Cellular basis of vasospasm: role of small diameter arteries and voltage-dependent Ca2+ channels

It has been proposed that gonadotropin-releasing hormone (GnRH) stimulates Ca2+ entry by activation of voltage-independent, receptor-mediated Ca2+ channels in the rat gonadotroph. Little work has been done on the role of calcium in GnRH-induced luteinizing hormone (LH) release in species other than the rat. Therefore, this study was done to compare the effects of agents that alter Ca2+ or Na+ entry on LH release from calf anterior pituitary primary cells in culture. GnRH (100 ng/ml), Ca2+ ionophore A23187 (2.5 microM), and the depolarizing agent ouabain (0.1-10 microM) all produced significant increases (P less than 0.05) in LH release; these effects were significantly reduced when the cells were preincubated with the organic Ca2+ channel blockers nifedipine (1-10 microM) and verapamil (1-10 microM) and with Co2+ (0.01-1 mM). The effect of ouabain was inhibited by tetrodotoxin (TTX; 1-10 nM) as well as by nifedipine at 0.1-10 microM. In contrast to its effect on rat pituitary LH release, TTX significantly inhibited GnRH-stimulated LH release at 1-100 nM. These results suggest that GnRH-induced LH release may employ Ca2+ as a second messenger in bovine gonadotrophs and support recent speculation that GnRH-induced Ca2+ mobilization may in part be voltage dependent.

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Modulation of voltage-dependent Ca2+ conductance by changing Cl- concentration in rat lactotrophs

AJP Cell Physiology ◽

10.1152/ajpcell.1997.272.4.c1178 ◽

1997 ◽

Vol 272 (4) ◽

pp. C1178-C1185 ◽

Cited By ~ 65

Author(s):

L. Garcia ◽

M. Fahmi ◽

N. Prevarskaya ◽

B. Dufy ◽

P. Sartor

Keyword(s):

Carboxylic Acid ◽

Fluorescence Probe ◽

Physiological Role ◽

Feedback Mechanism ◽

Pituitary Cells ◽

Physiological Processes ◽

Voltage Dependent ◽

Ca2 Channels ◽

Cl Conductance

In pituitary cells, voltage-dependent Ca2+ channels play an important role in such physiological processes as exocytosis, secretion, the cell cycle, and proliferation. Thus mechanisms that modulate voltage-dependent Ca2+ channel activity participate indirectly in regulating intracellular Ca2+ concentration. We have shown a new modulating mechanism for voltage-dependent Ca2+ channels by demonstrating that Ca2+ influx is influenced by Cl-. To evaluate the role of Cl- on Ca2+ conductance coupling, we first measured the intracellular Cl- concentration of rat lactotrophs using the Cl(-)-sensitive fluorescence probe sulfopropylquinolinium by simple microspectrofluorometry or combined with electrophysiology. We found an average intracellular Cl- concentration of rat lactotrophs of approximately 60 mM (n = 39). Using the whole cell tight-seal recording technique, we showed that a reduction in external Cl- concentration ([Cl-]o) and a decrease in Cl- conductances affected Ca2+ conductance as measured by Ba2+ movement through the Ca2+ channels (I(Ba)). Low [Cl-]o (39 mM) induced a decrease in Ca2+ entry via voltage-gated Ca2+ channels (-27.75 +/- 4% of normalized I(Ba)). Similarly, blockade of the Cl- conductance by 1 mM 9-anthracene carboxylic acid induced a decrease in I(Ba) (-26 +/- 6% of normalized I(Ba)). This modulation of I(Ba) was inhibited by 24-h pretreatment of the cells with pertussis toxin (1 microg/ml), suggesting that changes in Cl- concentration induced by low [Cl-]o and 9-anthracene carboxylic acid interfered with the phosphorylation of G proteins involved in Ca2+ channel activation. These results suggest a feedback mechanism based on constant interaction between Ca2+ and Cl-. Finally, they also emphasize the physiological role of Cl- in rat lactotrophs.

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Is there a role for T-type Ca2+ channels in regulation of vasomotor tone in mesenteric arterioles?This article is part of a Special Issue on Information Transfer in the Microcirculation.

