The negative inotropic effect of esmolol on isolated cardiac muscle.

OBJECTIVE: Esmolol is an ultra-short-term acting beta adrenergic blocker for intravenous use. The most common side effect is hypotension, which is often manageable by careful titration of the dose. We speculated whether esmolol had a direct negative inotropic effect on the cardiac muscle. DESIGN: Papillary muscles and trabeculae were excised from guinea pig and pig hearts. Force production was recorded together with action potentials. Membrane currents were recorded in isolated myocytes. The effects of two concentrations of esmolol were tested (55 and 110 micromol/L). RESULTS: Esmolol reduced action potential duration and plateau voltage, and decreased force production of isolated cardiac muscle. Voltage-clamp experiments from a holding potential of -40 mV and a step change to 0 mV showed a reduction in the inward current due to esmolol. CONCLUSION: Apart from being a beta adrenergic blocker esmolol also exerts a direct negative inotropic effect on cardiac muscle due to its inhibition of the calcium current during the action potential.

Disastrous physiological effects of saline on the cell membrane demonstrated in cardiac cells.

OBJECTIVE: Saline is not an ideal storage solution. It has a low pH, no buffering capacity, and lacks other ions and nutrients. The objective was to explore the effects of storing cardiac muscle in saline. DESIGN: Guinea pig papillary muscles and ventricular myocytes were exposed to saline. The effects on action potential, membrane current, contraction and cell shortening were recorded in vitro at 35-37 degrees C. RESULTS: Saline caused transient hyperpolarization of the resting potential (-140 mV), prolonged duration of the action potential, and increased contraction amplitude, which was later reversed. The membrane resting potential depolarized after a few minutes to about -15 mV and the preparations became unexcitable. The depolarized preparations remained slightly contracted. Upon reperfusion both papillary muscles and cells became unstable and spontaneously active. Storing myocytes in saline for only 2 h resulted in excessive cell death. CONCLUSION: Saline is disastrous for the function of the heart muscle and leads to depolarization, sustained contraction and unexcitable tissue. Saline should not be used as a storage medium, even for short periods of time.

Effects of dopamine on porcine myocardial action potentials and contractions at 37 degrees C and 32 degrees C.

BACKGROUND: Little information exists on the effects of drugs with cardiovascular action in hypothermia, and some findings have indicated paradoxic effects of dopamine in this setting. As we have not found any data on the electrophysiologic and contractile effects of dopamine on the heart in hypothermia, we decided to study this in pig myocardium, since pigs have a cardiovascular system more similar to that of humans than other animals. METHODS: Excised muscle strips from pig ventricular septum were mounted in an organ bath. After 45 min of equilibration at 37 degrees C or 32 degrees C, resting and action potentials, time to peak contraction and contractile force were recorded during pacing with a frequency of 60/min. Dopamine at 4 microM or 8 microM was added and new recordings were made after 15 min. RESULTS: Cooling to 32 degrees C caused a prolongation of contraction by 48% and the contractile force increased by 39%. The membrane action potential duration at 50% and 90% repolarization levels increased at 32 degrees C by 28% and 16% respectively. Dopamine significantly (P<0.05) increased the contractile force and membrane action potential duration at 50% and 90% repolarization levels both in normothermia and in hypothermia, whereas the duration of the contraction was not significantly changed. CONCLUSION: Cooling to 32 degrees C significantly prolongs the myocardial action potential and the contraction duration. Dopamine increases the contractile force and prolongs the action potential both at 37 degrees C and at 32 degrees C.

Effects of magnesium and glucose, insulin, potassium (GIK) solution on the action potential parameters of guinea-pig atrial muscle.

The present paper aims to explore the effects of [Mg2+]o and glucose, insulin and K+ (GIK) on action potential parameters in guinea-pig atrial muscle. Specimens of atrial appendages were taken from guinea-pig hearts. Action potentials were recorded in isolated atrial trabeculae. Resting potential (RP) and action potential duration at 90% repolarization (APD90) were measured with conventional microelectrode techniques. [Mg2+]o at 6 and 12 mmol L-1 depolarized the RP and prolonged the APD90, whereas 4 mmol L-1 had no effect at all. Glucose alone or in combination with insulin had no effect on action potential parameters. GIK solution with supernormal [K+]o at 6 mmol L-1 depolarized the RP and decreased the APD90. Intervention with [Mg2+]o at 4 mmol L-1 in combination with GIK solution with supernormal [K+]o of 6 mmol L-1, reversibly depolarized the RP, whereas the APD90 was not significantly changed. [Mg2+]o at 12 mmol L-1 in combination with GIK solution with a physiological [K+]o of 4 mmol L-1 prolonged the APD90 whereas the RP was unaffected. [Mg2+]o at 6 and 12 mmol L-1 slightly depolarized the RP and prolonged the APD90. The action potential of normally polarized atrial muscle was not sensitive to supernormal levels of glucose alone or in combination with insulin. The effects of [Mg2+]o in combination with the GIK solutions on action potential parameters seemed to be attributable to the supernormal [Mg2+]o and [K+]o alone, while these seemed to have opposite effects on APD90.

