scholarly journals Dihydropyridine-Insensitive Calcium Currents Contribute to Function of Small Cerebral Arteries

2010 ◽  
Vol 30 (6) ◽  
pp. 1226-1239 ◽  
Author(s):  
Ivana Y Kuo ◽  
Anthie Ellis ◽  
Victoria AL Seymour ◽  
Shaun L Sandow ◽  
Caryl E Hill
Keyword(s):  
Cerebral Arteries ◽  
Calcium Currents ◽  
Adult Rat ◽  
Cerebrovascular Function ◽  
Middle Cerebral Arteries ◽  
Voltage Dependent ◽  
Basilar Arteries ◽  
Voltage Dependent Calcium Channels ◽  
Patch Clamp Electrophysiology

Although dihydropyridines are widely used for the treatment of vasospasm, their effectiveness is questionable, suggesting that other voltage-dependent calcium channels (VDCCs) contribute to control of cerebrovascular tone. This study therefore investigated the role of dihydropyridine-insensitive VDCCs in cerebrovascular function. Using quantitative PCR and immunohistochemistry, we found mRNA and protein for L-type (CaV1.2) and T-type (CaV3.1 and CaV3.2) channels in adult rat basilar and middle cerebral arteries and their branches. Immunoelectron microscopy revealed both L- and T-type channels in smooth muscle cell (SMC) membranes. Using patch clamp electrophysiology, we found that a high-voltage-activated calcium current, showing T-type channel kinetics and insensitivity to nifedipine and nimodipine, comprised ∼20% of current in SMCs of the main arteries and ∼45% of current in SMCs from branches. Both components were abolished by the T-type antagonists mibefradil, NNC 55-0396, and efonidipine. Although nifedipine completely blocked vasoconstriction in pressurized basilar arteries, a nifedipine-insensitive constriction was found in branches and this increased in magnitude as vessel size decreased. We conclude that a heterogeneous population of VDCCs contributes to cerebrovascular function, with dihydropyridine-insensitive channels having a larger role in smaller vessels. Sensitivity of these currents to nonselective T-type channel antagonists suggests that these drugs may provide a more effective treatment for therapy-refractory cerebrovascular constriction.

scholarly journals Peroxynitrite Decomposition with FeTMPyP Improves Plasma-Induced Vascular Dysfunction and Infarction during Mild but not Severe Hyperglycemic Stroke

2012 ◽  
Vol 32 (6) ◽  
pp. 1035-1045 ◽  
Author(s):  
Sara Morales Palomares ◽  
Ira Gardner-Morse ◽  
Julie G Sweet ◽  
Marilyn J Cipolla
Keyword(s):  
Vascular Dysfunction ◽  
Cerebral Arteries ◽  
Stroke Outcome ◽  
Cerebrovascular Function ◽  
Middle Cerebral Arteries ◽  
Male Wistar Rats ◽  
Physiologic Saline ◽  
Severe Ischemia

We investigated mechanisms by which circulating factors during hyperglycemic (HG) stroke affect cerebrovascular function and the role of peroxynitrite in stroke outcome. Middle cerebral arteries (MCAs) were isolated from male Wistar rats and perfused with plasma from rats that were hyperglycemic for 5 to 6 days by streptozotocin and underwent either MCA occlusion (HG MCAO) or Sham surgery (HG Sham) compared with MCA perfused with physiologic saline (No plasma). Myogenic responses and endothelial function were compared in untreated MCA ( n=8/group) or with inhibitors of NADPH oxidase (apocynin; n=8), peroxynitrite (FeTMPyP; n=8) or endothelin-1 (ET-1)A (BQ-123; n=8). Finally, animals were treated in vivo before reperfusion after mild (<68% cerebral blood flow (CBF) decrease) or severe (>68% CBF decrease) MCAO with FeTMPyP ( n=12) or vehicle ( n=12) and CBF and infarction measured. The HG MCAO plasma increased tone in MCA versus No plasma ( P<0.05) that was reversed by FeTMPyP, but not by apocynin or BQ-123. The HG Sham plasma also increased tone in MCA ( P<0.05) that was reversed by BQ-123 only. In vivo, FeTMPyP was neuroprotective during mild, but not severe ischemia. These results show that circulating factors in plasma can affect cerebrovascular function through peroxynitrite generation and ET-1. In addition, peroxynitrite decomposition improves stroke outcome acutely during mild, but not severe HG ischemia.

