Guinea Pig Ventricular Muscle Research Articles

Tonic and Frequency-Dependent Vmax Block Induced by Imipramine in Guinea Pig Ventricular Muscle Fibers

The effects of imipramine (IMI) on transmembrane action potentials were studied in isolated guinea pig papillary muscles. In muscles driven at 0.02 and 1 Hz, IMI (10(-7) to 5 X 10(-5) M) produced a concentration-dependent decrease in the maximum upstroke velocity (Vmax) of the action potential, but it had no effect on the resting membrane potential. In the presence of 10(-5) M IMI, trains of stimuli at rates between 0.5 and 2 Hz led to an exponential decline in Vmax to a new steady-state level (K = 0.230 +/- 0.09 AP-1 at 2 Hz). This frequency-dependent Vmax block was augmented at higher stimulation frequencies and at higher drug concentrations. The time constant of the recovery of Vmax from the frequency-dependent block was 2.5 s, this value being independent of the drug concentration. These values of onset and offset kinetics of IMI lie between those of drugs with fast and intermediate kinetic properties. IMI also shifted the curve relating membrane potential and Vmax in hyperpolarizing directions. These results suggested that IMI exhibited a frequency- and voltage-dependent inhibition of the fast sodium channels similar to that exhibited by other class Ib antiarrhythmics. The possible role of this frequency- and voltage-dependent Vmax inhibition in the pro-antiarrhythmic effects of IMI is discussed.

Temperature dependence of myofilament Ca sensitivity of rat, guinea pig, and frog ventricular muscle

Cooling the superfusate of intact ventricular muscle, from 30 degrees C to below 4 degrees C in less than 2 s, leads to contractures thought to reflect the amount of Ca available for release from the sarcoplasmic reticulum (SR). On rewarming, tension transiently increases in guinea pig and rat ventricular muscle. It has been proposed that this rewarming tension spike reflects changes in myofilament Ca sensitivity and maximum Ca-activated force (Cmax) associated with rewarming. There are differences in intracellular Ca regulation among cardiac muscle preparations. Some characteristics of rapid-cooling contractures (e.g., the magnitude of the rewarming spike) also differ between species. Therefore, the Ca sensitivity of skinned ventricular muscle from the rat, guinea pig, and frog was determined at 29 (22 degrees C for frog ventricular preparations), 8, and 1 degrees C. The results show that cooling rat and guinea pig ventricular muscle from 29 to 1 degrees C shifts the pCa vs. tension relationship toward higher [Ca2+] by 0.65 and 0.55 pCa units, respectively. Cooling to 1 degrees C also reduced Cmax to 3.3 and 7.8% of that at 29 degrees C in rat and guinea pig ventricular muscle, respectively. Similar results were found for frog ventricular muscle, in which cooling from 22 to 1 degrees C reduced Ca sensitivity by 0.6 pCa units and Cmax to 45.7% of its value at 22 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of TYB-3823, a new antiarrhythmic drug, on the electrophysiological properties of guinea-pig ventricular muscles

1. The effects of TYB-3823 (B-GYKI 38233), a new antiarrhythmic drug, were electrophysiologically examined in the guinea-pig ventricular muscles. 2. TYB-3823 at concentrations of 1–3 × 10 −7 M significantly prolonged the action potential duration (APD) of the papillary muscle. However, the resting potential, action potential amplitude and maximum rate of depolarization ( V · max ) were unaffected by the drug at such concentrations. At a higher concentration (1 × 10 −4 M) TYB-3823 reduced V · max . 3. Voltage clamp experiments with single ventricular cells revealed that TYB-3823 at concentrations higher than 1 × 10 −7 M reduced the outward potassium currents, especially the time-dependent outward current, but that TYB-3823 failed to affect the calcium current. 4. These results suggested that TYB-3823 at low concentrations reduces the outward potassium current to give rise to a prolongation of APD and that at higher concentrations it additionally inhibits the sodium channels; both the effects may be related to the antiarrhythmic action of this drug.

