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PubMed1987

Inhibition by quinine of endothelium-dependent relaxation of rabbit aortic strips.

1 The effects of quinine sulphate, tetramethylammonium chloride (TMA) and tetraethylammonium chloride (TEA) (all blockers of the Ca2+-activated K+ channels) on the relaxations induced by acetylcholine (ACh), calcium ionophore A23187 and sodium nitrite were studied in helical strips of rabbit aorta. 2 The strips were contracted to a moderate stable tone with phenylephrine (10(-7) M). ACh (4 X 10(-9) to 10(-6) M) as well as A23187 (10(-8) to 3 X 10(-7) M) reduced this tone in a concentration- and endothelium-dependent manner. 3 Pretreatment of the tissues with quinine (2.5 X 10(-5) to 10(-4) M) for 60 min produced a concentration-dependent inhibition of the relaxation induced by ACh. Also 90 min incubation of the strips with TMA (3 X 10(-3) to 6.5 X 10(-2) M) or TEA (10(-3) to 3 X 10(-2) M) inhibited the ACh-evoked relaxation in a manner similar to quinine. 4 Quinine (10(-4) M, 60 min), TMA (6.5 X 10(-2) M, 90 min) or TEA (3 X 10(-2) M, 90 min) produced 5 to 10 fold reductions in the relaxant EC50 values of A23187 and ACh and depressed (by 40 to 95%) the maximal relaxations to the ionophore and ACh. 5. On a molar basis, quinine was more effective than the two tetraalkylammonium ions in reducing the endothelium-dependent relaxations of the aortic strips induced by ACh or A23187. The inhibitory actions were reversible after 60 to 90 min washout. 6. Exposure of the strips to either quinine (10-4M, 60 min), TMA (6.5 x 10-2 M, 90 min) or TEA (3 X 10-2 M, 90 min), however, did not influence significantly the relaxations evoked by sodium nitrite, a direct smooth muscle relaxant. 7. These results suggest that stimulation of the Ca2+-activated K' channels could be, at least partially, responsible for the endothelium-dependent relaxations induced by ACh or A23 187. Their activation might not be required for the endothelium-independent relaxant effects of sodium nitrite.

4-Aminopyridine↗
PubMed1992

In vitro denervation of the rat vas deferens through hypothermic storage.

1. The rat vas deferens was excised, stored at 4-6 degrees C and tested after 24, 48, 72 or 96 h for its contractile activity and for the presence of innervation. 2. The maximal contractile capacity of the vas, tested through cumulative concentrations of barium chloride (3 x 10(-2) M) was progressively reduced from about 110 mm to about 63 mm after 72 h, without further decay after 96 h. Spontaneous rhythmic contractions were practically absent. 3. A loss of endogenous pools of catecholamines was indicated by four parameters: (a) a decline of about 80% after 24 h and of more than 95% after 48 h of the contractile effect of the indirect sympathomimetic agonist tyramine; (b) a fall of about 20%, 50% and 85% on the concentration of noradrenaline, respectively after 24, 48 and 72 h; (c) a fall of about 25% and 90% after respectively 24 and 48 h, of the activity of dopamine-beta-hydroxylase (DBH); (d) a decline of noradrenaline-induced histofluorescence on cross sections of the vas. 4. A loss of neuronal uptake capacity was indicated by: (a) a progressive variation of the apparent affinity for adrenaline, expressed as pD2 values, that increased by about 1.5 log units (corresponding to a 30 fold potentiation) after 72 h, and (b) a reduction of the ability of cocaine to potentiate the contractile effects of adrenaline. 5. The pD2 values for barium chloride, 5-hydroxytryptamine (5-HT) and histamine were not significantly changed, while the corresponding value for acetylcholine was slightly but significantly reduced by about 0.8 log units. 6. The maximal heights of concentration-response curves for noradrenaline, acetylcholine, histamine and 5-HT were reduced by 42-66% in relation to controls. However, when this reduction was measured in relation to the corresponding barium effect, by means of the relative responsiveness ratio (p), a small though significant increase was observed for noradrenaline, and a fall for the other drugs.7. It is concluded that: (1) the values for the various biochemical and pharmacological parameters decline at different rates, though revealing altogether that denervation is completed by at least 85% after 72 h of hypothermic storage; (2) two of the results, i.e., the lack of spontaneous rhythmic contractions and the lack of increased contractile effects for acetylcholine, 5-HT and histamine, indicate that in these conditions the vas is devoid of the so-called nonspecific signs of denervation.

