Marked Negative Inotropic Effect Research Articles

Improved blood pressure control with isradipine in hypertensive patients treated with pindolol

Isradipine is a new calcium antagonist of the dihydropyridine type with marked vasodilator activity and minimal negative inotropic effects. It is a potent antihypertensive drug when given as monotherapy. This was a randomized double-blind crossover study of 16 weeks' duration, including 80 hypertensive patients with diastolic blood pressures of at least 95 mm Hg who had shown clinically relevant antihypertensive responses, but no normalization of blood pressure during pindolol 10 to 15 mg once daily as monotherapy. Either isradipine or placebo was added to the beta-blocker at doses of either 2.5 mg or 5 mg twice daily, which was doubled after four weeks if the diastolic blood pressure remained more than 90 mm Hg. The addition of isradipine (in either dose regimen) caused a pronounced reduction of blood pressure with no changes in heart rate. Five patients were withdrawn from the study because of adverse events while receiving isradipine compared with three taking placebo. A further three patients withdrew from the study because of adverse events (one patient) or lack of efficacy (two patients) during placebo treatment. These results indicate that isradipine is an effective and well-tolerated adjunct to beta-blockers in hypertensive patients.

Effects of contrast media on calcium transients and motion in cultured ventricular cells.

To investigate the mechanisms of the negative inotropic effects of contrast media, we superfused spontaneously contracting cultured chick embryo ventricular cells with Renografin-76 and iohexol (12% solutions), and hypertonic sucrose during simultaneous measurement of [Ca2+]i transients (indo-1) and motion (video-motion detector system). Exposure to contrast agents caused a significant reduction of contractility, with Renografin-76 having a much greater effect on amplitude of motion than iohexol. Renografin-76 significantly depressed [Ca2+]i transient amplitude, whereas iohexol had no effect. Addition of Ca2+ to correct for calcium binding by Renografin-76 completely reversed its depression of [Ca2+]i transients but only partially reversed the negative inotropic effects. Hypertonic sucrose caused a significant decrease in contraction amplitude, with no significant effects on [Ca2+]i transient amplitude. We conclude that the marked negative inotropic effect of Renografin-76 is caused by both calcium binding and hypertonicity. The less marked depression of contractility produced by iohexol likely is a result of hypertonicity and not caused by alteration of [Ca2+]i.

Bepridil, myocardial accumulation kinetics and dynamic effects in the isolated rabbit heart.

Both myocardial uptake and disposition of bepridil in the isolated rabbit heart showed two-compartment characteristics which possibly reflects the existence of superficial and deep binding sites. Terminal accumulation and disposition half-lives were 218 and 196 min., respectively. The half-times of the initial distributory processes were about 33 min. At a drug concentration in the perfusion liquid of 0.54 micrograms ml-1 (1.27 microM) the average concentration of bepridil in the myocardium at steady state was about 489 micrograms g-1 (1161 microM) with 43% referable to the deepest, presumably intracellular compartment. Increasing bepridil concentrations from 3 to 2333 ng ml-1 (7-5542 nM) in the perfusion liquid caused a terminal decrease in coronary flowrate to 58% of the mean control flowrate. Amplitude and velocity of myocardial contraction both decreased in a biphasic way to about 28.6 and 13.6%, respectively. Apparent dynamic steady states developed within about 20 min. Inhibitory Em-values related to the first phase were 39.8 and 53.2%, and to the second phase 97.7 and 98.5%, respectively. Heart beating frequency also decreased biphasically to 53.9% and showed inhibitory Em-values of 17.2 and 47.5% related to the two phases. Myocardial oxygen consumption decreased to 55.6%. The electrocardiographic PQ- and QRS-intervals increased to 147 and 133%, respectively. The frequency-corrected QT-interval also increased significantly from 100 to 123%. Our findings demonstrate a slow and very pronounced accumulation of bepridil in the rabbit heart. Biphasic and very marked negative inotropic and chronotropic effects and a less than proportional decrease in oxygen consumption developed much faster.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium channel antagonists. Part IV: Side effects and contraindications drug interactions and combinations.

