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The slow phase of the staircase in guinea-pig papillary muscle, influence of agents acting on transmembrane sodium flux.

Guinea-pig papillary muscles contracting at frequencies of 0.25 to 1 Hz after rest periods long enough to be followed by a rested-state contraction showed a biphasic staircase phenomenon. An initial phase was completed within about 6 beats (fast phase of the staircase). Then a slow phase followed reaching a steady state after about 4 min only. The effect on this slow phase exerted by drugs known to influence transmembrane Na-flux was investigated. Dihydroouabain in concentrations (1.5-5 X 10(-5) mol/l), causing no increase in the rested-state contraction considerably augmented the slow phase of the staircase thereby prolonging the time from the onset to the steady state by severalfold. The fast phase, however, remained unchanged as far as the steepening slow phase did not influence it. The rest decline of force of contraction, measured by repeated interruption of stimulation, was considerably prolonged by dihydroouabain (to about sixfold the control value by 5 X 10(-5) mol/l). However, dihydroouabain did not influence the time course by which the force of contraction decreased after lowering the [Ca]0 from 3.2 to 0.8 mmol/l. Stimulation of the muscles in Ca-free medium produced a transient increase in force of contraction as visualized by test contractions after addition of Ca. This positive inotropic aftereffect which depended on the frequency of stimulation in the Ca free solution was augmented severalfold by 1.5 to 3 X 10(-5) mol/l dihydroouabain.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Velocity transients and viscoelastic resistance to active shortening in cat papillary muscle.

When isotonic force steps were applied to activated papillary muscles, the velocity was almost never constant. Early rapid shortening associated with the step persisted for 2-7 ms after the step ends. The early rapid shortening is attributed to lightly damped series elastic recoil and velocity transients of the contractile elements. In most steps, the subsequent velocity declines progressively with shortening, and most of the decline in velocity can be accounted for by compression of a viscoelastic element in parallel with the contractile elements. To demonstrate this, the time course of isotonic velocity was compared with a model in which the force-velocity characteristics of the contractile element were assumed to be constant, and the decline in velocity was due to increasing compression of the viscoelastic element. This model predicted the observed results except that the predicted velocities rose progressively above the measured values for steps to light loads applied late in the twitch, and fell below the velocity trace for heavy loads applied early in the twitch. These deviations would occur if rapid shortening caused deactivation late in the twitch, and if activation were rising early in the twitch. A conditioning step applied to the muscle during the rise of force depressed both isometric force and maximum velocity measured at the peak of force; isometric force was more depressed with later conditioning steps than with earlier steps, while maximum velocity was depressed by about the same extent with both early and late steps. This difference between the effects on isometric force and maximum velocity are explained by a combination of deactivation and viscoelastic load.

Animals↗

The echocardiographic diagnosis of rupture of a papillary muscle.

The echocardiographic diagnosis of acute rupture of a papillary muscle is described. The pertinent findings included (1) decreased systolic motion of the posterior wall, (2) exaggerated septal motion, (3) left ventricular enlargement and pattern suggesting left ventricular diastolic overload, and (4) bizarre fluttering of posterior leaflet of the mitral valve in diastole, suggesting an unhinging of the mitral valvular apparatus. The echocardiogram is a useful noninvasive tool in the diagnosis of this often fatal complication of myocardial infarction.

Aged↗

Effects of D-600 and its optical isomers on force of contraction in cat papillary muscles and guinea-pig auricles.

1 (--)-D-600 and (+)-D-600 exerted concentration-dependent negative inotropic effects in papillary muscles from cats, the potency of (--)-D-600 being about 100 times greater than that of (+)-D-600. The action was more pronounced at high than at low frequencies of stimulation. Time to peak force, relaxation time and therefore also total duration of contraction were not significantly affected by the drugs. 2 The negative inotropic effects of both drugs were not reversible after washing in drug-free solution for 60 min at all concentrations tested. 3 The same negative inotropic effects were seen in guinea-pig left auricles with the racemic mixture of both isomers. 4 Uptake measurements of D-600-[nitrile-14C] in isolated left auricles of guinea-pigs showed the drug to be accumulated in the myocardial tissue; tissue-medium ratios from 1.25 to 6.0 were found at exposure times from 1 to 100 minutes. Preparations which were loaded first with D-600-[nitrile-14C] for 100 min and then washed in drug-free solution for different times lost up to about 80% of the initial radioactivity, whereas the depression of force of contraction was not reversible. 5 The results show that there are marked quantitative differences between the actions of (--)-D-600 and (+)-D-600 on isometric force of contraction in cat papillary muscles. Although the time course of the uptake of D-600-[nitrile-14C] and the development of the negative inotropy in guinea-pit left auricles were reasonably well related, the magnitude of the negative inotropy does not seem to be dependent on the total tissue concentration once the negative inotropic effect has been fully developed.