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y08-101 ◽

2009 ◽

Vol 87 (1) ◽

pp. 8-20 ◽

Cited By ~ 22

Author(s):

Lars Jørn Jensen ◽

Niels-Henrik Holstein-Rathlou

Keyword(s):

Information Transfer ◽

Electromechanical Coupling ◽

Low Voltage ◽

Vasomotor Tone ◽

Direct Demonstration ◽

Voltage Dependent ◽

Small Conductance ◽

Ca2 Channels ◽

Peripheral Blood Pressure

The largest peripheral blood pressure drop occurs in terminal arterioles (<40 µm lumen diameter). L-type voltage-dependent Ca2+ channels (VDCCs) are considered the primary pathway for Ca2+ influx during physiologic activation of vascular smooth muscle cells (VSMC). Recent evidence suggests that T-type VDCCs are expressed in renal afferent and efferent arterioles, mesenteric arterioles, and skeletal muscle arterioles. T-type channels are small-conductance, low voltage-activated, fast-inactivating channels. Thus, their role in supplying Ca2+ for contraction of VSMC has been disputed. However, T-type channels display non-inactivating window currents, which may play a role in sustained Ca2+ entry. Here, we review the possible role of T-type channels in vasomotor tone regulation in rat mesenteric terminal arterioles. The CaV3.1 channel was immunolocalized in VSMC, whereas the CaV3.2 channel was predominantly expressed in endothelial cells. Voltage-dependent Ca2+ entry was inhibited by the new specific T-type blockers R(–)-efonidipine and NNC 55-0396. The effect of NNC 55-0396 persisted in depolarized arterioles, suggesting an unusually high activation threshold of mesenteric T-type channels. T-type channels were not necessary for conduction of vasoconstriction, but appear to be important for local electromechanical coupling in VSMC. The first direct demonstration of endothelial T-type channels warrants new investigations of their role in vascular biology.

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Characterizing voltage-dependent Ca2+ channels coupled to VIP release and NO synthesis in enteric synaptosomes

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00400.2001 ◽

2002 ◽

Vol 283 (5) ◽

pp. G1027-G1034 ◽

Cited By ~ 4

Author(s):

M. Kurjak ◽

A. Sennefelder ◽

M. Aigner ◽

V. Schusdziarra ◽

H. D. Allescher

Keyword(s):

Nitric Oxide ◽

No Synthase ◽

Channel Blockers ◽

Voltage Dependent ◽

Intracellular Ca ◽

P Type ◽

Ca2 Channels

In enteric synaptosomes of the rat, the role of voltage-dependent Ca2+channels in K+-induced VIP release and nitric oxide (NO) synthesis was investigated. Basal VIP release was 39 ± 4 pg/mg, and cofactor-substituted NO synthase activity was 7.0 ± 0.8 fmol · mg−1 · min−1. K+ depolarization (65 mM) stimulated VIP release Ca2+ dependently (basal, 100%; K+, 172.2 ± 16.2%; P < 0.05, n = 5). K+-stimulated VIP release was reduced by blockers of the P-type (ω-agatoxin-IVA, 3 × 10−8 M) and N-type (ω-conotoxin-GVIA, 10−6 M) Ca2+ channels by ∼50 and 25%, respectively, but not by blockers of the L-type (isradipine, 10−8 M), Q-type (ω-conotoxin-MVIIC, 10−6 M), or T-type (Ni2+, 10−6 M) Ca2+ channels. In contrast, NO synthesis was suppressed by ω-agatoxin-IVA, ω-conotoxin-GVIA, and isradipine by ∼79, 70, and 70%, respectively, whereas Ni2+ and ω-conotoxin-MVIIC had no effect. These findings are suggestive of a coupling of depolarization-induced VIP release primarily to the P- and N-type Ca2+ channels, whereas NO synthesis is presumably dependent on Ca2+ influx not only via the P- and N- but also via the L-type Ca2+ channel. In contrast, none of the Ca2+ channel blockers affected VIP release evoked by exogenous NO, suggesting that NO induces VIP secretion by a different mechanism, presumably involving intracellular Ca2+ stores.