With the correct selection of drug and patient, the calcium antagonists as a group can be remarkably effective at relatively low cost of serious side effects. Almost all side effects are dose related. Minor side effects include those caused by vasodilation (flushing and headaches), constipation (verapamil), and ankle edema. Serious side effects are rare and result from improper use of these agents, as when intravenous verapamil (or diltiazem) is given to patients with sinus or atrioventricular nodal depression from drugs or disease, or nifedipine to patients with aortic stenosis. The potential of a marked negative inotropic effect is usually offset by afterload reduction, especially in the case of nifedipine which actually has the most marked negative inotropic effect. Yet caution is required when even calcium antagonists, especially verapamil, are given to patients with myocardial failure unless caused by hypertensive heart disease. Drug interactions of calcium antagonists occur with other cardiovascular agents such as alpha-adrenergic blockers, beta-adrenergic blockers, digoxin, quinidine, and disopyramide. The most marked interaction with digoxin is that with verapamil, which may raise digoxin levels by over 50%. Combination therapy of calcium antagonists with beta-blockers is increasingly common, and is probably safest in the case of dihydropyridines. Other combinations being explored are those with angiotensin-converting enzyme inhibitors and diuretics.

Cardiodepressant actions of the orally active male contraceptive, gossypol, in guinea-pig heart muscle

We have previously shown that gossypol has direct actions on isolated atrial muscle preparations. The possible mechanisms responsible for the transient positive and sustained negative inotropic effects of gossypol were examined under conditions that modify Ca 2+ pools involved in contractile activation. In Langendorff preparations obtained from guinea-pig or rat heart, gossypol produced marked negative inotropic and arrhythmogenic effects but failed to produce a positive inotropic effect. Langendorff preparations were significantly more sensitive than atrial muscle preparations. In atrial muscle preparations, the negative inotropic effect of gossypol was not specific to utilization of superficial or intracellular Ca 2+ pools; force-staircase phenomenon observed between 0.5 and 3 Hz, contractions elicited by slow action potentials in partially depolarized muscle, the inotropic effect of extracellular Ca 2+ and potentiated post-rest contractions were all suppressed by gossypol to the similar extent. Low external Na + concentrations abolished the positive inotropic effect of gossypol without affecting the negative inotropic effect. A low extracellular Ca 2+ concentration enhanced the transient positive inotropic effect and delayed development of the negative inotropic effect. Simultaneous reduction of extracellular Na + and Ca 2+ concentrations abolished the positive inotropic effect and enhanced the negative inotropic effect. Gossypol inhibited ATP-dependent Ca 2+ uptake by sarcolemmal vesicles obtained from dog heart. These results indicate that the actions of gossypol on cardiac muscle is not specific to utilization of either the superficial or intracellular Ca 2+ pools involved in contractile activation.

Direct actions of gossypol on cardiac muscle

Gossypol, an orally active male contraceptive, has been reported to produce cardiotoxity. In the present study, direct actions of gossypol on the heart muscle were examined using atrial muscle preparations isolated from guinea-pig heart. Gossypol (20–30 μM) produced a transient positive chronotropic effect in spontaneously beating right atrial muscle preparations and a transient positive inotropic effect which reached a peak at about 5 min followed by a marked negative inotropic effect in paced left atrial muscle. These effects of gossypol were not affected by blocking concentrations of phentolamine, nadolol or propranolol, cimetidine and atropine. Gossypol inhibited Na +, K +-ATPase isolated from guinea-pig brain, Na + pump activity in electrically stimulated left atrial muscle preparations of guinea-pig heart and Na +/Ca 2+ exchange in Na +-loaded sarcolemmal vesicles obtained from dog heart. Inhibition of Na +/Ca 2+ exchange required high concentrations of gossypol and was rapidly reversible whereas Na +, K +-ATPase inhibition was apparently irreversible. These results indicate that micromolar concentrations of gossypol have direct actions on cardiac muscle.

