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PubMed1992

Calcium currents in hearts with persistent truncus arteriosus.

We have used the neural crest model of defective heart development to characterize both L- and T-type Ca2+ currents (ICa,L and ICa,T) in ventricular myocytes from embryonic chick hearts with a severe outflow tract anomaly known as persistent truncus arteriosus (PTA). Because of smaller whole embryo weights but no significant change in the weights of ventricles with PTA, the ventricle to whole embryo weight ratios from hearts with PTA were 61% larger than normal at day 11 of incubation. There was a 51% reduction in the peak magnitude of ICa,L at a test potential of +10 mV (-1.4 vs. -0.7 microA/cm2), whereas ICa,T, a proportionately large fraction of the total Ca2+ current in the embryonic chick ventricle, was unaffected. In comparison to sham-operated controls, ICa,L was otherwise not different. Half-activation occurred at about -1 and -41 mV, whereas half-inactivation occurred at -19 and -61 mV for ICa,L and ICa,T, respectively. The time for half-recovery from inactivation were not different and were 200 and 230 ms for ICa,L and ICa,T, respectively. The time for half-decay of the currents and their responses to BAY K 8644 were also similar in both sham-operated and experimental hearts. Although the dihydropyridine receptor binding experiments suggest that the total number of L-type Ca2+ channels was not different, the results from the physiological experiments indicate that the number of functional L-type channels available for opening and/or the single-channel conductance may be reduced in hearts with PTA. Finally, our results with the neural crest model indicate that it is unlikely that the development of Ca2+ currents is influenced by the onset of cholinergic innervation in the heart.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1995

Evaluation of T- and L-type Ca2+ currents in shark ventricular myocytes.

Two types of Ca2+ currents with characteristics of T- and L-type Ca2+ currents were recorded in ventricular myocytes of dogfish (Squalus acanthias). The T-type Ca2+ current activated near -70 mV and had a peak current density of 9.8 pA/pF at -34 mV. The L-type Ca2+ current activated near -50 mV and had a peak current density of 10.6 pA/pF near 0 mV. The threshold for activation of the T-type Ca2+ current was 20 mV negative to that of the tetrodotoxin-sensitive Na+ current. Inactivation of the T-type Ca2+ current was rapid with a limiting time constant of 5 ms at positive potentials. The T-type Ca2+ current was not modulated by isoproterenol or acetylcholine. In dogfish the T-type Ca2+ channel has current densities equivalent to the L-type channel and is likely to activate before the Na+ channel, contributing significantly to generation of the foot of the action potential.

Amiloride↗

PubMed1991

Ca2+ channels and aldosterone secretion: modulation by K+ and atrial natriuretic peptide.

Two populations of voltage-dependent Ca2+ channels, T-type and L-type, are present in bovine adrenal glomerulosa cells. Activation of these channels by cell depolarization with the resultant increase in Ca2+ influx may be one way in which agonists regulate aldosterone secretion. In addition, these channels may be the site of antagonist action. In the present study, we have demonstrated that atrial natriuretic peptide (ANP), an antagonist of aldosterone secretion, alters only the voltage dependence of inactivation of the T-type channel while enhancing the voltage dependence of activation of a subpopulation of L-type channels. These patch-clamp data, which demonstrated contrasting effects of ANP on the activity of T- and L-type Ca2+ channels correlated with changes induced in cytosolic calcium [( Ca2+]i). In the weakly depolarized cell, ANP (greater than 30 pM) lowered [Ca2+]i, in contrast to the strongly depolarized cell, in which ANP (greater than 10 pM) raised [Ca2+]i. Similar alterations in the level of [Ca2+]i in the stimulated cell were induced by the Ca(2+)-channel blocker nitrendipine and the L-type channel agonist, (-)BAY K 8644. With increasing concentrations of extracellular K+ (3.5-60 mM) the rate of aldosterone secretion rose nonmonotonically. ANP inhibited secretion over this broad range of K+ concentrations; however, its potency as an inhibitor of secretion was diminished in the strongly depolarized cell. These data are discussed in the context of a model that proposes a role for sustained Ca2+ influx in cell activation.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1988

A slow calcium-dependent chloride conductance in clonal anterior pituitary cells.

