Blockade of the inotropic effect of Bay K 8644 by cytochalasin-B and phloretin.

1. The positive inotropic effect in rabbit atria and papillary muscles of Bay K 8644 is blocked by cytochalasin-B (Cyto-B) and phloretin, two compounds known to block the facilitated diffusion of glucose. These compounds do not change the concentration-response curve of calcium. 2. Cyto-B is more potent in atria than in papillary muscles, 10(-7) M having a maximal effect in atria whereas 2 x 10(-5) M was required for a maximal effect in papillary muscles. Phloretin was fully effective at 10(-4) M, the only concentration tested. 3. The inotropic effect of Bay K 8644 was virtually abolished in atria bathed in a glucose-free medium or one containing 5 mM pyruvate. The contractile response to Bay K 8644 of papillary muscles was not changed significantly in glucose-free or in pyruvate-containing medium. 4. Cyto-B (2 x 10(-5) M) caused a slight but significant increase in the KD for the binding of nitrendipine to a crude sarcolemnal preparation from rabbit ventricles. The Bmax was unchanged. 5. These results may best be explained by the hypothesis that there is a metabolic requirement for the inotropic effect of Bay K 8644.     

BAY K 8644-induced enhancement of 45Ca uptake by rabbit aortic rings

BAY K 8644, a Ca2+ channel activator, enhances uptake of 45Ca by rabbit aortic rings. This effect depends on the concentration of K+ in the medium: at 20 mM K+ the effect of BAY K 8644 was more pronounced than at 5 mM, whereas at 80 mM, no significant enhancement of 45Ca uptake by BAY K 8644 was found. In the medium containing 5 mM K+, BAY K 8644 was effective in experiments involving 10 or 30 (but not 3) min exposure of aortic rings to 45Ca. The dose-response curve for BAY K 8644 was established in 5 mM K+-containing medium and for 30 min exposure to 45Ca. BAY K 8644 was effective at 0.01 microM and higher concentrations. In the presence of norepinephrine (0.1 or 10 microM), BAY K 8644 had no greater effect on 45Ca uptake than in control 5 mM K+ medium. Our observation that the presence of norepinephrine in 5 mM K+ did not enhance BAY K 8644-induced 45Ca uptake suggests that activation of alpha-adrenergic receptor does not depolarize aortic membranes to the same extent as an increase in K+ concentration to 20 mM or that BAY K 8644 does not enhance Ca2+ entry through receptor-operated channels.     

The positive inotropic action of the nifedipine analogue, Bay K 8644, in guinea-pig and rat isolated cardiac preparations.

The inotropic effect of Bay K 8644 has been studied in rat and guinea-pig atria and ventricular strips stimulated at 1 Hz, in a medium containing CaCl2 1.8 mM. The positive inotropic effect at maximal effective concentrations of Bay K 8644 was in the following order: guinea-pig ventricle greater than rat ventricle greater than guinea-pig atria greater than greater than rat atria. In rat preparations, the tension recorded at maximum effective concentrations of Bay K 8644 was similar at three different calcium concentrations (0.7, 1.8, 3.0 mM). The amplitude of the positive inotropic effect evoked by Bay K 8644 increased when atrial and ventricular contractions were reduced by lowering the external calcium concentration. The contractile tension reached in the presence of maximum effective concentrations of Bay K 8644 (3 X 10(-7) -1 X 10(-6) M) was greater than that produced by the maximum effective concentration of external calcium (3 mM) in rat ventricles but not in rat atria. High doses of nifedipine (3 X 10(-7) -1 X 10(-6) M) depressed the contraction of rat atria more than the contraction of rat ventricles. In rat ventricles, nifedipine shifted to the right the inotropic dose-effect curve of Bay K 8644. It is concluded that the interaction between nifedipine and Bay K 8644 occurred at the same binding sites. These sites have some characteristics of the low affinity binding sites of nifedipine and other related dihydropyridines.     

Responses to amrinone in isolated cardiac muscles from cat, rabbit, and guinea pig

Amrinone (10(-5)-10(-2) M) produced a positive inotropic response in several electrically stimulated, isolated cardiac muscle preparations. The order of potencies for amrinone in the tissues studied was: cat papillary muscle greater than rabbit papillary muscle greater than muscle strips from rabbit left atria = guinea pig papillary muscle greater than guinea pig left atria. Amrinone also restored contractility to cat and rabbit papillary muscles which had been partially depolarized with 20 mM K+. The beta-adrenergic antagonists timolol and propranolol partially inhibited these responses in rabbit but not cat papillary muscles. Reserpine pretreatment did not influence the responses to amrinone in any of the preparations studied. In conclusion, (a) the cat papillary muscle was the most sensitive preparation to the inotropic effect of amrinone, and (b) in the rabbit papillary muscle, beta-adrenoceptors contribute to the amrinone response but are not solely responsible for the enhanced inotropy.     