Acetylcholine↗
PubMed1992

Effects of K+ channel blockers on the action potential of hypoxic rabbit myocardium.

1. In order to assess the role of different ionic currents in hypoxia-induced action potential shortening, we investigated the effects of blockers of voltage-dependent and ATP-sensitive K(+)-channel on the membrane potential of hypoxic rabbit hearts and papillary muscles. The response to blocking of the inward rectifier was studied at three external K+ concentration: 2.5, 5, and 7.5 mM. 2. Hypoxia produced a progressive decline in action potential duration (APD) that levelled off after 15 to 20 min. Steady state APD values at 25% and 95% repolarization (APD25 and APD95) were 26.0 +/- 1.9% and 42.2 +/- 2.4% of controls respectively. 3. Tetraethylammonium (TEA, 10 mM) delayed but did not reduce APD shortening at the steady state. 4. Blocking of IK1 with a mixture of 0.2 mM Ba2+ and 4 mM Cs+ lengthened APD in normoxia and prevented APD95 shortening in hypoxia. The APD25 shortening was significantly attenuated at all [K]o. 5. Glibenclamide (Glib, 30 microM) did not prevent APD shortening, but produced a progressive action potential (AP) lengthening after 15 min of hypoxia. Steady levels of 48 +/- 3.5% and 62 +/- 5.0% of controls for APD25 and APD95 respectively were reached after 45 min. 6. The relation between APD25 and pacing rate was determined in normoxic and hypoxic papillary muscles and the effects of 2 mM 4-aminopyridine (4-AP) were examined. Hypoxia attenuated the APD25 shortening currently observed when the stimulation rate was lowered from 1 to 0.1 Hz without altering the plateau reduction occurring at frequencies above 2 Hz. These effects were potentiated by 4-AP.7. Our data suggest that the accelerated AP repolarization in hypoxic rabbit myocardium represents a delicate balance of several outward currents: IKI, IK-ATP. and at least one yet unidentified current component rather insensitive to changes in [K]o and to K+ channel blockers.

Action Potentials↗
PubMed1993

Electrophysiological actions of alfentanil: intracellular studies in the rat locus coeruleus neurones.

1. The electrophysiological effects of alfentanil on 156 neurones of the rat locus coeruleus were investigated by use of intracellular recordings from the in vitro brain slice preparation. 2. Bath application of alfentanil (5-100 nM) reversibly decreased the firing rate of all neurones tested in a dose-dependent manner, with an IC50 4.1.nM. 3. Based on inhibition of the spontaneous firing rate, alfentanil was 22 times more potent than morphine. 4. At 100 nM, alfentanil produced a complete inhibition of firing of all neurones tested (n = 62); the inhibition was accompanied by a membrane hyperpolarization 17.0 +/- 0.8 mV (range 6.1-30.3 mV, n = 62) and a reduction in input resistance 26.4 +/- 1.7% (range 6.5-53%, n = 51). 5. The effects of alfentanil were antagonized by naloxone, with a dissociation equilibrium constant of 2.7 +/- 0.4 nM (n = 6). 6. The reversal potential for the alfentanil-induced hyperpolarization was -110 +/- 2 mV (n = 9), which is approximately the potassium equilibrium potential. 7. The alfentanil-induced hyperpolarization was blocked by caesium chloride and barium chloride. 8. These results indicate that alfentanil binds to mu-opioid receptors on the cell membrane of neurones of the locus coeruleus. This leads to opening of the inward-going rectification potassium channels, resulting in the observed hyperpolarization of the membrane.