1. Whole cell voltage-clamp recordings were made from GH3 cells, a clonal cell line initially derived from a rat anterior pituitary tumor, using patch electrodes filled with CsCl or N-methylglucamine chloride (NMG Cl). The bathing medium contained tetraethylammonium chloride (TEA; 20 mM) and NaCl (120 mM) or NMG Cl (140 mM). These conditions resulted in substantial blockade of outward currents. 2. Depolarizing voltage steps from a holding potential of -50 mV activated transient (T-type) and sustained (L-type) inward Ca2+ currents. In addition, prolonged depolarization (greater than 1 s) invariably elicited a slowly activating inward current that persisted with maintained depolarization, and deactivated slowly on repolarization, resulting in a prominent inward tail current. 3. This tail current could be recorded under conditions where Ca2+ and Cl- were the only membrane-permeant ions (symmetrical NMG Cl). The tail current nulled near 0 mV with symmetrical Cl- and showed a negative reversal potential with nominally Cl--free internal solution. Ba2+ substituted for Ca2+ as a carrier of inward current, but no tail current was expressed. These observations indicate that Cl- is the charge carrier of the slow inward tail current. 4. The voltage dependence for activation of the slow tail current was U-shaped with a peak at approximately -10 mV. This closely paralleled the voltage dependency of the Ca2+ currents. Recordings with 5 mM internal ethylene glycol-bis(beta-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA) to buffer intracellular Ca2+ to low nM levels exhibited slow inward tail currents that were of lower peak amplitude than with the usual 1.1 mM EGTA-containing pipette solution, but the kinetics of the currents were similar in both cases. In addition, the slow tail current was eliminated on superfusion with the Ca2+ channel blocker Cd2+ or with Ca2+-free medium. These results demonstrate that the current is dependent on Ca2+ influx; it is, therefore, referred to as ICl(Ca). 5. Activation of ICl(Ca) required depolarization of at least 1 s. More prolonged depolarizations activated progressively greater current, to a maximum with 6-s depolarization. In most cases, the decay of the tail current was described by a single exponential function with time constant approximately 0.8-0.9 s within the potential range -80 to -30 mV. At more depolarized potentials the decay was slower (increasing e-fold/20-mV change in membrane potential). 6. In a high proportion of cells, ICl(Ca) rapidly diminished in amplitude on repeated activation. This "rundown" occurred more rapidly than the rundown of the Ca2+ currents.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1990

Low-threshold calcium current in isolated Purkinje cell bodies of rat cerebellum.

1. The low- and high-threshold Ca2+ currents were observed in Purkinje cell bodies isolated from the cerebellum of newborn (2 wk old) and adult (8 wk old) rats under whole-cell clamp. A transient Ca2+ current (low-threshold or "T-type" ICa) was elicited by depolarizing step pulses to -60 mV or more positive potentials from a holding potential (VH) of -100 mV. In cells dissociated from newborn rats, a long-lasting Ca2+ current (high-threshold or "L-type" ICa) was also elicited by depolarizing command pulses beyond -30 mV. 2. The low-threshold ICa was resistant to the "washout" effect during the internal perfusion, whereas the high-threshold ICa faded gradually with time during the continuous internal perfusion. 3. In the current-voltage (I-V) relationship, the low-threshold ICa had a threshold potential around -60 mV and reached the maximum inward current around -20 mV. The activation and inactivation kinetics of the current depended on membrane potential: for a test-potential change from -60 to +40 mV, the time to peak of the current (activation) decreased from 31.9 to 5.0 ms, and the time constant of current decay (inactivation) decreased from 78.5 to 22.9 ms. 4. Steady-state inactivation of low-threshold ICa was membrane-potential dependent, and the inactivation of the 50% level was -79 mV. Recovery time constant from steady-state inactivation varied depending on the membrane potential. The time constants were 3.3 and 2.5 s at VHs of -100 and -120 mV, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

An active membrane model of the cerebellar Purkinje cell. I. Simulation of current clamps in slice.

