Increases in endothelial Ca²⁺activate K_Cachannels and elicit EDHF-type arteriolar dilation via gap junctions

Abstract

] i ). However, recent studies revealed that in the endothelium of skeletal muscle arterioles, vessels that contribute importantly to the development of peripheral resistance, nitric oxide (NO) synthesis is activated by increases in shear stress without substantial increases in endothelial [Ca 2ϩ ] i , most likely by activation of Ca 2ϩ -independent tyrosine kinase pathways (35).In contrast, arteriolar dilations to agonists that act on endothelial receptors, such as acetylcholine (ACh), are associated with significant increases in endothelial [Ca 2ϩ ] i (7,23,34). Interestingly, in the microcirculation, in contrast to large vessels, a major part of AChinduced dilation is insensitive to the inhibition of NO synthase and cyclooxygenase. Pathways associated with NO-and prostaglandin-independent mediation involve smooth muscle hyperpolarization (3,7,14,34); therefore, it is termed endothelium-derived hyperpolarizing factor (EDHF)-type dilation. Despite its profound effect on arteriolar myogenic tone, the intra-and intercellular pathways for EDHF-type signal transduction are not well understood.Skeletal muscle arterioles are known to develop significant myogenic tone in response to intraluminal pressure, which depends on pressure-induced increases in smooth muscle [Ca 2ϩ ] i due to an influx of Ca 2ϩ through voltage-operated Ca 2ϩ channels (VOC) (33). Recently, we (34) demonstrated that EDHF-type arteriolar dilation to ACh is elicited by a decrease in smooth muscle [Ca 2ϩ ] i due to a hyperpolarization-dependent closure of VOC. However, the role of increases in endothelial [Ca 2ϩ ] i and the nature of coupling between endothelial activation and hyperpolarizationinduced decreases in smooth muscle [Ca 2ϩ ] i in EDHFtype arteriolar dilation remained to be resolved.From previous studies, we hypothesized that agonist-induced increases in arteriolar endothelial [Ca 2ϩ ] i elicit opening of endothelial Ca 2ϩ -activated K ϩ (K Ca ) channels, and the consequent hyperpolarization (11, 40) is conducted to the smooth muscle, likely via gap junctions (13,14,28,40) eliciting decreases in smooth muscle [Ca 2ϩ ] i and arteriolar dilations. To demonstrate that this hypothetic pathway is responsible for signal transduction of EDHF-type dilation of skeletal muscle arterioles, we measured simultaneous changes in endothelial [Ca 2ϩ ] i and diameter and characterized the role of endothelial K Ca channels

Propagated Endothelial Ca 2+ Waves and Arteriolar Dilation In Vivo

“…Stimulation with ACh elicited an initial local rise in Ca 2ϩ and vasodilation, similar to observations in isolated arterioles 2,23 and consistent with findings that ACh-induced vasodilation is inhibited by chelation of intracellular Ca 2ϩ in ECs. 23 A local rise in EC Ca 2ϩ stimulates Ca 2ϩ -activated Kϩ channels, resulting in hyperpolarization and rapidlyconducted vasodilation.…”

Vascular Dysfunction in Aging: Potential Effects of Resveratrol, an Anti- Inflammatory Phytoestrogen

“…B: Effect of resveratrol pretreatment (10 −6 mol/L, for 30 min) on acetylcholine-induced dilations of young and aged arteries. The inner vascular diameter was measured by videomicroscopy as described [96][97][98]. The TXA 2 mimetic U46619 (10 −7 mol/L) was used for preconstriction.…”

EDHF-mediated vasodilation involves different mechanisms in normotensive and hypertensive rat lungs

“…To examine effects of gap junction inhibitors on "baseline" vascular tone and hypoxic vasoconstriction in meclofenamate-and L-NNA-pretreated normotensive and hypertensive lungs, 30 M 18␣-glycyrrhetinic acid (Sigma) (10,29), 50 M palmitoleic acid (Sigma) (3,13,27,56), or vehicle (DMSO) was added to the perfusate according to the above protocol for CYP450 inhibitors. The lungs were then challenged twice with 15 min of 3% O 2 at 15 and 40 min after the gap junction inhibitors or vehicle.…”

“…The incidence of myoendothelial gap junctions is higher in resistance than in conduit arteries (46). Putative gap junction inhibitors, such as palmitoleic acid (13,27,56), 18␣-glycyrrhetinic acid (10,16,23,27,29,36,52,53), and Gap 27 (9,16,47,52), a synthetic peptide with sequence homology to a region of the second extracellular loop of Cx37 and Cx43, reduce EDHF-mediated hyperpolarization and relaxation in various arteries. These observations suggest that the EDHF signal represents electrotonic spread of hyperpolarization from the endo-thelium into the medial smooth muscle via myoendothelial and homocellular smooth muscle gap junctions.…”