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PubMed2000

Ca2+ influx via the L-type Ca2+ channel during tail current and above current reversal potential in ferret ventricular myocytes.

1. Current through L-type Ca2+ channels (ICa) was measured electrophysiologically at the same time as Ca2+ influx was measured by trapping entering Ca2+ with a high concentration of indo-1 (> 1 mM) in ferret ventricular myocytes. 2. Na+-free conditions prevented Na+-Ca2+ exchange and K+ currents were blocked by Cs+ and TEA. Thapsigargin (5 microM) prevented Ca2+ uptake and release by the sarcoplasmic reticulum. ICa was pre-activated by brief pulses to +120 mV (the equilibrium potential for Ca2+, ECa), followed by steps to different membrane potentials (Em, -80 to +100 mV), in some cases in the presence of the Ca2+ channel agonist FPL-64176. 3. Integrated ICa ( 82 ICa) was linearly related to the change in the concentration of Ca2+ bound to indo-1, which was assessed by the fluorescence difference signal DeltaFd (Fd = F500 - F400). This created an internal calibration of DeltaFd as a measure of Ca2+ influx. 4. The DeltaFd/ 82 ICadt relationship was virtually unchanged at all measurable inward ICa (at Em from -80 to +50 mV). This indicates that the fractional current carried by Ca2+ and channel selectivity are unchanged over this Em range, and also that the selectivity for Ca2+ is very high. 5. Ca2+ influx was readily detected by DeltaFd beyond the ICa reversal potential (+65 to +100 mV) and was not abolished until Em was +120 mV (i.e. ECa). This is explained by the fact that inward Ca2+ flux at the ICa reversal potential is exactly balanced by outward Cs+ current through the Ca2+ channels and can be described by classic Goldman flux analysis with a Ca2+/Cs+ selectivity of the order of 5000. 6. This result also emphasizes that net Ca2+ influx via Ca2+ channels occurs over a voltage range where the net channel current is outward.

Animals↗

PubMed1999

BAY K 8644 modifies Ca2+ cross signaling between DHP and ryanodine receptors in rat ventricular myocytes.

The amplification factor of dihydropyridine (DHP)/ryanodine receptors was defined as the amount of Ca2+ released from the sarcoplasmic reticulum (SR) relative to the influx of Ca2+ through L-type Ca2+ channels in rat ventricular myocytes. The amplification factor showed steep voltage dependence at potentials negative to -10 mV but was less dependent on voltage at potentials positive to this value. In cells dialyzed with 0.2 mM cAMP in addition to 2 mM fura 2, the Ca2+-channel agonist (-)-BAY K 8644 enhanced Ca2+-channel current (ICa), shifted the activation curve by -10 mV, and significantly delayed its inactivation. Surprisingly, BAY K 8644 reduced the amplification factor by 50% at all potentials, even though the caffeine-releasable Ca2+ stores were mostly intact at holding potentials of -90 mV. In contrast, brief elevation of extracellular Ca2+ activity from 2 to 10 mM enhanced both ICa and intracellular Ca2+ transients in the absence or presence of BAY K 8644 but had no significant effect on the amplification factor. BAY K 8644 abolished the direct dependence of the rate of inactivation of ICa on the release of Ca2+ from the SR. These findings suggest that the gain of the Ca2+-induced Ca2+ release in cardiac myocytes is regulated by the gating kinetics of cardiac L-type Ca2+ channels via local exchange of Ca2+ signals between DHP and ryanodine receptors and that BAY K 8644 suppresses the amplification factor through attenuation of the Ca2+-dependent inactivation of Ca2+ channels.

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

PubMed1997

Multiple voltage-dependent calcium currents in acutely isolated mouse vestibular neurons.