Potentiation of the contraction following a prolonged depolarization in isolated ferret myocardium.

The contractile force was studied in ferret papillary muscles during voltage clamp depolarizations, using the single sucrose gap method. Prolongation of a test depolarization within a train produced potentiation of the following contraction. The effects of varied duration and membrane potential of the test depolarization upon the potentiated force of the following beat were studied. We assumed that force of a beat was an index of calcium entry on the previous depolarization. The relationship between the peak contractile force of the following potentiated beat and the systolic membrane potential of the test depolarization revealed an equilibrium around -18 mV. This was manifest after 100 ms of no effect. Positive potentials caused potentiation of force of the following beat; negative potentials caused suppression of force of the following beat. Calcium entry, if carried by an electrogenic exchange mechanism, would be revealed as a membrane current developing after 100 ms. Membrane current at these times was always outward. When the duration of the test depolarization was prolonged, outward current prior to repolarisation progressively increased. When the duration of the test depolarization was held constant, outward current was varied by variation in membrane potential. Force of the following beat was proportional to the test clamp membrane potential. The potentiation of the contraction following a prolonged depolarization was abolished by substituting 75% of the sodium in the perfusion medium with lithium. These results are compatible with the hypothesis that potentiation of force following a prolonged depolarization is derived from calcium entry into myocardial cells by reversed sodium-calcium exchange.

The inotropic mechanism of the phosphodiesterase inhibitor OPC 3911 alone and in combination with rolipram, studied in papillary muscles of ferret and guinea-pig and isolated myocytes of guinea-pig ventricular muscle.

OPC 3911 is a potent inhibitor and PDE III is a specific inhibitor in cardiac muscle. The effects of the drug alone and in combination with the non-inotropic PDE IV inhibitor rolipram were analysed using hearts from guinea-pigs and ferrets. OPC 3911 had an EC50 value of 0.1 microM. At 0.1 microM peak force was increased by 50.7 +/- 7.6% (n = 6, P < 0.001), time to peak tension (TPT) reduced by 18.7 +/- 5.6% (n = 6, P < 0.05). Time to half relaxation (THR) was prolonged by 19 +/- 4.2% (n = 6, P < 0.001). After addition of rolipram (30 microM), there was a potentiation of peak force at all concentrations of OPC 3911. At 0.1 microM OPC rolipram increased peak force by 82.8 +/- 8.9% (n = 6, P < 0.001), reduced TPT by 73 +/- 6% (n = 6, P < 0.005) and increased THR by 27 +/- 5% (P < 0.01). OPC 3911 shortened action potential duration (APD) at 50% repolarization by 5.3 +/- 2.5% (n = 6, P < 0.05). Addition of rolipram prolonged APD by 3.7 +/- 2.5% (n = 6, P < 0.05). Second inward current (Isi) was increased at 3 microM OPC 3911 by 46 +/- 6% (n = 6, P < 0.05). The combination of OPC 3911 and rolipram intensified the Isi to 101 +/- 5% (n = 3). Rolipram slowed the rate of restitution and the onset of restitution was prolonged. Relative maximum post-extrasystolic potentiation was reduced in the presence of OPC 3911 from 67 +/- 5% to 45 +/- 6%. Adding rolipram caused potentiation of 55 +/- 6%. OPC 3911 increased the recirculation fraction of activator calcium from 0.36 to 0.42 (n = 10, P < 0.05). After addition of rolipram the recirculation fraction was 0.41 +/- 0.04 (n = 10, P < 0.05). The results suggest that rolipram exerts its potentiating effect on OPC 3911 via an increased Isi.

The contractile and electrophysiological effects of rolipram in guinea-pig papillary muscles and isolated ventricular myocytes.

