BAY K 8644 depresses excitation-contraction coupling in cardiac muscle

1996 ◽  
Vol 270 (3) ◽  
pp. C878-C884 ◽  
Author(s):  
E. McCall ◽  
D. M. Bers
Keyword(s):  
Cardiac Tissue ◽  
Ventricular Myocytes ◽  
Cell Voltage ◽  
Bay K 8644 ◽  
Ca Channel ◽  
Ca Current ◽  
Release Channel ◽  
Dihydropyridine Receptors ◽  
Current Voltage ◽  
The Relationship

We determined the effect of the dihydropyridine L-type Ca channel agonist BAY K 8644 (BAY) on excitation-contraction (E-C) coupling in isolated ferret ventricular myocytes using whole cell voltage clamp. The sarcoplasmic reticulum (SR) Ca load during the test pulses, assessed by caffeine-induced contractures, was similar in the presence and absence of BAY, with extracellular Ca concentration lowered from 3 to 1 mM in BAY. The relationship between L-type Ca current (ICa) and contraction was assessed, with current and contractions measured during depolarizations from -40 to between -30 and +50 mV after a conditioning train (to ensure constant SR Ca load). BAY shifted the current-contraction relationship downward, such that, for a given ICa and SR Ca load, the contraction elicited was much smaller in the presence of BAY. BAY also induced a characteristic negative shift in the the current-voltage relationship. We conclude that BAY decreases the efficacy of a given Ca current to induce SR Ca release during E-C coupling in ferret cardiac tissue (in contrast to the BAY-induced increase of resting SR Ca release). This may reflect an alteration in the state of the SR Ca release channel due to BAY binding to dihydropyridine receptors.

Sodium-calcium exchange-mediated contractions in feline ventricular myocytes

1992 ◽  
Vol 263 (4) ◽  
pp. H1161-H1169 ◽  
Author(s):  
H. B. Nuss ◽  
S. R. Houser
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Ventricular Myocytes ◽  
Membrane Potentials ◽  
Exchange Mechanism ◽  
Ca Channel ◽  
Ca Current ◽  
Voltage Step ◽  
Reverse Mode ◽  
Sodium Calcium ◽  
Calcium Exchange

The hypothesis that Ca entry by the sarcolemmal Na-Ca exchange mechanism induces sarcoplasmic reticulum (SR) Ca release, loads the SR with Ca, and/or directly induces contractions by elevating cytosolic free Ca was tested in voltage-clamped feline ventricular myocytes. Intracellular Na concentration was increased by cellular dialysis to enhance Ca influx via "reverse-mode" Na-Ca exchange at positive membrane potentials, at which the "L-type" Ca current (ICa) should be small. Contractions were induced in the presence of Ca channel antagonists by depolarization to these potentials, suggesting that Ca influx via reverse-mode Na-Ca exchange was involved. These contractions had both phasic (SR related) and tonic components of shortening. They were smaller and began with more delay after depolarization than contractions which involved ICa. The magnitude of shortening was graded by the amount and duration of depolarization, suggesting that Ca influx via reverse-mode Na-Ca exchange has the capacity to induce and grade SR Ca release. Small slow contractions could be evoked in the presence of ryanodine (to impair SR function) and verapamil (to block ICa), supporting the idea that Ca influx via Na-Ca exchange is sufficient to directly activate the contractile proteins. Contractions induced by voltage steps to +10 mV, which were usually small when ICa was blocked, were potentiated if preceded by a voltage step to strongly positive potentials. This potentiation was inhibited by ryanodine, suggesting that Ca entry that occurs by Na-Ca exchange may be important for normal SR Ca loading.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Altered Na/Ca exchange distribution in ventricular myocytes from failing hearts

2016 ◽  
Vol 310 (2) ◽  
pp. H262-H268 ◽  
Author(s):  
Hanne C. Gadeberg ◽  
Simon M. Bryant ◽  
Andrew F. James ◽  
Clive H. Orchard
Keyword(s):  
Heart Failure ◽  
Ventricular Myocytes ◽  
Cell Voltage ◽  
Coronary Artery Ligation ◽  
Sham Operation ◽  
Ca Current ◽  
Artery Ligation ◽  
Whole Cell ◽  
Rat Hearts ◽  
T Tubules