Alfentanil↗
PubMed1995

BaCl2- and 4-aminopyridine-evoked phasic contractions in the rat vas deferens.

1. The actions of BaCl2 and 4-aminopyridine, blockers of K+ channels, on the mechanical activity of the epididymal half of the rat vas deferens were investigated. 2. Both BaCl2 and 4-aminopyridine dose-dependently evoked phasic contractions. High extracellular potassium (35-40 mM) caused a tonic contraction but abolished the BaCl2- and 4-aminopyridine-induced phasic activity and reduced the BaCl2-induced sustained component of contraction, but increased the 4-aminopyridine-induced tonic contraction. 3. Omission of calcium from the extracellular medium totally abolished the 4-aminopyridine-induced response but only reduced the mean amplitude of phasic contractions induced by BaCl. 4. Procaine (10 mM), an inhibitor of internal calcium release, completely abolished the phasic activity and reduced the sustained contraction induced by BaCl2. The remaining tone was abolished by nifedipine (1 microM). 5. Tetraethylammonium (1 mM) suppressed the amplitude of the BaCl2-induced phasic contractions, and induced a biphasic increase in tonic tension. 6. The BaCl2-induced responses were resistant to prazosin (1 microM), yohimbine (3 microM), propranolol (3 microM) or atropine (3 microM); in contrast, the 4-aminopyridine-induced activity was effectively inhibited by prazosin (1 microM) attenuated by yohimbine (1 microM) and atropine (1 microM) but not by propranolol (3 microM). The 4-aminopyridine-induced response was abolished by pretreatment of the vas deferens with 6-hydroxydopamine (0.5 mM). 7. The results indicate that the BaCl2-evoked activity in the vas deferens was mainly due to blockade of Ba(2+)-sensitive K+ channels on the smooth muscle plasma membrane. Subsequent calcium entry through the depolarized plasma membrane was needed to trigger generation of phasic contractions. 4-Aminopyridine-induced action, however, was largely mediated by neurotransmitters released from the depolarized nerve terminals as a result of blockade of K+ channels.

4-Aminopyridine↗
PubMedDate not supplied

Endothelium-dependent and -independent coronary relaxation induced by urocortin.

Urocortin, a newly identified polypeptide, possesses cardiac effects. However, the underlying mechanism of its coronary action is still unclear. In the present study we investigated the possible role of endothelial nitric oxide and Ba2+-sensitive K+ channels in the endothelium-dependent relaxant response to urocortin in the isolated rat left anterior descending coronary arteries. Changes of vessel tone were measured in microvessel myographs. Urocortin produced both endothelium-dependent and -independent relaxation with IC50 of 2.52 nM and 16.5 nM, respectively. Denuation of endothelium decreased the relaxing potency of urocortin. In the endothelium-intact rings pretreated with 100 microM N(G)-nitro-L-arginine methyl ester (L-NAME) or 10 microM 1H-[1,2,4]oxadiazolo[4,2-alpha]quinoxalin-1-one (ODQ), the urocortin-induced relaxation was similar to that observed in endothelium-denuded rings. The relaxant response to urocortin was markedly reduced in endothelium-intact rings preconstricted by 35 mM K+. Pretreatment with 100 microM BaCl2 significantly reduced urocortin-induced relaxation without an effect on the maximum relaxation. Combined treatment with BaCl2 plus L-NAME did not produce additive inhibition. In contrast, BaCl2 did not alter urocortin-induced relaxation in the endothelium-denuded rings. In the endothelium-denuded rings, BaCl2 at 100 microM also inhibited nitric oxide donor-induced relaxation. In conclusion, our results suggest that urocortin-induced endothelium-dependent relaxation of rat coronary arteries is primarily mediated by endothelial nitric oxide and subsequent activation of Ba2+-sensitive K+ channels. The urocortin-induced endothelium-dependent relaxation appears to be cyclic GMP-dependent.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1997

The effect of comonomer composition, silane heating, and filler type on aqueous TEGDMA leachability in model resin composites.