O-260 - Depressant effects of lidocaine on development of delayed afterdepolarization in guinea-pig ventricular muscle evaluated with intracellular Na and pH measurements

O-260 - Depressant effects of lidocaine on development of delayed afterdepolarization in guinea-pig ventricular muscle evaluated with intracellular Na and pH measurements

P-276 - Effects of NKH477, a novel water-soluble forskolin derivative, on contractile force and adenylate cyclase activity in isolated guinea-pig ventricular muscles

P-276 - Effects of NKH477, a novel water-soluble forskolin derivative, on contractile force and adenylate cyclase activity in isolated guinea-pig ventricular muscles

The inhibitory actions of amiodarone on rested-state contraction in isolated guinea-pig ventricular muscle

1. To assess the mechanism(s) of the negative inotropic effects of amiodarone (AM), an effective anti-arrhythmic agent, the effects of AM on rested-state contraction (RSC) were studied in isolated ventricular papillary muscle from control (untreated) and AM-pretreated guinea-pigs. 2. The RSC was induced by stimulation, following a 30 sec- or 10 min-rest period. 3. The drug's effects were evaluated on an initial response (T i) and steady-state response (T ss) of the RSC at the end of 1 min-stimulus train at 3.3 Hz. 4. In normal physiological solution, the magnitude of T i was 2.1 times that of T ss in papillary muscles from untreated animals, but, 1.3. times, in AM-pretreated ones. 5. The effects of superfused AM (4.4 × 10 −5 M) were also evaluated in both muscle types. 6. The drug markedly decreased T i and T ss in both control and AM-pretreated specimens. 7. However, the depression by superfused AM of RSC in control specimens was more likely to be marked than in AM-pretreated ones. 8. Further, verapamil and caffeine, which affect SR function, also depressed the RSC. 9. These results suggest that the negative inotropic actions of AM, at least in part, reflect a decrease in Ca 2+ via Ca 2+ channels and an impairment of Ca 2+-sequestrating system.

Changes in cytosolic calcium monitored by inward currents during action potentials in guinea-pig ventricular cells.

Action potentials were recorded from single cells isolated from guinea-pig ventricular muscle. Contraction was measured with an optical technique. Tail currents thought to be activated by cytosolic calcium were recorded when action potentials were interrupted by application of a voltage-clamp. A family of tail currents was recorded by interrupting the action potential at various times after the upstroke. The envelope of tail current amplitudes was taken as an index of changes in cytosolic calcium. Consistent with this interpretation, tail currents were negligible following intracellular loading with the calcium chelator BAPTA to suppress calcium transients. The cytosolic calcium transient estimated from the envelope of tails reached a peak approximately 50 ms after the upstroke of the action potential, and fell close to diastolic levels before repolarization was complete; 10 mM caffeine delayed the time to peak contraction, and caused a prolongation of the cytosolic calcium transient estimated from the envelope of tail currents. Caffeine also induced the appearance of a distinct late plateau phase of the action potential. Intracellular BAPTA suppressed the late plateau, contraction and tail currents in cells exposed to caffeine. Exposure to caffeine increased the time constant for decay of tail currents (from approximately 25 to 70 ms). When action potentials were greatly abbreviated by interruption with a voltage-clamp, a progressive decline occurred in the subsequent three contractions and tail currents. There was a progressive reversal of these effects over four responses when the full action potential duration was restored. None of these effects was observed in cells exposed to caffeine. Calcium-activated tail currents appear to be a useful qualitative index of changes in cytosolic calcium. The observations are consistent with the suggestion that cytosolic calcium is reduced during the plateau by a combination of calcium extrusion through Na-Ca exchange and calcium uptake into caffeine-sensitive stores. It also appears that reduction of stores loading during abbreviated action potentials reduces subsequent contraction in cells not exposed to caffeine.