Concealed positive force-frequency relationships in rat and mouse cardiac muscle revealed by ryanodine.

Increases in stimulation frequency between 0.3 and 2 Hz decrease developed tension in rat, seemingly inconsistent with the explanation that an elevation of intracellular Na+-ion concentration is responsible for the positive force-frequency relationships observed in most species. Thus the force-frequency relationships were reevaluated in isolated atrial muscle of rat and mouse heart that show negative relationships, comparing them with ferret and guinea pig that show positive relationships. Ryanodine (2 nM, 45-min exposure) markedly reduced potentiated postrest contractions in all four species and caused a marked negative inotropic effect especially at low stimulation frequencies in rat and mouse, a moderate effect in ferret, but only a modest effect in guinea pig. In the presence of ryanodine, all four species showed positive force-frequency relationships. These results indicate that activator calcium in rat, mouse, and ferret cardiac muscle has a large ryanodine-sensitive component that shows a negative force-frequency relationship, masking a component for positive force-frequency relationships that exists in all species.

Felodipine, pharmacodynamics and pharmacokinetics in the isolated rabbit heart.

Myocardial pharmacodynamics of the Ca2+-antagonist felodipine, a structural analogue of nifedipine, were studied in isolated, spontaneously beating and retrogradely perfused rabbit hearts. The concentration of felodipine in the Krebs-Henseleit perfusion liquid was stepwise increased from 0.7 ng/ml to 90.4 ng/ml (1.8 to 235.3 nmol/l). Increasing felodipine concentrations from 0.7 to 3.6 ng/ml produced an increase of up to 115% in coronary flow rate, which then decreased at higher concentrations to 84% of the control value. Oxygen consumption decreased progressively to 28% at concentrations from 3.6 to 90.4 ng/ml. Myocardial contractility measured by amplitude and rate of contraction decreased progressively to 45.7 and 41.5%, respectively, at concentrations from 0.7 to 9.4 ng/ml and further to 4.0 and 3.0%, respectively, at 90.4 ng/ml. Myocardial efficiency expressed as the percentual ratio of contraction amplitude times frequency to oxygen consumption decreased to 11% at the highest concentration of felodipine. Heart beat frequency decreased simultaneously to 45.6%. The electrocardiographic PQ and QRS intervals increased at the highest concentration to 174 and 111%, respectively, whereas the QT interval decreased to 86.6%. Asystolia occurred in several cases at felodipine concentrations of 90.4 ng/ml. Both myocardial accumulation and disposition pharmacokinetics of the drug showed one-compartment characteristics with half-lives of about 97 min. for both processes. Apparent Vd was about 480 ml/g myocardial tissue, which expresses a very pronounced binding and accumulation of felodipine in the rabbit myocardium in vitro. The findings demonstrate that lower concentrations of felodipine produces coronary vasodilation in the isolated rabbit heart accompanied by a marked negative inotropic effect and a less than proportional reduction in oxygen consumption. The drug seemed to cause direct cardiotoxic effects at higher concentrations.

ChemInform Abstract: SAR Studies in the Field of Calcium(II) Antagonists. Effect of Modifications at the Tetrasubstituted Carbon of Verapamil‐Like Compounds.

AbstractDie Verbindungen (III) und (VI) werden dargestellt.

