Cardiac alpha 1-adrenoceptors mediate positive inotropy via myofibrillar sensitization.
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Adrenergic alpha-Agonists↗
Biomedical subjects
S M Vogel
Publications and source records attributed to S M Vogel.
Opposite modulation of ouabain cardiotoxicity by hexamethyleneamiloride and phenylephrine.
To see whether the Na/H antiporter plays a role in digitalis cardiotoxicity, we investigated the influence of modulators of Na/H exchange on the toxic effects of ouabain in isolated, paced (0.4 Hz) rat left atria. Ouabain (1 mmol/l) caused a transient positive inotropic effect followed by toxic events, including a complete loss of developed force and a gradual increase in resting force. In the presence of hexamethyleneamiloride (3 and 10 mumol/l), an inhibitor of Na/H exchange, ouabain (1 mmol/l) caused a sustained positive inotropic effect without toxicity. By contrast, phenylephrine (100 mumol/l), an alpha-adrenoceptor agonist reported to stimulate the antiporter, hastened the development of ouabain's toxicity. Neither ouabain, at a subtoxic concentration (650 mumol/l), nor phenylephrine (100 mumol/l) affected diastolic force, but in their combined presence, a substantial contracture developed and twitch contractions disappeared. Phenylephrine (30 or 100 mumol/l) or adrenaline (30 mumol/l), in the presence of a beta-adrenoceptor antagonist, increased the intracellular pH by up to 0.15 pH unit, as measured using ion-selective microelectrodes in quiescent preparations. This effect on pHi was prevented by hexamethyleneamiloride (10 mumol/l). Consistent with phenylephrine's ability to stimulate Na+ influx via the Na/H antiporter, phenylephrine (100 mumol/l) increased intracellular Na+ activity by about 3 mmol/l in ouabain (650 mumol/l)-treated atria. These findings indicate that modulators of Na/H exchange affect the cardiotoxicity of digitalis glycosides and imply that the stimulation of myocardial alpha-adrenoceptors may aggravate digitalis toxicity.
Amiloride↗
On the mechanism of the positive inotropic action of the alpha adrenoceptor agonist, phenylephrine, in isolated rat left atria.
Alpha adrenoceptor agonists have been reported to increase contractile force and to stimulate Na+/H+ exchange in the heart. We studied the influence of hexamethylamiloride (HMA), a selective inhibitor of Na+/H+ exchange, on the positive inotropic action of phenylephrine in isolated, paced rat left atria (3 microM propranolol). HMA (10 microM) blocked the ouabain-induced contracture, an event dependent on Na+ uptake via the Na+/H+ exchanger. The same concentration of HMA prevented 50% of the positive inotropic effect of phenylephrine (10 microM), but had no effect on base-line developed force. HMA reduced the maximal effect (234 +/- 19 vs. 117 +/- 20% increase of base-line), but not the EC50 (4.4 +/- 1.0 vs. 3.6 +/- 2 microM) of phenylephrine. Phenylephrine (100 microM) caused both a leftward and upward shift of the Ca++ concentration-effect curve, but only a leftward shift, in the additional presence of HMA (3 microM). It is known that lithium, but not choline, will exchange for H+ via the Na+/H+ exchanger: phenylephrine's (100 microM) positive inotropic effect in choline-substituted solutions averaged 37% of that in lithium-substituted solutions. The positive inotropic effect of phenylephrine was amplified by ouabain (200 microM). These results are consistent with the hypothesis that alpha adrenoceptor agonists produce their positive inotropic effects, in part, via stimulation of Na+/H+ exchange. Such stimulation could cause an intracellular alkalinization and (in the presence of ouabain), elevated intracellular Na+.
Amiloride↗
Molecular modification of anticholinergics as probes for muscarinic receptors. Part 4. Ileal selective muscarinic antagonists.
Systematic studies of the structure-activity relationships of atropine-like anticholinergic drugs have provided valuable information about the nature of the muscarinic receptor. In this study, the pharmacological activities of the (Z) and (E)-isomers of 2-phenylcyclohexyl diethylaminoethyl ether (1 and 2, respectively) in the isolated rat left atrium were investigated and compared with their activities in the isolated rat ileum preparation. Compound 1 was found to be one of the most ileal selective muscarinic antagonists reported to date. Other data concerning possible differences in the receptor-bound conformations of tropate- versus benzilate-derived muscarinic antagonists are also presented.
Animals↗
Doxorubicin-induced automaticity in cultured chick heart cell aggregates.