We investigated the presence of voltage-gated calcium currents in vestibular neurons acutely isolated from postnatal mice vestibular ganglions using the whole-cell patch-clamp technique. The neuronal origin of the recorded cells was confirmed by immunohistochemical detection of neurofilaments and calretinin. High and low voltage-activated calcium currents were recorded. High voltage-activated currents were present in all investigated neurons. Low voltage-activated currents were recorded in only a few large vestibular neurons. High and low voltage-activated currents were distinguished by their thresholds of activation and their ability to run-up during early recordings. Among high voltage-activated currents. L-, N- and P-type currents were identified by their sensitivity to, respectively, the dihydropyridines agonist Bay K 8644 (3 microM) and antagonist nitrendipine (3 microM), the co-conotoxin GVIA (3 microM) and the omega-agatoxin IVA at low concentration (50 nM). An inactivating current sensitive to 1 microM omega-agatoxin IVA with characteristics similar to those of the Q-type current was also recorded in vestibular neurons. When L-, N-, P-, Q-type barium currents were blocked, a residual high voltage-activated current defined by its resistance to saturating concentrations of all above blockers was detected. This residual current was completely blocked by 0.5 mM nickel and cadmium. Our results reveal that primary vestibular neurons express a variety of voltage-activated calcium currents with distinct physiological and pharmacological properties. This diversity could be related both with their functional synaptic characteristic, and with the intrinsic physiological properties of each class of vestibular afferents.

Animals↗

PubMed2000

Kinetic effects of FPL 64176 on L-type Ca2+ channels in cardiac myocytes.

To characterize the effects of the Ca2+ channel agonist FPL 64176 on L-type Ca2+ current in isolated rat ventricular myocytes, certain of its effects were compared with those of a better known agonist, S (-) Bay K 8644. Both drugs enhance currents elicited by depolarizing pulses and enhance and slow the decay of tail currents elicited by subsequent repolarization. Both drugs shift the voltage dependence of activation and of inactivation approximately 10 mV in the negative direction, but FPL 64176 slows the rate of both activation and the decline of Ca2+ current during a depolarization, whereas Bay K 8644 accelerates the rate of current decay under the same conditions. In single channel studies in on-cell recording mode, FPL 64176 produced a great lengthening of the channel open time, produced very long openings when the channels were repolarized after a depolarizing stimulus, and had only modest effects on mean closed times and on first latency distributions. FPL 64176 and Bay K 8644 also had minimal effects on L-type channel "on" gating currents, while the "off" gating currents were slowed, particularly at positive potentials. However, the effects on gating currents were too small to account for the prolonged tails observed in FPL 64176. Once the channel is open, FPL 64176 slows transitions to closed or inactivated channel states.

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

PubMed2003

C terminus L-type Ca2+ channel calmodulin-binding domains are 'auto-agonist' ligands in rabbit ventricular myocytes.

L-type Ca2+ channel C terminus calmodulin (CaM)-binding domains are molecular determinants for Ca(2+)-CaM-dependent increases in L-type Ca2+ current (ICa), and a CaM-binding IQ domain mimetic peptide (IQmp) increases L-type Ca2+ channel current by promoting a gating mode with prolonged openings (mode 2), suggesting the intriguing possibility that CaM-binding domains are 'auto-agonist' signalling molecules. In order to test the breadth of this concept, we studied the effect of a second C terminus CaM-binding domain (CB) mp (CBmp), in conjunction with IQmp, on single L-type Ca2+ channel currents in excised cell membrane patches from rabbit ventricular myocytes. Here we show that both CBmp and IQmp are agonist ligands that non-additively increase L-type Ca2+ channel opening probability (Po) by inducing mode 2 gating. CBmp and IQmp agonist effects were lost under conditions favouring calcification of CaM (Ca(2+)-CaM, 150 nM free Ca2+ and 10-20 microM CaM), but persisted in the presence of CaM (0-20 microM) under conditions adverse to Ca(2+)-CaM (20 mM BAPTA), indicating that CaM-binding domains increase L-type Ca2+ channel Po by a low Ca(2+)-CaM activity mechanism. Increasing Ca(2+)-CaM in the bath (cytosol) reduced the efficacy of CBmp and IQmp signals with Ba2+ as charge carrier, suggesting that CaM binding motifs target a site outside of the pore region. We measured the combined effects of CBmp and Ca(2+)-CaM-dependent protein kinase II (CaMKII) on L-type Ca2+ channels by using an engineered Ca(2+)-CaM-independent form of CaMKII that remains active under low Ca(2+)-CaM conditions, permissive for CBmp signalling. CBmp and CaMKII increased L-type Ca2+ channel Po in a non-additive manner, suggesting that low and high Ca(2+)-CaM-dependent L-type Ca2+ channel facilitation pathways converge upon a common signalling mechanism.

