Role of endothelial intermediate conductance KCa channels in cerebral EDHF-mediated dilations

2003 ◽  
Vol 285 (4) ◽  
pp. H1590-H1599 ◽  
Author(s):  
Sean P. Marrelli ◽  
Maxim S. Eckmann ◽  
Michael S. Hunte
Keyword(s):  
Cerebral Arteries ◽  
Cyclooxygenase Inhibitors ◽  
Male Rat ◽  
Direct Stimulation ◽  
Kca Channels ◽  
Middle Cerebral Arteries ◽  
Intracellular Ca ◽  
Oxide Synthase ◽  
Stimulation Of

The present study evaluated the role of endothelial intermediate conductance calcium-sensitive potassium channels (IKCa) in the mechanism of endothelium-derived hyperpolarizing factor (EDHF)-mediated dilations in pressurized cerebral arteries. Male rat middle cerebral arteries (MCA) were mounted in an isolated vessel chamber, pressurized (85 mmHg), and luminally perfused (100 μl/min). Artery diameter was measured simultaneously with either endothelial intracellular Ca2+ concentration ([Ca2+]i; fura-2) or changes in endothelial membrane potential [4-{2-[6-(dioctylamino)-2-naphthalenyl]ethenyl}1-(3-sulfopropyl)-pyridinium (di-8-ANEPPS)]. Nitric oxide synthase and cyclooxygenase inhibitors were present throughout. Luminal application of UTP produced EDHF-mediated dilations that correlated with significant endothelial hyperpolarization. The dilation and endothelial hyperpolarization were virtually abolished by inhibitors of IKCa channels but not by selective inhibitors of small or large conductance KCa channels (apamin and iberiotoxin, respectively). Additionally, direct stimulation of endothelial IKCa channels with 1-ethyl-2-benzimidazolinone (1-EBIO) produced endothelial hyperpolarization and vasodilatation that were blocked by inhibitors of IKCa channels. 1-EBIO hyperpolarized the endothelium but did not affect endothelial [Ca2+]i. We conclude that the mechanism of EDHF-mediated dilations in cerebral arteries requires stimulation of endothelial IKCa channels to promote endothelial hyperpolarization and subsequent vasodilatation.

Mechanisms of endothelial P2Y1- and P2Y2-mediated vasodilatation involve differential [Ca2+]i responses

2001 ◽  
Vol 281 (4) ◽  
pp. H1759-H1766 ◽  
Author(s):  
Sean P. Marrelli
Keyword(s):  
Nitric Oxide ◽  
Simultaneous Measurement ◽  
Cerebral Arteries ◽  
No Synthase ◽  
Fura 2 ◽  
Middle Cerebral Arteries ◽  
Intracellular Ca ◽  
The Difference ◽  
Stimulation Of

The present study was designed to evaluate the role of endothelial intracellular Ca2+ concentration ([Ca2+]i) in the difference between P2Y1- and P2Y2-mediated vasodilatations in cerebral arteries. Rat middle cerebral arteries were cannulated, pressurized, and luminally perfused. The endothelium was selectively loaded with fura 2, a fluorescent Ca2+indicator, for simultaneous measurement of endothelial [Ca2+]i and diameter. Luminal administration of 2-methylthioadenosine 5′-triphosphate (2-MeS-ATP), an endothelial P2Y1 agonist, resulted in purely nitric oxide (NO)-dependent dilation and [Ca2+]i increases up to ∼300 nM (resting [Ca2+]i = 145 nM). UTP, an endothelial P2Y2 agonist, resulted in dilations that were both endothelium-derived hyperpolarizing factor (EDHF)- and NO-dependent with [Ca2+]iincreases to >400 nM. In the presence of N G-nitro-l-arginine-indomethacin to inhibit NO synthase and cyclooxygenase, UTP resulted in an EDHF-dependent dilation alone. The [Ca2+]ithreshold for NO-dependent dilation was 220 vs. 340 nM for EDHF. In summary, the differences in the mechanism of vasodilatation resulting from stimulation of endothelial P2Y1 and P2Y2purinoceptors result in part from differential [Ca2+]i responses. Consistent with this finding, these studies also demonstrate a higher [Ca2+]i threshold for EDHF-dependent responses compared with NO.