The use of doxorubicin, a clinically important antitumor agent, is associated with toxic cardiac side effects, including arrhythmias and, on rare occasions, sudden death. We have used aggregates of cultured chick embryonic heart cells, a preparation free of neuronal and vascular elements, to investigate the direct effects of doxorubicin on automaticity. Under control conditions, normally quiescent aggregates of ventricular origin could be induced to contract spontaneously during a 24- to 48-h incubation with doxorubicin. The percentage of aggregates exhibiting automaticity was concentration dependent between 0.01 and 1 microM doxorubicin. At relatively high drug exposure (e.g., 1 microM doxorubicin for 48 h), beating was shown to be dysrhythmic. Whereas control aggregates exhibited large stable resting potentials on impalement with intracellular microelectrodes, treated aggregates exhibited spontaneous action potentials with Phase 4 depolarization. Doxorubicin, in a dose-dependent manner, increased the rate of Phase 4 depolarization, reduced the maximum diastolic potential, and shortened the action potential duration. In dysrhythmic aggregates, microelectrode recordings also revealed examples of premature depolarizations, extrasystoles, and dropped beats. This study provides the first cellular electrophysiological recordings of doxorubicin-induced automaticity and rhythm disturbances in heart muscle. The results suggest that the induction of automaticity is due to a depolarizing action of doxorubicin on the cardiac membrane.
Action Potentials↗
Amiloride-sensitive actions of an alpha-adrenoceptor agonist and ouabain in rat atria.
The influence of amiloride, a known blocker of Na/H exchange, on the positive inotropic action of alpha-adrenoceptor stimulation was investigated in isolated rat left atria. Amiloride (300 microM) rapidly (within 10 min) and reversibly abolished the positive inotropic effect of phenylephrine (10 microM; 3 microM propranolol present). Lower concentrations of amiloride inhibited the increase in contractile force caused by phenylephrine in a concentration dependent manner (IC50 of 50 microM). At a concentration of 50 microM, amiloride caused a rightward and downward shift in the concentration-response curve to phenylephrine. Amiloride (10 to 300 microM) affected to only a small extent the increased contractile force in the presence of inotropic interventions known to increase Ca2+ influx via L-type calcium channels (Bay K 8644) and the Na/Ca exchanger (reduced extracellular Na+). To provide evidence that amiloride inhibits the Na/H antiporter intact atria, a contracture that depends on Na+ influx by the Na/H antiporter was examined. Amiloride fully relaxed the contracture induced by ouabain (1 mM) or potassium-free solutions in the identical concentration range over which amiloride inhibited the positive inotropic effect of phenylephrine. Phenylephrine increased the rate of development and the peak amplitude of the amiloride-sensitive contracture (ouabain-induced). The inhibitory action of amiloride on the positive inotropic response to phenylephrine may, in part, be the result of inhibition of the Na/H antiporter.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Alpha-adrenergic regulation of action potentials in isolated rat cardiomyocytes.
Radioligand binding studies and studies in which inositol phosphate levels were assayed have provided substantial evidence for the existence of alpha 1-adrenoceptors in isolated rat ventricular myocytes, a pure cardiac preparation free of neuronal and vascular elements. Since correlational electrophysiological studies have not been carried out in this model, we investigated alpha-adrenergic effects on action potentials using intracellular microelectrodes to impale the myocytes. Epinephrine, in the presence of propranolol (10(-6) M), rapidly increased the action potential duration in a concentration-dependent manner (threshold concentration of 30 nM, EC50 of 100 nM). The maximal upstroke velocity and overshoot of Ca2+-mediated action potentials (15 mM K+) were also increased. Epinephrine did not significantly affect the resting membrane potential. The alpha 1-adrenoceptor antagonist, prazosin (10(-7) M) blocked epinephrine's effects. LiCl (10 mM), an inhibitor of inositol-phosphate phosphatases potentiated the effects of epinephrine (30 nM). The results suggest that the isolated rat cardiomyocyte is a suitable preparation for examining the ionic and molecular mechanisms of direct alpha-adrenergic effects on the cardiac membrane.
Action Potentials↗
Cholinergic antagonism of beta-adrenergic stimulated action potentials and adenylate cyclase activity in rabbit ventricular cardiomyocytes.
