Pronounced Negative Inotropic Effect Research Articles

Interaction of Metabolic and Respiratory Acidosis with α and β-adrenoceptor Stimulation in Rat Myocardium

The effects of acute respiratory versus metabolic acidosis on the myocardium and their consequences on adrenoceptor stimulation remain poorly described. We compared the effects of metabolic and respiratory acidosis on inotropy and lusitropy in rat myocardium and their effects on the responses to α- and β-adrenoceptor stimulations. The effects of acute respiratory and metabolic acidosis (pH 7.10) and their interactions with α and β-adrenoceptor stimulations were studied in isolated rat left ventricular papillary muscle (n=8 per group). Intracellular pH was measured using confocal microscopy and a pH-sensitive fluorophore in isolated rat cardiomyocytes. Data are mean percentages of baseline±SD. Respiratory acidosis induced more pronounced negative inotropic effects than metabolic acidosis did both in isotonic (45±3 versus 63±6%, P<0.001) and isometric (44±5 versus 64±3%, P<0.001) conditions concomitant with a greater decrease in intracellular pH (6.85±0.07 versus 7.12±0.07, P<0.001). The response to α-adrenergic stimulation was not modified by respiratory or metabolic acidosis. The inotropic response to β-adrenergic stimulation was impaired only in metabolic acidosis (137±12 versus 200±33%, P<0.001), but this effect was not observed with administration of forskolin or dibutiryl-cyclic adenosine monophosphate. This effect might be explained by a change in transmembrane pH gradient only observed with metabolic acidosis. The lusitropic response to β-adrenergic stimulation was not modified by respiratory or metabolic acidosis. Acute metabolic and respiratory acidosis induce different myocardial effects related to different decreases in intracellular pH. Only metabolic acidosis impairs the positive inotropic effect of β-adrenergic stimulation.

Effects of thienopyridines and thienopyrimidinones on L-type calcium current in isolated cardiomyocytes

Thienopyridines (ticlopidine, clopidogrel) are frequently used drugs in antiplatelet therapy and have been shown to exert a more pronounced negative inotropic effect than thienopyrimidinones. We hypothesized that these differences are due to a differential impact of thienopyridines and thienopyrimidinones on L-type calcium current at the single-cell level. The effects of thienopyridines and thienopyrimidinones were studied on L-type calcium current and action potential parameters with the whole-cell patch-clamp technique in isolated myocytes from guinea pig ventricle and human atrial appendage. Ticlopidine showed the greatest impact on the L-type calcium current in guinea pig myocytes. It significantly reduced L-type calcium current density as well as shifted half maximal inactivation potential to more negative potentials compared to clopidogrel (at 30μmol/L) and to all thienopyrimidinones (30 and 100μmol/L). Clopidogrel significantly reduced the L-type calcium current density as well as shifted the half maximal inactivation potential to more negative potentials compared to all thienopyrimidinones at 100μmol/L only. In contrast, thienopyrimidinones did not affect L-type calcium current properties. The significant different effects of thienopyridines and thienopyrimidinones could also be demonstrated in human atrial myocytes. The more pronounced negative inotropic effect of thienopyridines is well explained by our results demonstrating a differential impairment of L-type calcium current by thienopyridines and thienopyrimidinones. L-type calcium current impairment by thienopyridines may be of special relevance for patients with cardiac diseases characterized by ionic remodelling.

ChemInform Abstract: 2-Aryl-Substituted 4H-3,1-Benzoxazin-4-ones as Novel Active Substances for the Cardiovascular System.

4H-3,1-Benzoxazin-4-ones of the structural types 3 and 4 are accessible by cyclization reactions. The introduction of the phosphonate group was achieved by way of Wohl-Ziegler bromination and subsequent Michaelis-Arbuzow reaction with a trialkyl phosphite. Pharmacological investigations on isolated left atria, ileum specimens, and Langendorff hearts as well as in vivo circulatory studies on anesthetized rats revealed that the phosphonates 4 exert calcium antagonistic effects. Whereas 2-(arylvinyl)benzoxazinones gave rise to pronounced negative inotropic effects, compound 3e exhibited relaxing effects on smooth musculature in particular and markedly increased the coronary flow through Langendorff hearts.