Amino Acid Sequence↗

PubMed1995

L- and N-type Ca2+ channels in adult rat carotid body chemoreceptor type I cells.

1. Whole-cell voltage-dependent Ca2+ currents recorded from chemoreceptor type I cells of the adult rat carotid body had maximum amplitudes of -94 pA in 10 mM Ca2+ and were half-inactivated at a holding potential of -38 mV. Somatostatin and dopamine inhibited whole-cell Ca2+ current in type I cells. 2. The dihydropyridine agonist (+)202-791 increased the Ca2+ current amplitude by 106% at a step potential of -18 mV. The dihydropyridine antagonist nimodipine decreased the Ca2+ current amplitude by 40% from a holding potential of -80 mV, and by 74% from a holding potential of -60 mV. The nimodipine-sensitive current had a maximum amplitude at a membrane potential of -12 mV. omega-Conotoxin GVIA (omega-CgTX GVIA) blocked the whole-cell Ca2+ current by 40%. The omega-CgTX GVIA-sensitive current had a maximum amplitude at a membrane potential of +2 mV. 3. In summary, type I cells of the adult rat carotid body have dihydropyridine-sensitive L-type and omega-conotoxin GVIA-sensitive N-type voltage-dependent Ca2+ channels. These channels may play a role in the voltage-gated entry of Ca2+ necessary for stimulus-secretion coupling in response to changes in arterial PO2, PCO2 and pH. Inhibition of the Ca2+ currents by somatostatin and dopamine may alter the chemotransduction signal in type I cells.

Animals↗

PubMed2002

Inhibitory effects of 1,4-DHP antagonists on synaptic GABA release modulated by BAY-K 8644 in mechanically dissociated rat substantia innominata.

The effects of dihydropyridine (1,4-DHP) agonist and antagonists on miniature inhibitory postsynaptic currents (mIPSCs) were investigated in mechanically dissociated rat substantia innominata neurons attached to native GABAergic presynaptic nerve terminals, namely 'synaptic bouton preparation', using nystatin perforated patch recording mode under voltage-clamp conditions. BAY-K 8644 (BAY-K), an L-type Ca(2+) channel agonist, reversibly and concentration dependently facilitated the GABAergic mIPSC frequency without altering the distribution of current amplitudes. Removal of extracellular Ca(2+) completely suppressed the facilitatory effect of BAY-K on mIPSC frequency. The facilitatory effect of BAY-K on mIPSC frequency was maintained even in the presence of selective N-, P- and Q-type Ca(2+) channel antagonists, such as 3 x 10(-6) M omega-conotoxin-GVIA (omega-CgTX-GVIA), 3 x 10(-8) M omega-agatoxin-IVA (omega-AgTX-IVA) and 3 x 10(-6)M omega-conotoxin-MVIIC (omega-CmTX-MVIIC). However, nicardipine (3 x 10(-6) M) and nimodipine (3 x 10(-6) M), 1,4-DHP antagonists, significantly inhibited the mIPSC frequency enhanced by BAY-K by 37 +/- 5 and 42 +/- 6%, respectively. These results suggest the possible existence of L-type Ca(2+) channels in GABAergic presynaptic nerve terminals.