Experimental composites using either bisGMA/TEGDMA or UEDMA/ TEGDMA matrices, quartz or barium glass fillers, and 2 different filler silanization methods were evaluated regarding monomer leachability in distilled water. The leached amount was detected and quantified using gas chromatography. The results showed that twice as much TEGDMA is leached from a bisGMA/TEGDMA based composite than from an UEDMA/ TEGDMA based composite, when both contain 50 wt% TEGDMA. The hypothesis suggested that the higher degree of cure of UEDMA/TEGDMA based composites would be reflected in a lower monomer leaching value, and this hypothesis was supported by the findings. Whether such a correlation exists within groups of UEDMA/TEGDMA based matrices having different degrees of cure was not determined and needs to be investigated in future studies. Variables such as filler composition and silane treatment did not affect the leaching values of TEGDMA in water. That finding suggests that future studies should target differences in matrices, and that the need for considering effects of filler composition and silane treatment methods should not receive the same priority.

Analysis of Variance↗
PubMed1999

Drying and rewetting anterior crown fragments prior to bonding.

Fractured anterior teeth can be restored by adhesive bonding of the fragment to the remaining tooth structure. This in vitro study describes the effect on fracture strength of fragments dried and rewetted for various periods of time prior to bonding. Seventy central incisors from sheep were fractured. The resulting incisal crown fragments were then stored in air at room temperature at ambient humidity (70 +/- 16%) for 5 s, 30 min, 1 h, 3 h, 6 h, 12 h, or 24 h. The apical parts of the fractured teeth were stored in water. After storage in air each fragment was then bonded to the matching apical tooth structure with a bonding agent and a low-viscosity composite resin. After water storage for 2 days, mean fracture strength was measured. Another group of teeth comprising 40 sheep central incisors was fractured and the fragments were stored in air at room temperature for 24 h as above. The fragments were then immersed in water for 10 min, 1 h, 1 day, or 7 days, prior to bonding and measurement as described above. Statistical analysis revealed that the fracture strength of the fragment-bonded teeth was unaffected by air storage of the fragment for up to 1 h prior to bonding, after which additional drying resulted in decreased fracture strength. Fragments dried for 24 h in air and rewetted by immersion in water for at least 1 day were fragment-bonded without loss of fracture strength.

Analysis of Variance↗
PubMed2006

Efflux of potassium ion is an important reason of HL-60 cells apoptosis induced by tachyplesin.

AIM: To investigate the role of intercellular potassium in tachyplesin-induced HL-60 cells apoptosis. METHODS: The concentration of intercellular potassium, cell volume and mitochondrial membrane potential were examined by flow cytometry. RESULTS: The concentration of intercellular potassium reduced in a time-dependent manner in tachyplesin-treated HL-60 cells. In addition, the loss of mitochondrial membrane potential was tightly coupled with the shrinkage of cell volume. Different caspase inhibitors protected against DNA degradation but did not prevent the loss of HL-60 cell viability induced by tachyplesin. Ba2+, which was a kind of blocker of volume-regulatory K+ channels, increased the viability of tachyplesin-treated HL-60 cells and maintained mitochondrial membrane potential and cell volume. CONCLUSION: Efflux of K+ was an important reason for apoptosis in tachyplesin-treated HL-60 cells. Efflux of K+ affected the viability of tachyplesin-treated HL-60 cells independent of the process of caspase activation.

Amino Acid Chloromethyl Ketones↗
PubMed1985

Possible mechanisms of inhibitory action of protamine on contractile activity of rat aorta.