Esmolol cardioplegia: the cellular mechanism of diastolic arrest

Esmolol, an ultra-short-acting beta-blocker, acts as a cardioplegic agent at millimolar concentrations. We investigated the mechanism by which esmolol induces diastolic ventricular arrest. In unpaced Langendorff-perfused rat hearts, esmolol (0.03-3 mmol/L) had a profound negative inotropic effect resulting in diastolic arrest at 1 mmol/L and above. This inhibition of contraction was maintained during ventricular pacing. At 3 mmol/L, esmolol also abolished action potential conduction. To determine the cellular mechanism for the negative inotropism, we measured contraction (sarcomere shortening) and the calcium transient (fura-2 fluorescence ratio; Ca(tr)) in electrically-stimulated rat ventricular myocytes at 23 and 34 degrees C. The decrease in contraction (by 72% at 23 degrees C, from 0.16 +/- 0.01 to 0.04 +/- 0.01 microm, P < 0.001) was similar to that of isolated hearts and was caused by a large decrease in Ca(tr) (from 0.13 +/- 0.02 to 0.07 +/- 0.02, P < 0.001). There was no additional effect on myofilament Ca(2+) sensitivity. Esmolol's effects on contraction and Ca(tr) were not shared or altered by the beta-blocker, atenolol (1 mmol/L). Sarcoplasmic reticulum inhibition with thapsigargin did not alter the inhibitory effects of esmolol. Whole-cell voltage-clamp experiments revealed that esmolol inhibited the L-type calcium current (I(Ca,L)) and the fast sodium current (I(Na)), with IC(50) values of 0.45 +/- 0.05 and 0.17 +/- 0.025 mmol/L, respectively. Esmolol at millimolar concentrations causes diastolic ventricular arrest by two mechanisms: at 1 mmol/L (and below), the pronounced negative inotropic effect is due largely to inhibition of L-type Ca(2+) channels; additionally, higher concentrations prevent action potential conduction, probably due to the inhibition of fast Na(+) channels.

Arginase: a modulator of myocardial function

when nitric oxide (NO) donors were first administered to isolated, normal cardiomyocytes, a negative, cGMP-dependent inotropic effect was observed, whereas inhibitors of NO synthases (NOS) had no effect. Further studies then demonstrated a biphasic contractile response to exogenous NO and cGMP,

Heparin Added to Cardioplegic Solution Inhibits Tumor Necrosis Factor-α Production and Attenuates Myocardial Ischemic-Reperfusion Injury

Tumor necrosis factor (TNF)-alpha is known to be a proinflammatory cytokine that has a pronounced negative inotropic effect and plays an important role in ischemic-reperfusion injury. Twenty isolated rat hearts were randomly divided equally into two groups (heparin and non-heparin) and were perfused with a Krebs-Henseleit solution using a modified Langendorff model. The influence of heparin on the synthesis and release of TNF-alpha by isolated rat hearts after 1 h of global cardioplegic ischemia and on left ventricular (LV) performances during 30 min of postischemic reperfusion was investigated. Significant mean (+/- SEM) amounts of TNF-alpha in myocardial tissue (1,149 +/- 33.7 pg/g) and effluent (951.8 +/- 27.3 pg/mL) from the coronary sinus were detected after global cardioplegic ischemia. The addition of heparin to the cardioplegic solution significantly improved the recovery of LV function in the postischemic heart (p < 0.0001 for all measurements). TNF-alpha protein production in the heparin-treated hearts was below detectable levels despite a postischemic increase of TNF-alpha messenger RNA expression in both heparin-treated hearts and nontreated hearts (0.71 +/- 0.06 and 0.8 +/- 0.12 relative optical density, respectively). This study shows, for the first time, that heparin causes the inhibition of TNF-alpha protein synthesis and release from the isolated ischemic rat heart within the posttranscriptional stage, and that it prevents the depression of LV function caused by ischemic-reperfusion injury.

Whether independent regulation of myocardial contractility and diastolic relaxation rate is possible?

In acute experiments on cats neural inotropic and lusitropic reactions of the heart to enhancement of pre- and afterload were assessed by changes in contractility and relaxation indices, which were preliminary chosen for their maximum specificity and sensitivity. The control cardiac responses to increased pre- and afterload were measured after treatment with ganglionic blocker arfonad. The myogenic component of these responses assessed under the action of arfonad was highly pronounced, therefore the neural inotropic and lusitropic reactions were measured as the difference between load-induced changes of indices in experiments with and without arfonad. Increased preload produced similar negative inotropic and lusitropic effects, while increased afterload produced a more pronounced negative inotropic effect, which indicated independent regulation of contractility and diastolic relaxation of the heart.

Effect of volatile anesthetics on the force-frequency relation in human ventricular myocardium: the role of the sarcoplasmic reticulum calcium-release channel.