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Selective inhibition of glucose-stimulated insulin release by dantrolene

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1982.243.1.e59 ◽

1982 ◽

Vol 243 (1) ◽

pp. E59-E67 ◽

Cited By ~ 1

Author(s):

D. Janjic ◽

C. B. Wollheim ◽

G. W. Sharp

Keyword(s):

Insulin Release ◽

Selective Inhibition ◽

Calcium Stores ◽

Dantrolene Sodium ◽

Voltage Dependent ◽

14Co2 Production ◽

Stimulus Secretion Coupling ◽

Primary Action ◽

Ca2 Channels

Dantrolene sodium, which interferes with excitation-contraction coupling by inhibiting the Ca2+ release from sarcoplasmic reticulum in muscle, was used to investigate the role of stored calcium in the stimulation of insulin release by various secretagogues. Insulin release was measured simultaneously with 45Ca2+ uptake or 45Ca2+ efflux from isolated rat pancreatic islets. Glucose-stimulated insulin release was inhibited by dantrolene (10–100 microM) as was glyceraldehyde- or mannose-stimulated release. In contrast, dantrolene failed to inhibit insulin release stimulated by leucine, arginine, ouabain, potassium, or 3-isobutyl-1-methylxanthine. Although dantrolene lowered glucose-stimulated 45Ca2+ uptake, nonspecific blockade of voltage-dependent Ca2+ channels may not be a primary action of dantrolene because K+-stimulated 45Ca2+ uptake was not inhibited. Glucose utilization (3H2O formation) was unaffected by dantrolene, whereas glucose oxidation (14CO2 production) was decreased. In the absence of Ca2+, the glucose-inhibited 45Ca2+ efflux was unchanged. At normal Ca2+, dantrolene inhibited glucose-stimulated 45Ca2+ efflux and veratridine induced insulin release. This suggests an interference with mobilization of beta-cell calcium stores. The selective action of dantrolene on insulin release makes it an interesting tool for further studies on stimulus-secretion coupling.

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Local Anesthetics Modulate Neuronal Calcium Signaling through Multiple Sites of Action

Anesthesiology ◽

10.1097/00000542-200305000-00016 ◽

2003 ◽

Vol 98 (5) ◽

pp. 1139-1146 ◽

Cited By ~ 14

Author(s):

Fang Xu ◽

Zayra Garavito-Aguilar ◽

Esperanza Recio-Pinto ◽

Jin Zhang ◽

Thomas J. J. Blanck

Keyword(s):

Local Anesthetics ◽

K Channel ◽

Na Channels ◽

Channel Blockade ◽

K Channels ◽

Voltage Dependent ◽

Sites Of Action ◽

A Site ◽

Ca2 Channels

Background Local anesthetics (LAs) are known to inhibit voltage-dependent Na+ channels, as well as K+ and Ca2+ channels, but with lower potency. Since cellular excitability and responsiveness are largely determined by intracellular Ca2+ availability, sites along the Ca2+ signaling pathways may be targets of LAs. This study was aimed to investigate the LA effects on depolarization and receptor-mediated intracellular Ca2+ changes and to examine the role of Na+ and K+ channels in such functional responses. Methods Effects of bupivacaine, ropivacaine, mepivacaine, and lidocaine (0.1-2.3 mm) on evoked [Ca2+](i) transients were investigated in neuronal SH-SY5Y cell suspensions using Fura-2 as the intracellular Ca2+ indicator. Potassium chloride (KCl, 100 mm) and carbachol (1 mm) were individually or sequentially applied to evoke increases in intracellular Ca2+. Coapplication of LA and Na+/K+ channel blockers was used to evaluate the role of Na+ and K+ channels in the LA effect on the evoked [Ca2+](i) transients. Results All four LAs concentration-dependently inhibited both KCl- and carbachol-evoked [Ca2+](i) transients with the potency order bupivacaine > ropivacaine > lidocaine >/= mepivacaine. The carbachol-evoked [Ca2+](i) transients were more sensitive to LAs without than with a KCl prestimulation, whereas the LA-effect on the KCl-evoked [Ca2+](i) transients was not uniformly affected by a carbachol prestimulation. Na+ channel blockade did not alter the evoked [Ca2+](i) transients with or without a LA. In the absence of LA, K+ channel blockade increased the KCl-, but decreased the carbachol-evoked [Ca2+](i) transients. A coapplication of LA and K+ channel blocker resulted in larger inhibition of both KCl- and carbachol-evoked [Ca2+](i) transients than by LA alone. Conclusions Different and overlapping sites of action of LAs are involved in inhibiting the KCl- and carbachol-evoked [Ca2+](i) transients, including voltage-dependent Ca2+ channels, a site associated with the caffeine-sensitive Ca2+ store and a possible site associated with the IP(3)-sensitive Ca2+ store, and a site in the muscarinic pathway. K+ channels, but not Na+ channels, seem to modulate the evoked [Ca2+](i) transients, as well as the LA-effects on such responses.