Experiments were performed to determine possible mechanisms of inhibitory action of protamine chloride on noradrenaline (10 microM)-, KCl (40 mM)-, BaCl2 (1 mM)- and CaCl2 (10 mM)-induced contractions in rat aorta. Protamine, La3+ and gallopamil (D600), inhibited the K+-induced contractions more effectively than the noradrenaline-induced responses on the basis of the concentrations giving 40% inhibition. Lanthanum (1-5 mM) reduced tissue Ca content in both normal and Ca2+-depleted Tris-buffered solutions and produced an increase in 45Ca efflux from the aortic strip into the Ca2+-depleted Tris solution. Protamine (1-5 mg ml-1) reduced tissue Ca content in normal Tris solution, but to a lesser extent than La3+ in the Ca2+-depleted solution. Furthermore, protamine (3 mg ml-1) produced no increase in 45Ca efflux from aorta. These results suggest that protamine chloride may preferentially inhibit the Ca2+ influx stimulated by K+ depolarization and that its inhibitory action on rat aorta may be due to non-specific displacement of the superficially located bound Ca2+ of the cell membrane, which can also be readily removed by treatment with Ca2+-depleted solution.

Animals↗
PubMed1990

Relaxant effects of alpha-adrenoceptor agonists in the rat isolated gastric fundus.

In rat gastric fundus preparations with tone raised by the addition of barium chloride or carbachol, and in the presence of propranolol (2 microM) to prevent beta-adrenoceptor mediated effects, the adrenoceptor agonists noradrenaline, adrenaline, alpha-methylnoradrenaline, isoprenaline, cirazoline and phenylephrine all caused concentration-related relaxant responses. Relaxations to the catecholamines were poorly antagonized by prazosin (0.01-1 microM) resulting in the slopes of Schild plots being less than unity, low pA2 values for prazosin against the catecholamines and a clear relaxant effect of the catecholamines even in the presence of 1 microM prazosin. The prazosin-resistant relaxations were unaffected by higher concentrations of prazosin (2 microM) and propranolol (30 microM) or by further additions of idazoxan (1 microM) or haloperidol (30 microM). The relaxations were not due to a non-specific effect of the catechol nucleus since neither dihydroxyphenylethylene glycol (DOPEG) nor dihydroxyphenylacetic acid (DOPAC) produced relaxant effects at concentrations up to 300 microM. In contrast to the results with the catecholamines, prazosin was a potent antagonist of the relaxant effect of cirazoline and phenylephrine, although the antagonism was difficult to quantify due to a lowering of the slope of the concentration response curves to cirazoline and phenylephrine with the higher concentrations of prazosin (0.1 and 1.0 microM). In conclusion postjunctional relaxatory effects of catecholamines in the rat gastric fundus are mediated partly via alpha 1-adrenoceptors and partly via an atypical adrenoceptor.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1988

Sodium-depletion-induced contractures in isolated rat vas deferens: possible role of endogenous catecholamines.

The mechanism involved in the development of contracture in an isolated smooth muscle in Na+-depleted saline solution is not clearly understood. Whereas most of the reported studies attribute it to direct myogenic action of Na+ depletion, a few suggested the contracture to be an indirect mechanism through the release of the neurotransmitter from presynaptic nerve endings. The present study employed rat vas deferens and it showed that the slowly developing contracture in Na+-depleted saline solution was blocked by prior treatment with in vitro prazosin and in vivo reserpine. Prior exposure of the tissue to verapamil caused the development of rhythmic contractions in Na+-free medium and these rhythmic contractions were blocked by prazosin. Exposure of the tissue to a Ca2+-free solution abolished the contractures induced by Na+-free solution. Na+-depletion increased the sensitivity of the vas deferens to exogenous noradrenaline. It is concluded that the contractures induced by Na+ depletion result from the stimulation of postjunctional alpha-adrenoceptors by endogenously released catecholamines from the adrenergic nerve terminals innervating the vas deferens smooth muscle. Further, these contractures result from an influx of extracellular Ca2+ through both voltage-dependent and receptor-operated calcium channels.

Animals↗
PubMed1983

The effect of barium chloride on intestinal secretion in the rat.

