Action Potential Height Research Articles

A model of beta-adrenergic effects on calcium and potassium current in bullfrog atrial myocytes.

A model of beta-adrenergic and muscarinic cholinergic effects on the bullfrog atrial myocyte has been developed to simulate the dose-dependent effects of isoprenaline (Iso) on the action potential duration (APD); i.e., low doses of Iso lengthen the APD, whereas high doses shorten the APD. In this model, the reduction in APD is the result of 1) calcium-dependent inactivation of calcium current (ICa) resulting from the enhancement of ICa by Iso and 2) an enhancement of potassium current (IK) due to both an Iso-induced increase in the rate of activation of IK and an increase in peak action potential height. The effect of acetylcholine (ACh) is simulated by a reduction in the Iso-induced increase in ICa and IK through a reduction in relative adenosine 3',5'-cyclic monophosphate concentration ([cAMP]), as well as activation of the ACh-sensitive potassium current. At low [Iso] levels in the presence of a high [ACh], the muscarinic cholinergic effects dominate the beta-adrenergic change. However, for a large [Iso] and a small [ACh], this pattern of changes in transmembrane currents is different; in this case the model predicts that ACh can actually increase APD.

The morphological basis of intracellular measurements in the cockroach tactile spine neuron

The femoral tactile spine of the cockroach (Periplaneta americana) contains a single sensory neuron, which adapts rapidly and completely to step deformations of the spine. Techniques for stable intracellular recording from the tactile spine neuron have recently been established, allowing electrophysiological investigation of mechanotransduction and adaptation in this sensory neuron. However, intracellular recordings from the neuron produce a wide range of action potential heights and thresholds, raising the possibility that some penetrations are in adjacent, but closely coupled supporting glial cells. This problem is exacerbated because the cell cannot be visualized during penetration. Systematic measurements of action potential heights and thresholds were made in tactile spine cells, together with identification of some penetrated cells by intracellular injection of Lucifer Yellow. All stained cells were clearly sensory neurons, although their action potential amplitudes varied from 9 mV to 80 mV. Smaller action potentials were broader than larger action potentials, and the changes in height and shape could be explained by a simple cable conduction model using measured morphological and electrical parameters. The model could also account for the observed relationship between action potential height and threshold. These results indicate that reliable recording from the tactile spine neuron is possible, but that variability in the positions of the penetration or the spike initiating zone cause an apparently wide range of electrophysiological measurements.

Modulation of collision-induced changes in canine heart repolarization by cycle length

The possibility that cycle length modulates the electronic effect of activation sequence on repolarization was investigated in experiments using isolated canine cardiac Purkinje strands, in situ canine ventricular myocardium, and computer simulations. Action potential durations and refractory periods during one-way propagation were compared to those obtained during action potential collision. In both the computer simulations and the Purkinje strand experiments, collision decreased action potential duration more at long cycle lengths than at short cycle lengths. Comparably, collision of activation fronts in ventricular myocardium was associated with greater reductions in refractory period during pacing at long cycle lengths than at short cycle lengths. Theoretic considerations indicate that the magnitude of electrotonic effects of activation sequence on repolarization are directly related to action potential height and the square root of membrane resistance during repolarization and are inversely related to conduction velocity. In computer simulations and Purkinje strand experiments, changes in conduction velocity and action potential height elicited by decreasing cycle length could not fully account for the cycle length dependence of collision-induced changes in repolarization. Time-varying membrane resistance of a single cell was calculated in the simulations by briefly hyperpolarizing the membrane and determining the change in total ionic current. Membrane resistance during repolarization was less at short cycle lengths than at long cycle lengths. The results suggest the cycle length dependence of collision-induced changes in repolarization results largely from the effect of cycle length on membrane resistance during action potential repolarization, with changes in action potential height and conduction velocity playing a lesser role.

The antiarrhythmic and cardiac electrophysiological effects of buprenorphine.