In mammalian cardiac ventricular myocytes, Ca efflux via Na/Ca exchange (NCX) occurs predominantly at T tubules. Heart failure is associated with disrupted t-tubular structure, but its effect on t-tubular function is less clear. We therefore investigated t-tubular NCX activity in ventricular myocytes isolated from rat hearts ∼18 wk after coronary artery ligation (CAL) or corresponding sham operation (Sham). NCX current ( INCX) and l-type Ca current ( ICa) were recorded using the whole cell, voltage-clamp technique in intact and detubulated (DT) myocytes; intracellular free Ca concentration ([Ca]i) was monitored simultaneously using fluo-4. INCX was activated and measured during application of caffeine to release Ca from sarcoplasmic reticulum (SR). Whole cell INCX was not significantly different in Sham and CAL myocytes and occurred predominantly in the T tubules in Sham myocytes. CAL was associated with redistribution of INCX and ICa away from the T tubules to the cell surface and an increase in t-tubular INCX/ ICa density from 0.12 in Sham to 0.30 in CAL myocytes. The decrease in t-tubular INCX in CAL myocytes was accompanied by an increase in the fraction of Ca sequestered by SR. However, SR Ca content was not significantly different in Sham, Sham DT, and CAL myocytes but was significantly increased by DT of CAL myocytes. In Sham myocytes, there was hysteresis between INCX and [Ca]i, which was absent in DT Sham but present in CAL and DT CAL myocytes. These data suggest altered distribution of NCX in CAL myocytes.

scholarly journals Properties of L-type calcium channel gating current in isolated guinea pig ventricular myocytes.

1991 ◽  
Vol 98 (2) ◽  
pp. 265-285 ◽  
Author(s):  
R W Hadley ◽  
W J Lederer
Keyword(s):  
Guinea Pig ◽  
Ventricular Myocytes ◽  
Channel Gating ◽  
Charge Movement ◽  
Ca Channel ◽  
Dependent Manner ◽  
Gating Current ◽  
Ca Current ◽  
Channel Inactivation ◽  
Time Dependencies

Nonlinear capacitative current (charge movement) was compared to the Ca current (ICa) in single guinea pig ventricular myocytes. It was concluded that the charge movement seen with depolarizing test steps from -50 mV is dominated by L-type Ca channel gating current, because of the following observations. (a) Ca channel inactivation and the immobilization of the gating current had similar voltage and time dependencies. The degree of channel inactivation was directly proportional to the amount of charge immobilization, unlike what has been reported for Na channels. (b) The degree of Ca channel activation was closely correlated with the amount of charge moved at all test potentials between -40 and +60 mV. (c) D600 was found to reduce the gating current in a voltage- and use-dependent manner. D600 was also found to induce "extra" charge movement at negative potentials. (d) Nitrendipine reduced the gating current in a voltage-dependent manner (KD = 200 nM at -40 mV). However, nitrendipine did not increase charge movement at negative test potentials. Although contamination of the Ca channel gating current from other sources cannot be fully excluded, it was not evident in the data and would appear to be small. However, it was noted that the amount of Ca channel gating charge was quite large compared with the magnitude of the Ca current. Indeed, the gating current was found to be a significant contaminant (19 +/- 7%) of the Ca tail currents in these cells. In addition, it was found that Ca channel rundown did not diminish the gating current. These results suggest that Ca channels can be "inactivated" by means that do not affect the voltage sensor.