Animals↗

Faster time to peak tension and velocity of shortening in right versus left ventricular trabeculae and papillary muscles of dogs.

Some of the mechanical characteristics of papillary muscles and trabeculae (n = 14) isolated from the free wall of the right ventricle of dogs were compared to those obtained from the free wall of the left ventricle (n = 14). Peak total tension (7.2 +/- 1.6 versus 7.9 +/- 1.7 g/mm2, p = NS) and peak velocity of tension development (31 +/- 8 vs. 28 +/- 4 g/mm2/sec, p = NS) were similar in both groups of muscles. However, right ventricular muscles shortened faster over nearly all loading conditions, and during isometric contraction, their time to attain peak total tension was shorter (336 +/- 26 vs. 401 +/- 42 msec, p less than 0.005) than that of left ventricular muscles. Varying stimulation rates (6, 12, 24, and 36 stimuli/min), increasing calcium concentration from 2.54 to 6.35 mM or adding norepinephrine 50 microM, did not significantly alter these differences. There were no differences in myosin isozymes (V1, V2, or V3) between ventricles to explain these differences. These results indicate that important mechanical differences exist between right and left ventricular myocardium and that these differences should be considered when extrapolations are made from myocardium of one area of the heart to another.

Animals↗

The effects of temperature on the energetics of rat papillary muscle.

The mechanical and myothermic responses of left ventricular papillary muscles from adult rats have been examined at 20 degrees and at 27 degrees C. Contraction trains of six isometric or isotonic twitches at 1/6 Hz were used to establish the heat-stress and load-enthalpy relations respectively. Peak isometric stress was slightly higher at 20 degrees than at 27 degrees C (45 vs. 41 mN/mm2) and was inversely related to muscle cross-sectional area. The stress-independent heat component, identified with the activation heat, was 75% greater at the lower temperature. The stress-dependent heat component, identified with the heat of actin-myosin interaction, was unaffected by temperature. In isotonic experiments the external work performance was similar at both temperatures but the heat liberation was significantly enhanced at the lower temperature so that mechanical efficiency (external work/enthalpy) was reduced. Evidence is presented suggesting that the preparations were not O2-diffusion limited at either temperature. The results are discussed in terms of known functional anomalies of rat cardiac tissue.

Animals↗

[Experimental studies on the mechanism of action of carbocromen on the isolated cat papillary muscle (author's transl)].

1. In isotonically shortening cat papillary muscle 3-(2-di-ethylaminoethyl)-4-methyl-7-(carbethoxy-methoxy)-2-oxo-1,2-chromene-hydrochloride (carbocromen; Intensain¿) (1-30 mug/ml) slightly increases contraction amplitude. 2. At low stimulation rates (6-12/min) the positive inotropic effect is more pronounced. 3. The maximal velocity of depolarization of the monophasic action potential is slightly reduced. 4. At all stimulation frequencies investigated (15-90/min) the total duration of the action potential -- especially at late repolarization level -- is strongly increased. Hence, functional refractory period is prolonged and maximal follow frequency reduced.

Action Potentials↗

Effects of phytoestrogen genistein on delayed after depolarization and triggered activity induced by ouabain in guinea pig papillary muscles.