1. The effects of buprenorphine, given intravenously, on the incidence and severity of early acute coronary artery occlusion-induced arrhythmias were examined in anaesthetised rats. The electrophysiological effects of buprenorphine were also examined in sheep Purkinje fibres and rat papillary muscles, superfused in vitro with either a normal or a hypoxic, hyperkalaemic and acidotic physiological salt solution (PSS). 2. In anaesthetised rats subjected to acute coronary artery occlusion, pretreatment with buprenorphine (1 mg kg-1 i.v.) markedly reduced the incidence of ventricular extra-systoles during the initial 30 min post-occlusion period. The incidence of ventricular fibrillation (VF) was also significantly reduced from 56% to 10%. 3. At the antiarrhythmic dose (1 mg kg -1), buprenorphine also attenuated the sudden fall in systemic arterial blood pressure induced by acute coronary artery ligation. 4. In normal sheep Purkinje fibres and rat papillary muscles, buprenorphine (10(-6)-10(-5) M) significantly reduced the action potential height and maximum rate of depolarisation of phase zero (MRD) and prolonged the duration of the action potential. 5. Superfusion of sheep Purkinje fibres and rat papillary muscles with a hypoxic, hyperkalaemic and acidotic PSS resulted in marked reductions in resting membrane potential, upstroke and duration of the action potential. 6. In the presence of the modified compared with normal PSS, buprenorphine reduced the action potential height and MRD of both sheep Purkinje fibres and rat papillary muscles to a greater extent, although its ability to prolong the action potential duration was attenuated. 7. The antiarrhythmic effects of buprenorphine observed in vivo may be explained by its direct cardiac electrophysiological effects. Buprenorphine might be useful in relieving pain and in reducing the severity of arrhythmias in the early stages of acute myocardial infarction.

Inhibitors of protein kinase C prevent enhancement of calcium current and action potentials in peptidergic neurons of Aplysia

Following brief stimulation of an afferent pathway, the bag cell neurons of Aplysia undergo a dramatic change in excitability, resulting in a prolonged discharge of spontaneous action potentials. During the discharge, the action potentials of the bag cell neurons become enhanced in height and width. The afterdischarge triggers release of neuroactive peptides that initiate egg-laying behavior in this animal. Evidence suggests that changes in excitability of the bag cell neurons may be mediated by activation of protein kinase C (PKC) and cAMP-dependent protein kinase (cAMP-PK). PKC activators, such as the phorbol ester TPA (12-O-tetradecanoyl-13-phorbol acetate), enhance the amplitude of action potentials in isolated bag cell neurons in cell culture. These agents act by unmasking a previously covert species of voltage-dependent calcium channel resulting in an increase in calcium current. In the accompanying paper (Conn et al., 1989), we showed that H-7, a protein kinase inhibitor, inhibits the effect of TPA, and is a selective inhibitor of PKC relative to cAMP-PK in these cells. We now report that another PKC inhibitor, sphinganine, also inhibits the effect of TPA on action potential height and calcium current in cultured bag cell neurons, and that N-acetylsphinganine, an inactive sphinganine analog, fails to inhibit the effects of PKC activators. Although both H-7 and sphinganine prevent the effects of TPA when added prior to TPA addition, neither compound reverses the effects of TPA when added after the action potentials have already become enhanced by TPA.(ABSTRACT TRUNCATED AT 250 WORDS)

The pH-Dependent Local Anesthetic Activity of Diethylaminoethanol, a Procaine Metabolite