Comparative Effects of Bupivacaine and Ropivacaine on Intracellular Calcium Transients and Tension in Ferret Ventricular Muscle

2004 ◽  
Vol 101 (4) ◽  
pp. 888-894 ◽  
Author(s):  
Yasushi Mio ◽  
Norio Fukuda ◽  
Yoichiro Kusakari ◽  
Yoshikiyo Amaki ◽  
Yasumasa Tanifuji ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Bay K 8644 ◽  
Clinical Settings ◽  
Ca Channel ◽  
Dependent Manner ◽  
Inhibitory Effects ◽  
Concentration Dependent Manner ◽  
Intracellular Ca ◽  
Slope Difference ◽  
The Relationship

Background Recent evidence suggests that ropivacaine exerts markedly less cardiotoxicity compared with bupivacaine; however, the mechanisms are not fully understood at the molecular level. Methods Isolated ferret ventricular papillary muscles were microinjected with the Ca-binding photoprotein aequorin, and intracellular Ca transients and tension were simultaneously measured during twitch in the absence and presence of bupivacaine or ropivacaine. Results Bupivacaine and ropivacaine (10, 30, and 100 microm) reduced peak systolic [Ca]i and tension in a concentration-dependent manner. The effects were significantly greater for bupivacaine, particularly on tension (approximately twofold). The percentage reduction of tension was linearly correlated with that of [Ca]i for both anesthetics, with the slope of the relationship being approximately equal to 1.0 for ropivacaine and approximately equal to 1.3 for bupivacaine (slope difference, P < 0.05), suggesting that the cardiodepressant effect of ropivacaine results predominantly from inhibition of Ca transients, whereas bupivacaine suppresses Ca transients and the reaction beyond Ca transients, i.e., myofibrillar activation, as well. BAY K 8644, a Ca channel opener, abolished the inhibitory effects of ropivacaine on Ca transients and tension, whereas BAY K 8644 only partially inhibited the effects of bupivacaine, particularly the effects on tension. Conclusion The cardiodepressant effect of bupivacaine is approximately twofold greater than that of ropivacaine. Bupivacaine suppresses Ca transients more markedly than does ropivacaine and reduces myofibrillar activation, which may at least in part underlie the greater inhibitory effect of bupivacaine on cardiac contractions. These results suggest that ropivacaine has a more favorable profile as a local anesthetic in the clinical settings.

Citrate decreases contraction and Ca current in cardiac muscle independent of its buffering action

1991 ◽  
Vol 260 (5) ◽  
pp. C900-C909 ◽  
Author(s):  
D. M. Bers ◽  
L. V. Hryshko ◽  
S. M. Harrison ◽  
D. D. Dawson
Keyword(s):  
Cardiac Muscle ◽  
Dipicolinic Acid ◽  
Reversal Potential ◽  
Cell Voltage ◽  
Nitrilotriacetic Acid ◽  
Ca Current ◽  
Current Voltage ◽  
Protonated Forms ◽  
Current Voltage Relationship ◽  
Voltage Relationship

Extracellular Ca (Cao) depletions that occur during cardiac muscle contractions are indicative of net Ca entry. Buffering Cao concentration ([Ca]o) with citrate can limit the magnitude of these Cao depletions [e.g., Shattock and Bers. Am. J. Physiol. 256 (Cell Physiol. 25): C813-C822, 1989] which theoretically would allow more Ca entry and consequently greater force at the same free [Ca]o. However, Shimoni and Ginsburg [Am. J. Physiol. 252 (Cell Physiol. 21): C248-C252, 1987] have shown that citrate inhibits cardiac contractions and suggested that this was due to its Ca-buffering action (i.e., dissipating a local elevation of [Ca] at the outer sarcolemmal surface and thereby decreasing Ca influx). To examine the effects of Ca buffering per se, we compared the effects of four low-affinity Ca buffers [citrate, nitrilotriacetic acid (NTA), dipicolinic acid (DPA), and acetamidoiminodiacetic acid (ADA)] on several cardiac preparations. In Mg-free medium with 2 mM free Ca (measured using murexide), citrate, DPA, and ADA (10 mM) decreased the force of twitch contractions in rabbit ventricle to 76 +/- 2, 60 +/- 2, and 85 +/- 2%, respectively, but 10 mM NTA increased force slightly to 105 +/- 2%. No simple correlation was observed between the Ca affinity of the buffer and its effect on tension. These effects were not due to changes in sarcoplasmic reticulum (SR) Ca loading because rapid cooling contractures were not affected and similar results were observed in the presence of caffeine or ryanodine. The depressant effects of citrate and ADA on tension were greater at pH 5.5-6 and ADA had no effect at pH 8.5. Thus the depressant effect is stronger with more protonated forms of citrate and ADA, which are also poorer Ca buffers. Citrate (but not NTA) decreased Ca current in whole cell voltage clamp and shifted the current-voltage relationship and reversal potential to more negative potentials. Citrate decreased Ca current more effectively at higher citrate and lower Ca concentrations. We conclude that citrate (and some other weak Ca buffers) may directly decrease Ca current and contraction in a manner independent of Ca buffering ability.