The purpose of this study was to investigate the effects of phytoestrogen genistein (GST) on delayed after depolarization (DAD) and triggered activity (TA) induced by ouabain in guinea pig papillary muscles. Action potentials (APs) were recorded from the guinea pig papillary muscles with standard glass microelectrode technique. The results are as follows: (1) DAD and TA induced by ouabain (1 micromol/L) were markedly inhibited by pretreatment with GST (10, 50, 100 micromol/L) in a concentration-dependent manner. (2) NG-nitro-L-arginine methyl ester (L-NAME, 1 mmol/L), an NO synthase inhibitor, failed to affect the above effects of GST. (3) 5 micromol/L 17beta-estradiol (E2) or 10 micromol/L GST alone showed no effects on DAD and TA, whereas GST combined with E(2) at the same doses exerted significant inhibitory effects on DAD and TA. Since GST is known to reduce the calcium influx, it is suggested that GST might have antiarrhythmic effects, possibly by reducing calcium influx. The antiarrhythmic effects of GST may contribute to its cardioprotective action.

Action Potentials↗

Effect of mercurascan on the contractility and excitability of dog papillary muscle in vitro.

The authors studied in 6 experimental series the effect of Mercurascan (2-hydromercurifluorescein and 4-hydroxymercurifluorescein) on isolated dog papillary muscle in vitro; they evaluated the magnitude and character of its electrically stimulated contractions. It was found that at concentration of 10(-3)M and 10(-4) M, Mercurascan (MSC) exerts a significant positive inotropic effect on papillary muscle. Incubation of the muscle in a medium containing MSC at the above-given concentrations significantly suppressed the positive inotropic and arrhythmogenic effect of adrenalin, added in an over-threshold dose into the nutrient medium.

Animals↗

Calcium channels and excitation-contraction coupling in cardiac cells. II. A pharmacological study of the biphasic contraction in guinea-pig papillary muscle.

Biphasic contractions were obtained in guinea-pig papillary muscle by inducing partial depolarization in K+-rich solution (17 mM) in the presence of 0.3 microM isoproterenol. Mn2+ ions inhibited the two components of contraction in a similar way. Nifedipine and particularly Cd2+ ions specifically inhibited the second component of contraction. Isoproterenol and BAY K 8644 markedly increased the amplitude of the second component (P2) of contraction. Nevertheless, a moderate positive inotropic effect of isoproterenol was found on the first component (P1) of contraction when excitability was restored by 0.2 mM Ba instead of isoproterenol. Acetylcholine and hypoxia decreased the amplitude of the second component of contraction to a greater extent. In the presence of digoxin or Na+-free solution, P1 was strongly increased. When sarcoplasmic reticular function was hindered by 1mM caffeine or in the presence of Ca2+-free Sr2+ solution, digoxin always induced a negative inotropic effect on P2. Inversely in these conditions the transient positive inotropic effect of Na+-free solution was strongly reduced. These results are consistent with the hypothesis that the late component of contraction is triggered by the slow inward Ca2+ current and that the early component is due to Ca2+ release from the sarcoplasmic reticulum.

Acetylcholine↗

Contractility of papillary muscle from rats exposed to 28 days of hypoxia, hypercapnia, and hypoxia with hypercapnia.

The effects of chronic respiratory failure (hypoxia and hypercapnia) on the contractile properties of cardiac muscle are not established. A study was performed of the isometric contractile properties of isolated papillary muscle removed from rats exposed in a normobaric environmental chamber to 28 days of hypoxia (fractional inspired oxygen (FIO2) 10%, fractional inspired carbon dioxide (FICO2) less than 1%), hypercapnia (FIO2 21%, FICO2 5%), and hypoxia with hypercapnia (FIO2 10%, FICO2 5%). Rats exposed to both hypoxia and hypoxia with hypercapnia developed selective right ventricular hypertrophy. Exposure to hypercapnia alone did not alter right ventricular weight. No change in right ventricular papillary muscle contractility per unit muscle mass was observed as measured by maximum active tension, maximum rate of rise or fall of tension, or time to peak tension. Rat cardiac muscle adapts successfully to the altered acid-base environment and increased work load associated with prolonged exposure to hypoxia and mild hypercapnia.

Animals↗

New surgical approach to reduce tethering in ischemic mitral regurgitation by relocation of separate heads of the posterior papillary muscle.

The surgical treatment of chronic ischemic mitral regurgitation remains a challenging issue. Several procedures have been developed to correct displacement of the papillary-ventricular complex and to reduce tethering-induced regurgitation. We report a geometric approach to relocate the laterally displaced posterior papillary muscle towards the mitral annulus. This procedure is believed to be technically easy and useful, especially in cases in which the displaced posterior papillary muscle contributes to tethering-induced regurgitation.