To test whether the products of procaine hydrolysis have local anesthetic actions resembling those of procaine, the authors compared the ability of procaine and its metabolites diethylaminoethanol (DEAE) and para-aminobenzoic acid (PABA) to block compound action potentials in excised, desheathed frog and rat sciatic nerves. Studies were performed in solutions of impermeant buffers at pH 7.4 (corresponding to mammalian physiologic pH) and at pH 9.2 (close to the pKa of procaine and DEAE) to test for extracellular pH-dependent increases in drug permeation and potency. Both procaine and DEAE inhibited compound action potentials at pH 7.4 and 9.2 in a reversible and dose-dependent manner, and both were approximately ten-fold more potent at pH 9.2 than at pH 7.4, procaine inhibiting the action potential height by 50% at 0.15 mM (pH 9.2) and 1.1 mM (pH 7.4), DEAE at 4 mM (pH 9.2) and 70 mM (pH 7.4). In contrast, PABA at concentrations up to 25 mM and at either pH failed to inhibit compound action potentials, and did not modify the effects of DEAE when both drugs were given together. Procaine produced greater use-dependent block at the higher pH and at higher stimulation rates (100 Hz vs. 40 Hz); DEAE produced almost no use-dependent block. These observations suggest: 1) that DEAE might account for some of the neuropharmacologic activity of procaine in techniques that favor the accumulation of metabolites (such as those requiring large doses or prolonged infusions); and 2) that alkalinization of procaine and DEAE solutions appears to increase their potency for both resting and use-dependent block of action potentials.

Activation of N-methyl-D-aspartate receptors parallels changes in cellular and synaptic properties of dentate gyrus granule cells after kindling.

1. The cellular and synaptic properties of rat dentate gyrus granule cells (GCs) were examined using intra-/extracellular and Ca2+-sensitive microelectrode recordings following epilepsy induced by kindling of the hippocampal commissures or amygdala. 2. The recordings were made in hippocampal slices prepared from sham-stimulated controls and animals that have received daily stimuli to reach stage IV-V of kindling. The average number of stimulation trials (60 Hz/1 s, 100-150 microA) required to reach full motor seizures (stage V) was 23 +/- 2 for commissural kindling and 14 +/- 1 for amygdala kindling. 3. The resting membrane potential of GCs following kindling (RMP; -72 +/- 3 mV) was not significantly different from the RMP of control GCs (-70 +/- 2 mV). Similarly, action potential height and threshold were unaffected by kindling. However, kindling altered other cellular properties of GCs regardless of the site of stimulation (hippocampal commissures or amygdala), the stage of kindling reached (IV or V), or the time elapsed between the last kindling stimulus and preparation of the hippocampal slices (24 h-6 wk). The input resistance of kindled GCs (55 +/- 4 M omega) was significantly higher than that of controls (40 +/- 3 M omega). In contrast to most control GCs, the slope conductance (GS) of kindled neurons, measured with constant-amplitude current injections at various membrane potentials, generally increased at membrane potentials more negative than rest. Furthermore, other voltage-dependent ionic conductances (see below), that were not normally encountered in control GCs, were present in kindled neurons. 4. The intracellularly recorded monosynaptic excitatory postsynaptic potentials (EPSPs) of kindled GCs, evoked through the stimulation of the lateral perforant pathway, differed significantly from the EPSPs of control GCs. The amplitudes of control EPSPs increased upon hyperpolarizations and decreased following depolarizations of the membrane, as expected for conventional EPSPs without contribution from voltage-dependent conductances. In contrast, the EPSPs of kindled GCs invariably increased in amplitude and duration at membrane potentials 5-20 mV depolarized from rest, indicating the presence of a characteristic voltage-dependent component. Frequently, following the synaptically triggered action potentials, kindled GCs displayed depolarizing afterpotentials. 5. Perfusion of the N-methyl-D-aspartate (NMDA) receptor antagonist DL-2-amino-5-phosphonovaleric acid (APV; 30 microM) had no effect on the EPSPs of control GCs, but consistently reduced the amplitude and duration of EPSPs in kindled GCs.(ABSTRACT TRUNCATED AT 400 WORDS)