The cholinergic antagonism of beta-adrenergic stimulation was examined by measuring adenylate cyclase activity and calcium-mediated action potentials in isolated ventricular cardiomyocytes of adult rabbits. The beta-adrenoceptor agonist isoproterenol and the direct adenylate cyclase activator forskolin increased adenylate cyclase activity in homogenates of the myocytes. The cholinergic agonist carbachol (10 nM-100 microM) inhibited in a concentration dependent manner basal, isoproterenol-stimulated and forskolin-stimulated adenylate cyclase activity. The carbachol effect on basal adenylate cyclase activity was antagonized by atropine (10 microM). In parallel experiments using intact cardiomyocytes, calcium action potentials were elicited by intracellular depolarizing current pulses in partially depolarized preparations. These action potentials were prolonged by isoproterenol, forskolin and dibutyryl cyclic AMP. Acetylcholine reversibly inhibited the prolongation of the action potential induced by isoproterenol and forskolin but not dibutyryl cyclic AMP. These results suggest that cholinergic agonists modulate the increase in the calcium current elicited by isoproterenol and forskolin in isolated ventricular cardiomyocytes by inhibiting adenylate cyclase activity.
1-Methyl-3-isobutylxanthine↗
Lindane but not deltamethrin blocks a component of GABA-activated chloride channels.
Effects of deltamethrin, a pyrethroid insecticide, and lindane, the gamma isomer of hexachlorocyclohexane, on the gamma-aminobutyric acid (GABA)-activated ion channels were studied using cultured neurons isolated from the newborn rat dorsal root ganglia. The neuron was voltage clamped using the whole cell patch clamp technique. Two components of inward chloride currents were generated in response to bath application of GABA. One of the components was selectively blocked by 1 x 10(-5)M lindane in a stereospecific manner, but neither component was affected by 1 x 10(-5)M deltamethrin, which drastically prolonged the voltage-activated sodium channel current. Thus, the action of lindane to stimulate the nervous system is partly because of an interaction with the GABA receptor-channel complex. The target site of deltamethrin is not the GABA receptor-channel complex but the sodium channel. The results suggest a multiplicity of the GABAA receptor-chloride channel complex.
Animals↗
Effects of lindane upon transmitter release and end-plate responsiveness in the neuromuscular junction of the frog.
Studies were carried out to determine whether the insecticide, lindane, influenced calcium-mediated electrical activity or release of neurotransmitter in vitro. In neuroblastoma cells, lindane (1-100 microM) did not appreciably modify action potentials elicited in normal or sodium-free solutions nor did it have a significant effect upon either transient or sustained-type calcium channels. Exposure of cutaneous pectoris neuromuscular junctions of the frog to 100 microM lindane increased spontaneous release of transmitter. In neuromuscular junctions perfused with 0.5 mM Ca++/6 mM Mg++ Ringer (low quantal release conditions), lindane increased evoked release of transmitter. The absolute increase amounted to just less than one quanta and the extent of the increase was inversely proportional to the mean number of quanta released by the nerve terminal before exposure to lindane. No effect on release of transmitter could be demonstrated when neuromuscular junctions were perfused in normal Ringer. Exposure of neuromuscular junctions to 100 microM lindane also decreased the amplitudes of miniature end-plate potentials. Amplitudes of responses to iontophoretically-applied acetylcholine (ACh) were similarly affected, suggesting that the decrease in amplitudes of miniature end-plate potentials was a reflection of decreased sensitivity of the end-plate to ACh. At neuromuscular junctions of the cutaneous pectoris of the frog, lindane appeared to produce two major effects. Presynaptically, it produced changes in spontaneous and evoked release of transmitter that were consistent with a small increase in free intracellular concentration of Ca++. Postsynaptically, it reduced the sensitivity of the end-plate to ACh.
Acetylcholine↗
Independent control of channel closure and block of open channels by methylxanthines at acetylcholine receptors in frog.
1. A series of related methylxanthines were studied for their effects on the kinetics of decay of end-plate currents (e.p.c.s) and miniature end-plate currents (m.e.p.c.s) at motor end-plates of the frog. 2. Isobutyl methylxanthine (IBMX, 50 microM-3 mM) produced a concentration-dependent depression of the peak e.p.c. and m.e.p.c. amplitude and a change in the kinetics of e.p.c. and m.e.p.c. decay from the normal single-exponential to a double-exponential function. Drug effects of this nature are generally attributed to open-channel blockade. 3. After wash-out of IBMX, the decay of the e.p.c. or m.e.p.c. was restored to a single-exponential function but with a significantly prolonged time constant. 4. Caffeine or theophylline derivatives (0.1-4 mM), during exposure to drug, produced effects similar to those observed after the application of IBMX; namely a prolongation of the time course of e.p.c.s and m.e.p.c.s without changing the single-exponential nature of the function. 5. Computer simulations were made of the m.e.p.c.s in IBMX. The effects of IBMX could be fitted to the sequential model of channel block only if the prolonged time constant observed upon wash-out was used for the rate constant of channel closure. Independent calculations of the rate constant of channel closure during IBMX application were in agreement with those measured during wash-out. 6. The theophylline derivative 8-phenyltheophylline, a selective adenosine receptor blocker with minimal effects on phosphodiesterase (PDE), increased the time constant of e.p.c. decay in a manner similar to theophylline and caffeine. Non-xanthine PDE inhibitors, either had no effect on m.e.p.c. decay (papaverine) or decreased the time constant of decay (RO 20-1724). It is thus unlikely that PDE inhibition is responsible for the post-junctional effects of IBMX. 7. IBMX (50 microM-2 mM) increased quantal ACh release in the virtual absence of extracellular calcium and also increased the efficacy of adenosine derivatives in inhibiting ACh release. Adenosine (10-100 microM) or 2-chloroadenosine (1-10 microM) had no effect on the time constant of e.p.c. decay nor did these adenosine receptor agonists alter the post-junctional actions of IBMX. The effects of IBMX on end-plate channel kinetics are thus not due to the blockade of adenosine receptors.(ABSTRACT TRUNCATED AT 400 WORDS)
Action Potentials↗
Block of single acetylcholine-activated channels in chick myotubes by alkylguanidines.
