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PubMed1984

Effects of cardioplegia induced by a Young's solution (YNG solution) on the blood-perfused canine papillary muscle preparation.

Experiments were carried out in the blood-perfused canine papillary muscle preparation to evaluate the protective effect of a cardioplegic solution, Young's solution (YNG solution), on the myocardial function. Both in spontaneously contracting preparations and in electrically paced (2 Hz) preparations, the time to the cardiac arrest and the time to the maximum blood flow were found to be significantly shorter when the cardiac arrest was induced with cardioplegic solutions than when it was induced with the cold modified Krebs-Ringer's solution (cold cardioplegia). The maximum blood flow of the paced preparation tended to be greater with cardioplegic solutions. The time to resumption of regular contractions was significantly shorter with YNG solution as compared with cold cardioplegia. The developed tension and the blood flow at the time of resumption of the regular contractions tended to approach the control value more quickly with YNG solution, as compared with other cardioplegic solutions and cold cardioplegia. It is concluded that YNG solution represents an optimal cardioplegic solution.

Animals↗

PubMed1994

Effects of adenosine on Ca2+ transients and tension in aequorin-injected ferret papillary muscles.

The effects of adenosine on Ca2+ transients and tension in ferret papillary muscles were investigated using the aequorin method. Adenosine (0.01-1 mM) reduced the peak of Ca2+ transients and caused a slight concentration-dependent decrease in tension. Adenosine prolonged the decay time of Ca2+ transients but did not alter the time course of tension. In isoproterenol (0.1 microM)-treated preparations, adenosine decreased the peak of Ca2+ transients but did not alter the peak of tension. Adenosine prolonged the isoproterenol-shortened decay time of Ca2+ transients. The effects of adenosine on Ca2+ transients were antagonized by the selective A1 receptor antagonist 8-cyclopentyl-1,3,-dipropylxanthine. In the presence of isoproterenol, adenosine (0.1 mM) shifted the intracellular [Ca2+]/tension relation to the left. These results can be explained by the hypothesis that adenosine inhibits the activity of adenylate cyclase via stimulation of the A1 receptor, other mechanisms however cannot be overlooked. The prolongation of the decay time of Ca2+ transients and the increase in the Ca2+ sensitivity of the contractile elements are the underlying mechanisms of adenosine which maintain developed tension in twitch response, although adenosine decreases the peak of Ca2+ transients.

Adenosine↗

PubMed1980

Action potential characteristics of rabbit papillary muscle.

The ionic components of the action potential (AP) in rabbit right papillary muscle (RRPM) were determined by simple methods such as changes in external concentrations of sodium and calcium ions and addition of MnCl2 ot the perfusion fluid. Two components (fast and slow) were clearly visible in the upstroke of AP in normal Tyrode solution. MnCl2 (5 mmol/l) eliminated the slow component which forms the overshoot (OS) leaving the fast one unaffected, indicating that the former was related to a slow inward current. Mn also drastically reduced AP duration without changing the slope of phase 3 of repolarization. Reduction of Na concentration to 90 mmol/l did not affect the peak voltage of the OS but shortened AP. This low-Na solution reduced both (Vmax)f and the amplitude of the fast component. Ca-free solution reduced OS and increased AP duration. In high-Ca Tyrode (7.2 mmol/l) OS was increased and AP shortened. The effects of MN were reversed in this solution. The results suggest that the upstroke of the RRPM action potential is determined by two different ionic currents: a fast Na current responsible for the fast component and a slow inward current carried mainly by Ca, this latter being responsible for the slow component in the upstroke and for the plateau phase. The existence of propagated, Ca-dependent slow responses was demonstrated. Emphasis is placed on the fact that the major determination of the repolarization process in this type of AP is probably the inactivation of the slow inward Ca current.

Action Potentials↗

PubMedDate not supplied

Influence of beta-adrenergic stimulation on the fast sodium current in the intact rat papillary muscle.