Mechanism of phospholipase A 2-induced conduction block in bullfrog

The effects of exogenously added phospholipase A 2 (PLA 2) and its hydrolytic products in isolated bullfrog sciatric nerve were investigated. Nerves were pretreated for 3 h with a dose of trypsin which did not affect conduction in order to enhance penetration of the added agents. Threatment of nerves with β-glucosidase, neuraminidase or chymotrypsin had no effect on conduction. Whereas incubatin of the nerves with normal Ringers for 2 h had no significant effect on conduction, incubation with PAL 2 in Ringers caused decrements in the height of the compound action potential in dose-related manner. In addition, incubation of the nerves with 10 mg/ml lysolecithin, arachidonic acid, or docosahexaenoic acid caused marked decrements in the height of the compound action potential. Electron microscopic analysis of nerves after each treatment which caused conduction block revealed varying levels of myelin damage. Although myelin was damaged at the paranodal and/or internodal region, depending on the agents used, the axonal membrane appeared to be intact at the ultrastructural level. It was concluded that the block in conduction resulting from PLA 2 was due to the formation of lysolecithin and long chain polyunsaturated fatty acids.

Increased dependency of cardiac pacemaker activity on extracellular Ca after adrenergic blockade in the frog heart.

The frog sinus venosus shows spontaneous regular pacemaker activity, even in the absence of extracellular Ca2+. When an alpha-adrenergic blocking agent (phentolamine) is applied, the rate of pacemaker activity, height of action potential, rate of slow diastolic depolarization, and the maximum diastolic potential become strongly dependent upon the extracellular Ca2+ concentration.

Action potential collision in heart tissue--computer simulations and tissue experiments.

The electrical effects of action potential collision were studied using a computer simulation of one-dimensional action potential propagation and tissue experiments from isolated cardiac Purkinje strands and papillary muscles. The effects of collision, when compared to normal one-way propagation, included quantitative changes in all of the measured indexes of action potential upstroke and repolarization. These changes can be attributed to spatiotemporal changes in the net membrane current. Parameter sensitivity and analytic techniques identified five factors which determine the collision-induced decrease in action potential area: conduction velocity, action potential height, cable radius, specific intracellular resistivity, and the specific membrane resistance during action potential repolarization. The simulations demonstrated that collision effects were independent of inhomogeneity in action potential duration, the spatial extent of the collision effects was greater than the passive space constant, and certain simulated abnormal conditions (e. g., discontinuous propagation, ischemic tissue) increased the magnitude of the collision effects. The tissue experiments supported the simulations regarding the changes in action potential configuration directly at and on each side of the collision site. Elevated [K+]0 increased the changes in action potential duration in both tissue preparations. In papillary muscles, collision effects in the transverse direction were confined to a narrower region than collision effects in the longitudinal direction with no difference in the peak magnitude of the changes. Action potential collision is a common occurrence in the heart.

Effects of selective channel blocking agents on contractions and action potentials in K+‐depolarized guinea‐pig atria

Contractions and transmembrane action potentials were induced by 1 microM isoprenaline in K+-depolarized guinea-pig left atria driven at 0.5 Hz. The stability of these responses was significantly increased by doubling the extracellular glucose concentration to 22 mM. Action potential overshoot increased by 28 mV per ten fold increase in extracellular calcium concentration suggesting that the inward current in this preparation is carried by Ca2+. In depolarized driven preparations, nanomolar concentrations of nifedipine and nisoldipine reduced contractility, maximum rate of depolarization (dV/dt max) and action potential height, whereas the fast channel blocking agents tetrodotoxin and mexiletine (in micromolar concentrations) produced little change. Nifedipine also rendered spontaneously beating depolarized right atrial preparations quiescent. In concentrations which reduced dV/dt of normal action potentials, the sodium channel blocking agents quinidine and Org 6001 reduced the amplitude of contractions and reduced the maximum rate of phase 0 depolarization (dV/dt) of action potentials in depolarized tissue. These actions were reversed by Ca2+ and suggest calcium antagonistic activity. However action potential height was not reduced. Like bepridil, both drugs also reduced the frequency of spontaneous contractions in depolarized right atrial preparations. Unlike Org 6001, quinidine failed to produce a shift in calcium log dose-response curves in driven depolarized preparations and induced positive inotropy in the presence of functional sodium channels. Bepridil inhibited contractions in depolarized atria in the absence of a reduction in dV/dt suggesting that any calcium antagonistic action in atrial tissue is mainly located at an intracellular site. In conclusion, action potentials elicited by isoprenaline in potassium-depolarized atria bathed in high glucose appear to be Ca2+ mediated. In concentrations which inhibit the inward Na+ current, both quinidine and Org 6001 exhibit calcium channel blocking properties.