Membrane hyperpolarization is a mechanism of endothelium-dependent cerebral vasodilation

1990 ◽  
Vol 259 (3) ◽  
pp. H668-H673 ◽  
Author(s):  
J. E. Brayden
Keyword(s):  
Nitric Oxide ◽  
Methylene Blue ◽  
Potassium Channel ◽  
Cerebral Arteries ◽  
Channel Blockers ◽  
Membrane Hyperpolarization ◽  
Middle Cerebral Arteries ◽  
Voltage Dependent ◽  
Voltage Dependent Calcium Channels ◽  
Cerebral Vasodilation

Acetylcholine (ACh)-induced hyperpolarization of cerebral arteries requires a functional endothelium. The hyperpolarization is reversed by potassium-channel blockers. The goal of this study was to determine whether the hyperpolarization is causally related to endothelium-dependent dilation of isolated cerebral arteries. ACh hyperpolarized rabbit middle cerebral arteries by up to 19 mV. The hyperpolarizations were sustained and did not occur in arteries without endothelial cells or in the presence of potassium-channel inhibitors (3 x 10(-6) M glibenclamide or 5 x 10(-5) M BaCl2). ACh-induced dilator responses were inhibited but not abolished by glibenclamide or BaCl2. Methylene blue also inhibited the dilator responses, and a combination of glibenclamide or BaCl2 and methylene blue greatly diminished the dilation. Nitric oxide relaxed but did not hyperpolarize the vascular smooth muscle cells, and BaCl2 had no effect on the nitric oxide-induced relaxations. These data indicate that the overall cerebral arterial dilator response to ACh is determined by the combined effects of membrane hyperpolarization, which closes voltage-dependent calcium channels, and the actions of a second endothelial factor, probably endothelium-derived relaxing factor.

Regulation of single calcium channels in cerebral arteries by voltage, serotonin, and dihydropyridines

1991 ◽  
Vol 261 (6) ◽  
pp. H1951-H1960 ◽  
Author(s):  
J. F. Worley ◽  
J. M. Quayle ◽  
N. B. Standen ◽  
M. T. Nelson
Keyword(s):  
Single Channel ◽  
Cerebral Arteries ◽  
Calcium Currents ◽  
Ca Channel ◽  
Ca Channels ◽  
Channel Conductance ◽  
Voltage Dependent ◽  
Basilar Arteries ◽  
Single Calcium Channels ◽  
Small Conductance

Unitary currents through Ca channels were measured from cell-attached patches on smooth muscle cells isolated from rabbit cerebral (basilar) arteries. Barium (80 and 10 mM) and calcium (80 and 10 mM) were used as the charge carriers. The dihydropyridine Ca channel agonist BAY R 5417 was used to increase open-state probability (Popen), with 500 nM BAY R 5417 increasing Popen 10-fold at 0 mV. Barium currents through single Ca channels were greater than calcium currents at any voltage, with single-channel conductances negative to -20 mV of 24.6 pS (80 mM barium), 15.1 pS (80 mM calcium), 17.2 pS (10 mM barium), and 5.8 pS (10 mM calcium). The single-channel Popen increased 2.7-fold per 5- to 7-mV membrane depolarization (negative to 0 mV) and was half maximal at +0.4 mV (80 mM calcium) and +13.5 mV (80 mM barium). Ca channels with calcium but not with barium as the charge carrier exhibited pronounced inactivation positive to -20 mV (half time, 112 ms at 0 mV). The dihydropyridine nimodipine (2 nM) inhibited average currents through Ca channels. The cerebral artery constrictor serotonin increased Popen of single Ca channels by as much as 200-fold without an effect on single-channel conductance. A second distinct amplitude of unitary currents was often observed, corresponding to a channel conductance of about one-half the more commonly observed level. The small-conductance-level channel was voltage dependent, did not inactivate over 0.5-s test pulses (with barium), and could be activated by serotonin.