The addition of BaCl2 to the serosal solution, at concentrations from 0 X 25 mM to 10 mM, caused increases in potential difference, short-circuit current and resistance across stripped sheets of rat mid-intestine, although mucosal application had little effect. The response to BaCl2 was significantly greater than that obtained with the same concentration of CaCl2. An increase in net Cl- secretion entirely accounted for the rise in short-circuit current induced by BaCl2. BaCl2 inhibited net fluid uptake by everted sacs. It also enhanced the accumulation of fluid by intestinal loops in vivo and this was associated with an increased potential difference. The response to BaCl2 in vitro was not reduced in the absence of serosal Ca2+ ions. The effect of BaCl2 was abolished by trifluoperazine and also by TMB-8 (8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate hydrochloride). BaCl2 did not alter cyclic AMP production by isolated enterocytes. It is concluded that BaCl2 induces intestinal secretion by releasing Ca2+ from intracellular stores which then combines with calmodulin to stimulate the secretory process.

Animals↗
PubMed1983

The intracellular pH of frog skeletal muscle: its regulation in isotonic solutions.

The behaviour of intracellular pH (pHi) was studied with micro-electrodes in frog semitendinosus muscle which was superfused with Ringer solution and with depolarizing solutions. The electrodes were introduced into the depolarized muscle about 40 min after contracture had subsided. All studies were done at external pH (pHo) of 7.35 and at 22 degrees C. The pHi in normal Ringer solution buffered with HEPES was 7.18 +/- 0.03 (S.E. of mean) (n = 10); the membrane potential, Vm, was -88 +/- 1.8 mV. When pHi was lowered to about 6.8 by replacing the HEPES by 5% CO2, 24 mM-HCO3 (constant pHo), it recovered at a very slow rate of 0.025 +/- 0.011 delta pHi h-1 (n = 6). When all the Na was replaced by N-methyl-D-glucamine (initial pHi 7.20 +/- 0.04, initial Vm -89 +/- 1.5 mV, n = 8), this slow alkalinization was converted into a slow acidification at a rate of 0.069 +/- 0.024 delta pHi h-1. In muscle depolarized in 15 mM-K (Vm approximately -50 mV), the rate of recovery from CO2 acidification was not increased above that in normal Ringer solution (2.5 mM-K). When, however, the muscle was depolarized in 50 mM-K to about -20 mV, the rate of recovery increased to 0.33 +/- 0.07 delta pHi h-1 (n = 6) when external Cl was kept constant, or to 0.21 +/- 0.03 (n = 9) when [K]. [Cl] product was kept constant. In the absence of Na, pHi recovery rate in 50 mM-K was reduced by at least 90%. Enhanced recovery from CO2-induced acidification was also observed in 2.5 mM-K when the fibres were depolarized to about -20 mV in one of two ways: (a) by previous exposure for 60 min to 50 mM-K at constant Cl, or (b) by reduction of external Cl to 5.9 mM in the presence of 0.5 mM-Ba. When pHi of depolarized fibres (50 mM-K) was lowered to about 6.8 by the weak acid dimethyl-2,4-oxazolidinedione (DMO), it recovered at a rate of 0.12 delta pHi h-1 in two experiments. In fibres depolarized in 50 mM-K and constant Cl, either 0.1 mM-SITS or 0.5 mM-amiloride slowed pHi recovery from CO2 exposure by about 50%. When the depolarization was achieved at constant [K]. [Cl] product, amiloride slowed pHi recovery by about 50%, while SITS had, at most, only a slight effect.(ABSTRACT TRUNCATED AT 400 WORDS)

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗
PubMed1985

The secretory action of barium chloride in rat colon.