BAY K 8644 and ClO4- potentiate caffeine contracture without Ca2+ release channel activation

1997 ◽  
Vol 272 (1) ◽  
pp. C41-C47 ◽  
Author(s):  
T. Oba ◽  
M. Koshita ◽  
T. Aoki ◽  
M. Yamaguchi
Keyword(s):  
Time Constant ◽  
Bay K 8644 ◽  
Open Probability ◽  
Release Channel ◽  
Channel Activation ◽  
Channel Current ◽  
Caffeine Contracture ◽  
Dihydropyridine Receptors ◽  
Open Time ◽  
External K

Effects of perchlorate (ClO4-) and BAY K 8644 on caffeine contracture and Ca2+ release channel current were studied in frog skeletal muscle. Single fibers produced a small transient contracture on addition of 2.2 mM caffeine. ClO4 at 10 mM enhanced caffeine contracture 3.7-fold. This effect was inhibited by 10 microM nifedipine pretreatment. An increase in caffeine contracture was also obtained after exposure to 0.1 microM BAY K 8644 for 1 h. At 20 mM, external K+ potentiated caffeine contracture 2.2-fold. ClO4- (< 10 mM) and BAY K 8644 (0.1-1 microM) did not affect open probability (Po), unitary conductance, and open and closed time constants of the Ca2+ release channel current. BAY K 8644 at 0.1 microM did not further enhance the channel that had been activated by 2 mM caffeine. However, 20-30 mM ClO4 increased Po significantly and led the channel to a long open state by increasing the slow open time constant and decreasing the fast closed time constant. These results suggest that binding of ClO4 and BAY K 8644 to dihydropyridine receptors elicits a further increase in Ca2+ release from the sarcoplasmic reticulum.

Palmitoylcarnitine increases [Na+]i and initiates transient inward current in adult ventricular myocytes

1995 ◽  
Vol 268 (6) ◽  
pp. H2405-H2417 ◽  
Author(s):  
J. Wu ◽  
P. B. Corr
Keyword(s):  
Ventricular Myocytes ◽  
Cell Voltage ◽  
Adult Rabbit ◽  
Inward Current ◽  
Transient Inward Current ◽  
Delayed Afterdepolarizations ◽  
Rabbit Ventricular Myocytes ◽  
The Relationship ◽  
Sensitive Electrode ◽  
Modest Effect

This study was performed to determine whether long-chain acylcarnitines, specifically palmitoylcarnitine, could account for the increase in intracellular Na+ ([Na+]i) during ischemia eliciting a secondary increase in intracellular Ca2+ ([Ca2+]i). Accordingly, whole cell voltage-clamp procedures and Na(+)-sensitive electrode recordings were employed simultaneously in isolated adult rabbit ventricular myocytes to assess the relationship between activation of a slow-inactivating Na+ current [INa(s)] and a potential increase in [Na+]i. The [Na+]i increased progressively from 8.4 +/- 1.2 to 22.5 +/- 1.8 mM (n = 8, P < 0.01) on exposure to palmitoylcarnitine (10 microM) accompanied by the activation of INa(s); both effects were reversible. Inhibition of INa(s) by tetrodotoxin (TTX, 10 microM) inhibited the increase in [Na+]i. Increasing [Na+]i to 20 mM without ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) to mimic effects measured with palmitoylcarnitine consistently elicited the transient inward current (Iti) and delayed afterdepolarizations (DADs). The percent inhibition (12.9 +/- 2.8%) of the Na(+)-K(+)-adenosinetriphosphatase pump activity by palmitoylcarnitine (10 microM) was much smaller than that induced by ouabain (10 microM, 90.5 +/- 2.5%), suggesting that this modest effect of palmitoylcarnitine on the pump is unlikely to account for the increase in [Na+]i induced by palmitoylcarnitine. Thus palmitoylcarnitine induces the INa(s) leading to an increase in [Na+]i, which elicits an increase in [Ca2+]i probably via the Na+/Ca2+ exchanger, thereby leading to the development of Iti and DADs.

scholarly journals Effects of magnesium on inactivation of the voltage-gated calcium current in cardiac myocytes.