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.

Role of Calcium Currents in E-C Coupling and Evolution of the T-System and SR in Developing Cultured Embryonic Amphibian Skeletal Muscle Cells

2000 ◽  
Vol 6 (S2) ◽  
pp. 92-93
Author(s):  
Gonzalez-Serratos H ◽  
Cordoba-Rodriguez R ◽  
Matteson D.R. ◽  
Rozycka M.
Keyword(s):  
Skeletal Muscle ◽  
Calcium Current ◽  
Muscle Cells ◽  
Calcium Currents ◽  
Skeletal Muscle Cells ◽  
Voltage Dependent ◽  
Voltage Dependent Calcium Channels ◽  
Slow Inward Calcium Current ◽  
T System

Adult frog phasic skeletal muscle cells have slow inward calcium current (ICa) (Stanfield, 1977) carried through L-type voltage dependent calcium channels. It has been suggested that ICa may play a role in E-C coupling (Cota & Stefani, 1981, 1989). However, phasic skeletal muscle cells contract for several minutes after the extracellular Ca2+ concentration ([Ca2+]o) is lowered to <10-8 M (Armstrong et al, 1972). Therefore, extracellular Ca2+ (Ca2+o) is not essential for contraction in these fibers. It has been also shown, by blocking Ica that Ica is not essential for triggering contraction (Gonzalez-Serratos et al., 1982). These results have led to the conclusion that Ica has no obvious role in E-C coupling in adult amphibian phasic skeletal muscle. The question arises then as to what is the biological role Ica in phasic skeletal muscle? We have observed that embryonic skeletal muscle cells are capable of contracting during the first day of development in culture (Cordoba-Rodriguez, et al., 1996), before the T-system and the sarcoplasmic reticulum (SR)may have fully developed (Flucher, et al., 1993).

scholarly journals Proteolytic maturation of α2δ represents a checkpoint for activation and neuronal trafficking of latent calcium channels

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Ivan Kadurin ◽  
Laurent Ferron ◽  
Simon W Rothwell ◽  
James O Meyer ◽  
Leon R Douglas ◽  
...  
Keyword(s):  
Calcium Channels ◽  
Proteolytic Cleavage ◽  
Proteolytic Processing ◽  
Calcium Currents ◽  
Cleavage Sites ◽  
Voltage Dependent ◽  
Neuronal Processes ◽  
Associated Proteins ◽  
Synaptic Boutons

The auxiliary α2δ subunits of voltage-gated calcium channels are extracellular membrane-associated proteins, which are post-translationally cleaved into disulfide-linked polypeptides α2 and δ. We now show, using α2δ constructs containing artificial cleavage sites, that this processing is an essential step permitting voltage-dependent activation of plasma membrane N-type (CaV2.2) calcium channels. Indeed, uncleaved α2δ inhibits native calcium currents in mammalian neurons. By inducing acute cell-surface proteolytic cleavage of α2δ, voltage-dependent activation of channels is promoted, independent from the trafficking role of α2δ. Uncleaved α2δ does not support trafficking of CaV2.2 channel complexes into neuronal processes, and inhibits Ca2+ entry into synaptic boutons, and we can reverse this by controlled intracellular proteolytic cleavage. We propose a model whereby uncleaved α2δ subunits maintain immature calcium channels in an inhibited state. Proteolytic processing of α2δ then permits voltage-dependent activation of the channels, acting as a checkpoint allowing trafficking only of mature calcium channel complexes into neuronal processes.

scholarly journals Cerebrovascular responses in mice deficient in the potassium channel, TREK-1

