Hydralazine-induced vasodilation involves opening of high conductance Ca2+-activated K+ channels

Bang, Lone; Nielsen‐Kudsk, Jens Erik; Gruhn, Nicolai; Trautner, Simon; Theilgaard, Sune A.; Olesen, Søren‐Peter; Boesgaard, Søren; Aldershvile, Jan

doi:10.1016/s0014-2999(98)00701-8

Cited by 40 publications

(26 citation statements)

References 13 publications

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“…Taken together, these results suggest that NO/PKG exerts a negative regulatory influence on JNK2 activity. An additional implication of these results is that the production of NO by the endothelium may increase in response to elevations in pressure, consistent with recent results from rat mesentery and cerebral arteries (55)(56)(57).…”

Section: Pressure Induction Of Nfatc3 Nuclear Accumulation Requires Bsupporting

confidence: 89%

Intraluminal Pressure Is a Stimulus for NFATc3 Nuclear Accumulation

Bosc¹,

Wilkerson²,

Bradley

et al. 2004

Journal of Biological Chemistry

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The transcription factor NFAT (nuclear factor of activated T-cells) is implicated in cardiac hypertrophy and vasculogenesis. NFAT activation, reflecting dephosphorylation by the calcium-dependent phosphatase, calcineurin, and subsequent nuclear localization, is generally thought to require a sustained increase in intracellular calcium. However, in smooth muscle we have found that elevation of calcium by membrane depolarization fails to induce an increase in nuclear localization of the NFATc3 isoform. Here, we demonstrate that physiological intravascular pressure (100 mm Hg) induces an increase in NFATc3 nuclear localization in mouse cerebral arteries. Pressure-induced NFATc3 nuclear accumulation is abrogated by endothelial denudation and by nitric-oxide synthase, cGMP-dependent kinase (PKG), and voltage-dependent calcium channels inhibition. We further show that exogenous nitric oxide, in combination with an elevation in calcium, is an effective stimulus for NFATc3 nuclear accumulation. c-Jun terminal kinase 2 (JNK) activity, which has been shown to regulate NFATc3 nuclear export, is also reduced by pressure, an effect that is prevented by pretreatment with a PKG inhibitor. Consistent with this, pressure-induced NFATc3 nuclear accumulation is independent of PKG in arteries from JNK2 ؊/؊ mice. Collectively, our results indicate that both activation of the NO/PKG pathway and elevation of smooth muscle calcium are required for NFATc3 nuclear accumulation and that PKG inhibits JNK2 to decrease NFAT nuclear export. Our findings suggest that at physiological intravascular pressures NFATc3 is localized to the nucleus in smooth muscle cells of intact arteries and indicate a novel and unexpected role for nitric oxide/PKG in NFAT activation.

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Section: Pressure Induction Of Nfatc3 Nuclear Accumulation Requires Bsupporting

confidence: 89%

Intraluminal Pressure Is a Stimulus for NFATc3 Nuclear Accumulation

Bosc¹,

Wilkerson²,

Bradley

et al. 2004

Journal of Biological Chemistry

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“…The transcription factors E26 transformation-specific sequence-1 and -2, implicated in controlling miR-126 expression, were unchanged 24 in CRVH compared with DRV ( Figure IIIC in the online-only Data Supplement). Although the beneficial effects of hydralazine as a vasodilator are attributed to K + channel opening in ECs, 41 other potential effects include DNMT inhibition 30 and thus DNA methylation, which is known to regulate miR-126 expression. 42 Even if the effects of hydralazine on DNA Figure IIID-IIIG in the online-only Data Supplement).…”

Section: Discussionmentioning

confidence: 99%

Downregulation of MicroRNA-126 Contributes to the Failing Right Ventricle in Pulmonary Arterial Hypertension