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

PubMed1998

Activation of inositol 1,4,5-trisphosphate receptors induces transient changes in cell shape of fertilized Xenopus eggs.

Injection of inositol 1,4,5-trisphosphate (InsP3) into fertilized Xenopus eggs induced transient changes in cell shape. The region around the injected site contracted during the first 2 min, followed by swelling. These changes which initiated at the injected site extended toward the opposite side. Injection of adenophostin B, a potent InsP3 receptor agonist, also induced similar morphological changes, which suggested that InsP3 receptor activation, and not the action of InsP3 metabolites, is responsible for these changes. To determine whether these changes correlate to InsP3 receptor-mediated calcium release, we examined the morphological changes and those in intracellular free calcium concentrations ([Ca2+]i). A calcium wave was observed to precede the propagation of changes in cell shape by about 2 min. The extent of propagation of cell shape changes varied with the eggs but consistently depended on the extent of the calcium wave propagation. Changes in cell shape were inhibited in eggs injected with the calcium chelator, BAPTA, indicating that calcium released from the InsP3-sensitive calcium store is required for cell shape changes. During the cell shape changes, the contracted region was strongly stained with rhodamine-phalloidin, which suggests that structural changes of actin filaments are involved in the cortical changes. We propose that spatiotemporally controlled elevation of intracellular calcium induces successive cortical cytoskeletal changes that are responsible for changes in cell shape. These observations provide insight into the potency of InsP3/calcium signaling in the regulation of cortical cytoskeleton.

Actin Cytoskeleton↗

PubMedDate not supplied

[Effects of agonists and antagonists of rhyanodine receptors on potassium contractures in twitch and tonic frog skeletal muscle fibers].

A comparative analysis of the effects of the concentrations of Ca2+ in external medium and the inhibitor (dantrolene) and activator (4-chloro-m-cresol) of rhyanodine-sensitive Ca2+ channels of carcoplasmic reticulum on the characteristics of potassium contracture in frog twitch and tonic skeletal muscles has been performed. It was shown that the duration of contracture in tonic muscles is not restricted by the presence of Ca2+, as distinct from twitch muscles. Dandrolene does not practically affect the contractile responses of tonic fibres, and the concentration of cresol eliciting the contracture for tonic fibres is substantially higher (1 mM) than for twitch fibers (0.25 mM). In twitch fibers, the potassium contracture activated in the presence of cresol is comparable in amplitude and dynamics with the contracture under control conditions, and in tonic fibers a summing of responses without relaxation after the washing of excessive potassium is observed. This suggests that, in twitch fibers, the influx of Ca2+ can directly create the concentration sufficient for the maintenance of contraction, and in tonic fibers its involvement is mediated through the Ca(2+)-dependent activation of the beta-isoform of rhyanodine-sensitive channels.

Animals↗

PubMed1998

Calcium store depletion activates two distinct calcium entry pathways in secretory cells of the blowfly salivary gland.

Ca2+ influx into secretory cells of the intact salivary gland of the blowfly Calliphora erythrocephala elicited by the agonist 5-hydroxytryptamine (5-HT) or the Ca2+ uptake inhibitor thapsigargin was studied by using Fura-2 and digital fluorescence imaging and by recordings of the transepithelial potential. Application of saturating [5-HT] in the absence of Ca2+ (Ca2+o) from the bathing saline did not affect the initial Ca2+ transient but greatly attenuated the subsequent sustained Ca2+ elevation observed in the presence of Ca2+o demonstrating that the latter component of the [Ca2+]i response is largely dependent on Ca2+ entry across the baso-lateral plasma membrane. La3+ or Gd3+ (10 microM) mimicked the effects of the withdrawal of Ca2+o. Experimental attempts temporally to uncouple 5-HT stimulation and Ca2+ influx by withdrawal of Ca2+o during agonist application revealed a second Ca2+ entry pathway. This pathway was insensitive to 10 microM La3+ and produced transient [Ca2+]i increases whose amplitudes were a function of the [5-HT] during the preceding stimulation and that were selectively suppressed by 50 microM SK&F 96365. Both (10 microM) La(3+)-insensitive [Ca2+]i transients and (10 microM) La3+ inhabitable tonic [Ca2+]i increases could be sequentially activated in the presence of 5-HT or thapsigargin (1 microM). These results indicate that Ca2+ store depletion by 5-HT or thapsigargin activates two distinct store-operated Ca2+ entry pathways, one of which supports tonic [Ca2+]i increases. The other is transiently activated, even under conditions that prohibit store refilling and does not significantly contribute to the [Ca2+]i responses evoked by saturating 5-HT concentrations.