Isometric force, action potentials and in voltage-clamp Isi (second inward current) and its current voltage relation were recorded in papillary muscles from guinea-pigs and from guinea-pig isolated ventricular myocytes (35-37 degrees C, 0.5-1 Hz). Rolipram (1-100 microM) had no significant effect on peak isometric twitch. The rate of rise of force and time to peak tension (TPT) was likewise unaffected. Time to half relaxation (THR) was increased in a dose-dependent manner and at 30 microM THR was prolonged by 25.3 +/- 6% (n = 10, P < 0.001). The effect of 30 microM rolipram on isometric force was frequency dependent. At 0.25 Hz peak force was increased by 6.3 +/- 3.1% (n = 7, P < 0.05). At 2 Hz rolipram exhibited a negative inotropic effect of 9.8 +/- 3.3% (n = 5, P < 0.02). Action potential duration at 90% repolarization was prolonged by 13 +/- 6 ms (n = 7, P < 0.05), and there was usually no effect on resting potential or action potential amplitude. Sometimes, however, a depressed plateau was recorded. Rolipram was without effect on Isi and its current-voltage relations. Time to full mechanical restitution after a test interval was not changed but the shape of the restitution curve was altered. The restitution process was much slower in the presence of rolipram. Hence, peak force was lower at test intervals shorter than 800 ms. Likewise, the shape of the curve relating postextrasystolic potentiation to test interval was altered by rolipram.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanical and electrophysiological effects of milrinone on the force-frequency relationship in mammalian myocardium.

Isometric force, action potential and current-voltage relation were studied in guinea-pig and ferret papillary muscles. Milrinone (1 microM) increased peak twitch force by 40 +/- 4%, reduced time to peak tension (TPT) by 12.1 +/- 3% (n = 6, P < 0.01) and reduced time to half relaxation by 17.3 +/- 4.1% (n = 6, P < 0.01). The effect of milrinone was potentiated by rolipram, a RI-PDE inhibitor which in itself had no inotropic effect. After the addition of rolipram peak isometric force was increased by 104 +/- 8% (n = 6, P < 0.001), TPT was further reduced whereas time to half relaxation was slightly increased after the addition of rolipram. Action potential duration at 75% repolarization was decreased by 11 +/- 5 ms (n = 6, P < 0.05). Milrinone also potentiated the second inward current (Isi) by 21 +/- 3.2% (n = 6, P < 0.01). Peak twitch force in response to a test stimulus after an interval, i.e. mechanical restitution was increased at all intervals. The onset of restitution was faster and time to full restitution also shortened. Maximum postextrasystolic potentiation was greater in the presence of milrinone, whereas relative potentiation was smaller in presence of milrinone (46 +/- 7%) than in control (74 +/- 7%). The recirculation fraction of activator calcium was enhanced by milrinone from 0.35 +/- 0.04 to 0.48 +/- 0.07. The results support the view that the positive inotropic effect of milrinone is due to a greater inflow of calcium during the action potential and a more efficient intracellular calcium handling.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms of excitation-contraction coupling studied using the principle of transient perturbation.

We have studied the responses to a brief interruption of a train of steady state beats, namely: (1) a single prolonged depolarisation within the train; (2) a single short interval within the train; (3) a single long interval within the train. These responses are predicted by a two compartment model of intracellular calcium handling. They are characterised by the following phenomena. (1) Prolongation of one depolarisation/action potential in the steady state train causes potentiation of the following beat. We postulate on the basis of the published evidence that this may be due to "reversed" sodium/calcium exchange during late systole leading to extra calcium entry during the prolonged depolarisation. (2) Postextrasystole potentiation is postulated to share this mechanism when a depolarisation (extrasystole) is introduced immediately after one of the steady state depolarisations (single short interval). The postextrasystolic beat is then potentiated. (3) A single short interval during the steady state train also leads to attenuation of contractile force on the beat immediately after the short interval, that is, the extrasystole. Mechanical restitution is the term applied to the recovery of this force with increasing interval. This consists of two phases. The initial rapid phase is ryanodine and caffeine insensitive, indicating possible independence of sarcoplasmic reticular function. We postulate that a "membrane compartment" of internal calcium may be responsible. The second, slower, phase of mechanical restitution is ryanodine and caffeine sensitive, indicating that it is likely to be a property of the sarcoplasmic reticulum.(ABSTRACT TRUNCATED AT 250 WORDS)

Simulation of the electrogram from ion currents.