Aged↗

Stereoselective effects of the enantiomers of bupivacaine on the electrophysiological properties of the guinea-pig papillary muscle.

1 Direct myocardial effects of the S(-)- and R(+)-enantiomers of bupivacaine were compared in the guinea-pig isolated papillary muscle by recording transmembrane action potentials with the standard microelectrode technique. 2 In 5.4 mM K+, at a stimulation rate of 1 Hz, the maximal rate of depolarization (Vmax) was reduced to 59.9 +/- 1.4% (n = 10) of control (mean +/- s.e.mean) in the presence of 10 microM R(+)-bupivacaine, and to 76.7 +/- 1.2% (n = 14) in the presence of the same concentration of S(-)-bupivacaine. This was mainly due to a difference in time constant at which block dissipated during the diastolic period. Recovery was slower in the presence of R(+)-bupivacaine. The slower recovery in the presence of R(+)-bupivacaine resulted also in a more pronounced frequency-dependent block of Vmax. 3 Time constants for recovery from use-dependent block became significantly faster for both enantiomers on hyperpolarization, while no significant change was observed at depolarization. At all membrane potentials recovery was slower in the presence of R(+)-bupivacaine. 4 The action potential duration (APD) was shortened to a greater extent in the presence of R(+)-bupivacaine over a large range of stimulation frequencies. 5 We conclude that S(-)-bupivacaine affects Vmax and APD in the guinea-pig papillary muscle less than the R(+)-enantiomer at different rates of stimulation and resting membrane potentials.

Action Potentials↗

Amrinone and energy output of rabbit papillary muscles.

We studied the effects of amrinone (300 micrograms X ml-1) on the mechanical and energetic outputs of nonfailing rabbit papillary muscles at 27 degrees C using a myothermic technique. Amrinone was found to markedly stimulate the basal (i.e., nonbeating) metabolism. In mechanical experiments, at a 0.5-Hz stimulus rate, amrinone increased the rate of stress development and peak active stress but shortened the time to peak stress and the contractile duration. The linear relationship between total (active + passive) stress and heat production was altered by amrinone such that there was a 68% increase in the activation heat component (intercept) and an 11% increase in the energy cost per unit stress development (slope). In afterloaded isotonic experiments amrinone increased the capacity of papillary muscles to accomplish external work (W) by approximately 50% on average; however, this effect was associated with an increased total energy usage per beat (ET) such that the overall mechanical efficiency (W/ET X 100%) was not significantly altered at any load level. We conclude that amrinone greatly increases calcium delivery to the myofilaments and slightly increases the cost of stress development. These effects are examined in the light of amrinone's postulated mode of action, and possible reasons for the clinical observation of a decrease in myocardial oxygen consumption after amrinone administration are considered.

Aminopyridines↗

Evidence for beta 2-adrenoceptor-mediated facilitation of 3H-noradrenaline release from isolated guinea pig papillary muscles.

The effects of beta-adrenoceptor agonists and antagonists on field-stimulated release of radioactivity from superfused guinea pig papillary muscles preincubated with 3H-noradrenaline were studied. Stimulation-evoked overflow of tritium was abolished in the absence of Ca2+ or the presence of tetrodotoxin. Isoprenaline (1 mumol/L) caused a slight facilitation of evoked overflow, whereas phentolamine (1 mumol/L) exerted a strong facilitatory action. However, when phentolamine (1 mumol/L) was present throughout superfusion, isoprenaline and the selective beta 2-adrenoceptor agonist, zinterol, caused concentration-dependent increases (half-maximal effects at 1 nmol/L). The effects of the agonists were inversely related to stimulation frequency. Furthermore, the concentration-response curve of isoprenaline was shifted to the right by the selective beta 2-adrenoceptor antagonist, ICI 118,551, but not by the selective beta 1-adrenoceptor antagonist, ICI 89,406. Schild-plot analysis revealed competitive antagonism and a pA2 value of 9.04 for ICI 118,551. Both ICI 118,551 and ICI 89,406, as well as beta-adrenoceptor antagonists with intrinsic sympathomimetic activity (pindolol and celiprolol; 1 mumol/L), had no effect on stimulation-evoked overflow of tritium (phentolamine present). It is concluded that guinea pig papillary muscles are endowed with prejunctional beta 2 adrenoceptors facilitating impulse-evoked noradrenaline release. The facilitation is markedly promoted by blockade of prejunctional alpha adrenoceptors.