The loose-patch-clamp technique was used on intact cardiac papillary muscle of the rat to examine whether the fast sodium inward current (INa+) is influenced by the beta-adrenergic stimulant isoproterenol (ISO) or by 8-bromo-3',5'-cyclic adenosine monophosphate (8-Br-cAMP), respectively. The amplitude of INa+ evoked by test pulses of 5 ms to a transmembrane potential of 0 mV and its time to peak were analyzed. The availability of INa+ was tested with conditioning pulses of 2.5 s to potentials between -130 mV and -50 mV. The potential of half-maximal availability was slightly shifted to more negative values by 1 microM ISO (2.0 mV, n.s.), as well as by 50 microM 8-Br-cAMP (4.0 mV; p less than 0.05). The peak amplitude of INa+ elicited from strongly negative potentials was increased by ISO (18%, n.s.), while 8-Br-cAMP exerted no directional effect. Depolarizing conditioning pulses (-60 mV) decreased INa+ to 13.3% of the maximal attainable current under control conditions, while ISO decreased INa+ to 9.1% of control (p less than 0.1). Corresponding values under the influence of 8-Br-cAMP were 11.4% and 8.3% (p less than 0.05). Moreover, in the presence of ISO there was a significant shortening of the time to peak of INa+ (0.56 ms to 0.50 ms at -80 mV conditioning potential, p less than 0.05) which could not be detected in the presence of 8-Br-cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1996

Effects of phenylephrine on intracellular Na+ and H+ activities in guinea-pig cardiac ventricular papillary muscles.

Effects of phenylephrine (PE) on the contractility, intracellular Na+ activity (aNai), intracellular H+ activity (pHi), and membrane potential in guinea-pig cardiac ventricular papillary muscles were studied. In beating fibers, PE significantly increased the twitch offsion, pHi and the action potential duration but decreased aNai. These effects could be inhibited by phentolamine, but not by propranolol. In quiescent fibers, PE also increased the resting tension and pHi, and decreased aNai. Pretreatment with phentolamine completely abolished the effect of PE. Methylisobutyl amiloride (MIA), a potent inhibitor of Na(+)-H+ exchanger, significantly decreased membrane potential, aNai, and pHi without changing the resting tension. PE in the presence of MIA increased the resting tension and further decreased aNai without significant changes in membrane potential and pHi. Ouabain significantly decreased membrane potential and pHi, and increased the resting tension and aNai. In the ouabain-treated fiber, PE further increased the resting tension without decreasing aNai or increasing pHi. From these results, it appears that PE activates the Na(+)-K+ pump and Na(+)-H+ exchange through alpha-adrenoceptors. Activation of the Na(+)-K+ pump contributes, at least in part, to the enhanced Na(+)-H+ exchange. The increase in contractile force associated with a decrease in aNai is suggested to result from the intracellular alkalization and increased sensitivity of contractile protein to Ca2+.

Animals↗

PubMed2002

Mitral valve surgery for acute papillary muscle rupture following myocardial infarction.

BACKGROUND AND AIM OF THE STUDY: Acute papillary muscle rupture (PMR) is a rare but fatal complication of myocardial infarction (MI). Surgery represents the best treatment option, but carries a high risk. Our experience of emergency mitral valve surgery in patients with acute PMR following MI during the past 22 years is reviewed. METHODS: Between 1978 and 2000, 33 patients (20 males, 13 females; mean age 64 years; range: 46-80) underwent emergency surgery for acute post-infarct PMR in our institution. The site of MI was anterior in three patients and inferior in 30. Preoperatively, 17 patients had an intra-aortic balloon pump (IABP) inserted, 26 were on inotropic support, and 17 were ventilated. Twenty patients (61%) underwent concomitant coronary bypass grafting (CABG). The valve was replaced in 31 patients and repaired in two. Mean (+/- SD) duration of follow up was 63+/-54 months (range: 0-183 months). RESULTS: Early mortality (in-hospital) was 21% (n = 7). Factors associated with significant risk of early mortality included raised preoperative serum creatinine (p = 0.02), need for preoperative inotropic support (p = 0.03) and preoperative ventilation (p = 0.03). Raised preoperative serum creatinine remained significant on multiple logistic regression (p = 0.04). Postoperatively, 21 patients required an IABP. Mean duration of intensive care unit stay was 4+/-2.5 days (range: 0-10 days). Survival, including in-hospital mortality, at one, five and 10 years was 75+/-7.4, 65+/-8.6 and 32+/-9.7%, respectively. Four patients required valve-related reoperation (three for a paraprosthetic leak, one for failed repair). CONCLUSION: Patients with acute post-infarct PMR present in a severely compromised state. Early mortality is high, but the intermediate outcome is encouraging for operative survivors.

Aged↗

PubMed1996

[Aberrant papillary muscle causes wall motion alterations: diagnostic implications].