BaCl2, applied serosally, caused a rise in the p.d. and short-circuit current (s.c.c), and a decrease in tissue resistance in stripped sheets of rat colon. This response was dose dependent. Mucosal application of BaCl2 was without effect. The BaCl2-induced rise in s.c.c. was inhibited by reducing the serosal Na+ concentration to 25 mM. Lowering the mucosal Na+ concentration was without effect. Ouabain (10(-3) M in serosal fluid) and furosemide (10(-3) M in serosal fluid) both reduced the rise in s.c.c. induced by BaCl2. Flux determinations indicated that BaCl2 inhibited Na+ absorption and stimulated Cl- secretion by the colon. In vivo, BaCl2 increased fluid accumulation within the colonic lumen, an effect that was associated with a rise in the transcolonic p.d. Increasing the serosal K+ concentration to 20 mM reduced the responses to BaCl2, acetylcholine and theophylline, and this could not be entirely accounted for by the concomitant reduction in the serosal Na+ concentration. As high serosal K+ did not mimic the secretory response it would appear that BaCl2 does not act by blocking K+ channels. The rise in s.c.c. induced by BaCl2 was not reduced by Ca2+-free conditions, but it was inhibited by 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate hydrochloride (TMB-8) and trifluoperazine. BaCl2 did not alter cyclic AMP production by colonic scrapes. It is concluded that BaCl2 induces colonic secretion by the release of intracellular Ca2+, which then combines with calmodulin to activate the secretory process.

Action Potentials↗
PubMed1990

A study of the developmental changes in outward currents of rat ventricular myocytes.

1. In ventricular muscle of rat heart, the action potential undergoes a major developmental change in shape in the days and weeks immediately after birth. Potassium (K+) currents which may affect the shape of the action potential have been studied using a whole-cell voltage-clamp technique with single cells from the ventricles of rats aged 1-10 days. All recordings were made at 22-23 degrees C. 2. Three discrete ages were chosen. 1-day (cells isolated within 24 h of birth), 5-day and 10-day rats. These parallel the developmental action potential shortening from neonatal towards adult type. Action potentials of single myocytes were initially of long duration at 1 day with a prominent plateau phase, but had shortened somewhat by 10 days of age. The 5-day group exhibited an action potential transitional in character between the earlier and later groups of cells. 3. Potassium current blocking agents were used to assess the importance of the various outward K+ currents for the action potential waveform at different ages. 4-Aminopyridine (4-AP; 2 x 10(-3) M) which preferentially blocks voltage-activated transient outward currents affected action potentials at all ages, but increases in duration were most pronounced in the 10-day group. Only a small prolongation of the initial phase of repolarization of 1-day action potentials was seen. Extracellular barium chloride, 0.1-2 x 10(-3) M, a blocker of inwardly rectifying potassium channels, had a marked slowing effect on repolarization in all the three age groups. Resting membrane depolarization was also produced by barium. 4. Developmental changes in the inwardly rectifying background current (IK1) and the cardiac transient outward current, It, were investigated. IK1 was recorded as the current sensitive to 2 x 10(-3) M-BaCl2 during voltage-clamp steps from a holding potential of -90 mV. It was found to decrease in magnitude, approximately by a factor of three, from 15 to 5 pA/pF during the first ten postnatal days. This reduction can explain the maturational slowing of repolarization during the final phase of the action potential in rat heart. 5. Current-voltage relations for IK1 from the three age groups crossed at the zero current potential at approximately -90 mV, near the calculated VK for the pipette filling solution and an external bath K+ concentration of 5 x 10(-3) M. This suggests that IK1 channels in these cells are quite selective for K+ ions and that developmental changes in the potassium selectivity are not responsible for changes in IK1.(ABSTRACT TRUNCATED AT 400 WORDS)

4-Aminopyridine↗
PubMed1994

Characterization of the potassium channel from frog skeletal muscle sarcoplasmic reticulum membrane.