Cardiac versus vascular effects of a new dihydropyridine derivative, CV-4093. In vitro comparison with other calcium antagonists

The effects of CV-4093, a new dihydropyridine derivative, on isolated cardiovascular tissues were compared with those of several dihydropyridine and non-dihydropyridine calcium antagonists. CV-4093 effectively inhibited the contractions induced in canine femoral arteries by high [K+]0 and Bay K 8644, but incompletely relaxed those induced by norepinephrine. CV-4093, 10(-6) M, abolished the electrically induced slow action potentials in guinea-pig papillary muscles partially depolarized by 25 mM K+ solution and attenuated those induced by isoproterenol, histamine and Bay K 8644. The rank order of potency of dihydropyridine and non-dihydropyridine calcium antagonists in canine femoral arteries and veins precontracted with 120 mM [K+]0 was as follows: nisoldipine greater than nicardipine greater than or equal to nifedipine greater than or equal to CV-4093 greater than verapamil greater than or equal to diltiazem. Nisoldipine was the most potent and CV-4093 was the least potent among these drugs in terms of negative inotropic effect in normally polarized papillary muscles and negative chronotropic effect in right atria of guinea pigs. The rank order of potency for these cardiodepressant actions was nisoldipine greater than or equal to nifedipine greater than nicardipine greater than verapamil greater than diltiazem greater than or equal to CV-4093. The duration of action potential in guinea-pig papillary muscles was shortened by nisoldipine and nifedipine, unchanged by nicardipine and CV-4093 and was slightly prolonged by verapamil and diltiazem. These results suggest that CV-4093 is a calcium antagonist with a highly selective vascular effect and little cardiodepressant action, and could be of value for the treatment of hypertension.     

Activators of Sodium,Calcium and Potassium Channels Modulate the Cardiac Effects of Quinidine in vitro

Abstract: Quinidine (25.5 μmol/l) reduced the beating frequency of isolated right guinea-pig atria, caused a negative inotropic effect in papillary muscles and slightly raised the contractile force of left atria. The functional refractory period of both tissues was prolonged. A 20% increase of the extracellular sodium concentration did not reverse the effects of quinidine. The Na-channel activator BDF 9148 (1 μmol/l) and the Ca-channel agonist Bay-K-8644 (0.5 μmol/l) further increased the contractile force and caused an additional prolongation of the functional refractory period in quinidine-pretreated atria. Only Bay-K-8644 was able to reverse the negative inotropic effect of quinidine in papillary muscles. The influence of Bay-K-8644 on the contractile force in quinidine-pretreated muscles was not attenuated by lemacalim (3 μmol/l), an activator of ATP-dependent potassium channels, but the duration of the functional refractory period was significantly reduced. These results suggest that a combination of a calcium channel activator and a potassium channel opener might be able to improve the treatment of quinidine intoxications.     

Negative inotropic and arrhythmic effects of high doses of ciguatoxin on guinea-pig atria and papillary muscles

Ciguatoxin, the toxin present in fish responsible for ciguatera, at doses equal or above the maximum positive inotropic dose in atria (greater than 0.15 mouse units/ml) induced arrhythmias in atria and papillary muscles stimulated at 1 Hz and dose-dependent negative inotropy in atria. Negative inotropy was enhanced by ouabain or by an increase in stimulation to 3 Hz, little affected by procaine or increasing Ringer [Ca2+] and reversed by lidocaine and tetrodotoxin (TTX). Ciguatoxin caused negative inotropy associated with cell depolarisation in 1.2 mM Ca2+-Ringer and additionally caused signs of Ca overload in 3.2 mM Ca2+-Ringer. Ciguatoxin induced transient after-contractions and contracture in atria which were common in 3.2 mM but not 1.2 mM Ca2+-Ringer and which were enhanced by ouabain. TTX and lidocaine abolished after-contractions and contracture while procaine was less effective. Extrasystoles consisting of short bursts of 1-2 extra contractions per sec were seen in atria and papillary muscles within 45 min of ciguatoxin being added. The effect was observed in 3.2 mM but seldom in 1.2 mM Ca2+-Ringer and was absent when low doses of propranolol or TTX were added prior to ciguatoxin. Flutter was observed in a few papillary muscles after ciguatoxin. These results suggest that the toxic effects of ciguatoxin stem from its direct action of opening myocardial Na+ channels. Extrasystoles appeared to result mainly from its effect on neural Na+ channels causing an increased release of noradrenaline from the nerves associated with the myocardium.     