scholarly journals Neuropeptide Y—Mediated Constriction and Dilation in Rat Middle Cerebral Arteries

2001 ◽  
Vol 21 (1) ◽  
pp. 77-84 ◽  
Author(s):  
Junping You ◽  
Lars Edvinsson ◽  
Robert M. Bryan
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Neuropeptide Y ◽  
Cerebral Arteries ◽  
Npy Receptor ◽  
Middle Cerebral Arteries ◽  
Oxide Synthase ◽  
Npy Receptors ◽  
Stimulation Of

Neuropeptide Y (NPY) is an important vasoconstrictor in the cerebral circulation. Its constrictor response is because of activation of NPY receptors on the vascular smooth muscle (VSM). Little is known regarding the effects of NPY on the endothelium. In the current study, the authors tested the hypothesis that NPY can either constrict or dilate rat middle cerebral arteries (MCAs). Constriction is elicited by stimulating receptors on the VSM; dilation is elicited by stimulating receptors on the endothelium. Middle cerebral arteries were isolated, cannulated with micropipettes, pressurized to 85 mm Hg, and luminally perfused. The extraluminal application of NPY (mixed agonist), [Leu31, Pro34]-NPY (Y1 agonist), or NPY-[13–36] (Y2 agonist) produced concentration-dependent constrictions. BIBP 3226 (Y1 selective antagonist) significantly attenuated the NPY-and [Leu31, Pro34]-NPY–induced constrictions. The luminal application of NPY, [Leu31, Pro34]-NPY, and NPY-[13–36] produced concentration-dependent dilations of MCAs. The maximum dilation produced by the NPY receptor agonists was approximately 40% of the dilation elicited by the luminal administration of 10−5 mol/L ATP. Dilations elicited by luminal NPY, [Leu31, Pro34]-NPY, or NPY-[13–36] were abolished by inhibition of nitric oxide synthase with 10−5 mol/L Nω-nitro-L-arginine methyl ester (L-NAME) or removal of the endothelium. Dilations produced by luminal NPY or luminal [Leu31, Pro34]-NPY were not affected by BIBP 3226. Stimulation of NPY receptors on vascular smooth muscle constricted MCAs. Stimulation of an NPY receptor other than the Y1 subtype on endothelium dilated the MCAs by releasing nitric oxide.

Endothelial L-arginine pathway and regional cerebral arterial reactivity to vasopressin

1992 ◽  
Vol 262 (5) ◽  
pp. H1557-H1562 ◽  
Author(s):  
Z. S. Katusic
Keyword(s):  
Brain Stem ◽  
Cerebral Arteries ◽  
Signal Transduction Pathway ◽  
Inhibitory Effect ◽  
Middle Cerebral Arteries ◽  
Half Maximal Effective Concentration ◽  
Basilar Arteries ◽  
Oxide Synthase ◽  
Endothelium Dependent Relaxation