Adrenergic beta-Agonists↗

Cardiac effects of amrinone on rabbit papillary muscle and guinea pig Langendorff heart preparations.

Amrinone (50-1,000 microgram/ml) produces a dose-dependent inotropic action on rabbit papillary muscle. The hypodynamic state following prolonged stimulation is prevented or abolished by amrinone, and contractile force remains significantly elevated over drug-free controls throughout the ensuing 3-h duration of exposure. In a concentration of 1 mg/ml, dysrhythmic phenomena occasionally appeared, e.g., bigeminy, automaticity, and elevated threshold to electrical stimulation. Bigeminy could be abolished either by increasing the external K+ concentration in the bathing media, or by raising the stimulating voltage. However, amrinone failed to alter the refractory period following 60 min of exposure. In isolated perfused guinea pig Langendorff heart preparations, amrinone (50 microgram/ml) significantly increased coronary flow, myocardial oxygen consumption (MVO2), cardiac work, and, during the period of peak activity, dP/dt. However, it had no significant effect on cardiac efficiency. And, as in the papillary muscle preparation, the effect of amrinone was easily reversed by perfusing the preparation with fresh (no-drug) media. Preliminary evidence shows that amrinone fails to reverse the negative inotropic action of verapamil as well as calcium-free media, although the effects on heart rate, coronary flow, and MVO2 were reversed. However, the higher the external calcium concentration, the greater was the level of contractile response achieved by amrinone. Thus, the mechanism of amrinone-induced augmentation appears to be dependent upon the availability of calcium.

Aminopyridines↗

Simultaneous assessment of effects of coronary vasodilators on the coronary blood flow and the myocardial contractility by using the blood-perfused canine papillary muscle.

Effects of 6 coronary vasodilators on the coronary blood flow and the contractile force of the ventricular muscle were examined simultaneously by injecting these drugs to the arterially blood-perfused canine papillary muscle preparation. All compounds produced a dose-dependent increase in blood flow rate, and relative potencies determined on the basis of doses producing a 100% increase in blood flow rate, ED100, were in the descending order : nifedipine greater than verapamil greater than diltiazem greater than dilazep greater than dipyridamole greater than carbochromen, and approximately 1 : 1/12 : 1/26 : 1/100 : 1/300 : 1/500. All drugs except for dipyridamole caused a dose-dependent decrease in the developed tension of the papillary muscle, although nifedipine and diltiazem in low doses produced a slight increase. Relative potencies determined on the basis of doses producing a 50% decrease in developed tension, ID50, were as follows: nifedipine (1), verapamil (1/13), diltiazem (1/40), dilazep (1/100), and carbochromen (1/270). Ratios of the ID50 to ED100 were as follows: diltiazem (5.2), nifedipine (3.5), verapamil (3.5), dilazep (2.5), and carbochromen (1.8). The higher the value the more predominant on the coronary vascular bed or the less depressant on the myocardial contractility were their actions.

Animals↗

Functional changes in isolated guinea-pig papillary muscle induced by monensin and digoxin.

The effects of digoxin and monensin on contraction force (CF), initial contraction velocity (ICV), average contraction velocity (ACV), initial relaxation velocity (IRV) and stimulus to response time (ST) in 'fatigued' (tired) and 'non-fatigued' (fresh) guinea-pig papillary muscles were investigated. 'Fatigued' muscles had lost 30% of their original CF with the elapse of time before they were treated. The 5 h of measurement were divided into five periods (T0 was equilibration, T1, T2, T3 and T4 were, respectively, 1, 2, 3 and 4 h after drug administration). It was found that both monensin and digoxin increased the CF, ICV and ACV at T1 and increased the IRV at T2. Digoxin lost its effect with the elapse of time while monensin did not. Digoxin also decreased the ST at T2, T3 and T4. However, monensin did not change the ST. It was also found that 'fatigued' and 'non-fatigued' guinea-pig papillary muscles did not respond to the drug treatment differently. It was concluded that the initial effects of these two drugs on guinea-pig papillary muscles are similar regarding contractility but in time digoxin loses its effect while monensin does not.

Animals↗