Characterization of MS-857, a New and Potent Cardiotonic Agent, in Isolated Mammalian Cardiac Muscles

The positive inotropic activity of MS-857, a novel cardiotonic agent, was assessed in isolated atrial and ventricular muscle of several mammalian species. MS-857 (0.1-300 microM) increased the developed tension of the dog, rabbit, monkey, cat, and guinea pig ventricular muscles in a concentration-dependent manner. However, MS-857 failed to cause a positive inotropic effect in isolated rat ventricular muscle. In isolated guinea pig atria, MS-857 caused both positive inotropic and chronotropic effects. MS-857 was more selective for inotropy than for chronotropy as compared with either milrinone or 3-isobutyl-1-methylxanthine (IBMX). The positive inotropic and chronotropic effects of MS-857 do not appear to be mediated by direct stimulation of alpha- or beta-adrenoceptors, histamine H1- or H2-receptors, or by release of endogenous catecholamines. The inotropic response to isoproterenol or histamine was potentiated by a relatively low concentration of MS-857. MS-857 increased both developed tension and intracellular cyclic AMP level in isolated dog right ventricular muscle. The time course of the elevation in cyclic AMP level was paralleled by that of increase in developed tension. Carbachol inhibited the increase in developed tension and cyclic AMP level caused by MS-857. These findings support the idea that cyclic AMP may be involved in the positive inotropic effect of MS-857.

Electrophysiological effects of thyroid hormones in guinea pig ventricular muscle: Time course and relationships to blood levels

Electrophysiological effects of thyroid hormones in guinea pig ventricular muscle: Time course and relationships to blood levels

Electrophysiological effects of thyroid hormones in guinea-pig ventricular muscle: Time course and relationships to blood levels

Chronic alterations in the thyroid state have been shown to induce marked changes in action potential characteristics, the most pronounced being shortening of action potential duration (APD) by hyperthyroidism and an increase in duration by hypothyroidism. In the present study our major objectives were to investigate the time course of the effect of thyroid hormone on action potential characteristics, to examine the relationships between thyroid hormone levels and these changes, and to test whether the electrophysiological alterations are induced both by thyroxine ( T 4) and triiodothyronine ( T 3). The major findings were that a single dose of either hormone (100 μg/kg) caused a marked shortening of APD, while resting potential, action potential amplitude and V ̇ max were unchanged. APD shortening was observed promptly after ip T 4 or T 3 administration, with maximal effect occurring within 2 to 3 hrs. Having determined thyroid hormone levels in the guinea-pigs used for the electrophysiological experiments, we found a close temporal association and inverse linear relationships (r = −0.82) between total T 4 levels and APD. To determine whether APD shortening is induced due to a direct effect of thyroid hormone on the myocardium, euthyroid papillary muscles were superfused with 10 −6 m T 3; within 3 hrs of superfusion with T 3, APD was shortened from 148.8 ± 4.7 ms to 117.7 ± 6.4 ms ( P < 0.01), an effect blocked by the protein synthesis inhibitor cycloheximide. Our results demonstrate that thyroid hormones affect the duration of the ventricular action potential in a concentration dependent fashion. Furthermore, the study suggests that thyroid hormones affect the myocardium directly via mechanism(s) that are probably associated with thyroid hormone-related protein synthesis.

Comparative Positive Inotropic Effects of TA-064 (Denopamine), a New Cardiotonic Agent, and Isoproterenol and Ouabain on Guinea Pig Ventricular Muscles