We report a case of 77 year old man who never complained cardiac symptoms, with progress septal myocardial infarction diagnosed by electrocardiographic signs and akinesia of the septum-apical segment, detected by echocardiography. He underwent a new echocardiographic examination that pointed out an aberrant papillary muscle in the left ventricle which base (19 mm) was situated on the middle of the anterior-septum and apex connected with the apical portion of the lateral wall, inducing a dissinergic movement of the septum-apical segment as for the adjacent wall segments and with a reduced sistolic thickening. An exercise myocardial perfusion scintigraphy (Tl 201) detected no reversible or irreversible uptake defects, continuous ecg monitoring and an exercise test did not show any ischemic event. We discuss the electrogenetic and wall motion implication due to an aberrant papillary muscle that can be errorly considered secondary to a progress myocardial infarction.

Aged↗

PubMed1976

[Disopyramide phosphate: electrophysiological and inotropic effects in isolated cat papillary muscles and comparison with quinidine (author's transl)].

The effects of 4-diisopropylamino-2-phenyl-2-(2-pyridyl)-butyramide monophosphate (disopyramide phosphate; D; 10(-6)--10(-4) M) on transmembrane resting potential, action potential, effective refractory period and twitch tension were simultaneously studied in electrically driven (frequency 1 Hz) papillary muscles isolated from the right ventricles of cats. The experiments were performed at 35degrees C with intracellular glass microelectrodes. Quinidine sulfate (10(-6)--10(-4) M) was used for comparison. D increased the duration of the action potential during phase 3 (90% repolarization) in a concentration-dependent manner. The effective refractory period was prolonged by nearly the same extent whereas the maximal rate of rise of the action potential was reduced. The overshoot was slightly decreased only at 10(-4) M. Resting potential and plateau phase of the action potential were not affected by D. The effects of D on the electrical events were accompanied by concomitant decreases in twitch tension. The effects of quinidine were essentially similar to those obtained with D. It is concluded that the effects of D on dV/dtmax and effective refractory period observed in cat papillary muscle may account for the clinically observed efficacy of D to overcome ventricular arrhythmias. The results suggest also that the mechanism of the ventricular effects of D is similar to that of quinidine.

Action Potentials↗

PubMed1992

Effect of perfusion pressure on force of contraction in thin papillary muscles and trabeculae from rat heart.

1. Increased coronary perfusion leads to increased myocardial contraction and oxygen consumption (Gregg's phenomenon) even when oxygen supply is presumably sufficient. Previous studies concerned whole hearts, however, in which local hypoxia may play a role. We developed techniques for internal perfusion of thin papillary muscles from rat heart. The influence of perfusion pressure on muscle contraction was studied. We investigated whether Gregg's phenomenon is due to (a) hypoxia, (b) stretch of the muscle fibres, or (c) increased contractility. 2. The effectiveness of the perfusion technique was demonstrated in four ways: (a) the diameter of the capillaries increased with perfusion pressure; (b) 14 +/- 4% (mean +/- S.D., n = 11) increase in muscle diameter was observed on a change of perfusion pressure from 0 to 50 cmH2O; (c) addition of India ink to the perfusate caused rapid staining of the entire muscle; (d) during internal perfusion and external superfusion peak force was mainly determined by the [Ca2+] in the internal perfusate. 3. An increase of perfusion pressure from 0 to 70 cmH2O induced 74 +/- 20% (mean +/- S.D., n = 11) increase in peak force of contraction. In the absence of internal perfusion peak force was not affected by approximately 50% reduction of the PO2 in the bathing solution (from 700 to 350 mmHg). Hence, oxygen supply was not a limiting factor, i.e. the effect of internal perfusion on force was not related to hypoxia. 4. Segment length was measured with markers attached to the surface of the muscle. Perfusion-induced changes in segment length were negligible (-0.2 +/- 1.5%, n = 11). Force-length relationships at different perfusion pressures show that the perfusion-induced increase in force was generally larger than the maximum increase in force that could be induced by stretch. Furthermore, the time course of stretch and perfusion effects on force was different. We conclude that Gregg's phenomenon is not related to changes in fibre length, i.e. the hypothesis of pressure-induced stretch ('garden hose' effect) does not apply to papillary muscles. 5. The pressure-induced changes in the force-length relationship were similar to the changes obtained with interventions that increase contractility, such as increased [Ca2+]. 6. Since hypoxia and length effects were not involved, and the effect of perfusion pressure was similar to that of inotropic interventions, we conclude that Gregg's phenomenon is a change in contractility. Possible explanations include changes in the ionic composition or volume of the interstitium, and inotropic factors produced by the endothelium or intramyocardial neurons.

