Reduced arteriolar conducted vasoconstriction in septic mouse cremaster muscle is mediated by nNOS-derived NO

McKinnon, Rebecca L.; Lidington, Darcy; Bolon, Michael L.; Ouellette, Yves; Kidder, Gerald M.; Tyml, Karel

doi:10.1016/j.cardiores.2005.09.003

Cited by 47 publications

(64 citation statements)

References 39 publications

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“…The role of Cx37 in the vasculature has previously been analyzed in mice deficient for Cx37, which showed impaired conduction of arteriolar vasoconstriction (19) and susceptibility to atherogenesis (35). Colocalization of Cx37 with renin suggests a role for Cx37 in renin release, although Cx40 Ϫ/Ϫ rather than Cx37 Ϫ/Ϫ mice showed an obvious renin-related phenotype with increased circulating renin levels and hypertension (14).…”

Section: Discussionmentioning

confidence: 99%

“…It displayed a high homology with other Cx in its extracellular domains, whereas little or no homology was found in the cytoplasmic loop connecting the second and third hydrophobic region and the COOH-terminal chain. Modulations of Cx37 occurred via posttranslational modifications including phosphorylation and probably nitrosylation (19). Functionally Cx37 has been shown to form intercellular channels that exhibit specific channel properties such as voltage gating (34).…”

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confidence: 99%

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Connexin 37 is localized in renal epithelia and responds to changes in dietary salt intake

Stoessel

Himmerkus

Bleich

et al. 2010

American Journal of Physiology-Renal Physiology

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Connexin 37 is localized in renal epithelia and responds to changes in dietary salt intake

Stoessel

Himmerkus

Bleich

et al. 2010

American Journal of Physiology-Renal Physiology

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“…However, under pathophysiological conditions with supposedly even higher NO levels a further attenuation seems to be possible, since treatment with LPS (33,34) or induction of sepsis attenuated the conduction process in vivo without prior inhibition of endogenous NO release (22,34). These authors demonstrated that the effect of LPS was mediated by NO and have identified neuronal NO synthase as the source of NO under these conditions (26). Nevertheless, these observations are in good agreement with the data presented in this report, and the present study extends these findings by demonstrating a role for the basal NO release from eNOS and thus expanding the regulatory role for NO toward physiological conditions.…”

Section: Discussionmentioning

confidence: 97%

“…In addition, it is rather unclear which connexin is targeted by such a regulatory mechanisms in vivo. Initially, Cx43 was proposed as a target (23), and later Cx37 (26) and Cx40 during study of hypoxia/ reoxygenation (4). Therefore, we hypothesized that endogenous NO acts as a regulatory factor on GJIC in vivo in a cGMP-dependent fashion.…”

mentioning

confidence: 98%

“…In fact, most connexins that are expressed in vascular cells (Cx40, Cx45, Cx43) and form gap junctions are targets of phosphorylation (21,35,36). Moreover, inflammatory mediators have been demonstrated to modulate intercellular coupling in arterioles in vivo (34), supposedly in a NO-dependent manner (22,26). In addition, it is rather unclear which connexin is targeted by such a regulatory mechanisms in vivo.…”

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confidence: 99%

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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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Reactive oxygen and nitrogen species in sepsis-induced hepatic microvascular dysfunction

2012

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Objective and designHepatic microvascular dysfunction is a critical event in the development of liver failure during sepsis. Activated blood cells and reactive oxygen and nitrogen species (RONS) have been implicated in the pathogenesis of sepsis.MethodsIntravital-videomicroscopy was used to determine whether RONS contribute to the recruitment of leukocytes/platelets in the hepatic microvasculature during sepsis. Six hours following cecal-ligation and puncture (CLP), disturbances of the hepatic microvasculature were assessed in WT-mice (C57Bl/6 J; n = 8), in mice lacking gp91phox(n = 5), overexpressing superoxide-dismutase (SOD, n = 8), in WT-mice treated with a NOS-inhibitor (l-NAME, n = 5), lacking nNOS, eNOS or iNOS (n = 5 each), treated with the NO-donor DetaNO (n = 5), in WT-mice treated with gadolinium-chloride (GdCl2, n = 5) and compared to a group of WT-mice following a sham operation (n = 8). Six hours post-CLP, the adhesion of leukocytes and platelets in terminal hepatic venules (THV) and sinusoids was quantified.ResultsIn WT-mice, CLP elicited increases in the number of adherent leukocytes and platelets. Similar responses to CLP were noted in mice overexpressing SOD or lacking either eNOS or gp91phox. The blood-cell recruitment was significantly blunted in septic iNOS-knockout mice and this response was reversed by pre-treatment with DetaNO.ConclusionThese findings suggest that iNOS-derived NO is a determinant of the pro-inflammatory phenotype assumed by the hepatic microvasculature during sepsis.

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Reduced arteriolar conducted vasoconstriction in septic mouse cremaster muscle is mediated by nNOS-derived NO

Cited by 47 publications

References 39 publications

Connexin 37 is localized in renal epithelia and responds to changes in dietary salt intake

Connexin 37 is localized in renal epithelia and responds to changes in dietary salt intake

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

Reactive oxygen and nitrogen species in sepsis-induced hepatic microvascular dysfunction

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