Animals↗

PubMed1991

Interactions of dihydropyridine Ca2+ channel agonists with the human platelet thromboxane A2/prostaglandin H2 receptor.

The specific interactions at the human platelet thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptor by four 1-4 dihydropyridine (DHP) agonists were studied. Using competition equilibrium binding assays with the TXA2/PGH2 receptor agonist [125I]BOP and the antagonist [125I]PTA-OH, the affinities of racemic BAY K 8644 (BAY), racemic CGP 28392 (CGP) and (+) and (-) SDZ 202-791 (SDZ) for the TXA2/PGH2 receptor were determined. The rank order potencies for competition were BAY greater than (-)SDZ greater than CGP greater than or equal to (+)SDZ. Bay, CGP and SDZ (stereoselectively) inhibited specific incorporation of the TXA2/PGH2 receptor photoaffinity probe [125I]PTA Azido into three proteins associated with the TXA2/PGH2 receptor with Mr of 43, 39 and 27 kDa as assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis autoradiography. Using the fluorescent Ca2+ probe Fura-2, it was observed that I-BOP failed to stimulate classical divalent cation channels. However, SDZ stereoselectively inhibited the rise in [Ca2+]i induced by I-BOP while not affecting that induced by thrombin. Although DHPs specifically and stereoselectively interact with the TXA2/PGH2 receptor on human platelets, the TXA2/PGH2 receptor-mediated rise in [Ca2+]i is not through stimulation of a classical divalent cation channel.

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

PubMed2002

L-type Ca(2+) currents overlapping threshold Na(+) currents: could they be responsible for the "slip-mode" phenomenon in cardiac myocytes?

Phosphorylation of Na channels has been suggested to increase their Ca permeability. Termed "slip-mode conductance" (SMC), this hypothesis predicts that Ca influx via protein kinase A (PKA)-modified Na channels can induce sarcoplasmic reticulum (SR) Ca release. We tested this hypothesis by determining if SR Ca release is graded with I(Na) in the presence of activated PKA (with Isoproterenol, ISO). V(m), I(m), and [Ca](i) were measured in feline (n=26) and failing human (n=19) ventricular myocytes. Voltage steps from -70 through -40 mV were used to grade I(Na). Na channel antagonists (tetrodotoxin), L-type Ca channel (I(Ca,L)) antagonists (nifedipine, cadmium, verapamil), and agonists (Bay K 8644, FPL 64176) were used to separate SMC from I(Ca,L). In the absence of ISO, I(Na) was associated with SR Ca release in human but not feline myocytes. After ISO, graded I(Na) was associated with small amounts of SR Ca release in feline myocytes and the magnitude of release increased in human myocytes. I(Na)-related SR Ca release was insensitive to tetrodotoxin (n=10) but was blocked by nifedipine (n=10) and cadmium (n=3). SR Ca release was induced over the same voltage range in the absence of ISO with Bay K 8644 and FPL 64176 (n=9). Positive voltage steps (to 0 mV) to fully activate Na channels (SMC) in the presence of ISO and Verapamil only caused SR Ca release when block of I(Ca,L) was incomplete. We conclude that PKA-mediated increases in I(Ca,L) and SR Ca loading can reproduce many of the experimental features of SMC.