1. The sarcoplasmic reticulum (SR) membrane of skeletal muscle contains potassium channels which are thought to support charge neutralization during calcium release by providing a permeability pathway for counter-ion movement. To describe the behaviour of the SR K+ channel under physiological conditions, single channel activity was recorded from excised patches of SR membrane. Patches were made from membrane blebs extruded from contracted muscle fibres whose surface membranes had been removed previously by mechanical dissection. 2. The channel was active over a large voltage range from -80 to +100 mV. The current-voltage relationship of the channel was linear over most of this voltage range (slope conductance equal to 60 pS in 130 mM potassium), but showed rectification at voltages below -50 mV. 3. The activity of the channel (number of state transitions per unit time) was greater at positive voltages than at negative voltages. Analysis of dwell-time distributions showed that the time spent in the open state is best fitted by a double Gaussian, suggesting that the channel possesses both a long (l)- and a short (s)-lived open state with identical conductances. The dwell times for the two states were Ts = 0.3 ms and Tl = 2.6 ms at +90 mV and Ts = 0.1 ms and Tl = 15.1 ms at -40 mV. Thus, positive voltage decreased the long open time significantly which was consistent with the observed increase in channel activity at positive potentials. 4. The permeability sequence of the channel to various monovalent cations was deduced from the channel reversal potential under bi-ionic conditions and was found to be: K+ > Rb+ > Na+ > Cs+ > Li+. 5. Channel activity was reduced when the patch was perfused with 1,10-bis-guanidino-n-decane (BisG10), a drug reported to block the SR K+ channel with high affinity. The drug concentration necessary to reduce the open probability (P(o)) by 50% was 19.8 microM at -40 mV and 338.2 microM at +50 mV. The zero voltage dissociation constant (Kd) was calculated to be 48 microM. 6. Pharmacological agents known to affect surface membrane K+ channels, such as 0.5 mM Ba2+ or 3.0 mM 4-aminopyridine, were much less effective in blocking the channel than BisG10. Physiological calcium concentrations (pCa = 8.0 and 3.0) did not affect channel behaviour.4

4-Aminopyridine↗
PubMed1995

Potassium currents in adult rat intracardiac neurones.

1. Properties of K+ currents were studied in isolated adult rat parasympathetic intracardiac neurones with the use of single-electrode voltage-clamp techniques. 2. A hyperpolarization-activated inward rectifier current was revealed when the membrane was clamped close to the resting level (-60 mV). The slowly developing inward relaxation had a mean amplitude of 450 pA at -150 mV, an activation threshold of -60 to -70 mV and a relaxation time constant of 41 ms at -120 mV. The current was reversibly blocked by Cs+ (1 mM) and became smaller with reduced [K+]o and [Na+]o, indicating that this inward rectifier current probably is a time- and voltage-dependent Na(+)-K+ current. 3. Step depolarizations from the holding potential of -80 mV evoked a transient (< 100 ms at -40 mV) outward K+ current (IA) which was blocked by 4-aminopyridine (4-AP, 1 mM). The time constants for IA inactivation were 20 ms at -50 mV and 16 ms at -20 mV. The steady-state activation and (removal of) inactivation curve showed a small overlap between -70 and -40 mV; the reversal potential of IA was close to EK. 4. Step hyperpolarizations from the depolarized potentials, i.e. -30 mV, revealed a slow inward relaxation associated with the deactivation of a time- and voltage-dependent current. The inward relaxation became faster at more hyperpolarized potentials and reversed at -85 and -53 mV in 4.7 and 15 mM [K+]o. This current was blocked by muscarine (20 microM) and Ba2+ (1 mM) but not affected by Cs+ (1 mM); this current may correspond to the M-current (IM). 5. Depolarization-activated outward K+ currents were evoked by holding the membrane close to the resting potential in the presence of tetrodotoxin (TTX, 3 microM), 4-AP (1 mM) and Ba2+ (1 mM). The amplitude of the outward relaxation and the tail current became smaller as the [K+]o was elevated. The outward tail current was reduced in a Ca(2+)-free solution and the residual current was eliminated by the addition of tetraethylammonium (TEA, 10 mM); the reversal potential was shifted in a direction predicted by the Nernst equation. These findings suggest the presence of delayed rectifier K+ current and Ca(2+)-activated K+ current. 6. Superfusion of TEA, Ba2+ and 4-AP, but not Cs+, induced rhythmic discharges in some of the otherwise quiescent intracardiac neurones.(ABSTRACT TRUNCATED AT 400 WORDS)

4-Aminopyridine↗