The mechanism of block of single acetylcholine-activated channels by alkylguanidines was studied by means of the gigaohm seal, patch clamp technique on chick myotubes. The single channel current-voltage relationship in symmetrical Cs solutions was linear over membrane potentials from -100 mV to +100 mV with the reversal potential close to 0 mV. Single channel conductance was estimated to be 40 pS with 120 mM cesium in both external and internal solutions and 54 pS with 360 mM cesium in both solutions. Cs binds within the channel with an apparent KD of approximately 100 mM and the channel has a saturating current of 8 -9 pA at +100 mV. External application of 10 mM and 20 mM methylguanidine decreased single channel current amplitude in a manner dependent upon concentration and membrane potential. The block was greater for inward currents than for outward currents. Ethylguanidine was more potent when applied externally (2 mM) than when applied internally (2-20 mM) and reduced single channel current amplitude in a voltage dependent manner. Increasing internal cesium concentration from 60 to 360 mM decreased the block of the single channel by internally applied ethylguanidine. There appear to be at least two channel binding sites for methyl- and ethylguanidine located approximately 25% of the membrane electric field from either membrane surface. The acetylcholine-activated ionic channel is symmetric with respect to cesium permeation but not to block by ethylguanidine. Permeant ions and blocking ions appear to compete for channel occupancy.
Acetylcholine↗
Nerve membrane sodium channels as the target site of brevetoxins at neuromuscular junctions.
Actions of two structurally related toxins, T-17 and brevetoxin-B, isolated from the red-tide dinoflagellate, Ptychodiscus brevis, were studied on the giant axon of the squid and the neuromuscular junctions of the frog and rat. T-17 toxin caused a large increase in the frequency of miniature endplate potentials at nanomolar concentrations. In one typical case with a frog endplate, the frequency increased from 1.9 s-1 before application of 3.5 nM T-17 to 69.3 s-1 within 5 min after application. In the rat muscle, the mean frequency increased from 1.39 s-1 in control to 11.93 s-1 after application of 23.2 nM T-17. The increase in miniature endplate potential frequency was reversed by the addition of 1 microM tetrodotoxin, and was not observed in a solution containing elevated Mg2+ and reduced Ca2+ concentrations. External or internal application of T-17 toxin (2-5 microM) or brevetoxin-B (10-30 microM) to intact or internally perfused squid axons caused a depolarization of the membrane. This depolarization was abolished by the removal of external Na+ or by addition of tetrodotoxin to the external solution. In voltage clamped squid giant axons, exposure to T-17 toxin or brevetoxin-B increased the non-inactivating component of the tetrodotoxin-sensitive sodium current. The sodium current was activated at potentials 15 to 40 mV more negative than control. It is proposed that these toxins modify a fraction of the sodium channels to a form which opens at potentials more negative than normal and which inactivates to a lesser extent. This mechanism would predict a depolarization of the nerve membrane at the neuromuscular junction, thus explaining the increased discharge of transmitter.
Animals↗
The effects of an adenylate cyclase inhibitor on the electrophysiological correlates of neuromuscular transmission in the frog.