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

PubMed2001

Contribution of L-type Ca(2+) channels to evoked transmitter release in cultured Xenopus nerve-muscle synapses.

1. Simultaneous pre- and postsynaptic patch recordings were obtained from the varicosity synapses formed by Xenopus motoneurons on muscle cells in embryonic cultures, in order to elucidate the contribution of N- and L-type Ca(2+) channels to the varicosity Ca(2+) current (I(Ca)) and evoked transmitter release. 2. Although N-type channels are predominant in the varicosities and generally thought to be responsible for all evoked release, in most synapses a fraction of I(Ca) and release could be reversibly blocked by the L-type channel antagonist nifedipine, and enhanced by the agonist Bay K8644. Up to 50 % (mean, 21 %) of the I(Ca) evoked by a voltage clamp waveform mimicking a normal presynaptic action potential (APWF) is composed of L-type current. 3. Surprisingly, the nifedipine-sensitive (L) channels activated more rapidly (time-constant, 0.46 ms at +30 mV) than the nifedipine-insensitive (N) channels (time constant, 1.42 ms). Thus the L-type current would play a disproportionate role in the I(Ca) linked to a normal action potential. 4. The relationship between I(Ca) and release was the same for nifedipine-sensitive and -resistant components. The N- and L-components of I(Ca) are thus equally potent in evoking release. This may represent an immature stage before N-type channels become predominant. 5. Replacing Ca(2+) in the medium with Ba(2+) strongly enhanced the L-type component, suggesting that L-type channels may be inactivated at Ca(2+) levels close to those at rest. 6. We speculate that populations of L-type channels in different parts of the neuron may be recruited or inactivated by fluctuations of the cytosolic Ca(2+) concentration within the physiological range.

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

PubMed1999

Type 1 iodothyronine deiodinase in heart --effects of triiodothyronine and angiotensin II on its activity and mRNA in cultured rat myocytes.

We previously demonstrated that iodothyronine 5'-deiodination (5'D) activity is present and increased by triiodothyronine (T3) and angiotensin II (Ang II) in cultured rat cardiac myocytes. To further elucidate the stimulatory mechanism of Ang II, we investigated the effect of intracellular Ca2+ and protein kinase C on myocardial 5'D activity. Moreover, to elucidate the molecular mechanism of the stimulatory effect of T3 and Ang II, we detected the mRNA levels by means of a reverse-transcriptase polymerase chain reaction (RT-PCR). 5'D activity was increased by adding Bay-k 8644, Ca2+ channel agonist and the effect of Bay-k 8644 was completely blocked by nifedipine, a Ca2+ channel antagonist. 12-O-tetradecanoylphorbol-13-acetate, a protein kinase C activator, similarly stimulated 5'D activity. The addition of a high concentration (20-40 mM) of K+, which caused the depolarization of the membrane had significant stimulatory effects on 5'D activity. Type 1 deiodinase (D1) mRNA was evident in myocardial cells by RT-PCR in a single 758 bp band similar to that in the liver. Cardiac fibroblasts did not express the D1 mRNA. A significant increase in D1 mRNA was also evident after adding T3 and Ang II. These findings indicate that 5'D activity in myocardial cells is increased by activating the voltage sensitive Ca2+ channel, protein kinase C, and membrane depolarization, and that the D1 mRNA is present in cardiac myocytes and is increased by T3 and Ang II. This study therefore suggests that Ang II could affect the action of thyroid hormone on the heart by increasing the D1 gene expression.

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

PubMed1993

Influence of Ca2+ channel agonists and antagonists on the post-rest staircase.