et al. 2015

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R ight ventricular (RV) function is a major determinant of functional capacity and survival in pulmonary arterial hypertension (PAH) and other types of pulmonary hypertension.1 Although afterload is a prominent determinant for RV systolic function in PAH, there remains significant variability between patients with PAH in the ability of the RV to adapt to pressure overload and pulmonary resistance.2,3 The mechanisms accounting for this variability in RV adaptability to increased pulmonary load and for the transition to RV failure remain elusive. Despite the tremendous attention that left ventricular (LV) failure has received, RV failure has remained understudied at both the preclinical and clinical levels. 3 As a result, RV failure has emerged as an important research priority in the cardiopulmonary research field. Clinical Perspective on p 943Magnetic resonance imaging performed in patients with PAH has shown that the hypertrophied RV is ischemic 5 andBackground-Right ventricular (RV) failure is the most important factor of both morbidity and mortality in pulmonary arterial hypertension (PAH). However, the underlying mechanisms resulting in the failed RV in PAH remain unknown. There is growing evidence that angiogenesis and microRNAs are involved in PAH-associated RV failure. We hypothesized that microRNA-126 (miR-126) downregulation decreases microvessel density and promotes the transition from a compensated to a decompensated RV in PAH. Methods and Results-We studied RV free wall tissues from humans with normal RV (n=17), those with compensated RV hypertrophy (n=8), and patients with PAH with decompensated RV failure (n=14). Compared with RV tissues from patients with compensated RV hypertrophy, patients with decompensated RV failure had decreased miR-126 expression (quantitative reverse transcription-polymerase chain reaction; P<0.01) and capillary density (CD31 + immunofluorescence; P<0.001), whereas left ventricular tissues were not affected. miR-126 downregulation was associated with increased Sprouty-related EVH1 domain-containing protein 1 (SPRED-1), leading to decreased activation of RAF (phosphorylated RAF/RAF) and mitogen-activated protein kinase (MAPK); (phosphorylated MAPK/MAPK), thus inhibiting the vascular endothelial growth factor pathway. In vitro, Matrigel assay showed that miR-126 upregulation increased angiogenesis of primary cultured endothelial cells from patients with decompensated RV failure. Furthermore, in vivo miR-126 upregulation (mimic intravenous injection) improved cardiac vascular density and function of monocrotaline-induced PAH animals. Conclusions-RV failure in PAH is associated with a specific molecular signature within the RV, contributing to a decrease in RV vascular density and promoting the progression to RV failure. More importantly, miR-126 upregulation in the RV improves microvessel density and RV function in experimental PAH. Key Words: hypertension, pulmonary ◼ microRNAs ◼ microvessels ◼ pulmonary heart disease ◼ right ventricular failure © 2015 American Heart Assoc...

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“…Although BK Ca channels are absent from the endothelium in some vascular beds (29 -31), their presence has been well documented in others, such as endothelial cells of the human cerebral microvasculature (32) and aorta (33), as well as porcine (34 -36) and rat coronary arteries (36). The present finding that iberiotoxin inhibits abn-cbd-induced vasorelaxation in intact, but not in denuded, rat mesenteric artery segments is similar to observations in rat and porcine coronary arteries (36) and indicates that activation of BK Ca channels is involved in the vasodilator response to abn-cbd. This justifies drawing analogies between the effects of abn-cbd in cultured HUVEC and those reported earlier using rat mesenteric artery segments.…”

Section: Discussionmentioning

confidence: 99%

G Protein-coupled Endothelial Receptor for Atypical Cannabinoid Ligands Modulates a Ca2+-dependent K+ Current

Begg

Offertáler

et al. 2003

Journal of Biological Chemistry

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The cannabinoid analog "abnormal cannabidiol" (abn-cbd) causes endothelium-dependent vasodilation in rat isolated mesenteric arteries through a G protein-coupled receptor distinct from CB 1 or CB 2 . We examined the actions of abn-cbd on the electrophysiology of human umbilical vein endothelial cells (HU-VEC), using the whole cell version of the patch clamp technique. Voltage steps produced noninactivating outward currents, which were abolished by iberiotoxin or by chelation of intracellular calcium. The presence of a BK Ca channel in HUVEC was documented by reverse transcriptase-PCR. Abn-cbd concentration dependently potentiated the outward current produced by a single voltage step. This potentiation was abolished by the cannabidiol analog O-1918 or by pertussis toxin but was unaffected by CB 1 or CB 2 antagonists. HU-210, a CB 1 /CB 2 receptor agonist, had no effect on the outward current. Clamping The marijuana plant contains more than 60 chemical substances of which ⌬ 9 -tetrahydrocannabinol is the main psychoactive ingredient (1).

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Hydralazine-induced vasodilation involves opening of high conductance Ca2+-activated K+ channels

Cited by 40 publications

References 13 publications

Intraluminal Pressure Is a Stimulus for NFATc3 Nuclear Accumulation

Intraluminal Pressure Is a Stimulus for NFATc3 Nuclear Accumulation

Downregulation of MicroRNA-126 Contributes to the Failing Right Ventricle in Pulmonary Arterial Hypertension

G Protein-coupled Endothelial Receptor for Atypical Cannabinoid Ligands Modulates a Ca2+-dependent K+ Current

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