The effects of P1- and muscarinic-receptor agonists upon cAMP-dependent and independent inotropic responses of guinea-pig cardiac preparations.

1. The indirect negative inotropic effects of P1- and muscarinic-receptor agonists were compared by examining how the responses of isolated guinea-pig left atria and papillary muscles to positive inotropes were affected by the presence of the P1-receptor agonist, L-PIA or the muscarinic-receptor agonist, carbachol. 2. The indirect negative inotropic effects of L-PIA and carbachol were similar: both attenuated the responses of left atria more effectively than those of papillary muscles; and both more effectively attenuated responses to the cAMP-dependent positive inotropes, isoprenaline and forskolin. 3. However, there were differences: L-PIA, but not carbachol, was able at high concentrations to inhibit the responses of left atria to the calcium channel opener Bay K 8644; and at concentrations that produced similar direct negative inotropic effects, L-PIA consistently attenuated the positive inotropes more effectively than carbachol. 4. These findings are consistent with L-PIA being able to activate an additional negative inotropic mechanism that carbachol cannot.     

Role of Na-H exchange in the inotropic action of Bay K 8644 and of ouabain in guinea-pig isolated atria.

1. The inotropic effects of two concentrations of ouabain and of Bay K 8644 have been studied in isolated left atria of the guinea-pig in physiological solutions at pH lowered from 7.4 to 6.0 and in the presence of ethylisopropylamiloride (EIPA) an inhibitor of Na+/H+ exchange. The low concentration of ouabain (300 nM) was chosen to saturate the high affinity binding sites (it occupied about 7% of the low affinity sites). The high concentration of ouabain saturated both high and low binding sites. Bay K 8644 evoked a positive inotropic effect of a magnitude similar to ouabain (300 nM). 2. When comparing the positive inotropic effects of equi-effective concentrations of ouabain (300 nM) and of Bay K 8644 (100 nM), it was observed that extracellular acidification specifically depressed the inotropic effect of ouabain 300 nM; the positive inotropic effect of the high concentration of ouabain (3 microM) was barely affected by extracellular acidification. 3. EIPA 10 microM depressed the positive inotropic effect of ouabain 300 nM, but did not affect the peak response to Bay K 8644. The depressant action of EIPA on the positive inotropic effect of ouabain was concentration-dependent and was much more obvious on the effect of ouabain 300 nm than on ouabain 3 microM. 4. An increase in diastolic tension was evoked by 3 microM but not by 300 nM ouabain. This increase in tone was reduced dose-dependently by EIPA (10-30 microM). It was also significantly reduced when the extracellular pH was equal to 6.4 or 6.0. 5. Ouabain (300 nM) evoked a gain in tissue Na and an equivalent loss in tissue K.(ABSTRACT TRUNCATED AT 250 WORDS)     

Positive inotropic effects of the calcium channel activator Bay K 8644 on guinea-pig and human isolated myocardium

Summary 1. The positive inotropic effects of the dihydropyridine calcium activator Bay K 8644 were studied in guinea-pig isolated contracting myocardium and human papillary muscle strips obtained from patients undergoing mitral valve replacement or cardiac transplantation. 2. Bay K 8644 produced a slowly developing, concentration-dependent positive inotropic response in all cardiac tissues studied. In guinea-pig papillary muscle, the increase in force of contraction was half-maximal at 3.9 × 10^–8 mol/l and the maximal inotropic effect was comparable to that obtained with ouabain, dobutamine or calcium. The guinea-pig left atrium (EC₅₀, 2.1 × 10^–7 mol/l) was fivefold less sensitive than the papillary muscle. 3. The maximal inotropic response to dihydroouabain was significantly increased after preincubation with Bay K 8644 (1 × 10^–6 mol/l) in papillary muscles from both guinea-pig and human. In guinea-pig papillary muscles, the maximal inotropic response to dobutamine was not changed by preincubation with Bay K 8644 whereas in human papillary muscle strips, Bay K 8644 increased the inotropic response to dobutamine. 4. Bay K 8644 increased force of contraction (EC₅₀, 4 × 10^–8 mol/l) in human papillary muscle strips from patients undergoing mitral valve replacement. However, the maximal inotropic response to Bay K 8644 was reduced to 32 ± 4.4% that of calcium (15 mmol/l) measured in the same muscle strips. 5. A further reduction in maximal inotropic response to Bay K 8644 to 13 ± 1.2% that of calcium (15 mmol/l) with no change in potency was measured in human papillary muscle strips taken from terminally failing hearts of cardiac transplant recipients. 6. There was a significant correlation between the preoperative left ventricular ejection fraction and the maximal inotropic response to Bay K 8644 in isolated human papillary muscle strips. 7. These results suggest that Bay K 8644 affects excitation-contraction coupling of cardiac muscle so as to increase the maximal inotropic effect of the digitalis glycosides. Further, the inotropic response of human myocardial tissue to calcium channel activator Bay K 8644 may be reduced in states of pathological heart function.The human heart papillary muscles were provided by Prof. E. Kreuzer, Prof. B. Kemkes, Dr. C. Weinhold and their colleagues, Herzchirurgische Klinik der Universität, Klinikum Grosshadern, D-8000 München 70, Federal Republic of Germany Send offprint requests to E. Erdmann     