Experiments were designed to characterize the mechanism of vasopressin action in small arteries of brain stem and cerebrum and to determine the role of L-arginine pathway in reactivity of these vessels to vasopressin. Secondary branches of canine basilar arteries (425 +/- 63 microns ID, n = 6) and middle cerebral arteries (466 +/- 30 microns ID, n = 6) were dissected and mounted on glass microcannulas in organ chambers. Changes in intraluminal diameter of the pressurized arteries were measured using a video dimension analyzer. Vasopressin caused endothelium-dependent relaxation in the brain stem arteries [-log half-maximal effective concentration (EC50) = 9.2 +/- 0.4, n = 5] but not in the branches of middle cerebral arteries. In contrast, bradykinin caused identical endothelium-dependent relaxations in arteries of both regions (-log EC50 = 8.0 +/- 0.2, n = 5, and 7.7 +/- 0.1, n = 4 for brain stem and cerebrum, respectively). Relaxations to vasopressin (but not to bradykinin) were reduced in the presence of V1-vasopressinergic antagonist [1-(beta-mercapto-beta-cyclopentamethylenepropionic acid),2-(O-methyl)tyrosine]arginine vasopressin [d(CH2)5-Tyr(Me)AVP;10(-7) M], pertussin toxin (100 ng/ml), and NG-monomethyl-L-arginine (L-NMMA; 10(-4) M). The inhibitory effect of L-NMMA was prevented by L-arginine (3 x 10(-4) M) but not D-arginine (3 x 10(-4) M). These studies suggest that vasopressin causes endothelium-dependent relaxation in canine brain stem arteries. The effect of the neuropeptide appears to be mediated by activation of endothelial V1-vasopressinergic receptors coupled to nitric oxide synthase. This signal transduction pathway is not functional in endothelial cells of branches of middle cerebral arteries.

Permissive role of NO in alpha 2-adrenoceptor-mediated dilations in rat cerebral arteries

1995 ◽  
Vol 269 (3) ◽  
pp. H1171-H1174 ◽  
Author(s):  
R. M. Bryan ◽  
M. L. Steenberg ◽  
M. Y. Eichler ◽  
T. D. Johnson ◽  
M. W. Swafford ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cerebral Arteries ◽  
No Donor ◽  
Cyclic Monophosphate ◽  
Adrenoceptor Agonist ◽  
Middle Cerebral Arteries ◽  
Basal Release ◽  
Oxide Synthase ◽  
Permissive Role

Dilations produced with UK-14304, a selective alpha 2-adrenoceptor agonist, in rat middle cerebral arteries (MCAs) were blocked after removal of the endothelium or inhibition of nitric oxide synthase (NOS). After endothelium removal or inhibition of NOS, the addition of subthreshold doses of an exogenous nitric oxide (NO) donor, S-nitroso-N-acetylpenicillamine, restored the dilations produced by UK-14304. In a similar manner the guanosine 3',5'-cyclic monophosphate (cGMP) analogues 8-bromoguanosine 3',5'-cyclic monophosphate and N2,2'-O-dibutyrylguanosine 3',5'-cyclic monophosphate restored the dilations of MCAs after endothelial removal. Because NO cannot be synthesized and released in MCAs after inhibition of NOS, it cannot be directly responsible for the dilation. The basal release of NO from the endothelium acts permissively in the vasodilation by maintaining adequate levels of cGMP. Removal of this basal release of NO by removal of endothelium or inhibition of NOS abolishes the alpha 2-adrenoceptor-mediated dilation.

scholarly journals The Role of BMP Signaling in Osteoclast Regulation

2021 ◽  
Vol 9 (3) ◽  
pp. 24
Author(s):  
Brian Heubel ◽  
Anja Nohe
Keyword(s):  
Bone Formation ◽  
Bone Morphogenetic Proteins ◽  
Bone Diseases ◽  
Bmp Signaling ◽  
Bone Homeostasis ◽  
Direct Stimulation ◽  
Federal Drug Administration ◽  
Bmp Pathway ◽  
Stimulation Of

The osteogenic effects of Bone Morphogenetic Proteins (BMPs) were delineated in 1965 when Urist et al. showed that BMPs could induce ectopic bone formation. In subsequent decades, the effects of BMPs on bone formation and maintenance were established. BMPs induce proliferation in osteoprogenitor cells and increase mineralization activity in osteoblasts. The role of BMPs in bone homeostasis and repair led to the approval of BMP2 by the Federal Drug Administration (FDA) for anterior lumbar interbody fusion (ALIF) to increase the bone formation in the treated area. However, the use of BMP2 for treatment of degenerative bone diseases such as osteoporosis is still uncertain as patients treated with BMP2 results in the stimulation of not only osteoblast mineralization, but also osteoclast absorption, leading to early bone graft subsidence. The increase in absorption activity is the result of direct stimulation of osteoclasts by BMP2 working synergistically with the RANK signaling pathway. The dual effect of BMPs on bone resorption and mineralization highlights the essential role of BMP-signaling in bone homeostasis, making it a putative therapeutic target for diseases like osteoporosis. Before the BMP pathway can be utilized in the treatment of osteoporosis a better understanding of how BMP-signaling regulates osteoclasts must be established.

