EDHF, but not NO or prostaglandins, is critical to evoke  a conducted dilation upon ACh in hamster arterioles

Hoepfl, Bernd; Rodenwaldt, Barbara; Pohl, Ulrich; Wit, Cor de

doi:10.1152/ajpheart.01082.2001

Cited by 80 publications

(88 citation statements)

References 33 publications

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“…Inhibition of NO synthase did not reduce local or remote acetylcholine dilations. This suggests that NO does not contribute to the initiation or the conduction process in this preparation as was observed similarly in the hamster cremaster (14), but NO may contribute in other tissues (5). Conversely, NO synthase inhibition also did not enhance the conduction of dilations in wild-type mice.…”

Section: Discussionsupporting

confidence: 60%

Endogenous and exogenous NO attenuates conduction of vasoconstrictions along arterioles in the microcirculation

Rodenwaldt

Pohl²,

Wit³

2007

American Journal of Physiology-Heart and Circulatory Physiology

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Vascular coordination in the microcirculation depends on gap junctional intercellular communication (GJIC), which is reflected by the conduction of locally initiated vasomotor responses. However, little is known about the regulation of GJIC in vivo. We hypothesized that endothelial NO regulates GJIC and therefore studied whether conduction of constrictions and dilations along the vessel wall is modulated by modifying the level of microcirculatory NO. Arterioles were focally stimulated using high K ϩ or acetylcholine in the cremaster muscle in situ, and diameter changes were assessed at the local and remote upstream sites by intravital microscopy. Local stimulation with K ϩ initiated a constriction that conducted along the arteriole with diminishing amplitude (length constant :, increased to 507 Ϯ 30 m, indicating that GJIC is attenuated by endogenous NO. Exogenous NO, but not adenosine, reduced after L-NNA in a reversible, concentrationdependent, and mainly cGMP-dependent manner as assessed by inhibition of soluble guanylate cyclase. In endothelial NO synthasedeficient mice, was 530 Ϯ 80 m and thus similar to that in wild-type mice after L-NNA. Exogenous NO likewise reduced in these mice. The effects of NO were comparable to those of wild-type animals in Cx40-deficient mice, which excludes Cx40 as a specific target of NO. In contrast to constrictions, the amplitude of conducted dilations on acetylcholine did not diminish up to 1,300 m and were not altered by L-NNA or exogenous NO. We conclude that endogenously released NO attenuates the conduction of vasoconstrictions most likely due to a modulation of gap junctional conductivity. We suggest that this effect is specific for smooth muscle cells, which probably transmit constricting signals, and involves connexins other than Cx40. This mechanism may support the dilatory potency of NO by preventing the conduction of remote vasoconstrictions into areas with basal or activated NO release. conducted responses; gap junctional communication; connexins; nitric oxide BLOOD FLOW IS REGULATED to precisely meet the metabolic tissue demands. The adjustment of flow requires a coordination of diameter changes over substantial distances along the vessel length in the microcirculation that is believed to depend on intercellular communication through gap junctions (31). Such a communication along the vessel wall gives rise to coordinated vasomotor responses, e.g., conducted constrictions and dilations, that reflect the synchronous activity of vascular cells. It has been proposed that the mechanism underlying conduction of vasomotor responses entails the spread of membrane potential changes along endothelial and

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Section: Discussionsupporting

confidence: 60%

Endogenous and exogenous NO attenuates conduction of vasoconstrictions along arterioles in the microcirculation

Rodenwaldt

Pohl²,

Wit³

2007

American Journal of Physiology-Heart and Circulatory Physiology

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“…Despite the presence of antioxidant or PKC inhibition, xanthine-induced reduction in NO production was not restored though attenuated relaxation to ACh was improved. This observation suggests that ACh-induced relaxation may be mediated via other mechanism(s) that is independent of NO for example via endothelium-dependent hyperpolarizing factor, or epoxides (Cohen and Vanhoutte, 1995;Hoepfl et al, 2002). However, this speculation is beyond the scope of this study.…”

Section: Discussionmentioning

confidence: 78%

Link between free radicals and protein kinase C in glucose-induced alteration of vascular dilation

et al. 2004

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Development of vascular complications in diabetes has been linked to the quality of glucose regulation and characterized by endothelial dysfunction. The exact mechanism behind vascular complications in diabetes is poorly understood. However, alteration of nitric oxide (NO) biosynthesis or bioactivity is strongly implicated and the mechanism behind such alterations is still a subject for research investigations. In the present study, we tested the hypothesis that glucoseinduced attenuation of vascular relaxation involves protein kinase C (PKC)-linked generation of free radicals. Vascular relaxation to acetylcholine (ACh; 10 −9 -10 −5 M), isoproterenol (10 −9 -10 −5 M), or NO donor, sodium nitropruside (SNP; 10 −9 -10 −6 M) was determined in phenylephrine (PE, 10 −7 M) pre-constricted aortic rings from Sprague-Dawley rats in the presence or absence of 30 mM glucose (30 min), L-nitro-arginine methyl ester (L-NAME; 10 −4 M for 15 min), a NO synthase inhibitor, or xanthine (10 −5 M), a free radical generator. ACh dose-dependently caused relaxation that was attenuated by L-NAME, glucose, or xanthine. Pre-incubation (15 min) of the rings with vitamin C (10 −4 M), an antioxidant or calphostin C (10 −6 M), a PKC inhibitor, restored the ACh responses. However, high glucose had no significant effects on SNP or isoproterenolinduced relaxation. ACh-induced NO production by aortic ring was significantly reduced by glucose or xanthine. The reduced NO production was restored by pretreatment with vitamin C or calphostin C in the presence of glucose, but not xanthine. These data demonstrate that oxidants or PKC contribute to glucose-induced attenuation of vasorelaxation which could be mediated via impaired endothelial NO production and bioavailability. Thus, pathogenesis of glucose-induced vasculopathy involves PKC-coupled generation of oxygen free radicals which inhibit NO production and selectively inhibit NO-dependent relaxation.