The positive inotropic dihydropyridine BAY K 8644 does not affect calium sensitivity or calcium release of skinned cardiac fibres

Summary BAY K 8644 is a positive inotropic dihydropyridine which concentration-dependently increased contractile force in guinea-pig atria at 10 to 1000 nmol/l. In chemically skinned cardiac fibres from guinea-pig hearts the substance did not change the tension induced by calcium. Also BAY K 8644 did not release calcium from intracellular myocardial stores like caffeine since it failed to evoke a contractile response in saponin-treated, calcium-loaded cardic muscle. Thus, the drug exerts its effects neither by sensitizing the contractile apparatus to calcium nor by a caffeine-like action.     

Stimulation frequency alters the inotropic response of atrial muscle to BAY K-8644

The inotropic and chronotropic effects of BAY K-8644 were examined in isolated guinea pig atria. The compound increased both rate and contractile force. Sensitivity to the inotropic effect was enhanced by increasing stimulation frequency between 0.5 and 3.3 Hz. The maximum developed tension elicited by the agent was reduced at 3.3 Hz. At BAY K-8644 concentrations up of to 3 X 10(-5) M, no dysrhythmic effects or other toxic signs such as an increase in resting tension were observed. These results are consistent with the suggestion that BAY K-8644 acts as a partial 'calcium agonist'.     

Positive inotropic effect of bay K 8644: cAMP-independence and lack of inhibitory effect of adenosine

Summary The aim of the present study was to characterize the positive inotropic effect of the Ca²⁺ channel activator Bay K 8644. In isolated guinea-pig papillary muscles we investigated whether adenosine and the R site adenosine receptor agonist (–)-N⁶-phenylisopropyladenosine (PIA) were able to antagonize the positive inotropic effect of Bay K 8644. The effect of Bay K 8644 and adenosine or PIA on myocardial cAMP content was also measured. The influence of adenosine and PIA on the positive inotropic effect of the -adrenoceptor agonist isoprenaline and of the phosphodiesterase inhibitor amrinone was studied for comparison.Adenosine and PIA antagonized the positive inotropic effects of isoprenaline and amrinone in a concentration-dependent manner. In contrast, adenosine or PIA did not affect the positive inotropic effect of Bay K 8644.The positive inotropic effect of Bay K 8644 was not accompanied by a change in the cAMP content of the papillary muscles. Additionally applied adenosine or PIA also failed to affect the cAMP content.It is concluded that an increased myocardial cAMP content is not involved in the positive inotropic effect of Bay K 8644. Moreover, the results support the view that adenosine and PIA only antagonize the positive inotropic effects of drugs known to increase myocardial cAMP content and that an increased myocardial cAMP content is a prerequisite for the manifestation of a negative inotropic effect of the nucleosides in ventricular cardiac muscle.     

Aging: inotropic effects of Bay K-8644 and nifedipine on rat cardiac muscle.