Animals↗

PubMed1999

Diazepam reduces action potential duration in guinea-pig papillary muscle by a cAMP-dependent mechanism.

In this study, we have analyzed the role of cyclic AMP (cAMP) as the mediator of the decrease in action potential duration induced by diazepam. Diazepam (1-100 microM) reduced, in a dose-dependent manner, the duration of intracellular action potential recorded in the papillary muscle obtained from the right ventricle of the guinea pig heart. This effect was mimicked by the analog of cyclic AMP, 8-Br-cAMP (100 microM), but not by gamma-amino-butyric acid (GABA). Also, the selective antagonist of the benzodiazepine receptors, flumazenil did not modify the effect of diazepam. The diazepam-induced shortening of action potential duration was partially antagonized by the inhibitor of cAMP synthesis carbachol (1 microM) or the blocker of the cAMP-dependent protein kinase A, Rp-cAMP[S] (1 microM). These results indicate that cyclic AMP is involved in the diazepam-induced shortening of the action potential duration of the guinea pig papillary muscle.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1997

Changes in electrophysiological and mechanical responses of the rat papillary muscle to alpha- and beta-agonist in streptozotocin-induced diabetes.

To clarify the changes occurring in diabetic animals in the responsiveness of the myocardium to alpha 1- and beta-adrenoceptor agonists, we examined both alpha- and beta-adrenoceptor-mediated electrophysiological and mechanical responses in the depolarized right ventricular papillary muscle of streptozotocin (STZ) induced diabetic rats and age-matched controls. Both methoxamine (10(-7)-10(-4) M) and isoproterenol (10(-9)-10(-6) M) enhanced the slow response action potential in a concentration-department manner. The amplitude and the APD50 (time required for 50% repolarization) of the methoxamine-induced slow response action potential were both markedly increased in STZ-induced diabetic rats in comparison with control rats, whereas those of the isoproterenol-induced slow response were significantly decreased. The methoxamine-induced contraction in depolarized muscle was slightly but not significantly increased in STZ-induced diabetic rats, whereas the isoproterenol-induced contractile response was significantly attenuated. The maximum number of binding sites (Bmax) for [3H]dihydroalprenolol and for [3H]prazosin were both significantly decreased in diabetic rats, compared with age-matched control rats, without any change in the affinity constants. The slow response action potential induced by methoxamine but not isoproterenol was attenuated by IAP (islet-activating factor) treatment (50 micrograms/kg, i.v. for 3 days). These results suggest that an alpha-adrenoceptor-mediated electrophysiological response is unmasked when the beta-adrenoceptor-mediated response is desensitized in the papillary muscle of STZ-induced diabetic rats.

Action Potentials↗

PubMed1990

Short incubation with 7-oxo-prostacyclin induces long lasting prolongation of repolarisation time and effective refractory period in rabbit papillary muscle preparation.

STUDY OBJECTIVE - To determine whether the long lasting protection from early postocclusion and reperfusion arrhythmias induced by 7-oxo-prostacyclin is due to an anti-ischaemic effect alone or in combination with direct membrane effects. DESIGN - The study was performed on electrically stimulated isolated rabbit papillary muscle preparations with or without incubation with a stable prostacyclin analogue, 7-oxo-prostacyclinephedrine (7-oxo-PgI2). In some experiments, rabbits were pretreated with 7-oxo-PgI2. MEASUREMENTS and RESULTS - Marked prolongation of action potential duration (APD90) and effective refractory period developed 2 h after 20 min incubation with and subsequent washout of 7-oxo-PgI2, 1.1 X 10(-8) mol.litre-1. The same occurred if incubation with 7-oxo-PgI2 was maintained throughout the experiment. The only other change was a small diminution in amplitude of the action potential. During the 20 min incubation period neither APD90 nor effective refractory period was affected and only a transitory increase in the maximum rate of depolarisation, disappearing after washout, was seen. During the 4 h observation period there were no changes in the control preparations. The long lasting electrophysiological changes induced by 7-oxo-PgI2 were not affected by 60 min incubation with indomethacin, 2.8 X 10(-6) mol.litre-1. Pretreatment of rabbits with 7-oxo-PgI2, 50 micrograms.kg-1 intramuscularly, 48 h before the experiments prolonged effective refractory period v untreated controls. CONCLUSIONS - 7-oxo-PgI2 induces prolongation of APD90 and effective refractory period in adequately oxygenated normal papillary muscles as well as in ischaemic hearts. Therefore a direct membrane effect may contribute to its antiarrhythmic action, as well as an indirect anti-ischaemic effect. Such a direct effect is unlikely to be related to activation of the degradation products of the arachidonic acid cascade since it was not influenced by indomethacin.

