoendothelial Coupling In Vivo-no Evidence Yet?mentioning

confidence: 99%

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Connexins and gap junctions in the EDHF phenomenon and conducted vasomotor responses

Wit

Griffith

2010

Pflugers Arch - Eur J Physiol

134

141

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It is becoming increasingly evident that electrical signaling via gap junctions plays a central role in the physiological control of vascular tone via two related mechanisms (1) the endothelium-derived hyperpolarizing factor (EDHF) phenomenon, in which radial transmission of hyperpolarization from the endothelium to subjacent smooth muscle promotes relaxation, and (2) responses that propagate longitudinally, in which electrical signaling within the intimal and medial layers of the arteriolar wall orchestrates mechanical behavior over biologically large distances. In the EDHF phenomenon, the transmitted endothelial hyperpolarization is initiated by the activation of Ca(2+)-activated K(+) channels channels by InsP(3)-induced Ca(2+) release from the endoplasmic reticulum and/or store-operated Ca(2+) entry triggered by the depletion of such stores. Pharmacological inhibitors of direct cell-cell coupling may thus attenuate EDHF-type smooth muscle hyperpolarizations and relaxations, confirming the participation of electrotonic signaling via myoendothelial and homocellular smooth muscle gap junctions. In contrast to isolated vessels, surprisingly little experimental evidence argues in favor of myoendothelial coupling acting as the EDHF mechanism in arterioles in vivo. However, it now seems established that the endothelium plays the leading role in the spatial propagation of arteriolar responses and that these involve poorly understood regenerative mechanisms. The present review will focus on the complex interactions between the diverse cellular signaling mechanisms that contribute to these phenomena.

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Section: Myoendothelial Gap Junctions Allow Transfer Of Charge and Smmentioning

confidence: 98%

Section: Myoendothelial Coupling In Vivo-no Evidence Yet?mentioning

confidence: 99%

Connexins and gap junctions in the EDHF phenomenon and conducted vasomotor responses

Wit

Griffith

2010

Pflugers Arch - Eur J Physiol

134

141

View full text Add to dashboard Cite

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“…Mitochondrial energetics and mK ATP channel activation may contribute, but the changes in membrane potential and cytosolic Ca 2+ suggest that other ion channels (particularly endothelial K ATP channels) may also be involved. K ATP channel-mediated endothelial hyperpolarization may be propagated to the coronary smooth muscle through connexin-mediated myo-endothelial electrical communication (Murai, et al, 1999). It is also possible that endothelial K ATP channel opening (and associated changes in cytosolic Ca 2+ ) may benefit the secretion of vasoactive substances such as nitric oxide (Luckhoff & Busse, 1990; H.…”

Section: Are Endothelial Katp Channels Involved?mentioning

confidence: 99%

Multiplicity of effectors of the cardioprotective agent, diazoxide

Coetzee

2013

Pharmacology & Therapeutics

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Diazoxide has been identified over the past 50 years to have a number of physiological effects, including lowering the blood pressure and rectifying hypoglycemia. Today it is used clinically to treat these conditions. More recently, another important mode of action emerged: diazoxide has powerful protective properties against cardiac ischemia. The heart has intrinsic protective mechanisms against ischemia injury; one of which is ischemic preconditioning. Diazoxide mimics ischemic preconditioning. The purpose of this treatise is to review the literature in an attempt to identify the many effectors of diazoxide and discuss how they may contribute diazoxide’s cardioprotective properties. Particular emphasis is placed on the concentration ranges in which diazoxide affects its different targets and how this compares with the concentrations commonly used to study cardioprotection. It is concluded that diazoxide may have several potential effectors that may potentially contribute to cardioprotection, including KATP channels in the pancreas, smooth muscle, endothelium, neurons and the mitochondrial inner membrane. Diazoxide may also affect other ion channels and ATPases and may directly regulate mitochondrial energetics. It is possible that the success of diazoxide lies in this promiscuity and that the compound acts to rebalance multiple physiological processes during cardiac ischemia.