Role of iPLA2 and store-operated channels in agonist-induced Ca2+ influx and constriction in cerebral, mesenteric, and carotid arteries

2008 ◽  
Vol 294 (3) ◽  
pp. H1183-H1187 ◽  
Author(s):  
Kristen M. Park ◽  
Mario Trucillo ◽  
Nicolas Serban ◽  
Richard A. Cohen ◽  
Victoria M. Bolotina
Keyword(s):  
Carotid Arteries ◽  
Cerebral Arteries ◽  
Present Evidence ◽  
Voltage Gated ◽  
Functional Inhibition ◽  
Intracellular Ca ◽  
Dependent Pathway ◽  
Secondary Activation

Store-operated channels (SOC) and store-operated Ca2+ entry are known to play a major role in agonist-induced constriction of smooth muscle cells (SMC) in conduit vessels. In microvessels the role of SOC remains uncertain, in as much as voltage-gated L-type Ca2+ (CaL2+) channels are thought to be fully responsible for agonist-induced Ca2+ influx and vasoconstriction. We present evidence that SOC and their activation via a Ca2+-independent phospholipase A2 (iPLA2)-mediated pathway play a crucial role in agonist-induced constriction of cerebral, mesenteric, and carotid arteries. Intracellular Ca2+ in SMC and intraluminal diameter were measured simultaneously in intact pressurized vessels in vitro. We demonstrated that 1) Ca2+ and contractile responses to phenylephrine (PE) in cerebral and carotid arteries were equally abolished by nimodipine (a CaL2+ inhibitor) and 2-aminoethyl diphenylborinate (an inhibitor of SOC), suggesting that SOC and CaL2+ channels may be involved in agonist-induced constriction of cerebral arteries, and 2) functional inhibition of iPLA2β totally inhibited PE-induced Ca2+ influx and constriction in cerebral, mesenteric, and carotid arteries, whereas K+-induced Ca2+ influx and vasoconstriction mediated by CaL2+ channels were not affected. Thus iPLA2-dependent activation of SOC is crucial for agonist-induced Ca2+ influx and vasoconstriction in cerebral, mesenteric, and carotid arteries. We propose that, on PE-induced depletion of Ca2+ stores, nonselective SOC are activated via an iPLA2-dependent pathway and may produce a depolarization of SMC, which could trigger a secondary activation of CaL2+ channels and lead to Ca2+ entry and vasoconstriction.

L-type Ca2+ channels in fetal and adult ovine cerebral arteries

2002 ◽  
Vol 282 (1) ◽  
pp. R131-R138 ◽  
Author(s):  
Arlin B. Blood ◽  
Yu Zhao ◽  
Wen Long ◽  
Lubo Zhang ◽  
Lawrence D. Longo
Keyword(s):  
Carotid Arteries ◽  
Cerebral Arteries ◽  
Bay K 8644 ◽  
Channel Density ◽  
Immunoblotting Assay ◽  
Intracellular Ca ◽  
Common Carotid Arteries ◽  
Fetal Vessels ◽  
Ca2 Channels