An analysis of the effects of clonidine and three structural isomers on transmission in rat superior cervical ganglia in vitro

α-Adrenoceptors mediating inhibition of release of acetylcholine in the superior cervical ganglia of the rat have previously been characterized as of the α 2-subtype (Brown and Caulfield, 1981). In the present study, the effects of clonidine (2,6-dichlorophenylimino-2-imidazolidine), the 2,3- 2,4- and 2,5-dichloro isomers (St 476, St 363 and St 475) and the 3,4-dihydroxy analogue (DPI) were examined on transmission in this tissue. Compound action potentials (CAP; supramaximal preganglionic stimulation at 0.2 Hz) were recorded extracellularly. Clonidine, DPI and adrenaline inhibited the compound action potential; concentration-response curves were shifted to the right by phentolamine. The maximum inhibition of the compound action potential was similar for epinephrine and DPI. However, for clonidine a secondary inhibitory component, leading to almost complete blockade of the compound action potential, was seen in concentrations > 10 μM; similar effects were seen for the lipid-soluble analogues St 476, St 363 and St 475, suggesting a non-specific effect. In smaller concentrations, St 476, St 363 and St 475 exerted only weak inhibition of the CAP; St 363 and St 475 actually increased the height of the compound action potential, in a similar manner to phentolamine (0.1–3 μM), and all three analogues blocked the inhibitory effects of adrenaline. These latter data suggest partial agonist actions for St 476, St 363 and St 475. The rak order of inhibitory effectiveness (clonidine > St 476 > St 363 > St 475) parallels that for acute hypotensive effects in rats (Timmermans and van Zwieten, 1977a). The results suggest that sympatho-inhibitory effects of some imidazolidines may not result solely from activation of presynaptic α 2-adrenoceptors.

The action of cholinomimetic substances on impulse conduction in the habenulointerpeduncular pathway of the rat in vitro.

The effects of some cholinomimetic substances and their antagonists on the peak height of compound action potentials recorded from the terminal region of the habenulointerpeduncular pathway have been studied using a rat brain slice preparation. Carbachol and acetylcholine (ACh) depressed the peak height of the compound action potential and increased the latency to peak. The nicotinic agonists nicotine and dimethylphenylpiperazinium depressed the peak height of the compound action potential while muscarine and glutamate had no effect. The depressant effect of carbachol was blocked by the nicotinic antagonists hexamethonium, mecamylamine and d-tubocurarine but not by atropine. Physostigmine enhanced the effects of ACh and, to a lesser extent, carbachol. In the presence of physostigmine, carbachol or ACh initiated a spontaneous oscillation of the amplitude of the compound action potential which was Ca2+ dependent and was blocked by mecamylamine. It is concluded that depression of the amplitude of the compound action potential is due to activation of presynaptic nicotinic receptors. The results are discussed with reference to possible cholinergic mechanisms in the habenulointerpeduncular pathway.

Intracellular potential changes following coronary occlusion in isolated perfused rat hearts.