Inotropic effects of Bay K-8644, nifedipine, isoproterenol and extracellular calcium (Ca2+o) were examined in right ventricular strips, papillary muscle and left atria isolated from 4, 14 and 25 month old, male F344 rats. Under the experimental conditions used (37 degrees C, 1.4 mM Ca2+o and 4 Hz), control developed tension (expressed per mg wet weight) increased with age in right ventricular strips and papillary muscle, but decreased in left atria. The maximal positive inotropic response to Bay K-8644 was diminished with age in right ventricular strips and papillary muscle (but not left atria), while the negative inotropic action of nifedipine was not affected in any of the three tissues. Age decreased the inotropic efficacy of isoproterenol in right ventricular strips and papillary muscle (not left atria), had no effect on the efficacy of Ca2+o in right ventricular strips and left atria, but diminished the maximum response to Ca2+o in papillary muscle. Kd and B(max) values for [3H]nitrendipine binding were not significantly different in the three age groups. These data suggest: (1) that age-related changes in basal contractility and inotropic responsiveness differ in atrial and ventricular muscle; and (2) that these changes may result from alterations in excitation-contraction coupling which are not mediated by changes in Ca2+ channel density.     

Pharmacodynamics of BAY K 8644 alone and in combination with dobutamine in the isolated rabbit heart

The haemodynamic effects of the Ca-agonist BAY K 8644 alone and in combination with the selective beta-I-adrenoceptor agonist dobutamine were studied in the isolated rabbit heart. BAY K 8644 produced a concentration-dependent increase in contraction amplitude and shortening velocity, oxygen consumption and heart rate. In combination with a small fixed concentration of dobutamine (40 nM), Bay K 8644 produced similar alterations. When Bay K 8644 was infused at a fixed concentration (38 nM), dobutamine likewise produced similar increments in contraction amplitude, shortening velocity and heart rate, whereas oxygen consumption was considerably argumented. Both BAY K 8644 and dobutamine showed definite positive inotropic effects in the isolated rabbit heart. Combination of the two drugs did not yield a stronger positive inotropic effect than that seen on single drug administration, and oxygen consumption was even increased.     

Effects of calcium channel agonists (BAY K 8644, CGP28392 and YC-170) on 45Ca uptake by rat uterine segments.

The characteristics of the stimulating effects of the calcium channel agonists BAY K 8644, CGP28392 and YC-170 on 45Ca uptake by rat uterine segments were investigated. BAY K 8644, CGP28392 and YC-170 caused about 150, 100 and 150% increase, respectively in the 45Ca uptake induced by 20 mM KCl. The ED50 values of BAY K 8644, CGP28392 and YC-170 were 1.8 X 10(-9), 2.5 X 10(-8) and 9.8 X 10(-9) M, respectively. These agonists had little effect on the 45Ca uptake induced by 10(-6) M acetylcholine. They also did not affect the basal 45Ca uptake. Their enhancing effects were blocked by the Ca channel antagonist nitrendipine. We conclude that rat uterine segments have voltage-sensitive Ca channels that are stimulated by Ca channel agonists (BAY K 8644, CGP28392 and YC-170) under depolarizing conditions and that the characteristics of the stimulating effects of CGP28392 and YC-170 on 45Ca uptake by rat uterine segments are qualitatively the same as those of BAY K 8644.     

Positive inotropic and electrophysiological effects of APP 201-533 can be explained by an increase of cardiac cyclic AMP

The possible mechanism of action of the positive inotropic agent APP 201-533 [3-amino-6-methyl-5-phenyl-2(1H)-pyridinone] was investigated. In guinea pig papillary muscles, APP 201-533 increased force of contraction concentration dependently at 10(-4)-10(-3) M. The effect was associated with an abbreviation of contraction and relaxation time. In guinea pig papillary muscles partially depolarized with 22 mM K+, APP 201-533 in concentrations of 10(-4) and 10(-5) M restored slow action potentials, which were not influenced by cimetidine, propranolol, and prazosin but were blocked by the Ca2+ antagonist PY 108-068 and by carbachol in an atropine-sensitive manner. The concentration-effect curve of histamine was shifted to the left in the presence of APP 201-533. These actions can be explained by the increase in cardiac cyclic AMP level that was found in rabbit papillary muscles and guinea pig left atria treated with APP 201-533 due to the known phosphodiesterase inhibitory effect of pyridinones. APP 201-533 increased the inotropic potency of dihydroouabain in guinea pig papillary muscles. It seems possible that this effect is based on an increased Ca2+ sensitivity of myocardial contractile structures as described previously for APP 201-533.     