Recently, we reported that, whereas in cerebral arteries of the adult a majority of norepinephrine (NE)-induced increase in intracellular Ca2+ concentration ([Ca2+]i) comes from release of the sarcoplasmic reticulum (SR) Ca2+ stores, in the fetus the SR Ca2+ stores are relatively small, and NE-induced increase in [Ca2+]i results mainly from activation of plasma membrane L-type Ca2+ channels (20). In an effort to establish further the role of L-type Ca2+ channels in the developing cerebral arteries, we tested the hypothesis that, in the fetus, increased reliance on plasmalemmal L-type Ca2+ channels is mediated, in part, by increased L-type Ca2+ channel density. We used3H-labeled (+)isopropyl-4-(2,1,3-benzoxadiazol-4-y1)-1,4-dihydro-(2,6-dimethyl-5-methoxycarbonyl)pyridine-3-carboxylate (PN200–110, isradipine) to measure L-type Ca2+ channel density (Bmax) in the cerebral arteries, common carotid artery (CCA), and descending aortae of fetal (∼140 gestation days), newborn (7–10 days), and adult sheep. In the cerebral and common carotid arteries, Bmax values (fmol/mg protein) of fetuses and newborns were significantly greater than those of adults. Western immunoblotting assay also revealed that the density of L-type Ca2+ channel protein in the cerebral arteries and CCA was about twofold greater in the fetus than the adult. Finally, compared with the adult, fetal cerebral arteries demonstrated a significantly greater maximum tension and [Ca2+]i in response to stimulation with the L-type Ca2+ channel agonist Bay K 8644. In addition, Bay K 8644-stimulated fetal vessels demonstrated a maximal tension and [Ca2+]isimilar to that observed in response to stimulation with 10−4 NE. These results support the idea that fetal cerebrovascular smooth muscle relies more on extracellular Ca2+ and L-type Ca2+ channels for contraction than does the adult and that this increased reliance is mediated, in part, by greater L-type Ca2+ channel density. This may have important implications in the regulation of cerebral blood flow in the developing organism.

Replicating the Role of the Human Retina for a Cortical Visual Neuroprosthesis

2013 ◽  
pp. 1532-1551
Author(s):  
Samuel Romero ◽  
Christian Morillas ◽  
Antonio Martínez ◽  
Begoña del Pino ◽  
Francisco Pelayo ◽  
...  
Keyword(s):  
Visual Cortex ◽  
Significant Degree ◽  
Research Field ◽  
Human Retina ◽  
Direct Stimulation ◽  
Biologically Inspired ◽  
Visual Inputs ◽  
Response Modeling ◽  
Stimulation Of

Neuroengineering is an emerging research field combining the latest findings from neuroscience with developments in a variety of engineering disciplines to create artificial devices, mainly for therapeutical purposes. In this chapter, an application of this field to the development of a visual neuroprosthesis for the blind is described. Electrical stimulation of the visual cortex in blind subjects elicits the perception of visual sensations called phosphenes, a finding that encourages the development of future electronic visual prostheses. However, direct stimulation of the visual cortex would miss a significant degree of image processing that is carried out by the retina. The authors describe a biologically-inspired retina-like processor designed to drive the implanted stimulator using visual inputs from one or two cameras. This includes dynamic response modeling with minimal latency. The outputs of the retina-like processor are comparable to those recorded in biological retinas that are exposed to the same stimuli and allow estimation of the original scene.

scholarly journals Hepatic Encephalopathy-Associated Cerebral Vasculopathy in Acute-on-Chronic Liver Failure: Alterations on Endothelial Factor Release and Influence on Cerebrovascular Function

2020 ◽  
Vol 11 ◽  
Author(s):  
Laura Caracuel ◽  
Esther Sastre ◽  
María Callejo ◽  
Raquel Rodrigues-Díez ◽  
Ana B. García-Redondo ◽  
...  
Keyword(s):  
Hepatic Encephalopathy ◽  
Liver Failure ◽  
Cerebral Arteries ◽  
Chronic Liver ◽  
Chronic Liver Failure ◽  
Cerebrovascular Function ◽  
Liver Decompensation ◽  
Middle Cerebral Arteries ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