1. A detailed compartmental model of a cerebellar Purkinje cell with active dendritic membrane was constructed. The model was based on anatomic reconstructions of single Purkinje cells and included 10 different types of voltage-dependent channels described by Hodgkin-Huxley equations, derived from Purkinje cell-specific voltage-clamp data where available. These channels included a fast and persistent Na+ channel, three voltage-dependent K+ channels, T-type and P-type Ca2+ channels, and two types of Ca(2+)-activated K+ channels. 2. The ionic channels were distributed differentially over three zones of the model, with Na+ channels in the soma, fast K+ channels in the soma and main dendrite, and Ca2+ channels and Ca(2+)-activated K+ channels in the entire dendrite. Channel densities in the model were varied until it could reproduce Purkinje cell responses to current injections in the soma or dendrite, as observed in slice recordings. 3. As in real Purkinje cells, the model generated two types of spiking behavior. In response to small current injections the model fired exclusively fast somatic spikes. These somatic spikes were caused by Na+ channels and repolarized by the delayed rectifier. When higher-amplitude current injections were given, sodium spiking increased in frequency until the model generated large dendritic Ca2+ spikes. Analysis of membrane currents underlying this behavior showed that these Ca2+ spikes were caused by the P-type Ca2+ channel and repolarized by the BK-type Ca(2+)-activated K+ channel. As in pharmacological blocking experiments, removal of Na+ channels abolished the fast spikes and removal of Ca2+ channels removed Ca2+ spiking. 4. In addition to spiking behavior, the model also produced slow plateau potentials in both the dendrite and soma. These longer-duration potentials occurred in response to both short and prolonged current steps. Analysis of the model demonstrated that the plateau potentials in the soma were caused by the window current component of the fast Na+ current, which was much larger than the current through the persistent Na+ channels. Plateau potentials in the dendrite were carried by the same P-type Ca2+ channel that was also responsible for Ca2+ spike generation. The P channel could participate in both model functions because of the low-threshold K2-type Ca(2+)-activated K+ channel, which dynamically changed the threshold for dendritic spike generation through a negative feedback loop with the activation kinetics of the P-type Ca2+ channel. 5. These model responses were robust to changes in the densities of all of the ionic channels.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1988

Phorbol ester increases the dihydropyridine-sensitive calcium conductance in a vascular smooth muscle cell line.

In vascular smooth muscle, phorbol esters cause a slowly developing contraction and an associated transmembrane calcium flux, both of which are inhibited by dihydropyridine calcium channel antagonists. In the A7r5 cultured vascular cell line, we used the whole-cell voltage-clamp technique to identify voltage-dependent calcium conductances and investigate the effect of phorbol esters on that conductance having characteristic dihydropyridine sensitivity (slowly inactivating, high-threshold, "L-type"). With barium as the charge carrier, large-amplitude (100-800 pA) inward currents of two types were characterized by their kinetics and voltage dependence. With holding potential--80 mV, a rapidly inactivating, low-threshold current ("T-type") was activated by depolarizations above-40 mV and was maximal at -10 mV. With holding potential -30 mV, this component was inactivated, and a second slowly inactivating, high-threshold current was activated above -10 mV and was maximal at +10 to +20 mV. These currents are similar to the T-type and L-type currents previously described in vascular smooth muscle cells. When added to the bath, the active phorbol ester, 12-O-tetradecanoyl phorbol-13-acetate (100 nM) increased the slowly inactivating (L-type) current by 32 +/- 20% (n = 8, +/- SD). Phorbol-12,13-dibutyrate (100 nM) caused a similar effect, but the inactive phorbol, 4-alpha-phorbol (100 nM), did not. We conclude that at least two distinct calcium conductances are expressed in A7r5 vascular smooth muscle cells, and that the dihydropyridine-sensitive calcium conductance is acutely modulated by phorbol esters, presumably acting through stimulation of protein kinase C. Such modulation may play a role in increasing transmembrane calcium influx mediated by agonist-receptor interactions that lead to activation of protein kinase C and may help to sustain or amplify calcium-dependent cell responses.

Animals↗

PubMed1990

Reduced L-type calcium current in the embryonic chick heart with persistent truncus arteriosus.