Important differences between short- and long-term hemodynamic effects of amiodarone in patients with chronic ischemic heart disease at rest and during ischemia-induced left ventricular dysfunction

To assess and compare the hemodynamic profile of short-and long-term amiodarone administration in the same set of patients and to investigate hemodynamic mechanisms responsible for the antianginal effect of this drug, 10 patients with documented coronary artery disease and stable angina pectoris were studied. Simultaneous right heart catheterization and equilibrium radionuclide angiocardiography were performed at rest and during exercise before therapy (control), after a 5 minute intravenous infusion of 7.5 mg/kg of amiodarone and after 21.0 +/- 4.3 days of peroral therapy (10 days 800 mg/day, 7 days 400 mg/day and then 200 mg/day). After acute drug administration, ejection fraction, stroke index and systolic blood pressure decreased, whereas heart rate, left and right ventricular filling pressures and systemic vascular resistance increased. These effects were reversed after long-term therapy; all measured values returned to control levels except for heart rate, which decreased below the control value, and right atrial pressure, which remained slightly elevated. Amiodarone drug levels decreased from 4.8 +/- 1.8 after intravenous infusion to 1.2 +/- 0.6 mg/liter after long-term therapy. After adjustment for hemodynamic changes at rest, there were still significant reductions in heart rate, mean arterial pressure and rate-pressure product during exercise. It is concluded that the marked negative inotropic effect of amiodarone administered acutely in the dose applied calls for cautious use of this drug when administered intravenously. In contrast, long-term oral amiodarone therapy seems hemodynamically safe, even in patients with moderately depressed left ventricular function.(ABSTRACT TRUNCATED AT 250 WORDS)

A drug used in traditional medicine: Harpagophytum procumbens DC II. Cardiovascular activity

In conscious normotensive rats the dried crude methanolic extract of Harpagophytum procumbens secondary roots caused a significant dosedependent reduction of arterial blood pressure. The decrease was significant only at higher doses given by gavage (dried extract = 400 mg kg ). At the same time a decrease of heart rate was observed. In the same experimental conditions, harpagoside presented an activity lower than doses of Harpagophytum procumbens extract containing corresponding quantities of harpagoside. In spontaneously beating Langendorff preparations of rabbit heart, the Harpagophytum procumbens methanolic extract caused a mild decrease in the heart rate with a concomitant mild positive inotropic effect at lower doses but a marked negative inotropic effect at higher doses. The coronary flow decreased at higher doses only. The negative chronotropic and positive inotropic effects of harpagoside were comparatively higher with respect to that of the extract, whereas harpagide had only a slight negative chronotropic effect and a considerable negative inotropic one. Both in experiments on intact rats and on isolated rabbit heart, the Harpagophytum procumbens extract also demonstrated a protective action with regard to arrhythmias induced by aconitine, and particularly to those provoked by calcium chloride and epinephrine—chloroform.

Pharmacological basis for the therapeutic applications of slow-channel blocking drugs.

Excitation-contraction coupling in cardiac muscle as well as in smooth muscle is mediated by the transmembrane fluxes of calcium. In the case of cardiac muscle, this transfer occurs through the slow-inward channel. Agents that selectively inhibit the myocardial slow-channel also block calcium entry in smooth muscle cells, particularly in arteries. Thus, such selective inhibitors of the slow channel, exemplified by verapamil, nifedipine, and diltiazem, produce a marked negative inotropic effect in cardiac muscle; in whole animals or in man, such a propensity is largely nullified or even reversed by the profound vasodilator effects of these compounds. The drugs known as calcium antagonists are chemically heterogeneous and they may exhibit associated pharmacological properties such as noncompetitive sympathetic inhibition while having varying potencies for inhibiting the calcium influx in smooth muscle and in the heart and nodal tissues. These similarities and differences influence the net electrophysiologic and hemodynamic effects of calcium antagonists in man. Electrophysiologically, the main effect is a depressant one on the AV node in which most agents of the class lengthen AV conduction and enhance refractoriness, a property that is relevant in the termination of PSVT and to the slowing of the ventricular response in atrial flutter and fibrillation. The effective refractory periods of atrial, ventricular, and His-Purkinje tissues or the bypass tracts are not altered by calcium antagonists, but conduction may be improved in ischemic tissues. On the surface ECG, the only effect is the short-term lengthening of the PR interval with no change in the QRS or Q-Tc intervals. The sinus frequency is variably affected relative to the competing influences of the direct effect, reflex response to hypotension and of sympathetic antagonism. The sinus node recovery time is affected little normally, but may be prolonged dramatically in the sick sinus syndrome. Hemodynamically, as a class of drugs, calcium antagonists produce a complex interplay of simultaneous changes in preload, afterload, contractility, coronary flow, and heart rate. The net hemodynamic effect that becomes apparent will be dependent on the agent used, on the cardiac condition and the level of ventricular function present, on the intactness of the autonomic nervous system, and on the route of drug administration. An appreciation of the electrophysiological and hemodynamic actions of calcium antagonists relative to their individual pharmacologic properties permits the rational choice of the appropriate agent in the control of a wide spectrum of cardiocirculatory disorders.