The acute-on-chronic liver failure (ACLF) is a syndrome characterized by liver decompensation, hepatic encephalopathy (HE) and high mortality. We aimed to determine the mechanisms implicated in the development of HE-associated cerebral vasculopathy in a microsurgical liver cholestasis (MHC) model of ACLF. Microsurgical liver cholestasis was induced by ligating and extracting the common bile duct and four bile ducts. Sham-operated and MHC rats were maintained for eight postoperative weeks Bradykinin-induced vasodilation was greater in middle cerebral arteries from MHC rats. Both Nω-Nitro-L-arginine methyl ester and indomethacin diminished bradykinin-induced vasodilation largely in arteries from MHC rats. Nitrite and prostaglandin (PG) F1α releases were increased, whereas thromboxane (TX) B2 was not modified in arteries from MHC. Expressions of endothelial nitric oxide synthase (eNOS), inducible NOS, and cyclooxygenase (COX) 2 were augmented, and neuronal NOS (nNOS), COX-1, PGI2 synthase, and TXA2S were unmodified. Phosphorylation was augmented for eNOS and unmodified for nNOS. Altogether, these endothelial alterations might collaborate to increase brain blood flow in HE.

Cerebral artery KATP- and KCa-channel activity and contractility: changes with development

2000 ◽  
Vol 279 (6) ◽  
pp. R2004-R2014 ◽  
Author(s):  
Wen Long ◽  
Lubo Zhang ◽  
Lawrence D. Longo
Keyword(s):  
Channel Blocker ◽  
Cerebral Arteries ◽  
Dependent Manner ◽  
Channel Activity ◽  
Channel Opener ◽  
Channel Inhibition ◽  
Middle Cerebral Arteries ◽  
Intracellular Ca ◽  
Near Term ◽  
Nonpregnant Adult

The present study was designed to test the hypothesis that in cerebral arteries of the fetus, ATP-sensitive (KATP) and Ca2+-activated K+channels (KCa) play an important role in the regulation of intracellular Ca2+ concentration ([Ca2+]i) and that this differs significantly from that of the adult. In main branch middle cerebral arteries (MCA) from near-term fetal (∼140 days) and nonpregnant adult sheep, simultaneously we measured norepinephrine (NE)-induced responses of vascular tension and [Ca2+]i in the absence and presence of selective K+-channel openers/blockers. In fetal MCA, in a dose-dependent manner, both the KATP-channel opener pinacidil and the KCa-channel opener NS 1619 significantly inhibited NE-induced tension [negative logarithm of the half-maximal inhibitory concentration (pIC50) = 5.0 ± 0.1 and 8.2 ± 0.1, respectively], with a modest decrease of [Ca2+]i. In the adult MCA, in contrast, both pinacidil and NS 1619 produced a significant tension decrease (pIC50 = 5.1 ± 0.1 and 7.6 ± 0.1, respectively) with no change in [Ca2+]i. In addition, the KCa-channel blocker iberiotoxin (10−7 to 10−6 M) resulted in increased tension and [Ca2+]i in both adult and fetal MCA, although the KATP-channel blocker glibenclamide (10−7 to 3 × 10−5 M) failed to do so. Of interest, administration of 10−7 M iberiotoxin totally eliminated vascular contraction and increase in [Ca2+]i seen in response to 10−5M ryanodine. In precontracted fetal cerebral arteries, activation of the KATP and KCa channels significantly decreased both tension and [Ca2+]i, suggesting that both K+ channels play an important role in regulating L-type channel Ca2+ flux and therefore vascular tone in these vessels. In the adult, KATP and the KCa channels also appear to play an important role in this regard; however, in the adult vessel, activation of these channels with resultant vasorelaxation can occur with no significant change in [Ca2+]i. These channels show differing responses to inhibition, e.g., KCa-channel inhibition, resulting in increased tension and [Ca2+]i, whereas KATP-channel inhibition showed no such effect. In addition, the KCa channel appears to be coupled to the sarcoplasmic reticulum ryanodine receptor. Thus differences in plasma membrane K+-channel activity may account, in part, for the differences in the regulation of contractility of fetal and adult cerebral arteries.

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