Calcium currents were examined in an experimental model in the embryonic chick heart with a congenital malformation known as persistent truncus arteriosus. This is a severe defect characterized by failure of conotruncal and aorticopulmonary septation of the embryonic heart tube. As a result, no separation into the aortic and pulmonary arteries occurs, and there is a common outflow tract. The hearts with persistent truncus arteriosus had a 26% greater ventricular to whole embryo weight, which indicated that the ventricles were enlarged. Both the low-threshold T-type (ICa.T) and the 1,4-dihydropyridine-sensitive L-type (ICa.L) Ca2+ currents were present in the ventricular myocytes from hearts at day 11 of incubation. However, day 11 hearts with persistent truncus arteriosus showed a twofold reduction in the peak magnitude of ICa.L at a test potential of + 10 mV without a concomitant reduction in the number of L channels detected by 1,4-dihydropyridine antagonist [(+)[3H]PN200-110] and agonist (Bay K 8644) receptor binding. The results indicated that an L channel regulatory mechanism other than protein synthesis was affected. These changes are consistent with responses to conditions of excessive hemodynamic burden that have been characterized in adult hearts.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1990

Actions of Ca2+ antagonists on two types of Ca2+ channels in rat aorta smooth muscle cells in primary culture.

Mechanisms of blockade of two types of Ca2+ channels by the organic Ca2+ antagonists, nicardipine, diltiazem, verapamil, and flunarizine, were examined in rat aorta smooth muscle cells in primary culture by using the whole-cell voltage-clamp method. T-type Ca2+ current (T-type ICa) was isolated by an internal perfusion of 5 mM F-, which irreversibly suppressed the L-type ICa, without affecting T-type ICa. L-type ICa was isolated by setting a holding potential at -60 mV, at which most of the T-type Ca2+ channels were inactivated. L-type ICa is halved by 0.1 microM nicardipine, 3.0 microM diltiazem, 0.6 microM verapamil, and 0.1 microM flunarizine, whereas T-type ICa is halved by the same drugs at 0.6, 30, 30, and 0.1 microM, respectively. Diltiazem and verapamil accelerated the decay of L-type ICa and cumulatively blocked L-type ICa during repetitive step depolarizations elicited every 30 seconds ("use-dependent block"). Diltiazem and verapamil neither changed the decay of T-type ICa nor showed a use-dependent block of T-type ICa. Nicardipine and flunarizine blocked both L- and T-type ICa from the first depolarization step after drug treatment ("tonic block") and shifted their steady-state inactivation curves to the left. The estimated binding constants of nicardipine and flunarizine for the inactivated state of T-type Ca2+ channels (48 and 19 nM, respectively) were smaller than those for the resting state of L-type Ca2+ channels (160 and 90 nM, respectively). A low concentration (0.1 microM) of nicardipine initially potentiated T-type ICa and then reduced it. We conclude from these results that 1) nicardipine and flunarizine block not only the resting state but, more preferentially, the inactivated state of both the L- and T-type Ca2+ channels; 2) verapamil and diltiazem preferentially act on the open state of the L-type Ca2+ channel and on the resting and inactivated state of the T-type Ca2+ channel; and 3) the T-type Ca2+ channel of the rat aorta smooth muscle cells appears to be more sensitive to nicardipine and flunarizine than does the L-type Ca2+ channel at around the resting membrane potential.

Animals↗

PubMed1992

Cholesterol increases the L-type voltage-sensitive calcium channel current in arterial smooth muscle cells.

To determine whether membrane free cholesterol affects calcium currents in vascular smooth muscle cells, whole-cell patch clamp recordings were made before and after cholesterol enrichment of cells by exposure to cholesterol-rich liposomes. Exposure to cholesterol-rich liposomes resulted in a gradual increase in the L-type current over 20 hours and a plateau (73 +/- 7% increase over basal) between 20 and 32 hours. This effect was associated with a rightward shift in the inactivation potential and a decrease in the sensitivity to (-)-PN-202-791, a dihydropyridine antagonist. There was no change in the maximum L-type current stimulated by (+)-PN-202-791, a dihydropyridine agonist. Liposome exposure caused a small, transient increase in the T-type current (peak effect, 20 minutes). We conclude that membrane cholesterol has important effects on the L-type calcium current in vascular smooth muscle cells, which is most likely due to an alteration in channel functional state rather than an increase in channel expression.

Animals↗

PubMed1990

Dopamine inhibits two characterized voltage-dependent calcium currents in identified rat lactotroph cells.