The effects of TA-064 (TA) on "fast" and "slow" response action potentials and contractile tensions were studied in isolated guinea pig papillary muscles, and the findings were compared with those of isoproterenol (ISP) and ouabain. The results are as follows: (a) TA produced a dose-dependent (10(-7)-10(-5) M) increase in developed tension, with no significant changes in the resting membrane potential (RMP), action potential duration (APD), and maximum rate of rise of action potential (Vmax). (b) The concentration required to increase the developed tension by threefold ("equivalent concentration") were 10(-6) M with both TA and ouabain, while that of ISP was 5 x 10(-8) M. (c) TA increased the maximum rate of rise, dP/dtmax, and the maximum rate of fall, dR/dtmax, of the developed tension to the same extent, unlike those of ISP and ouabain. (d) Positive inotropic effects of TA (10(-7)-10(-5) M) were not completely abolished by atenolol (3.8 x 10(-5) M), a specific beta 1 blocker, whereas those of ISP were completely abolished. (e) The increasing effects of "equivalent concentration" of TA (10(-6) M) on the Vmax of the slow response were less than those of ISP (5 x 10(-8) M). These results suggest that the positive inotropic effects of TA are mainly due to stimulation of beta 1 adrenoceptors, but that the mode of action of the drug differs in several respects from that of ISP or ouabain.

Comparative Electrophysiological Effects of Propafenone, 5-Hydroxy-Propafenone, and N-Depropylpropafenone on Guinea Pig Ventricular Muscle Fibers

Propafenone (Pf) is a class I antiarrhythmic drug that can be given both orally and intravenously. In order to examine whether its two major metabolites [5-hydroxypropafenone (5-OH-Pf) and N-depropylpropafenone (N-DP-Pf)] possess pharmacodynamical properties, we compared their electrophysiological effects to those of the parent drug on papillary muscle fibers from guinea pig ventricular myocardium. After baseline action potential and refractory period characteristics were measured at different pacing rates, the tissue preparations were superfused with either Pf, 5-OH-Pf, or N-DP-Pf at five different concentrations and electrophysiological characteristics were studied again. The maximal rate of depolarization (Vmax) was depressed by the three compounds only at the highest concentration, although the effect of N-DP-Pf was slightly less than the other two. Refractory periods were altered only by the highest concentration of 5-OH-Pf. Propafenone and N-DP-Pf exhibited equally slow on-set/off-set kinetics of the sodium channel block, whereas those of 5-OH-Pf were twice as long, which seems to suggest a slower rate of dissociation of the latter from the inactivated sodium channels. Thus, 5-OH-Pf and N-DP-Pf comply with the definition of the class IC antiarrhythmic drugs. The cumulative in vivo effects of the two metabolites and of the parent drug could have far reaching clinical implications, especially in the genetically predisposed extensive metabolizing subject.

Acidosis depresses delayed afterdepolarization in guinea pig myocardium.

We examined the relationship among intracellular sodium activity (aiNa), intracellular pH (pHi), and delayed afterdepolarization (DAD) in guinea pig ventricular papillary muscle fibers exposed to K-free solution in vitro, using Na+- and H+-selective microelectrodes. In unstimulated papillary muscles, exposure to K-free solution caused a rapid increase in aiNa of 16.2-22 mM at the end of a 20-min superfusion period with rates of 0.51-0.73 mM/min. This was paralleled by a decrease in intracellular pH of 0.10-0.15 units. DADs were induced after a train of driven action potentials 5-15 min after superfusion with K-free solution at the elevated aiNa from the steady-state level. Prevention of intracellular acidosis associated with the increased aiNa in K-free solution by external alkalosis at pH 8.0 enhanced the amplitude of the DAD, whereas restoration of external pH to 7.4 and a further acidification of external pH to 6.4 suppressed DADs. We concluded that intracellular acidosis associated with the increased aiNa per se increased the likelihood for inhibition of sarcoplasmic reticulum Ca2+ release in spite of increased cytosolic Ca2+.