On the ionic mechanism underlying adrenergic-cholinergic antagonism in ventricular muscle.

In atrial muscle, acetylcholine (ACh) decreases the slow inward current (Isi) and increases the time-independent outward K+ current. However, in ventricular muscle, ACh produces a marked negative inotropic effect only in the presence of positive inotropic agents that elevate cyclic adenosine monophosphate (AMP). A two-microelectrode voltage-clamp method was used on cultured reaggregates of cells from 16--20-d-old embryonic chick ventricles to determine the effects of ACh on Isi and outward current during beta-adrenergic stimulation. Only double penetrations displaying low-resistance coupling were voltage-clamped. Cultured reaggregates are advantageous because their small size (50--250 microns) permits better control of membrane potential and adequate space clamp. Tetrodotoxin (10(-6) M) and a holding potential of --50 to --40 mV were used to eliminate the fast Na+ current. Depolarizing voltage steps above --40 mV caused a slow inward current to flow that was sensitive to changes in [Ca]o and was depressed by verapamil (10(-6) M). Maximal Isi was obtained at --10 mV and the reversal potential was about +25 mV. Isoproterenol (10(-6) M) increased Isi at all clamp potentials. Subsequent addition of ACh (10(-6) M) rapidly reduced Isi to control values (before isoproterenol) without a significant effect on the net outward current measured at 300 ms. The effects of ACh were reversed by muscarinic blockade with atropine (5 X 10(-6) M). We conclude that the anti-adrenergic effects of ACh in ventricular muscle are mediated by a reduction in Ca2+ influx during excitation.

Inotropic responses of isolated atrial and ventricular muscle from the dog heart to inosine, guanosine and adenosine.

1. The inotropic effects of inosine, adenosine and guanosine were compared in isolated and blood-perfused canine atrial and ventricular muscle preparations paced at 1.5-2.5 Hz. 2. In isolated atria, guanosine and inosine usually had positive inotropic effects, but adenosine consistently had a marked negative inotropic effect. 3. In ventricular muscles, the three purine compounds examined produced dose-related positive inotropic responses, but adenosine also produced a slight negative inotropic response which preceded the positive inotropic response.

Negative inotropic effect of β-blockers in the guinea-pig atrium after preincubation with isoprenaline

In the isolated guinea-pig atrium, pretreated with a high concentration of isoprenaline (8 × 10 −7 M), β-blockers produced a marked negative inotropic effect in a concentration which by itself was too low to have a direct depressing action. No negative inotropic effect was caused by isoprenaline when β-blockers were applied first. The depressing action of β-blockers was unaffected by phentolamine or atropine. During the depression, the electrical parameters of the action potential were not significantly different from those of the control, though the contractions were much smaller than control ones. the negative inotropic effect of β-blockers was weaker in excess Ca (7.5–10 mM). The observations indicate that isoprenaline possesses a dual action but that the negative inotropic effect is usually masked by the positive inotropic effect and that β-blockers, by quickly abolishing the positive inotropic effect, reveal the underlying negative inotropic effect.