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Spontaneous activity in the microvasculature of visceral organs: role of pericytes and voltage-dependent Ca2+channels

The Journal of Physiology ◽

10.1113/jp271438 ◽

2016 ◽

Vol 594 (3) ◽

pp. 555-565 ◽

Cited By ~ 13

Author(s):

Hikaru Hashitani ◽

Richard J. Lang

Keyword(s):

Spontaneous Activity ◽

Visceral Organs ◽

Voltage Dependent ◽

Ca2 Channels

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Regulation of voltage-dependent Ca2+ channels in the early developing heart: role of ?1 integrins

Basic Research in Cardiology ◽

10.1007/s003950200044 ◽

2002 ◽

Vol 97 (7) ◽

pp. 1-1 ◽

Cited By ~ 4

Author(s):

J�rgen Hescheler ◽

Bernd K. Fleischmann

Keyword(s):

Developing Heart ◽

Voltage Dependent ◽

Ca2 Channels

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Contribution of Cav1.2 Ca2+ channels and store-operated Ca2+ entry to pig urethral smooth muscle contraction

AJP Renal Physiology ◽

10.1152/ajprenal.00514.2019 ◽

2020 ◽

Vol 318 (2) ◽

pp. F496-F505

Author(s):

Benjamin E. Rembetski ◽

Kenton M. Sanders ◽

Bernard T. Drumm

Keyword(s):

Smooth Muscle ◽

Electrical Field Stimulation ◽

Smooth Muscle Contraction ◽

Isometric Tension ◽

Electrical Field ◽

Voltage Dependent ◽

Urethral Smooth Muscle ◽

Evoked Contractions ◽

Ca2 Channels

Urethral smooth muscle (USM) generates tone to prevent urine leakage from the bladder during filling. USM tone has been thought to be a voltage-dependent process, relying on Ca2+ influx via voltage-dependent Ca2+ channels in USM cells, modulated by the activation of Ca2+-activated Cl− channels encoded by Ano1. However, recent findings in the mouse have suggested that USM tone is voltage independent, relying on Ca2+ influx through Orai channels via store-operated Ca2+ entry (SOCE). We explored if this pathway also occurred in the pig using isometric tension recordings of USM tone. Pig USM strips generated myogenic tone, which was nearly abolished by the Cav1.2 channel antagonist nifedipine and the ATP-dependent K+ channel agonist pinacidil. Pig USM tone was reduced by the Orai channel blocker GSK-7975A. Electrical field stimulation (EFS) led to phentolamine-sensitive contractions of USM strips. Contractions of pig USM were also induced by phenylephrine. Phenylephrine-evoked and EFS-evoked contractions of pig USM were reduced by ~50–75% by nifedipine and ~30% by GSK-7975A. Inhibition of Ano1 channels had no effect on tone or EFS-evoked contractions of pig USM. In conclusion, unlike the mouse, pig USM exhibited voltage-dependent tone and agonist/EFS-evoked contractions. Whereas SOCE plays a role in generating tone and agonist/neural-evoked contractions in both species, this dominates in the mouse. Tone and agonist/EFS-evoked contractions of pig USM are the result of Ca2+ influx primarily through Cav1.2 channels, and no evidence was found supporting a role of Ano1 channels in modulating these mechanisms.

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