Electrophysiological effects of H 2O 2 on guinea pig ventricular muscle. Permissive role of iron : L. Firek, A. Ber [formula omitted]sewicz. Dept of Clin. Physiol., Medical Centre of Postgraduate Education, Warsaw, Poland

Electrophysiological effects of H 2O 2 on guinea pig ventricular muscle. Permissive role of iron : L. Firek, A. Ber [formula omitted]sewicz. Dept of Clin. Physiol., Medical Centre of Postgraduate Education, Warsaw, Poland

Frequency- and voltage-dependent effects of AN-132, a new class I antiarrhythmic agent, on the maximum upstroke velocity (Vmax) of action potential upstroke in guinea pig ventricular muscles

Frequency- and voltage-dependent effects of AN-132, a new class I antiarrhythmic agent, on the maximum upstroke velocity (Vmax) of action potential upstroke in guinea pig ventricular muscles

Possible Increases in Potassium Conductance by Apamin in Mammalian Ventricular Papillary Muscles

Apamin, a bee venom polypeptide, is reported to block the Ca2+-dependent K+ channel in smooth muscle, hepatocyte, and neuroblastoma cells. In embryonic chick hearts, it was found to block the Ca2+ channel. We report here that apamin (10(-9)-10(-7) M) hyperpolarizes the resting membrane potential and shortens the duration of the action potential (AP) in the fast response of adult guinea pig ventricular papillary muscles. This peptide also depresses the isoproterenol or Ba2+-induced slow response APs in the presence of high K+ (21.6 mM) Tyrode solution, without affecting the resting potential. The most striking effect of apamin on the slow response was to shorten the duration of AP with only slight decreases in the maximal rate of increase (Vmax) of the AP, a nonlinear measure of Ca2+ currents. These findings suggest that apamin increases membrane K+ conductance in the mammalian ventricular myocardium. However, in enzymatically isolated single ventricular cells and at wide range of concentrations (10(-7)-10(-11) M), apamin did not affect the AP configuration and did not alter the membrane Ca2+ or K+ current, perhaps because of a loss of apamin sensitivity secondary to enzymatic digestion of the tissue with collagenase.

Positive inotropic effect of somatostatin in guinea-pig ventricular muscles

We investigated the effect of somatostatin (SS) in guinea-pig ventricular muscles using a force transducer and a conventional microelectrode method. Instead of a negative inotropic effect in atrial muscles, SS (10 −11 to 10 −7 m) elicited a positive inotropic effect in ventricular muscles in a concentration-dependent fashion, without changing the time course of contraction. The positive inotropic effect of SS was accompanied by a significant enhancement of the slow action potentials and was suppressed by diltiazem and phentolamine. An increase of extracellular Ca 2+ concentration or stimulation frequency enhanced the positive inotropic effect of SS. The positive inotropic effect of SS was not suppressed in the presence of propranolol, metoclopramide, cimetidine or indomethacine, and it appeared even under cold conditions. These results suggest that SS has a positive inotropic effect in guinea-pig ventricular muscle, which is at least partly due to an increase in the slow inward Ca 2+ current.

Electrophysiological effects of FK664, a new cardiotonic agent, on preparations from guinea pig ventricle and from rabbit sino-atrial node

Effects of the cardiotonic agent FK664, 6-(3, 4-dimethoxy-phenyl)-1-ethyl-4-mesitylimino-3-methyl-3,4-dihydro-2 (1H)-pyrimidone, on isolated guinea pig ventricular muscles and rabbit sinus node pacemaker cells were studied using micro-electrode techniques. In ventricular muscles driven at 0.5-1.0 Hz, FK664 above 3 mumol.litre-1 caused an increase in contractile force and a shortening of time to peak tension. This positive inotropic effect of FK664 was accompanied by a slight elevation of the early plateau phase of the action potential, while other action potential variables were unaffected. The change in contractile force induced by FK664 was abolished in a low Ca2+ medium (0.12 mmol.litre-1) or by treatment with ryanodine (2 mumol.litre-1), whereas it was relatively well preserved in the preparations pretreated with nefedipine (1 mumol.litre-1). The slow action potentials induced by isoprenaline (0.3 mumol.litre-1) in high K+ medium (30 mmol.litre-1) and the slow inward current measured by single sucrose gap voltage clamp at a holding potential of -40 mV were unaffected by FK664. In sinus node pacemaker cells, FK664 (1-10 mumol.litre-1) caused a dose dependent acceleration of phase 4 depolarisation and a shortening of spontaneous firing cycle length. This positive chronotropic effect of FK664 was markedly inhibited in a low Ca2+ medium (0.3 mmol.litre-1). These findings suggest that FK664 has positive inotropic and chronotropic effects on the heart, due to an enhancement of transsarcolemmal calcium influx through the low threshold, dihydropyridine insensitive Ca2+ channel population.