It is now generally accepted that the post-rest staircase consists of two phases, an initial fast phase occurring over the first five to six beats followed by a slow phase which occurs over a period of minutes. In this study, the influence of Ca2+ channel antagonists (Cd2+ and nifedipine) and agonists (Bay K 8644 and noradrenaline) on developed tension is investigated to assess the role played by the L-type Ca2+ current (iCa) during post-rest recovery. The results show that, at a range of stimulus frequencies, exposure of guinea-pig papillary muscles to either Cd2+ or nifedipine greatly reduces the fast phase of the staircase and reduces the slow phase of the staircase compared to control (both effects being more prominent at higher stimulus frequencies). Exposure of guinea-pig papillary muscles to Bay K 8644 or noradrenaline potentiated both the fast and slow phases of the staircase with greater proportionate effects observed at higher stimulus frequencies. These results suggest that iCa plays an important role in both phases of the staircase. The first post-rest beat (the rested state contraction) proved very resistant to Ca2+ channel blockade suggesting that iCa plays little role in this contraction which may be the result of entry of Ca2+ into the cell via a relatively Cd2+ insensitive pathway, for example the Na(+)-Ca2+ exchanger.

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

PubMed1996

Anti- and proconvulsive actions of levcromakalim, an opener of ATP-sensitive K+ channel, in the model of hippocampus-generating partial seizures in rats.

We assessed the effect of an opener of ATP-sensitive K+ channel, levcromakalim (BRL 38227, (-)6-cyano-3,4-dihydro-2, 2-dimethyl-trans-4-(2-oxo-1-pyrrolidyl)-2H-1-benzopyran-3-ol) on seizure threshold and severity of the hippocampus-generating partial seizures in rats. For comparison, an ATP-sensitive K+ channel blocker, glibenclamide; K+ channel blocker, tetraethylammonium; Ca2+ channel antagonist, nimodipine and Ca2+ channel agonist, (+/-)-BAY K 8644 (1,4-dihydro-2, 6-dimethyl-5-nitro-4-[2-(trifluoromethyl)-phenyl]-3-pyridinecarboxyli c acid methyl ester) were also examined. Seizure threshold was determined using pulse number threshold and seizure severity was ascertained using afterdischarge duration. Levcromakalim decreased afterdischarge duration at 10 nmol i.c.v. and decreased pulse number threshold at 100 nmol i.c.v. Tetraethylammonium at 10 nmol i.c.v. increased afterdischarge duration selectively and at 100 nmol i.c.v. induced spontaneous seizures. Glibenclamide (1-100 nmol i.c.v.) failed to change pulse number threshold and afterdischarge duration. Nimodipine (40 mg/kg i.p.) decreased afterdischarge duration and pulse number threshold. BAY K 8644 (1 mg/kg i.p.) decreased pulse number threshold and increased afterdischarge duration. In addition, voltage-clamp recording from neuroblastoma x glioma hybrid cells indicates that levcromakalim inhibited the fast component of Ca(2+)-dependent K+ currents, in addition to the inhibition of T- and L-types of voltage-dependent Ca2+ currents reported (Ito et al., FEBS Lett. 262, 313, 1990). These results suggest that levcromakalim shows anti- and proconvulsive actions in the hippocampus-generating partial seizures in rats and these effects might be, at least partly, caused by inhibiting Ca2+ channel and Ca(2+)-dependent K+ channel, respectively.

Adenosine Triphosphate↗

PubMed1999

1-Ethyl-2-benzimidazolinone stimulates endothelial K(Ca) channels and nitric oxide formation in rat mesenteric vessels.

