Ebselen reduces nitration and restores voltage-gated potassium channel function in small coronary arteries of diabetic rats

2007 ◽  
Vol 293 (4) ◽  
pp. H2231-H2237 ◽  
Author(s):  
Aaron H. Bubolz ◽  
Qingping Wu ◽  
Brandon T. Larsen ◽  
David D. Gutterman ◽  
Yanping Liu
Keyword(s):  
Diabetes Mellitus ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Coronary Arteries ◽  
Nitrosative Stress ◽  
Muscle Cells ◽  
Diabetic Rats ◽  
Causative Role ◽  
Α Subunit ◽  
Channel Function

Small coronary arteries (SCA) from diabetic rats exhibit enhanced peroxynitrite (ONOO−) formation and concurrent impairment of voltage-dependent potassium (Kv) channel function. However, it is unclear whether ONOO− plays a causative role in this impairment. We hypothesized that functional loss of Kv channels in coronary smooth muscle cells (SMC) in diabetes is due to ONOO− with subsequent tyrosine nitration of Kv channel proteins. Diabetic rats and nondiabetic controls were treated with or without ebselen (Eb) for 4 wk. SCA were prepared for immunohistochemistry (IHC), immunoprecipitation (IP) followed by Western blot (WB), videomicroscopy, and patch-clamp analysis. IHC revealed excess ONOO− in SCA from diabetic rats. IP and WB revealed elevated nitration of the Kv1.2 α-subunit and reduced Kv1.2 protein expression in diabetic rats. Each of these changes was improved in Eb-treated rats. Protein nitration and Kv1.5 expression were unchanged in SCA from diabetic rats. Forskolin, a direct cAMP activator that induces Kv1 channel activity, dilated SCA from nondiabetic rats in a correolide (Cor; a selective Kv1 channel blocker)-sensitive fashion. Cor did not alter the reduced dilation to forskolin in diabetic rats; however, Eb partially restored the Cor-sensitive component of dilation. Basal Kv current density and response to forskolin were improved in smooth muscle cells from Eb-treated DM rats. We conclude that enhanced nitrosative stress in diabetes mellitus contributes to Kv1 channel dysfunction in the coronary microcirculation. Eb may be beneficial for the therapeutic treatment of vascular complications in diabetes mellitus.

scholarly journals Apelin Does Not Impair Coronary Artery Relaxation Mediated by Nitric Oxide-Induced Activation of BKCa Channels

2021 ◽  
Vol 12 ◽  
Author(s):  
Amreen Mughal ◽  
Chengwen Sun ◽  
Stephen T. O’Rourke
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Coronary Arteries ◽  
Muscle Cells ◽  
Inhibitory Effect ◽  
Receptor Signaling ◽  
Patch Clamp Recording ◽  
Bkca Channels ◽  
Channel Function

Apelin-APJ receptor signaling regulates vascular tone in cerebral and peripheral arteries. We recently reported that apelin inhibits BKCa channel function in cerebral arteries, resulting in impaired endothelium-dependent relaxations. In contrast, apelin causes endothelium-dependent relaxation of coronary arteries. However, the effects of apelin on BKCa channel function in coronary arterial myocytes have not yet been explored. We hypothesized that apelin-APJ receptor signaling does not have an inhibitory effect on coronary arterial BKCa channels and hence does not alter nitric oxide (NO)-dependent relaxation of coronary arteries. Patch clamp recording was used to measure whole cell K+ currents in freshly isolated coronary smooth muscle cells. Apelin had no effect on the increases in current density in response to membrane depolarization or to NS1619 (a BKCa channel opener). Moreover, apelin did not inhibit NO/cGMP-dependent relaxations that required activation of BKCa channels in isolated coronary arteries. Apelin-APJ receptor signaling caused a marked increase in intracellular Ca2+ levels in coronary arterial smooth muscle cells, but failed to activate PI3-kinase to increase phosphorylation of Akt protein. Collectively, these data provide mechanistic evidence that apelin has no inhibitory effects on BKCa channel function in coronary arteries. The lack of inhibitory effect on BKCa channels makes it unlikely that activation of APJ receptors in coronary arteries would adversely affect coronary flow by creating a vasoconstrictive environment. It can be expected that apelin or other APJ receptor agonists in development will not interfere with the vasodilator effects of endogenous BKCa channel openers.