A method of perfusing rat ventricles has been developed which permits the recording of intracellular potentials from up to 10 cell layers below the endocardial surface. Intracellular potentials from all layers remained the same for up to 1.5 h before occlusion. Regional occlusion of flow was produced by occluding the left anterior descending coronary artery and then intracellular potentials were recorded from normal and occluded cells for up to 2 h after occlusion. Immediately after occlusion, marked changes in potentials were recorded from occluded tissue. The greatest change was in the duration of the action potential which showed a marked shortening. There was also a reduction in the maximum rise rate and action potential height with smaller falls in resting membrane potential. Changes were greatest in the deeper cells (layers 6-10) and least in superficial subendocardial cells which were always superfused with perfusion fluid. Occlusion increased the number of quiescent cells (no action potential) as well as the number of cells showing aberrant action potential configurations (e.g., double peaks). Similar changes in intracellular potentials following occlusion were also recorded from the subepicardial surface of anaesthetized rats in situ. Arrhythmias induced by occlusion were similar to those seen in conscious rats following occlusion of a coronary artery.

The interaction between metoclopramide and dopaminergic agonists at the level of sympathetic ganglion.

The interaction of metoclopramide and two dopaminergic agonists, dopamine and apomorphine, was investigated on ganglionic transmission at the superior cervical ganglion of the anaesthetized cat. Dopamine (100 micrograms, i.a.) and apomorphine (100 micrograms, i.a.) decreased the height of action potential induced by supramaximal preganglionic stimulation. Metoclopramide (3 mg/kg, i.v.) antagonized the inhibition caused by dopamine and apomorphine. But it did not alter the transmission block caused by hexamethonium (100 micrograms, i.a.) or noradrenaline (100 micrograms, i.a.). The results suggest that dopamine-induced inhibition of the ganglionic transmission is related to the activation of dopaminergic receptors of the ganglion cells.

Experimental study of the conducted action potential in cardiac Purkinje strands

Conduction velocity is a complex physiological process that integrates the active and passive properties of the excitable cell. The relations between these properties in determining the conduction velocity are not intuitively obvious, and models have been used frequently to illustrate important relationships. To study the relationships of important parameters and to evaluate commonly used models, we changed conduction velocity experimentally in sheep cardiac Purkinje strands by reducing extracellular Na systematically. Cable analyses were also performed to obtain passive membrane and cable properties. Resting membrane resistance and capacitance did not change, nor did core resistance. Active properties measured in addition to conduction velocity included maximal upstroke velocity, action potential height, time constant of the foot, peak inward current, and upstroke power. With reduction in extracellular Na, all of these parameters of the action potential changed nonlinearly and not in direct proportion to the change in conduction velocity. The only simple relation found was a linear relationship between maximal upstroke velocity and peak inward current, normalized by the capacity of the foot. Models based on the cable equation and the wave equation offer a basis for quantitative analysis of conduction, and these data can be used to test the models.

Effect of acute compartmental pressure change on response to vibratory stimuli in primates.

This study investigated the possibility that a vibratory stimulus could discriminate the effect of relatively low pressures on nerve function in an acute compartmental syndrome in a primate model. The first phase of the study utilized somatosensory-evoked potentials to determine the outcome of varying pressures in an acute carpal tunnel syndrome in the anesthetized monkey. For increasing carpal tunnel pressures above 30 mmHg, the amplitude of the compound action potential of the A beta wave (touch fiber) generated in the median nerve by an electric stimulus to the index finger progressively decreased to a complete conduction block. It took progressively less time to achieve the conduction block at higher compartmental pressures. When compartmental pressure was released, the time required for the conduction block to return to normal was in direct relationship to the time required to complete the block. For carpal tunnel pressure between 15 and 30 mmHg, an increase in the height of this compound action potential was observed. The second phase of the study utilized the perceptual judgments of an awake monkey trained to discriminate differences in amplitude of a 10-Hz vibratory stimulus to the hairs of the dorsum of the foot. An anterior compartment pressure of 37 mmHg for 1 1/2 hours significantly decreased the monkey's ability to discriminate between the two amplitudes. At 50 mmHg in the anterior compartment, ability to discriminate between vibratory stimuli was further impaired. This study supports the use of noninvasive vibratory stimuli, such as a tuning fork, to evaluate acute compartmental syndromes.