Properties of the Inotropic Response in Rat Papillary Muscles to the Dihydropyridine “Ca-Channel Activator” BAY K 8644

Abstract: The aim of the present study was 1) to characterize qualitatively the positive inotropic effect of the Ca-channel activator BAY K 8644 and to compare this response to response-types with known and different relationship to the cyclic AMP (cAMP) system (e.g. responses elicited through α- and β-adrenergic receptor stimulation) and 2) to study the effect of simultaneous muscarinic cholinergic stimulation upon the BAY K 8644 response in order to further evaluate the role of the cAMP system in this response. The responses were evaluated in isolated, electrically paced, isometrically contracting papillary muscles from rat heart. Isometric tension (T_max), rate of rise and decline of tension (first derivative = T′) and rate of transition from tension rise to tension decline (negative part of second derivative = T”) were recorded. In the presence of the α₁-adrenergic receptor blocker prazosin (10^?7 mol/l) and the β-adrenergic receptor blocker timolol (10^?6 mol/l), the positive inotropic effect of 1.7 × 10^?6 mol/l BAY K 8644 developed rather slowly with a time to half maximal effect of about 4 minutes. Qualitatively the response was characterized by an almost proportional (“symmetrical”) increase in all parts of the contraction-relaxation cycle with a small prolongation of time to peak tension and of the duration of the whole cycle. This response contrasted sharply with the cAMP-dependent response to β-receptor stimulation (β-type response with shortening of time to peak tension), but was very similar to the cAMP-independent response to α-receptor stimulation (α-type response). Additional cholinergic muscarinic stimulation by carbachol did not counteract the effect of BAY K 8644, but rather increased the inotropic response. It is concluded that both the qualitative characteristics of the BAY K 8644 response and the effect of simultaneous cholinergic stimulation upon this response are those expected for a cAMP-independent response. The results also support the assumption that the response type can be used as a first step in classifying whether an inotropic agent is dependent or independent upon activation of the cAMP system.     

Antagonism between (-)-N6-phenylisopropyladenosine and the calcium channel facilitator Bay K 8644, on guinea-pig isolated atria.

Antagonism between (-)-N6-phenylisopropyladenosine (PIA) and the dihydropyridine calcium channel facilitator Bay K 8644 was investigated in guinea-pig spontaneously beating or electrically driven isolated atria, taken from normal and from reserpine-treated animals. PIA (3-100 nM) produced a dose-dependent decrease in contractile tension and frequency in spontaneously beating atria being more effective in reserpinized preparations. Bay K 8644 (5-200 nM) produced an increase in contractile tension in both normal and reserpinized atria. In electrically driven left atria the positive inotropic effect of Bay K 8644 was similar to that in spontaneously beating preparations. The positive chronotropic effect of Bay K 8644 was slight and variable. PIA produced a rightward parallel shift of the concentration-response curves for the positive inotropic effects of Bay K 8644 in all experimental conditions. In spontaneously beating atria from normal guinea-pigs, the Schild regression plot was linear and its slope near to unity; pA2 of PIA 8.63 +/- 0.05 (IC50 2.35 +/- 0.25 nM). In electrically driven atria the antagonism by PIA of the effects of Bay K 8644 was apparently competitive, and the IC50 of PIA was 18.6 +/- 0.4 nM. PIA antagonized the positive chronotropic effect of Bay K 8644 in spontaneously beating preparations, both from normal and from reserpine-treated animals. Carbachol did not modify the positive inotropic effects of Bay K 8644. These data indicate that PIA may interact with Bay K 8644 at the level of the slow calcium channels, and may decrease the transmembrane calcium flux into the cell.     

Positive inotropic action of saponins on isolated atrial and papillary muscles from the guinea-pig.

The effects of several saponins of animal and plant origin on the contractile activity of atrial and papillary muscles of the guinea-pig were tested. In a concentration of 1 X 10(-5)M, holothurin-A (HL-A), holothurin-B, echinoside-A, echinoside-B and sakuraso-saponin (Saku) exhibited positive inotropic and chronotropic actions whereas desacyl-jego-saponin and ginsenoside-Rd did not. Saponins having a positive inotropic action caused haemolysis of rabbit erythrocytes whereas those without inotropic action did not cause haemolysis. The positive inotropic action of saponins was not affected by practolol, chlorpheniramine, cimetidine and indomethacin. Verapamil (10(-6)M) inhibited the inotropic actions due to HL-A and isoprenaline (10(-8)M) to the same extent but had a small effect on those due to ouabain (10(-7)M). In high K+ (30 mM K+) medium where the action potential and the contraction were depressed, HL-A, Saku and isoprenaline restored the action potential and the contraction of the 'slow response' type whereas ouabain failed to do so. In normal medium HL-A and Saku reduced the resting membrane potential by 15-20 mV. These results suggest that modification of the Ca channel is involved in the positive inotropic action of saponins.