2010 ◽  
Vol 299 (2) ◽  
pp. R461-R469 ◽  
Author(s):  
Khodadad Namiranian ◽  
Eric E. Lloyd ◽  
Randy F. Crossland ◽  
Sean P. Marrelli ◽  
George E. Taffet ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Linolenic Acid ◽  
Basilar Artery ◽  
Cerebral Arteries ◽  
K Channel ◽  
Whole Cell ◽  
Middle Cerebral Arteries ◽  
Basilar Arteries ◽  
Cerebrovascular Smooth Muscle Cells ◽  
Pore Domain

We tested the hypothesis that TREK-1, a two-pore domain K channel, is involved with dilations in arteries. Because there are no selective activators or inhibitors of TREK-1, we generated a mouse line deficient in TREK-1. Endothelium-mediated dilations were not different in arteries from wild-type (WT) and TREK-1 knockout (KO) mice. This includes dilations of the middle cerebral artery to ATP, dilations of the basilar artery to ACh, and relaxations of the aorta to carbachol, a cholinergic agonist. The nitric oxide (NO) and endothelium-dependent hyperpolarizing factor components of ATP dilations were identical in the middle cerebral arteries of WT and TREK-1 KO mice. Furthermore, the NO and cyclooxygenase-dependent components were identical in the basilar arteries of the different genotypes. Dilations of the basilar artery to α-linolenic acid, an activator of TREK-1, were not affected by the absence of TREK-1. Whole cell currents recorded using patch-clamp techniques were similar in cerebrovascular smooth muscle cells (CVSMCs) from WT and TREK-1 KO mice. α-linolenic acid or arachidonic acid increased whole cell currents in CVSMCs from both WT and TREK-1 KO mice. The selective blockers of large-conductance Ca-activated K channels, penitrem A and iberiotoxin, blocked the increased currents elicited by either α-linolenic or arachidonic acid. In summary, dilations were similar in arteries from WT and TREK-1 KO mice. There was no sign of TREK-1-like currents in CVSMCs from WT mice, and there were no major differences in currents between the genotypes. We conclude that regulation of arterial diameter is not altered in mice lacking TREK-1.

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.

The role of voltage-dependent calcium channels in angiotensin-stmulated glomerulosa cells

1996 ◽  
Vol 22 (4) ◽  
pp. 569-576 ◽  
Author(s):  
A. Spät ◽  
T. Rohács ◽  
A. Horváth ◽  
G Y. Szabadkai ◽  
P. Enyedi
Keyword(s):  
Calcium Channels ◽  
Voltage Dependent ◽  
Voltage Dependent Calcium Channels ◽  
Glomerulosa Cells

Ifenprodil reduces excitatory synaptic transmission by blocking presynaptic P/Q type calcium channels

2012 ◽  
Vol 107 (6) ◽  
pp. 1571-1575 ◽  
Author(s):  
Andrew J. Delaney ◽  
John M. Power ◽  
Pankaj Sah
Keyword(s):  
Calcium Channels ◽  
Synaptic Transmission ◽  
Nmda Receptors ◽  
Basolateral Amygdala ◽  
Excitatory Transmission ◽  
Voltage Dependent ◽  
Voltage Dependent Calcium Channels ◽  
P Type ◽  
Selective Blocker

Ifenprodil is a selective blocker of NMDA receptors that are heterodimers composed of GluN1/GluN2B subunits. This pharmacological profile has been extensively used to test the role of GluN2B-containing NMDA receptors in learning and memory formation. However, ifenprodil has also been reported to have actions at a number of other receptors, including high voltage-activated calcium channels. Here we show that, in the basolateral amygdala, ifenprodil dose dependently blocks excitatory transmission to principal neurons by a presynaptic mechanism. This action of ifenprodil has an IC50 of ∼10 μM and is fully occluded by the P/Q type calcium channel blocker ω-agatoxin. We conclude that ifenprodil reduces synaptic transmission in the basolateral amygdala by partially blocking P-type voltage-dependent calcium channels.

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