Action Potentials↗

PubMed2005

Quantification of annular dilatation and papillary muscle separation in functional mitral regurgitation: role of anterior mitral leaflet length as reference.

BACKGROUND: We hypothesized that anterior mitral leaflet length (ALL) does not differ significantly between normal subjects and patients with functional mitral regurgitation (FMR) and hence may be used as a reference measurement to quantify annular dilatation and papillary muscle separation. METHODS AND RESULTS: We prospectively studied 50 controls, 15 patients with systolic left ventricular dysfunction (LVD) with significant FMR, and 15 patients with LVD without significant FMR. Significant MR was defined as an effective regurgitant orifice area > or = 0.2 cm2 as measured by the flow convergence method. Annular diameter, interpapillary distance, and ALL were measured, and the following ratios were derived: annular diameter indexed to ALL (ADI) and interpapillary distance indexed to ALL (IPDI). There was no significant difference in ALL among the three groups. The mean ADI was 1.26 times controls in patients with LVD without significant FMR compared to 1.33 times controls in patients with LVD with significant FMR (P = 0.06, no significant difference between groups). The mean IPDI was 1.42 times controls in patients with LVD without significant FMR compared to 2.1 times controls in patients with LVD with significant FMR (P < 0.0001, significant difference between groups). CONCLUSION: There was no significant difference in ALL between controls and patients with LVD. ALL can be used as a reference measurement to quantify annular dilatation and papillary muscle separation in patients with FMR. Interpapillary distance but not annular diameter indexed to ALL correlates with severity of FMR.

Aged↗

PubMed1991

[A case of acute postinfarction mitral insufficiency and cardiogenic shock caused by total rupture of a papillary muscle].

A 61-year-old male in cardiogenic shock was transferred to our hospital with an intra-aortic balloon pumping (IABP). He had had acute posterior myocardial infarction previous day. He had developed progressively increasing dyspnea and physical signs of severe congestive failure. On admission, his blood pressure was 60 mmHg even with IABP. He was anuric with a high blood urea nitrogen and serum creatinine level. An echocardiogram demonstrated a rupture of a posterior papillary muscle and massive mitral insufficiency. His deteriorating condition did not allow us to perform cardiac catheterization. He underwent an emergency operation. Total rupture of a posterior papillary muscle was confirmed. Mitral valve replacement with a SJM prosthetic valve was performed. A postoperative course was uneventful.

Humans↗

PubMed2005

QT PRODACT: evaluation of the potential of compounds to cause QT interval prolongation by action potential assays using guinea-pig papillary muscles.

Certain compounds that prolong QT interval in humans have little or no effect on action-potential (AP) duration used traditionally, but they inhibit rapidly-activated-delayed-rectifier potassium currents (IKr) and/or human ether-a-go-go-related gene (hERG) currents. In this study using isolated guinea-pig papillary muscles, we investigated whether new parameters in AP assays can detect the inhibitory effects of various compounds on IKr and/or hERG currents with high sensitivity. The difference in AP duration between 60% and 30% repolarization, 90% and 60% repolarization, and 90% and 30% repolarization (APD30-60, APD60-90, and APD30-90, respectively) were calculated as the new parameters. All the 15 IKr and/or hERG current inhibitors that have been reported (9 compounds) or not reported (6 compounds) to inhibit calcium currents prolonged APD30-60, APD60-90, and/or APD30-90; and 8 of the 15 inhibitors prolonged APD30-60, APD60-90, and/or APD30-90 more potently than APD90. The APD30-60, APD60-90, and APD30-90 measurements revealed no difference in sensitivity when evaluating the effects of the IKr and/or hERG current inhibitors on the three parameters. On the other hand, compounds with little or no effect on hERG currents had no effect on APD30-60, APD60-90, or APD30-90. Therefore, it is concluded that in AP assays using isolated guinea-pig papillary muscles, APD30-60, APD60-90, and APD30-90 are useful indexes for evaluating the inhibitory effects of compounds including mixed ion-channel blockers on IKr and/or hERG currents.