Phenotype modulation in primary cultures of aortic smooth muscle cells from streptozotocin-diabetic rats

1998 ◽  
Vol 63 (4) ◽  
pp. 225-236 ◽  
Author(s):  
Pascale Etienne ◽  
Núria Parés-Herbuté ◽  
Louis Monnier ◽  
Herisoa Rabesandratana ◽  
Laurence Mani-Ponset ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Primary Cultures ◽  
Muscle Cells ◽  
Diabetic Rats ◽  
Aortic Smooth Muscle Cells ◽  
Aortic Smooth Muscle ◽  
Streptozotocin Diabetic Rats

scholarly journals Minimally Modified LDL Upregulates Endothelin Type A Receptors in Rat Coronary Arterial Smooth Muscle Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Jie Li ◽  
Lei Cao ◽  
Cang-Bao Xu ◽  
Jun-Jie Wang ◽  
Yong-Xiao Cao
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Smooth Muscle Cells ◽  
Coronary Arteries ◽  
Muscle Cells ◽  
Type A ◽  
Receptor Mrna ◽  
Kinase C ◽  
Arterial Smooth Muscle Cells

Minimally modified low-density lipoprotein (mmLDL) is a risk factor for cardiovascular disease. The present study investigated the effects of mmLDL on the expression of endothelin type A () receptors in coronary arteries. Rat coronary arteries were organ-cultured for 24 h. The contractile responses were recorded using a myographic system. receptor mRNA and protein expressions were determined using real-time PCR and western blotting, respectively. The results showed that organ-culturing in the presence of mmLDL enhanced the arterial contractility mediated by the receptor in a concentration-dependent and time-dependent manner. Culturing with mmLDL (10 μg/mL) for 24 h shifted the concentration-contractile curves toward the left significantly with increased of from control of and significantly increased receptor mRNA and protein levels. Inhibition of the protein kinase C, extracellular signal-related kinases 1 and 2 (ERK1/2), or NF-κB activities significantly attenuated the effects of mmLDL. The c-Jun N-terminal kinase inhibitor or the p38 pathway inhibitor, however, had no such effects. The results indicate that mmLDL upregulates the receptors in rat coronary arterial smooth muscle cells mainlyviaactivating protein kinase C, ERK1/2, and the downstream transcriptional factor, NF-κB.

scholarly journals Maternal nutrient restriction during pregnancy impairs an endothelium-derived hyperpolarizing factor-like pathway in sheep fetal coronary arteries

2014 ◽  
Vol 307 (2) ◽  
pp. H134-H142 ◽  
Author(s):  
Praveen Shukla ◽  
Srinivas Ghatta ◽  
Nidhi Dubey ◽  
Caleb O. Lemley ◽  
Mary Lynn Johnson ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Coronary Arteries ◽  
National Research Council ◽  
Muscle Cells ◽  
Nutrient Restriction ◽  
Epoxyeicosatrienoic Acid ◽  
Coronary Smooth Muscle ◽  
Maternal Undernutrition ◽  
Current Activation

The mechanisms underlying developmental programming are poorly understood but may be associated with adaptations by the fetus in response to changes in the maternal environment during pregnancy. We hypothesized that maternal nutrient restriction during pregnancy alters vasodilator responses in fetal coronary arteries. Pregnant ewes were fed a control [100% U.S. National Research Council (NRC)] or nutrient-restricted (60% NRC) diet from days 50 to 130 of gestation (term = 145 days); fetal tissues were collected at day 130. In coronary arteries isolated from control fetal lambs, relaxation to bradykinin was unaffected by nitro-l-arginine (NLA). Iberiotoxin or contraction with KCl abolished the NLA-resistant response to bradykinin. In fetal coronary arteries from nutrient-restricted ewes, relaxation to bradykinin was fully suppressed by NLA. Large-conductance, calcium-activated potassium channel (BKCa) currents did not differ in coronary smooth muscle cells from control and nutrient-restricted animals. The BKCa openers, BMS 191011 and NS1619, and 14,15-epoxyeicosatrienoic acid [a putative endothelium-derived hyperpolarizing factor (EDHF)] each caused fetal coronary artery relaxation and BKCa current activation that was unaffected by maternal nutrient restriction. Expression of BKCa-channel subunits did not differ in fetal coronary arteries from control or undernourished ewes. The results indicate that maternal undernutrition during pregnancy results in loss of the EDHF-like pathway in fetal coronary arteries in response to bradykinin, an effect that cannot be explained by a decreased number or activity of BKCa channels or by decreased sensitivity to mediators that activate BKCa channels in vascular smooth muscle cells. Under these conditions, bradykinin-induced relaxation is completely dependent on nitric oxide, which may represent an adaptive response to compensate for the absence of the EDHF-like pathway.