Electrophysiologic Effects of TYB-3823, a New Antiarrhythmic Agent, on Isolated Guinea Pig Ventricular Muscles

The effects of a newly synthesized antiarrhythmic agent, TYB-3823 on the transmembrane action potential were examined in isolated papillary muscles of guinea pig. TYB-3823 (3 x 10(-6)-3 x 10(-5)M) caused a dose-dependent decrease in the maximum upstroke velocity (Vmax) and a shortening of action potential duration (APD). In the presence of TYB-3823, trains of stimuli at rates greater than or equal to 0.2 Hz led to an exponential decline in Vmax. This use-dependent block was enhanced at higher stimulation frequency. The time constant for the recovery of Vmax from the use-dependent block was 12.6-13.4 s. The curves relating membrane potential and Vmax were shifted by TYB-3823 (3 x 10(-5)M) to the direction of more negative potentials (5.7 mV). In preparations treated with TYB-3823 (10(-5)-3 x 10(-5) M), the Vmax of test action potentials preceded by conditioning clamp pulses to 0 mV was progressively decreased by increasing the duration of a single clamp pulse or by increasing the number of multiple brief clamp pulses. These findings suggest that TYB-3823 has use- and voltage-dependent inhibitory action on the fast sodium channel by binding to the channel during its activated and inactivated states, and that the unbinding rate of the drug from the channel is very slow. Such characteristics of sodium channel block in combination with APD shortening effect would provide unique antiarrhythmic activities of this substance.

Electrophysiologic Effects of TYB-3823, a New Antiarrhythmic Agent, on Isolated Guinea Pig Ventricular Muscles

Summary: The effects of a newly synthesized antiarrhythmic agent, TYB-3823 on the transmembrane action potential were examined in isolated papillary muscles of guinea pig. TYB-3823 (3 × 10−6−3 × 10−5M) caused a dose-dependent decrease in the maximum upstroke velocity (JOURNAL/jcph/04.03/00005344-198904000-00015/OV0312_1/v/2021-02-06T190858Z/r/image-pngmax) and a shortening of action potential duration (APD). In the presence of TYB-3823, trains of stimuli at rates ≥ 0.2 Hz led to an exponential decline in JOURNAL/jcph/04.03/00005344-198904000-00015/OV0312_1/v/2021-02-06T190858Z/r/image-pngmax. This use-dependent block was enhanced at higher stimulation frequency. The time constant for the recovery of JOURNAL/jcph/04.03/00005344-198904000-00015/OV0312_1/v/2021-02-06T190858Z/r/image-pngmax from the use-dependent block was 12.6-13.4 s. The curves relating membrane potential and JOURNAL/jcph/04.03/00005344-198904000-00015/OV0312_1/v/2021-02-06T190858Z/r/image-pngmax were shifted by TYB-3823 (3 × 10−5M) to the direction of more negative potentials (5.7 mV). In preparations treated with TYB-3823 (10−5−3 × 10−5M), the JOURNAL/jcph/04.03/00005344-198904000-00015/OV0312_1/v/2021-02-06T190858Z/r/image-pngmax of test action potentials preceded by conditioning clamp pulses to 0 mV was progressively decreased by increasing the duration of a single clamp pulse or by increasing the number of multiple brief clamp pulses. These findings suggest that TYB-3823 has use- and voltage-dependent inhibitory action on the fast sodium channel by binding to the channel during its activated and inactivated states, and that the unbinding rate of the drug from the channel is very slow. Such characteristics of sodium channel block in combination with APD shortening effect would provide unique antiarrhythmic activities of this substance.