The electrogram can be constructed as the difference between two action potentials starting with a slight time difference. In the present study, the action potentials were simulated from ion currents showing time- and voltage-dependent activation and inactivation. Simple mathematics like straight lines and single exponential functions were used. The aim was not to give a precise description of the action potential but to obtain a model with electronic interaction between action potentials. Four currents were incorporated. The upstroke of the action potential was due to the inflow of sodium ions. The plateau was maintained by a calcium current and repolarization followed from a slowly activated and outwardly directed potassium current. There was also a time-independent background current of potassium showing inward rectification. Basically the same equations were used for calculation of the four current voltage relations. Also, currents during a depolarizing voltage step could be reproduced by the model. Two action potentials were coupled to each other by means of a resistor to simulate the behaviour of gap junctions. A flat T-wave in the electrogram occurred when the action potentials had the same characteristics because of the electrotonic interaction. When the first action potential was longer than the second in a pair positive T-waves were seen. A negative T-wave occurred when the second action potential of the pair was made longer. The model forms a base for further simulations of ECG.

Neuropeptide Y potentiates noradrenaline-evoked vasoconstriction by an intracellular calcium-dependent mechanism.

The potentiating effect of neuropeptide Y (NPY) was examined by testing the influence of putative inhibitors of calcium entry on the NPY-enhanced contractile response to noradrenaline in the guinea pig uterine artery. In order to examine the involvement of voltage sensitive calcium entry mechanisms we recorded the effect of noradrenaline and NPY on the membrane potential. NPY (100-300 nM) enhanced noradrenaline-evoked vasoconstriction. The potentiation by NPY was most prominent in low noradrenaline concentrations (30-300 nM) and the pD10 (-log molar concentration of agonist eliciting 10% of maximum contraction) value was increased from 6.43 +/- 0.07 to 6.97 +/- 0.11 (P < 0.001, n = 6). Inhibition of extracellular calcium influx shifted concentration-dependently to the right the concentration-response curve for noradrenaline but potentiation by NPY still remained. The intracellular calcium chelator quin-2 AM selectively abolished the NPY-induced enhancement of the contractile response to noradrenaline. In contrast, quin-2 AM (10-30 microM) had no inhibitory effect on the contractile response to noradrenaline per se. It is suggested that NPY initiates an intracellular calcium-sensitive mechanism which increase alpha-adrenoceptor sensitivity. This results in a significant increase of sarcoplasmic calcium and stronger contractile responses to noradrenaline.

Metabolic and electrophysiological changes in rabbit skeletal muscle during ischaemia and reperfusion.

OBJECTIVE: To clarify the effects of ischaemia and reperfusion on membrane potential of skeletal muscle in rabbits, and to study its correlation with the energy charge and the lactate content. DESIGN: Open experimental study. MATERIAL: 20 isolated rabbits' hindlimbs. INTERVENTIONS: The femoral arteries were cannulated and the limbs amputated at the level of the hip joint. Blood was removed by thorough perfusion with Ringer's solution. Below knee fasciotomies were done, and the whole limbs were immersed in Ringer's solution during periods of ischaemia. Reperfusion was with a modified Krebs' buffer with Dextran T70 saturated with oxygen. OUTCOME MEASURES: Measurements of membrane potential; ATP, ADP, and AMP concentrations; and lactate concentrations in muscles after 1 (n = 8), 2 (n = 4), 4 (n = 4), or 6 (n = 4) hour periods of ischaemia followed by a 2 hour period of reperfusion compared with those in 4 limbs that were made ischaemic for 8 hours and not reperfused. RESULTS: During the first hour of ischaemia the membrane potential decreased from -90 mV to -63 mV and the energy charge remained unchanged at 0.9. After 8 hours of ischaemia the membrane potential had decreased to -20 mV, the energy charge was 0.2, and the lactate content had increased by a factor of 12. During reperfusion the membrane potential was restored only in limbs that had been subjected to 1 hour of ischaemia, whereas energy charge was also restored in those subjected to 2 and 4 hours of ischaemia. The lactate content decreased during reperfusion in all limbs. CONCLUSION: Assessment of membrane potential is more sensitive than that of energy charge as an indicator of recovery of skeletal muscle after a period of ischaemia followed by reperfusion.

Force production in voltage-clamped human atrial muscle.