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“…1 However, some studies that question the existence of EDHF suggest that electrical coupling of endothelial and smooth muscle cells through gap junctions mediates the activity. The idea that EDHF/EETs activate potassium channels in endothelial cells, leading to either the release of K ϩ , 2-4 or spread of current from endothelial cells, [5][6][7][8][9] to hyperpolarize smooth muscle, has attracted attention, because histological evidence of the existence of gap junctions between endothelial and smooth muscle cells and between endothelial cells was provided. 10,11 It was also reported that hyperpolarization of endothelial cells by injection of current or administration of ACh was conducted downstream to cause dilation of arterioles through endothelial gap junctions, 12,13 a response that was inhibited by removal of the endothelium, or attenuated in arteries of mice deficient in connexin 40, a protein component of endothelial gap junctions.…”

mentioning

confidence: 99%

Epoxyeicosatrienoic Acids Are Released to Mediate Shear Stress–Dependent Hyperpolarization of Arteriolar Smooth Muscle

Huang

Sun

Jacobson

et al. 2005

Circulation Research

105

100

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Abstract-We hypothesized that shear stress stimulates the release of epoxyeicosatrienoic acids (EETs) from arteriolar endothelium, which directly hyperpolarize smooth muscle. To test this hypothesis, a perfusion system, consisting of two separate, serially connected chambers (A and B), was used. A donor vessel, isolated from gracilis muscle of female NO-deficient mice and rats, was cannulated in chamber A. In chamber B, an endothelium-denuded detector vessel isolated from mesentery of these animals was cannulated. In the presence of indomethacin, 5, 10, and 20 dyne/cm 2 shear stress elicited dilation of donor vessels, followed by dilation of detector vessels. Changes in membrane potential of the detector vessel smooth muscle cells in response to the perfusate from 5 and 10 dyne/cm 2 shear stress-stimulated donor vessels was also recorded (by ϷϪ12 to Ϫ15 and Ϫ20 to Ϫ30 mV, respectively). Exposing detector vessels to 30 mmol/L KCl or pretreating them with iberiotoxin abolished their hyperpolarization and dilation to the flow of perfusate. Pretreatment of donor vessels with PPOH, an inhibitor of cytochrome P-450/epoxygenase, eliminated dilator responses in both donor and detector vessels, as well as the hyperpolarization of detector vessels. GC-MS analysis showed increasing release of EETs into the perfusate collected from 1, 5, and 10 dyne/cm 2 shear stress-stimulated arterioles, which was abolished by PPOH. Thus, EETs, released from endothelial cells of donor vessels stimulated with shear stress, hyperpolarize smooth muscle of downstream detector vessels, confirming their identity as endotheliumderived hyperpolarizing factors and suggesting that gap junctional communication may not be necessary for shear stress-stimulated EDHF-mediated vasodilation. Key Words: NO deficiency Ⅲ shear stress Ⅲ EET Ⅲ hyperpolarization Ⅲ arterioles A lthough the chemical identity of endothelium-derived hyperpolarizing factor (EDHF) remains controversial, epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acids by cytochrome P450 (CYP)/epoxygenase, have been identified as a potential EDHF in a variety of vascular beds, including coronary, cerebral, renal, skeletal muscle vasculature, and human forearm and subcutaneous microvessels. 1 However, some studies that question the existence of EDHF suggest that electrical coupling of endothelial and smooth muscle cells through gap junctions mediates the activity. The idea that EDHF/EETs activate potassium channels in endothelial cells, leading to either the release of K ϩ , 2-4 or spread of current from endothelial cells, [5][6][7][8][9] to hyperpolarize smooth muscle, has attracted attention, because histological evidence of the existence of gap junctions between endothelial and smooth muscle cells and between endothelial cells was provided. 10,11 It was also reported that hyperpolarization of endothelial cells by injection of current or administration of ACh was conducted downstream to cause dilation of arterioles through endothelial gap junctions, 12,13 a response that was inhibit...

show abstract

EDHF, but not NO or prostaglandins, is critical to evoke a conducted dilation upon ACh in hamster arterioles

Cited by 80 publications

References 33 publications

Endogenous and exogenous NO attenuates conduction of vasoconstrictions along arterioles in the microcirculation

Endogenous and exogenous NO attenuates conduction of vasoconstrictions along arterioles in the microcirculation

Link between free radicals and protein kinase C in glucose-induced alteration of vascular dilation

Epoxyeicosatrienoic Acids Are Released to Mediate Shear Stress–Dependent Hyperpolarization of Arteriolar Smooth Muscle

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