Action Potentials↗

PubMed1990

The energy cost of relaxation in control and hypertrophic rabbit papillary muscles.

The energy cost of the onset and relaxation phases of cardiac isometric contractions has been investigated by ergometer controlled-length releases occurring at different times during the contraction cycle, to test the hypothesis that the energy cost of relaxation is normally small. Energy flux has been measured myothermically in 20 or 30 contractions of rabbit papillary muscles. The ergometer releases took place after different delays, starting during the latency period and incrementing in 50 ms steps, until eventually, releases were occurring late into the relaxation phase. The release step was kept constant and of a magnitude sufficient to prevent significant redevelopment of active stress at any release interval. The rate of release was several times greater than the maximum shortening velocity of the papillary muscle preparations. The heat production in each train of contractions was measured, but in order to estimate the total energy output, the elastic energy in the muscle-lever system which was removed by the ergometer release had to be added to the heat. This was estimated by integration of the stress-strain relationship found for each muscle. In normal animals the contraction peak, at 27 degrees C and a 1.0 Hz stimulus rate, was located between the 215 and 265 ms release times, at which point the total energy flux was estimated to be 80%-90% of that measured in a normal isometric contraction. Additional experiments were performed in a group of volume-overloaded hearts and the data were compared with results from sham-operated controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Effects of hypoxia and reoxygenation on regular contractions and postrest contraction in rat papillary muscles.

The effects of hypoxia and reoxygenation on regular contractions and postrest contractions (PRC) of papillary muscle of rats were studied. Isometric tension was measured during two cycles of hypoxia and reoxygenation. Trains of 80 externally continuous stimulations at 40/min were applied. PRCs were evoked by a stimulus train after a 60 sec resting interval. After 90 min of hypoxia (the first hypoxia period), regular contractions and PRCs decreased to 5.6 +/- 2.0% and 23.4 +/- 2.4% of baseline values, respectively (p less than 0.001; n = 18). After 90 min of reoxygenation, the recovery of the PRCs (44.4 +/- 3.4%) was better than that of the regular contractions (23.3 +/- 3.3%) (p less than 0.01; n = 18). After 30 min of hypoxia (the second hypoxic period), regular contractions and PRCs decreased to 2.2 +/- 0.6% and 13.6 +/- 1.6% of baseline values, respectively (p less than 0.001; n = 18). However, the recovery from the second hypoxic injury was not significant for either regular contractions or PRCs. The % diastolic tension, which was normalized to the baseline for regular contractions, increased to 113.2 +/- 6.9% and 133.6 +/- 8.4% at the end of the first and the second hypoxic periods, respectively. There was statistically significant correlation between the % diastolic tension and the % hypoxic injury of PRCs (p less than 0.002; n = 18). There was no significant relationship between % diastolic tension and % hypoxic injury of regular contractions. There was no statistically significant correlation between % diastolic tension and % recovery from the hypoxic injury of either regular contractions or PRCs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

The cellular electropharmacology of mexiletine combined with sotalol in porcine papillary muscle and Purkinje fibre. I. Alteration of mexiletine-induced Vmax depression.

Using standard microelectrode techniques, the authors compared the effects of 15 to 125 microM concentrations of mexiletine, 31 to 500 microM concentrations of sotalol and 15 to 125 microM of mexiletine combined with 125 microM sotalol, on the beat-to-beat maximum rate of depolarization of phase 0 of the action potential (Vmax) of porcine papillary muscles and Purkinje fibres stimulated by 30 beat trains at a frequency of 1 Hz. Sotalol alone had no effect on Vmax. Mexiletine caused both tonic and use-dependent depression of Vmax in papillary muscle. In the presence of sotalol, tonic Vmax depression was exaggerated, while use-dependent depression was attenuated. In Purkinje fibres, mexiletine exposure resulted in tonic Vmax depression, but no use-dependence could be demonstrated at this frequency. These results are best explained in the context of the modulated receptor hypothesis with the added consideration of two receptors--one within and one external to the sodium channel.

Action Potentials↗