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“…In rat and rabbit mesenteric arteries, the ATP-sensitive K ϩ channel opener levcromakalim generates hyperpolarization in SMCs. 42,43 Levcromakalim evoked SMC hyperpolarization in both femoral and mesenteric arteries, but hyperpolarization was recorded in the ECs in only the mesenteric artery ( Figure 3A). Intermediate-conductance Ca 2ϩ -sensitive K ϩ channels, present on native ECs, can be activated using 1-EBIO.…”

Section: Separate Generation Of Hyperpolarization In Ecs and Smcsmentioning

confidence: 99%

Involvement of Myoendothelial Gap Junctions in the Actions of Endothelium-Derived Hyperpolarizing Factor

Sandow

Tare

Coleman

et al. 2002

Circulation Research

258

302

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Abstract-The nature of the vasodilator endothelium-derived hyperpolarizing factor (EDHF) is controversial, putatively involving diffusible factors and/or electrotonic spread of hyperpolarization generated in the endothelium via myoendothelial gap junctions (MEGJs). In this study, we investigated the relationship between the existence of MEGJs, endothelial cell (EC) hyperpolarization, and EDHF-attributed smooth muscle cell (SMC) hyperpolarization in two different arteries: the rat mesenteric artery, where EDHF-mediated vasodilation is prominent, and the femoral artery, where there is no EDHF-dependent relaxation. In the rat mesenteric artery, stimulation of the endothelium with acetylcholine (ACh) evoked hyperpolarization of both ECs and SMCs, and characteristic pentalaminar MEGJs were found connecting the two cell layers. Key Words: endothelium-derived hyperpolarizing factor Ⅲ myoendothelial gap junctions Ⅲ endothelium Ⅲ smooth muscle Ⅲ electrical coupling T he endothelium plays a central role in the regulation of vascular tone. 1 The endothelium is capable of exerting a profound relaxing influence on the underlying smooth muscle, mediated by at least three different factors, depending on the vascular bed. These include nitric oxide (NO) and prostacyclin, both diffusible factors. [2][3][4][5][6] In addition, after blockade of NO and prostacyclin synthesis, stimulation of the endothelium is capable of evoking vascular smooth muscle relaxation that has been attributed to a third factor, endothelium-derived hyperpolarizing factor (EDHF). [7][8][9][10][11][12][13][14][15] The hallmark of the vasorelaxation attributed to EDHF is that it is accompanied by membrane hyperpolarization. Consensus regarding the nature of EDHF is lacking, with evidence suggesting the involvement of a diffusible factor(s) released from the endothelium in some vascular beds. 11,12,16,17 Others propose that the hyperpolarization generated in endothelial cells (ECs) is capable of spreading electrotonically to the underlying smooth muscle cells (SMCs), 18,19,21,23,25 most likely via myoendothelial gap junctions (MEGJs). 9,18,19,21,[23][24][25][26] Evidence to support the transfer of a small molecule (eg, cAMP) via MEGJs has also been presented. 20,22 Support for the MEGJ hypothesis has come from studies in which gap junctions have been pharmacologically blocked, either with peptide mimetics of connexin 43 (Cx43) [27][28][29][30] or with glycyrrhetinic acid derivatives. 13,26,[31][32][33] Although the former have been demonstrated to indeed reduce dye coupling between Cx-transfected cells, 34 the latter seem to have some nonspecific actions. [31][32][33]35 An alternative and complementary approach would be to study an artery that lacked an EDHF-dependent relaxation and to test for the existence of agonist-induced hyperpolarization in the ECs and for the presence of MEGJs. The femoral artery represents such a tissue because EDHF does not contribute to endothelium-dependent SMC relaxation in this vessel. 36,37 In the present study, this artery was ...

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Levcromakalim causes indirect endothelial hyperpolarization via a myo‐endothelial pathway

Cited by 29 publications

References 33 publications

Connexins and gap junctions in the EDHF phenomenon and conducted vasomotor responses

Connexins and gap junctions in the EDHF phenomenon and conducted vasomotor responses

Multiplicity of effectors of the cardioprotective agent, diazoxide

Involvement of Myoendothelial Gap Junctions in the Actions of Endothelium-Derived Hyperpolarizing Factor

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