Effects of vanadate on Na +,K +-ATPase and on the force of contraction in guinea-pig hearts

Vanadate has been shown to be a potent inhibitor of isolated Na +,K +-ATPase. Since the inhibition of this enzyme system has been implicated in a mechanism for the positive inotropic action of cardiac glycosides, the cardiac actions of vanadate were examined in connection with its action on Na +,K +-ATPase. Vanadate inhibited isolated Na +,K +-ATPase obtained from various tissues. The differences in the vanadate sensitivity due to enzyme source were relatively small. K +-stimulated phosphatase activity was more sensitive than Na +,K +-stimulated ATP hydrolysis. The compounds was more potent than phosphate in supporting [ 3H] oubain binding in the presence of Mg 2+, indicating a higher affinity of the enzyme for vanadate. It, however, failed to inhibit oubain sensitive 86Rb uptake in electrically stimulated atrial muscle of guinea-pig hearts in concentrations which would inhibit isolated Na +,K +-ATPase. These latter concentrations of vanadate also failed to produce positive inotropic effects in electrically stimulated left atrial preparations of guinea-pig hearts. Higher concentrations produced marked negative inotropic effects associated with a shortening of the action potential duration. These results indicate that vanadate is a potent inhibitor of isolated Na +,K +-ATPase, but cannot inhibit the enzyme in intact myocardial cells or produce positive inotropic effects when applied extracellularly. Inhibitory sites on the enzyme are probably located at the internal surface of the cell membrane which are normally inaccessible to vanadate in intact tissue.

Verapamil and Pulmonary Hypertension

We report on the effect of verapamil in 12 patients suffering from pulmonary hypertension. The drug caused a slight, but statistically significant decrease in mean pulmonary artery pressure and in the work performance by the right ventricle. The mean pressure of the right atrium, the end-diastolic pressure of the right ventricle, the pulmonary arteriolar resistance, the cardiac index and the stroke volume were not significantly changed, however, and there was a wide spread of the values observed. In some patients the drug exerted a marked negative inotropic effect, with a concomitant increase in the pulmonary arteriolar resistance.

Effect of papaverine on the frequency—force relationship in guinea-pig left atria

Contractile responses of guinea-pig atria to papaverine were analyzed under different stimulation frequencies. Atria, driven at 2 Hz, showed positive inotropic responses to papaverine which were maximal within 10–15 min. These responses were maintained for 60 min in the presence of low concentrations of papaverine (up to 10 −5 M), but reversed into marked negative inotropic effects under the influence of higher concentrations. The well-known frequency—force relationship was reversed by papaverine. At low stimulation rates papaverine elicited positive inotropic responses, which gradually decreased with increasing frequencies until strong cardiodepression occurred. A frequency—force curve obtained in the presence of both the Ca 2+-antagonistic drug D 600 and the inhibitor of the phosphodiesterase theophylline was similar to that obtained under the influence of papaverine. Theophylline alone evoked positive inotropic effects at all frequencies studied and left the character of the ascending staircase unchanged. In contrast, D 600 was ineffective at low, but cardiodepressive at high stimulation frequencies. In the presence of D 600 or papaverine high external Ca 2+ could not restore a normal frequency—force relationship. The reversal of the frequency—force relationship as produced by D 600 and papaverine could not be obtained by lowering of the external Ca 2+. The present results show that papaverine is able to evoke marked positive inotropic effects at low stimulation frequencies by inhibition of phosphodiesterase. At high frequencies, however, these effects are masked by negative inotropic responses due to the inhibitory action of papaverine on Ca 2+ -exchange of the cardiac muscle cell.

Evidence for improved cardiac performance after beta-blockade in patients with coronary artery disease.