Modulation of transmission in rat sympathetic ganglia by activation of presynaptic alpha- and beta-adrenoceptors.

1 Conditions under which transmission in rat isolated superior cervical ganglia may be affected by activation of presynaptic alpha- and beta-adrenoceptors have been investigated by means of an extracellular recording method. 2 Clonidine caused a small hyperpolarization of the ganglia (mean EC50 approximately 2 nM) in unstimulated preparations; with continuous preganglionic stimulation at 0.2 Hz, clonidine markedly decreased the height of the compound action potential (mean EC50 approximately 18 nM). 3 Phentolamine (0.1-3 microM) per se increased the height of the compound action potential by up to 15%, and antagonized the inhibitory effects of adrenaline and clonidine. 4 Using a higher frequency of stimulation (0.5 Hz), the effect of phentolamine (1 microM) was unchanged, whereas the inhibitory effectiveness of adrenaline on the height of the compound action potential was reduced. 5 (+/-)-Propranolol (0.1 microM) did not affect the height of the compound action potential, whereas the inhibitory effects of high concentrations of adrenaline were enhanced. 6 During an infusion of clonidine (1 microM), adrenaline (1-100 microM) and, less effectively, noradrenaline (10-100 microM) increased the height of the compound action potential by up to 14%; these effects were antagonized by propranolol (0.1 microM). 7 In the presence of noradrenaline (10 and 30 microM) adrenaline (100 microM) caused a small (up to 5%) enhancement of the height of the compound action potential. 8 The results obtained are consistent with the existence of presynaptic alpha- and beta-adrenoceptors on preganglionic terminals. The alpha-adrenoceptor may be part of a trans-synaptic inhibitory feedback. mechanism; however the functional role of the facilitatory beta-adrenoceptor is not clear.

Carotid sinus distension and superior cervical ganglion transmission.

The functional relationship between sinusal distension and the sympathetic innervation of the feline carotid sinus was investigated by neurophysiological techniques. A balloon catheter was used to distend the sinus region while recording evoked postganglionic activity from the superior cervical ganglion. When the SCG was stimulated at 1.0 or 10.0/s, balloon inflation reduced postganglionic action potential height by 25-50% and increased ganglionic negativity. These effects were subsequently abolished by section of one of the remaining intact postganglionic trunks. This evidence suggests that a pressure-modulated reflex arc, similar to the intestinointestinal reflex, might exist between the carotid sinus and superior and cervical ganglion.

Antidysrhythmic and electrophysiological effects of a new antianginal agent, bepridil.

The antidysrhythmic effects of a new antianginal agent, bepridil, were compared with those of disopyramide, a known antidysrhythmic drug. Bepridil (20, 50, and 100 mg/kg, i.p.) conferred little protection against aconitine-induced dysrhythmias in mice, whereas similar doses of disopyramide exerted a marked dose-dependent antidysrhythmic effect. Intravenous administration of either bepridil (2 mg/kg) or disopyramide (10 mg/kg) significantly reduced the number of ventricular extrasystoles and completely abolished the occurrence of ventricular fibrillation following coronary artery ligation in the rat. Local anesthetic and electrophysiological effects in vitro of bepridil were also investigated. A marked but slowly developing reduction in action potential height of desheathed frog sciatic nerves was observed at concentrations of 0.01-0.05 mM. In sheep Purkinje fibres, a similar decrease in action potential height, associated with a pronounced reduction in the maximum rate of depolarization of phase zero of the action potential (MRD) was seen with bepridil (0.5-2 X 10(-5) M). Higher concentrations (2-8 X 10(-5) M) were required to reduce MRD of guinea pig ventricular muscle. The antidysrhythmic actions of bepridil may at least in part be explained by the electrophysiological effects observed.