The effects of dopamine (DA) on voltage-dependent Ca2+ currents were investigated in cultured rat lactotroph cells using the patch clamp recording technique. Each recorded cell was identified by the reverse hemolytic plaque assay. In the whole-cell configuration, two types of Ca2+ currents, L and T, were characterized on the basis of their kinetics, voltage sensitivity, and pharmacology. The L component had a threshold of -25 mV, showed little inactivation during a 150-msec voltage step, and was maximal at +10 mV. Cadmium ions (100 microM) significantly reduced its amplitude (75%). The T component was activated at a membrane potential close to -50 mV, was maximal at -10 mV, and showed a voltage-dependent inactivation between -90 and -30 mV. It was quickly inactivated during a maintained depolarization (time constant, 27 ms at -30 mV) and was strongly reduced (80%) by nickel ions (100 microM). Bath application of DA (10 nM) caused a markedly general depression of inward Ca2+ currents, acting differently on the T- and L-type currents. DA application shifted the voltage-dependence of the L-type current activation toward depolarization values (8 mV) without modifying its time- and voltage-dependent inactivation. In contrast, DA enhanced the inactivation of the T-type current by accelerating its time-dependent inactivation (25% decrease in the time constant of inactivation) and by shifting the voltage-dependence of the T-type current inactivation toward hyperpolarizing values (-63 mV in control vs. -77 mV in the presence of DA). These effects of DA were dose-dependent and involved the activation of a D2 receptor type. They were mimicked by bromocriptine application (10 nM), whereas sulpiride (100 nM) blocked the DA-evoked response. The D1 antagonist SCH 23390 was ineffective up to 100 microM. All of these DA-induced modifications in Ca2+ currents were abolished using a GTP-free pipette solution or after pretreatment of cells with pertussis toxin, suggesting that DA can regulate the function of Ca2+ channels through GTP-binding proteins (G-proteins). Our results show that DA acts simultaneously by reducing both voltage-dependent Ca2+ currents on lactotroph cells. Thus, DA reduces the entry of Ca2+ ions across the surface membrane and thereby influences electrical activity and the cytosolic free Ca2+ concentration involved in both basal and evoked PRL release.

Animals↗

PubMed1991

Reevaluation of the electrophysiological actions of thyrotropin-releasing hormone in a rat pituitary cell line (GH3).

The electrophysiological actions of TRH were examined in the clonal pituitary cell line GH3 with the use of the perforated patch variation of the standard whole cell patch-clamp technique. The action of TRH on spontaneously spiking cells was to cause a brief hyperpolarization (first phase action), followed by a period during which action potential behavior was significantly modified (second phase action). The modifications during second phase action included a reduction in the slope of the up-stroke, a reduced peak potential, an increase in duration, and a depolarizing shift of the after-hyperpolarization. The modification of voltage- and calcium-dependent conductances that underlie these changes were investigated in voltage clamp experiments. During first phase action TRH was found to increase calcium-dependent potassium current. During second phase action TRH was found to significantly reduce the L-type calcium current (35%), with no alteration in the T-type calcium current. The second phase action of TRH on calcium-dependent potassium conductance was complex. First, a decrease was observed. This was followed by an increase that did not become fully manifest until after TRH was washed from the cell. TRH caused no change in voltage-dependent potassium current. These results indicate that the second phase action of TRH on action potential behavior in GH3 cells is mediated by a reduction in L-type calcium current and alterations in the behavior of calcium-dependent potassium currents, but not through changes in voltage-dependent potassium currents.

Action Potentials↗

PubMed1992

Fast Na+ channels and slow Ca2+ current in smooth muscle from pregnant rat uterus.