Hyperpolarization of most blood vessels occurs by the opening of K(Ca) channels. 1-Ethyl-2-benzimidazolinone (1-EBIO) is a direct activator of K(Ca) channels in epithelial cells and is potentially valuable for studying cellular hyperpolarization. This study reports the effects of 1-EBIO on isolated rat mesenteric beds perfused with normal (4.7 mM), or high (20 or 80 mM) K+ physiological salt solution (PSS) and constricted with an alpha1-adrenoceptor agonist, cirazoline (0.3-1 microM). Arterial perfusion pressures were decreased by 1-EBIO (0.1-30 nmol) in a dose- and endothelium-dependent manner. Infusion of penitrem A (100 nM), a maxi-K+ channel blocker, or apamin (0.5 microM), a small-conductance (SK(Ca)) K+ channel blocker, produced significant increases in cirazoline-mediated tone (mm Hg): 103.3 +/- 8.7 (control) vs. 156.3 +/- 14.3 (penitrem A); or 93.0 +/- 15.8 (control) vs. 114.0 +/- 15.4 (apamin). 1-EBIO relaxations were attenuated by penitrem A, while apamin, dendrotoxin (50 nM; a Kv channel antagonist), or ouabain (100 microM; a sodium pump blocker) failed to alter the responses. I-EBIO-mediated relaxations decreased significantly with increasing extracellular [K+]: relaxations to 30 nmol were 89.3% +/- 3.2% (4.7 mM K+, normal PSS) vs. 59.5% +/- 3.4% and 19.0% +/- 3.9% for 20 and 80 mM K+ PSS, respectively. Nomega-nitro-L-arginine-methyl ester (L-NAME; 100 microM), and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 10 microM), selective inhibitors of nitric oxide synthase, and nitric oxide-sensitive guanylate cyclase, respectively, abolished 1-EBIO relaxations in vessels perfused with 20 or 80 mM K+ PSS. We conclude that: (1) maxi-K+ and SK(Ca) channels are present in rat mesenteric arterial vessels and actively contribute to vascular tone, (2) vasodilator action of 1-EBIO involves the opening of endothelial maxi-K+ channels and nitric oxide synthesis.

Acetylcholine↗

PubMed1985

Differential antagonism by Bay k 8644, a dihydropyridine calcium agonist, of the negative inotropic effects of nifedipine, verapamil, diltiazem and manganese ions in canine ventricular muscle.

Antagonism between either the dihydropyridine calcium agonist, Bay k 8644, or high external Ca2+ and the calcium antagonists, nifedipine, verapamil and diltiazem, and Mn2+ was investigated in canine isolated ventricular trabeculae. Bay k 8644 (10(-7)-10(-5)M) produced a slowly developing increase in developed tension which reached a maximum at 10(-6)M. A small decrease in the positive inotropic effect of Bay k 8644 at 10(-5)M was probably due to the negative inotropic effect of the solvent, 0.5% ethanol. Bay k 8644 (10(-7)-10(-5)M) produced a rightward parallel shift of the concentration-response curves for the negative inotropic effects of nifedipine (10(-8)-10(-5)M) and verapamil (10(-7)-3 X 10(-5)M). The slopes of the Schild plots were -0.92 for nifedipine (pA2 value = 6.58) and -0.48 for verapamil. Bay k 8644 (10(-6) and 10(-5)M) produced only a slight rightward shift of the concentration-response curves for the negative inotropic effect of diltiazem (10(-7)-3 X 10(-5)M) and did not affect the negative inotropic effect of Mn2+ (10(-4)-10(-2)M). Addition of 2.5 X 10(-3)M Ca2+ (5.05 X 10(-3)M Ca2+) to the medium produced a greater maximum positive inotropic effect than Bay k 8644. The concentration-response curves for the negative inotropic effects of nifedipine, verapamil and diltiazem obtained under these conditions were not essentially different from those under control conditions (2.55 X 10(-3)M Ca2+). 6 These results indicate that Bay k 8644, while producing a positive inotropic effect, antagonizes the negative inotropic effect of nifedipine by competing with the latter for the same site closely associated with the calcium channel. In contrast, Bay k 8644 antagonizes the negative inotropic effects of verapamil and diltiazem by interfering allosterically with the binding of these calcium antagonists to their sites of action. Bay k 8644 does not antagonize the negative inotropic effect of Mn2+. No pharmacological antagonism was observed between the three organic calcium antagonists and high external Ca2+_

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