The presynaptic and postsynaptic effects of MDL 12,330A, an adenylate cyclase inhibitor in several biological tissues, were studied at motor endplates in frog cutaneous pectoris nerve-muscle preparations. This agent increased both spontaneous quantal acetylcholine (ACh) release and neurally-evoked ACh release approximately twofold during the first 20-40 min of application. The increased ACh release was accompanied by a profound irreversible depression in the amplitudes of the miniature endplate potentials (m.e.p.ps) and endplate potentials (e.p.ps). The response to iontophoretically-applied ACh was reduced in parallel with the amplitude of the spontaneous m.e.p.ps, indicating that the depression of synaptic transmission was postsynaptic in origin. Endplates were voltage-clamped to study the postsynaptic depression in more detail. It was observed that the peak endplate current (e.p.c.) was depressed without concomitant changes in: the kinetics of e.p.c. decay, the relationship between peak e.p.c. and membrane potential, the ACh equilibrium potential or the voltage sensitivity of the e.p.c. decay. This suggests that MDL 12,330A reduces the postsynaptic sensitivity to ACh by a voltage-dependent block of the cholinoceptor. The presynaptic enhancement and the postsynaptic depression of junctional transmission produced by MDL 12,330A are discussed in conjunction with current theories of the role of adenylate cyclase and cyclic nucleotides at nicotinic cholinergic synapses.
Acetylcholine↗
Actions of Ptychodiscus brevis toxins on nerve and muscle membranes.
Pharmacological actions of two brevetoxins isolated from Ptychodiscus brevis, T17 and T34, on nerve and muscle membranes were studied using vertebrate and invertebrate preparations. T17 (10 ng/ml) caused an increase in the frequency of miniature endplate potentials (MEPPs) in rat and frog neuromuscular junctions. Application of tetrodotoxin (TTX) completely abolished the increase in MEPP frequency. The results suggest that T17 depolarizes the nerve terminal through opening of the sodium channel. Application of either T17 or T34 to the crayfish and squid giant axons caused a dose-dependent depolarization of the axon membranes with a maximum depolarization of about 30 mV. The depolarizing action was antagonized by sodium-free external saline solution or TTX. Voltage clamp experiments demonstrated that the primary action of the toxins is to cause the sodium channels to open at the normal resting potential. The binding of toxin to a channel site could be prevented by procaine, but not by TTX. The binding site for T17 is presumably separate from the TTX receptor, but related or identical to the binding site for procaine. The brevetoxin-induced depolarization of the nerve terminal membrane with the subsequent enhanced transmitter release is the underlying mechanism for a number of pharmacological actions on various neuro-effector systems.
Animals↗
Current-dependent block of endplate channels by guanidine derivatives.
Methyl- and ethylguanidine block the endplate current in frog muscle. Both derivatives blocked inward-going endplate currents without affecting outward endplate currents. Repetitive stimulation that evoked several inward endplate currents enhanced the block, which suggests that these agents interact with open endplate channels. The relative conductance vs. potential curve exhibited a transition from a low to a high value near the reversal potential for the endplate current, both in normal and in 50% Na solution. In the latter solution, the reversal potential for endplate current was shifted by a mean value of 16 mV in the direction of hyperpolarization. The results suggest that methyl- and ethylguanidine block open endplate channels in a manner dependent on the direction of current flow rather than on the membrane potential.
Acetylcholine↗
Endplate blocking actions of lophotoxin.
Effects of lophotoxin (LTX), a neurotoxin isolated from Pacific sea whips Lophogorgia rigida and Lophogorgia chelensis, on neuromuscular transmission were assessed in the rat phrenic nerve-hemidiaphragm preparation using conventional microelectrode recording techniques, and in the frog cutaneous pectoris preparation using two microelectrode voltage clamp techniques. LTX (2-25 microM) produced a progressive, irreversible block of miniature endplate potential (m.e.p.p.) and endplate potential (e.p.p.) amplitude. M.e.p.p. amplitude histograms were shifted markedly in the direction of lower amplitude by LTX. These effects occurred following a latency of 25-40 min. The latency to onset of block was decreased with increasing LTX concentrations. In some preparations, LTX produced a transient increase in m.e.p.p. frequency during the first 5 min of application; however, m.e.p.p. frequency then declined to complete block. The depressant effect of LTX on m.e.p.p. and e.p.p. amplitude progressed to complete block irrespective of the LTX concentration. LTX also blocked the endplate depolarization produced by iontophoretic application of acetylcholine (ACh). The resting membrane potential of skeletal muscle fibres was unaffected by LTX. In voltage clamp experiments, LTX (15 microM) depressed the peak amplitude of the endplate current (e.p.c.) nearly uniformly at potentials between -120 and +60 mV. LTX did not affect the e.p.c. reversal potential or the kinetics of e.p.c. decay suggesting that LTX does not block open ACh channels. E.p.c. block by LTX was also progressive and irreversible. The results indicate that LTX blocks neuromuscular transmission by a postjunctional action. The binding site of LTX may be different from that of ACh.
Acetylcholine↗
[Myocardial action potentials and energy metabolism].
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Action Potentials↗