The study was undertaken to investigate the acute haemodynamic effects of bunitrolol (0-2-hydroxy-3-(tert.butylamino)-propoxy)-bity. Right and left heart catheterization was performed in eleven patients with documented coronary artery disease. After bunitrolol (10 mg i.v.), there was a statistically significant decrease in left ventricular and aortic systolic pressures left ventricular end-diastolic pressure, aortic diastolic and mean pressures, pressure-rate product and compliance index (delta P/delta V). Left ventricular dp/dt, left ventricular dp/dt over isovolumic pressure, systemic resistance and heart rate tended to decrease, stroke volume and left ventricular stroke work index tended to increase, without statistical significance. Cardiac index showed individual variations, the mean values for the group being unchanged. Correlation of left ventricular end-diastolic pressure and left ventricular stroke work index showed a shift toward improved ventricular function curve in most cases, deterioration in no instance. Supine exercise was performed in ten patients. Angina occurred in nine patients; in five only before and in four before and after beta-blockade. Post-drug exercise heart rate, pressure-rate product and left ventricular end-diastolic pressure were significantly lower, the latter also in the four patients who still presented exercise angina. It is concluded that certain beta-blockers can improve cardiac performance at rest and during exercise in patients with coronary artery disease. This is explainable on the basis of a more favourable balance between oxygen supply and demand, together with a less marked negative inotropic effect due to the partial agonist activity of the agent used in the study.

Influence of glyceryl trinitrate on force of contraction and action potential of guinea-pig myocardium.

1. The inotropic effect of glyceryl trinitrate (GTN) was studied in guinea-pig papillary muscles and atrial strips by analysing the isometric contraction curve and the monophasic action potential (AP). 2. GTN, 7X10(-5)M in papillary muscles and at 1.4x10(-4)M in atrial strips. The maximum of the contractile force was reached in both preparations at 2x10(-4)M GTN. Positive inotropic effects were transitory (3--5 min) and were followed by marked negative inotropic effects. 3. In the presence of GTN, only 15 of 26 papillary muscles showed a positive inotropic response and there was a great variance in its intensity. Prior exposure of papillary muscles to a low GTN concentration, which by itself reduced force of contraction (like every single GTN application), was the prereqch by itself reduced force of contraction (like every single GTN application), was the prerequisite for the positive inotropic effect of a subsequent higher GTN concentration. In atrial strips the positive inotropic action was consistent and uniform. The maximum force of contraction in response to single applications of GTN was only about 50% of that in response to cumulatively increased GTN concentrations. 4. In the presence of 5x10(-4)M GTN, the tyramine concentration-effect curve was shifted to the left (by one log unit at the ED50 level). 5. Beta-Adrenoceptor blockade by(+/-)-propranolol (5x10(-6)M) or noradrenaline depletion by pretreatment of the animals with reserpine (5 mg/kg, 18--22 hrs prior to the experiment)prevented the positive inotropic effects of GTN in both preparations. Hence, the GTN-induced increase in contractile force is induced by the liberation of noradrenaline and an inhibitory effect on the monoamine oxidase (MAO) of sympathetic nerve endings might be involved. 6. In atrial preparations exposed to 5x10(-4)M GTN, time to peak force (tu) and relaxation time(t2) were shortened by 12% and 33%, respectively. Pretreatment of the animals with reserpine prevented the shortening og t1 and changed the shortening of t2 from 33% to 19%. 7. In papillary muscles, 5x10(-4) M GTN shortened t1 by 10%, while t2 was prolonged by 17% in noradrenaline-depleted, and by 36% in control muscles. Prolongation of t2 at 5x10(-4)M GTN was accompanied by an increase in the duration of the monophasic action patential (AP) in reserpine-pretreated as well as in control muscles by 12% and 26%, respectively (measured at 90% repolarization). The same GTN concentration slowed the maximum rate of depolarisiation by 32%. After 35 min the AP returned to approximately the control value. In the presence of 5x10(-4) M GTN, noradrenalin (1x10(-5)M) lengthened the AP by 38% in both, control muscles and noradrenaline-depleted preparations.