14,15-Dihydroxyeicosatrienoic acid relaxes bovine coronary arteries by activation of KCa channels

2002 ◽  
Vol 282 (5) ◽  
pp. H1656-H1664 ◽  
Author(s):  
William B. Campbell ◽  
Christine Deeter ◽  
Kathryn M. Gauthier ◽  
Richard H. Ingraham ◽  
J. R. Falck ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Coronary Arteries ◽  
Epoxide Hydrolase ◽  
Muscle Cells ◽  
Kca Channels ◽  
Vasodilator Activity ◽  
Inside Out ◽  
Isolated Smooth Muscle Cells

Epoxyeicosatrienoic acids (EETs) cause vascular relaxation by activating smooth muscle large conductance Ca2+-activated K+ (KCa) channels. EETs are metabolized to dihydroxyeicosatrienoic acids (DHETs) by epoxide hydrolase. We examined the contribution of 14,15-DHET to 14,15-EET-induced relaxations and characterized its mechanism of action. 14,15-DHET relaxed U-46619-precontracted bovine coronary artery rings but was approximately fivefold less potent than 14,15-EET. The relaxations were inhibited by charybdotoxin, iberiotoxin, and increasing extracellular K+ to 20 mM. In isolated smooth muscle cells, 14,15-DHET increased an iberiotoxin-sensitive, outward K+ current and increased KCa channel activity in cell-attached patches and inside-out patches only when GTP was present. 14,15-[14C]EET methyl ester (Me) was converted to 14,15-[14C]DHET-Me, 14,15-[14C]DHET, and 14,15-[14C]EET by coronary arterial rings and endothelial cells but not by smooth muscle cells. The metabolism to 14,15-DHET was inhibited by the epoxide hydrolase inhibitors 4-phenylchalcone oxide (4-PCO) and BIRD-0826. Neither inhibitor altered relaxations to acetylcholine, whereas relaxations to 14,15-EET-Me were increased slightly by BIRD-0826 but not by 4-PCO. 14,15-DHET relaxes coronary arteries through activation of KCa channels. Endothelial cells, but not smooth muscle cells, convert EETs to DHETs, and this conversion results in a loss of vasodilator activity.

scholarly journals Antioxidant Activity Mediates Pirfenidone Antifibrotic Effects in Human Pulmonary Vascular Smooth Muscle Cells Exposed to Sera of Idiopathic Pulmonary Fibrosis Patients

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Alessandro Giuseppe Fois ◽  
Anna Maria Posadino ◽  
Roberta Giordo ◽  
Annalisa Cossu ◽  
Abdelali Agouni ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Smooth Muscle Cells ◽  
Antioxidant Properties ◽  
Muscle Cells ◽  
Pulmonary Vasculature ◽  
Ros Generation ◽  
Type I ◽  
Causative Role

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by an exacerbated fibrotic response. Although molecular and cellular determinants involved in the onset and progression of this devastating disease are largely unknown, an aberrant remodeling of the pulmonary vasculature appears to have implications in IPF pathogenesis. Here, we demonstrated for the first time that an increase of reactive oxygen species (ROS) generation induced by sera from IPF patients drives both collagen type I deposition and proliferation of primary human pulmonary artery smooth muscle cells (HPASMCs). IPF sera-induced cellular effects were significantly blunted in cells exposed to the NADPH oxidase inhibitor diphenyleneiodonium (DPI) proving the causative role of ROS and suggesting their potential cellular source. Contrary to IPF naive patients, sera from Pirfenidone-treated IPF patients failed to significantly induce both ROS generation and collagen synthesis in HPASMCs, mechanistically implicating antioxidant properties as the basis for the in vivo effect of this drug.

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