Smooth muscle cells normally do not possess fast Na+ channels, but inward current is carried through two types of Ca2+ channels: slow (L-type) Ca2+ channels and fast (T-type) Ca2+ channels. Using whole-cell voltage clamp of single smooth muscle cells isolated from the longitudinal layer of 18-day pregnant rat uterus, depolarizing pulses, applied from a holding potential of -90 mV, evoked two types of inward current, fast and slow [8]. The fast inward current decayed within 30 ms, depended on [Na]o, and was inhibited by TTX (K0.5 = 27 nM). The slow inward current decayed slowly, was dependent on [Ca]o, and was inhibited by nifedipine. These results suggest that the fast inward current is a fast Na+ channel current, and that the slow inward current is a Ca2+ slow channel current. A fast-inactivating Ca2+ channel current was not evident. Thus, the ion channels which generate inward currents in pregnant rat uterine cells are TTX-sensitive fast Na+ channels and dihydropyridine-sensitive slow Ca2+ channels. The number of fast Na+ channels increased during gestation. The averaged current density increased from 0 on day 5, to 0.19 on day 9, to 0.56 on day 14, to 0.90 on day 18, and to 0.86 pA/pF on day 21. This almost linear increase occurs because of an increase in the fraction of cells which possess fast Na+ channels, and it is suggested that the fast Na+ current may be involved in spread of excitation. The Ca2+ channel current density also was higher during the latter half of gestation. These results indicate that the fast Na+ channels and Ca2+ slow channels in myometrium become more numerous as term approaches, and may facilitate parturition. Isoproterenol (beta-agonist) did not affect either ICa(s) or INa(f), whereas Mg2+ (K0.5 of 12 mM) and nifedipine (K0.5 of 3.3 nM) depressed ICa(s). Oxytocin had no effect on INa(f) and actually depressed ICa(s) to a small extent. Therefore, the tocolytic action of beta-agonists cannot be explained by an inhibition of ICa(s), whereas that of Mg2+ can be so explained. The stimulating action of oxytocin on uterine contractions is not due to stimulation of ICa(s). Figure 11 summarizes the possible mechanisms by which uterine contractility can be modulated. In contrast to vascular smooth muscle, neither ISO nor adenosine, which produce elevation of cyclic AMP, affected ICa and INa. Therefore, no arrow can be drawn between cA-PK/cG-PK and the Ca2+ slow channel.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine↗

PubMed1992

Interaction between stannous chloride and calcium channel blockers in frog neuromuscular transmission.

We have investigated the interactions between stannous chloride (SnCl2) and calcium (Ca) channel blockers on endplate potentials (e.p.p.) and on miniature endplate potentials (m.e.p.p.) to determine which type of channel (among L-, N-, and T-type) participates in the SnCl2-induced increase in Ca entry into motor nerve terminals. The e.p.p. amplitude augmented by 30 microM SnCl2 was decreased by cumulative addition of 10 microM CdCl2 or 0.5 microM omega-conotoxin but not by 10 microM NiCl2 or 5 microM nicardipine. The SnCl2 (30 microM)-induced rise in m.e.p.p. frequency in high-potassium medium was reduced by 0.5 microM omega-conotoxin but not by 5 microM nicardipine. These results suggest that activation of the N-type Ca channel is involved in the SnCl2-induced increase in Ca entry into the nerve terminals.

Animals↗

PubMed1992

Fast Na+ channels and slow Ca2+ current in smooth muscle from pregnant rat uterus.

Smooth muscle cells normally do not possess fast Na+ channels, but inward current is carried through two types of Ca2+ channels: slow (L-type) Ca2+ channels and fast (T-type) Ca2+ channels. Whole-cell voltage clamp was done on single smooth muscle cells isolated from the longitudinal layer of 18-day pregnant rat uterus. Depolarizing pulses, applied from a holding potential of -90 mV, evoked two types of inward current, fast and slow. The fast inward current decayed within 30 ms, depended on [Na]o, and was inhibited by TTX (K0.5 = 27 nM). The slow inward current decayed slowly, was dependent on [Ca]o (or Ba2+), and was inhibited by nifedipine. These results suggest that the fast inward current is a fast Na+ channel current, and that the slow inward current is a Ca2+ slow channel current. A fast-inactivating Ca2+ channel current was not evident. We conclude that the ion channels which generate inward currents in pregnant rat uterine cells are TTX-sensitive fast Na+ channels and dihydropyridine-sensitive slow Ca2+ channels. The number of fast Na+ channels increased during gestation. The averaged current density increased from 0 on day 5, to 0.19 on day 9, 0.56 on day 14, 0.90 on day 18, and 0.86 pA/pF on day 21. This almost linear increase occurs because of an increase in the fraction of cells which possess fast Na+ channels. The Ca2+ channel current density also was higher during the latter half of gestation. These results indicate that the fast Na+ channels and Ca2+ slow channels in myometrium become more numerous as term approaches, and we suggest that the fast Na+ current may be involved in spread of excitation. Isoproterenol (beta-agonist) did not affect either ICa(s) or INa(f), whereas Mg2+ (K0.5 of 12 mM) and nifedipine (K0.5 of 3.3 nM) depressed ICa(s). Oxytocin had no effect on INa(f) and actually depressed ICa(s) (but not IBa) to a small extent. Therefore, the tocolytic action of beta-agonists cannot be explained by an inhibition of ICa(s), whereas that of Mg2+ can be so explained. The stimulating action of oxytocin on uterine contractions cannot be explained by a stimulation of ICa(s).