Human atrial muscle preparations obtained during open heart surgery were mounted in a sucrose gap. Force and membrane currents were recorded during voltage clamp. After a 20-s rest, 10 clamps from a holding potential of -40 to 0 mV at 1.0 Hz were given. This was followed by a test clamp (called 1) of a varied duration and amplitude and two more test clamps (called 2 and 3) as during the priming period. Peak force of contraction 1 (F1) was independent of clamp duration from 2s to about 100 ms but declined at shorter durations. Peak force of contraction 2 (F2) and 3 (F3) increased with the duration and became potentiated. Increasing the clamp amplitude raised F1 to an optimum value at about +10 mV and there was a decline at higher voltages. Both F2 and F3 increased at higher amplitudes. A conventional bell-shaped current-voltage relation for the second inward current was obtained during clamp 1 with maximum inward current around -10 mV. In control experiments on isolated human myocytes peak current was recorded at somewhat more positive potentials. The relation between F3 and F2 was linear both when duration and amplitude of clamp 1 was varied. The slope of the line, interpreted as a measure of recirculation of activator calcium, was 0.4. It is concluded that force during voltage clamp in human atrial muscle is similarly related to membrane voltage as previously reported for guinea pig and ferret preparations.

Cardiac cell membrane repolarization is required for onset of mechanical restitution in papillary muscle.

In 10 voltage clamped ferret papillary muscles at 37 degrees C (single sucrose gap), the duration of resting (diastolic, holding) potential was varied in order to define the mechanical restitution process. Following a period of steady state voltage clamp depolarizations to +20 mV, a single test depolarization clamp of 200 or 500 ms duration was introduced. Then, the following period at resting (holding) potential was varied. All the mechanical restitution curves for the 500 ms clamps were delayed by 300 ms compared with the 200 ms clamps. When mechanical restitution was plotted as the relationship between contractile force and test electrical diastolic interval, all processes started from zero interval (i.e. the time of repolarization). Variation of diastolic holding potential between -70 mV and -40 mV did not affect the starting time, but the final force values at full restitution were approached faster and were higher for -70 mV than for -40 mV. There was an inverse relationship between force and second inward current during mechanical restitution after an initial phase of restitution of current. Mechanical restitution is postulated to be due to passage of contractile calcium with time from an uptake to a release compartment within the sarcoplasmic reticulum. Thus the rise of contractile force with increasing test cycle duration should have been independent of whether a 200 or 500 ms depolarization was used. In order to accommodate the discrepancy, we postulate either that (1) sarcoplasmic reticulum calcium release channels require sarcolemmal repolarization to begin to be reactivated or (2) that trigger calcium (calcium induced calcium release from the sarcoplasmic reticulum) is derived from the sarcolemma.

Temperature effects on the Na and Ca currents in rat and hedgehog ventricular muscle.

Cardiac transmembrane potentials and Na and Ca currents were recorded at different temperatures in rat and hedgehog ventricular muscle. At 35 degrees C in both species resting potential was about -80 mV and upstroke velocity (Vmax) of the action potential above 100 V/s. The shape of the action potential in hedgehog ventricular cells at 35 degrees C was similar to that in the rat showing a fast repolarization phase. When temperature was decreased, the membrane resting potential depolarized and action potential amplitude and Vmax declined. In rat ventricular cells at 10 degrees C, the resting potential was about -40 to -50 mV and Vmax was reduced to about 5 V/s. In hedgehog ventricular cells, however, the transmembrane potentials and Vmax were better maintained at low temperature. Phase 3 of the action potential was markedly prolonged below 20 degrees C in hedgehog but not in rat ventricular cells. When temperature was decreased to 10 degrees C the availability curve of the Na current shifted toward more negative potentials and ICa.peak declined in rat ventricular cells. In hedgehog cardiac preparations, the Na current was less influenced by the cooling and ICa.peak did not change very much at low temperatures. A transient inward current usually considered to induce cardiac arrhythmias could be recorded in rat ventricular cells below 20 degrees C but not in hedgehog preparations. These features of hedgehog cardiac membranes may contribute to the cold tolerance and the resistance to ventricular fibrillation during the hypothermia in mammalian hibernators.

Force production following transient potential changes in voltage-clamped myocardium.