1989 ◽  
Vol 94 (4) ◽  
pp. 745-767 ◽  
Author(s):  
H C Hartzell ◽  
R E White
Keyword(s):  
Steady State ◽  
Ventricular Myocytes ◽  
Internal Surface ◽  
State Level ◽  
Inactivation Kinetics ◽  
Ca Channel ◽  
Patch Clamp Technique ◽  
Inactivation Curve ◽  
Current Voltage ◽  
Voltage Dependent

The effects of changes in intracellular and extracellular free ionized [Mg2+] on inactivation of ICa and IBa in isolated ventricular myocytes of the frog were investigated using the whole-cell configuration of the patch-clamp technique. Intracellular [Mg2+] was varied by internal perfusion with solutions having different calculated free [Mg2+]. Increasing [Mg2+]i from 0.3 mM to 3.0 mM caused a 16% reduction in peak ICa amplitude and a 36% reduction in peak IBa amplitude, shifted the current-voltage relationship and the inactivation curve approximately 10 mV to the left, decreased relief from inactivation, and caused a dramatic increase in the rate of inactivation of IBa. The shifts in the current-voltage and inactivation curves were attributed to screening of internal surface charge by Mg2+. The increased rate of inactivation of IBa was due to an increase in both the steady-state level of inactivation as well as an increase in the rate of inactivation, as measured by two-pulse inactivation protocols. Increasing external [Mg2+] decreased IBa amplitude and shifted the current-voltage and inactivation curves to the right, but, in contrast to the effect of internal Mg2+, had little effect on the inactivation kinetics or the steady-state inactivation of IBa at potentials positive to 0 mV. These observations suggest that the Ca channel can be blocked quite rapidly by external Mg2+, whereas the block by [Mg2+]i is time and voltage dependent. We propose that inactivation of Ca channels can occur by both calcium-dependent and purely voltage-dependent mechanisms, and that a component of voltage-dependent inactivation can be modulated by changes in cytoplasmic Mg2+.

Measurement and simulation of noninactivating Ca current in smooth muscle cells

1989 ◽  
Vol 256 (4) ◽  
pp. C880-C885 ◽  
Author(s):  
Y. Imaizumi ◽  
K. Muraki ◽  
M. Takeda ◽  
M. Watanabe
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Cell Voltage ◽  
Muscle Cells ◽  
Ca Channel ◽  
Ca Current ◽  
Dependent Inactivation ◽  
High K ◽  
Voltage Dependent ◽  
Rabbit Portal Vein

An attempt was made to obtain electrophysiological evidence for continuous influx of Ca ion through voltage-dependent Ca channel (VDCC) in smooth muscle during long depolarization, for example in high K solution. Noninactivated Ca current [ICa(ni)] remaining after the accomplishment of voltage-dependent inactivation by prolonged depolarization for approximately 1 min was detected by three means under whole cell voltage clamp in several types of smooth muscle cells. The measurement of ICa(ni) was performed by micropuff application of Cd2+ or Ca2+ in the presence or absence of 5 mM extracellular Ca, respectively, or jump of extracellular Ca concentration [( Ca]o). The current-voltage relationship of ICa(ni) evaluated by these means had a peak at approximately -10 mV. The peak amplitude ranged from 5 to 25 pA, depending on whether the cells were isolated from guinea pig urinary bladder, ureter, vas deferens, taenia caecum, or rabbit portal vein. The ICa(ni) may be large enough to explain sustained contraction in high K solution, at least in these smooth muscle tissues. A window current simulated from the steady-state activation and inactivation curves and the maximum conductance of Ca current (ICa) in these cells suggests a theoretical basis for the observed ICa(ni).

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