Animals↗

PubMed1991

Activation of N-type calcium channels by stannous chloride at frog motor nerve terminals.

Stannous chloride (SnCl2) increases the calcium (Ca) entry into motor nerve terminals through the voltage-dependent Ca channels. The present study has been conducted to determine which type of channel (i.e., L-, N-, or T-type) participates in the Ca entry increased by SnCl2 (0.1 mM)-induced enhancement of the inward Ca current was more strongly inhibited by CdCl2 (50 microM) or omega-conotoxin (0.1 microM) than by NiCl2 (50 microM) or nifedipine (10 microM), respectively. From the results obtained, it is concluded that SnCl2 increases the Ca entry into the nerve terminal by activating the N-type Ca channels.

Animals↗

PubMed1990

Blockade of low and high threshold Ca2+ channels by diphenylbutylpiperidine antipsychotics linked to inhibition of prolactin gene expression.

The effects of diphenylbutylpiperidine (DPBP) antipsychotics on Ca2+ currents and prolactin (PRL) synthesis were studied in rat pituitary growth hormone (GH) cell lines (GH3 and GH4C1). In whole-cell patch-clamp experiments, DPBPs including fluspirilene, penfluridol, and pimozide at concentrations ranging from 0.25 to 5 microM each blocked current through low threshold T-type as well as high threshold L-type channels. Each of the drugs preferentially blocked T-type current, and complete inhibition was observed at concentrations as low as 1 microM. Inhibition of L-type channels by DPBPS was enhanced at depolarized holding potentials and promoted by prolonged channel activation. At concentrations similar to those which blocked Ca2+ currents, each of the three DPBPs markedly reduced basal PRL production by GH cells. PRL synthesis stimulated by the dihydropyridine Ca2+ agonist R5417 or thyrotropin releasing hormone (TRH) was also inhibited. The inhibitory effects of the DPBPs were observed at the level of gene transcription. Penfluridol and fluspirilene inhibited basal, Ca2(+)- and TRH-stimulated expression of a fusion gene construct containing the 5'-flanking sequence of the rat PRL gene linked to the luciferase gene. The effect was concentration-dependent with the IC50 values for both drugs of less than 1 microM. Nimodipine also reduced basal, R5417, and TRH-stimulated expression of the reporter gene construct. Similar results were obtained with a reporter gene construct containing the 5'-flanking sequence of the rat GH gene. The GH luciferase construct was only slightly responsive to R5417 and TRH; however, these responses were reduced by fluspirilene and nimodipine at concentrations of less than 1 microM. These studies demonstrate that the DPBP antipsychotics block T- as well as L-type Ca2+ channels in GH cells and inhibit PRL production at the level of transcription. They also indicate that functioning Ca2+ channels are necessary for TRH-stimulated PRL gene transcription.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1986

Calcium channel types in cardiac myocytes: modulation by dihydropyridines and beta-adrenergic stimulation.

We used the patch clamp technique to record unitary calcium (Ca2+) channel activity in freshly dissociated ventricular myocytes from adult guinea pigs. We found two types of Ca2+ channels with distinct permeation and gating properties and different sensitivity to pharmacological agents. One channel (T-type) requires negative membrane potentials to remove inactivation. It gives rise to a transient mean current and is not affected by dihydropyridines or isoproterenol. The other Ca2+ channel (L-type) has a larger unitary barium-conductance, activates at more positive potentials and its averaged current decays much more slowly. It shows a distinct gating pattern with different gating modes, the proportion of which is drastically altered by dihydropyridine Ca2+-channel agonists and antagonists. L-type channel activity is modulated by beta-adrenergic stimulation by a mechanism of action which differs from that of dihydropyridine Ca2+-channel agonists.

Animals↗