Inter-relationships between force, membrane voltage and currents were studied in ferret and guinea-pig papillary muscles using the single sucrose gap technique (37 degrees C). The preparations were held at -90 or -40 mV and depolarized (excited) to 0 mV for 180 ms at 1.0 Hz. At regular intervals the shape of a single clamp pulse (called '1') was varied and its effects were investigated during the same test cycle and in two subsequent test cycles ('2' and '3'). Peak force of contraction 1 (F1) increased with the duration of the test clamp up to 90 ms and was constant thereafter. F1 increased with clamp amplitude (V1) between -30 and 10 mV and decreased at greater amplitudes. This relation was similar to the relation between peak second inward current (I1) and V1. The peak force of contractions 2 and 3 rose with the clamp duration and clamp amplitudes of cycle 1. The relation between F3 and F2 was linear (slope 0.40), except at the lowest and highest F2 values where there was a small deviation. There was an inverse relation between I2 and F2. The results support the idea that increased duration or amplitude of the voltage clamp pulse leads to a greater calcium entry which is manifested in the following potentiated contraction. The relation between F3 and F2 implies that about 40% of calcium recirculates between the contractions. The inverse relationship between F2 and I2 indicates that the second inward current is regulated by release from the sarcoplasmic reticulum via negative feedback.

Neuropeptide Y in cerebrovascular function: comparison of membrane potential changes and vasomotor responses evoked by NPY and other vasoconstrictors in the guinea pig basilar artery.

The membrane depolarization and vasomotor response evoked by NPY and other vasoconstrictors were compared in guinea pig basilar artery. Concentrations below the pD2 value of amines and PGF2 alpha induced contractions without significant membrane depolarization, while higher agonist concentrations depolarized the membrane slightly. Potassium-induced contractions were paralleled by strong depolarization. NPY evoked a slow depolarization which correlated to vasoconstriction over a wide concentration range. The mechanism of activation did not appear to involve the endothelium. The results suggest that NPY induces prolonged cerebrovascular smooth muscle tone by evoking longlasting depolarization, at least partly in conjunction with activation of voltage-operated calcium channels.

Actions of three local anaesthetics: lidocaine, bupivacaine and ropivacaine on guinea pig papillary muscle sodium channels (Vmax).

The new local anaesthetic ropivacaine (LEA 103) like lidocaine and bupivacaine used as references, blocked cardiac sodium channels in a use-dependent fashion. At equimolar concentrations lidocaine had the lowest efficacy and bupivacaine the highest. The action potential was shortened and the plateau was depressed at high concentrations of each drug. Pacing a papillary muscle at 3.3 Hz in the presence of all three drugs resulted in a marked use-dependent accumulation of block (P less than 0.01). The accumulated block slowly dissipated after rest. At -90 mV holding (= resting) potential, and at a concentration of 10 microM, the time constant for recovery from block was 186 msec. in lidocaine (n = 4), 1.4 sec. in ropivacaine (n = 7), and 2.1 sec. in bupivacaine (n = 7). Lidocaine decreased Vmax progressively at high rates of stimulation, but not significantly at rates below 2 Hz. Ropivacaine progressively decreased Vmax significantly at rates above 1 Hz, but to a lesser degree than bupivacaine. The use-dependent action of the drugs was increased at more depolarized (less negative) holding potentials, whereas at more hyperpolarized potentials the block was diminished. Lidocaine and ropivacaine could be readily dissociated from the receptors at more hyperpolarized membrane potentials (-100 to -120 mV), whereas bupivacaine bound much harder. All three drugs blocked sodium channels more effectively after a long single conditioning pulse. Bupivacaine had the most prominent effect, and lidocaine was least effective. Bupivacaine and ropivacaine seem to interact with the inactivated state of the sodium channels, whereas lidocaine acted on both the open and on the inactivated state of the channels.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrophysiological effects of amperozide in papillary muscles from ferrets, guinea-pigs and rabbits.

Amperozide, a novel psychotropic agent, in concentrations lower than 10 microM caused a homogenous prolongation only of the action potential in both guinea-pig and rabbit papillary muscle. In concentrations greater than or equal to 10 microM, amperozide caused a flattening of the action potential plateau and the later part of the repolarization phase became slower (longer), probably reflecting an impaired repolarizing Na-Ca exchange current. The overshoot (OS) and the rate of rise of the action potential (dV/dtmax) were depressed. It is concluded that amperozide has a blocking action on the transmembrane calcium current since Isi (second inward current), DIA (depolarization induced automaticity) and the peak force of contraction were depressed. The blocking of the Isi was use-dependent resembling the actions of calcium-antagonists like verapamil, except that it was less potent at equimolar concentrations. Amperozide in concentrations where it acted as an Isi-blocker (above 10 microM), had depressing effects only on ouabain-induced oscillatory events. No major differences in the effects of amperozide were apparent between guinea-pig, ferret or rabbit papillary muscles.