In human ventricular myocardium, contractile force increases at higher stimulation frequencies (positive force-frequency relation). In failing hearts, the force-frequency relation (FFR) is negative. Data on the effect of volatile anesthetics on FFR are very limited. The authors obtained left ventricular tissue from 18 explanted hearts from patients undergoing cardiac transplantation and tissue of 8 organ donors. The negative inotropic effect of halothane, isoflurane, and sevoflurane on isometric force of contraction of isolated muscle preparations at a stimulation frequency of 1 and 3 Hz and the effect of each anesthetic on the FFR were studied. Ryanodine and verapamil were studied for comparison. In addition, the effect of the anesthetics on Ca(2+)-dependent (3)H-ryanodine binding was investigated. In nonfailing myocardium, halothane was the strongest negative inotropic compound, and the positive FFR was not affected by either drug. In failing myocardium, halothane also showed the strongest negative inotropic effect, but the positive shape of FFR was restored by halothane and ryanodine. In contrast, isoflurane, sevoflurane, and verapamil did not change FFR. Only halothane shifted the Ca(2+)-dependent (3)H-ryanodine binding curve toward lower Ca(2+) concentrations. In nonfailing human myocardium, none of the anesthetics affect FFR, but halothane is the strongest negative inotropic compound. In failing myocardium, halothane, but not isoflurane or sevoflurane, restores the positive shape of FFR. Both the more pronounced negative inotropic effect of halothane and the restoration of the positive shape of FFR in failing myocardium in the presence of halothane can be explained by its interaction with the myocardial sarcoplasmic reticulum calcium-release channel.

Effects of dantrolene on rat diaphragm muscle during postnatal maturation.

Dantrolene is the only known effective treatment for malignant hyperthermia. However, its effects on diaphragm muscle during postnatal maturation remain unknown. The effects of dantrolene (10(-8) to 10(-4) M) were investigated in vitro on diaphragm muscle strips in adult rats and in postnatal rats aged 3, 10, and 17 days, and compared with those of ryanodine (10(-8) to 10(-6) M). The authors studied contraction and relaxation under isotonic and isometric conditions (29 degrees C, Krebs-Henseleit solution, tetanic stimulation at 50 Hz). Data are mean +/- SD. During postnatal maturation, the authors observed a progressive increase in active force developed per cross-sectional area (from 34 +/- 25 to 69 +/- 32 mN/mm2; P < 0.05) and maximum shortening velocity (from 2.9 +/- 0.5 to 4.9 +/- 1.4 Lmax/s; P < 0.05). Dantrolene induced a negative inotropic effect in diaphragm muscles in isotonic and isometric conditions in all groups, but this effect was significantly less marked in the 3-day-old rats compared with older rats. Dantrolene did not induce significant lusitropic effects during postnatal maturation. Developmental changes in the pharmacologic response to dantrolene were more rapid than those of ryanodine. Dantrolene induced less pronounced negative inotropic effects on the diaphragm in neonatal rats as compared with adult rats. Our study suggests that developmental changes in the pharmacologic response to dantrolene are more rapid than those of ryanodine.

Negative chronotropic and inotropic effects of endothelin isopeptides in mammalian cardiac muscle

In isolated rabbit right atria, endothelin (ET) isopeptides ET-1 and ET-3 elicited a concentration-dependent negative chronotropic effect (NCE) in the presence of isoproterenol (Iso): ET-1 was approximately 10 times more potent than ET-3. The NCE of ET-1 was abolished by the ETA- and ETB-receptor antagonist TAK-044 (1 microM) or the ETA-receptor antagonist BQ-123 (10 microM), but it was not affected by the ETB-receptor antagonist RES-701-1 or BQ-788. ET-1 decreased the adenosine 3',5'-cyclic monophosphate (cAMP) level in the presence of Iso in rabbit atria. Pretreatment with pertussis toxin (PTX) markedly attenuated the NCE of ET-1 and abolished the decrease in the cAMP level induced by ET-1. In isolated dog ventricular trabeculae, ET-1 elicited a pronounced negative inotropic effect (NIE), whereas ET-3 induced a small but significant positive inotropic effect in the presence of Iso. The NIE was abolished by the ETA-receptor antagonist BQ-123 (1 microM) and partially attenuated by the ETB-receptor antagonist RES-701-1. The positive inotropic effect of ET-3 was abolished by RES-701-1. Although pretreatment with PTX markedly attenuated the NIE of ET-1, cAMP levels in dog ventricular muscle were not decreased by ET-1. These results indicate that activation of an ETA receptor that is coupled to the PTX-sensitive G protein plays a dominant role in the NCE and NIE of ET-1. The NCE of ET-1 may, in part, be due to a decrease in cAMP level. By contrast, the NIE of ET-1 does not involve an alteration of cAMP accumulation. The present findings imply that ET isopeptides might antagonize the cardiostimulatory action of catecholamines mediated by beta-adrenoceptors when the blood level of both endogenous regulators are increased under cardiovascular pathophysiological situations.

Polyamine effects on [Ca2+]i homeostasis and contractility in isolated rat ventricular cardiomyocytes.

In electrically stimulated myocytes loaded with the fluorescent Ca2+ indicator indo 1-acetoxymethyl ester, spermine induced a dose-dependent (100-500 microM) negative inotropic effect, which was associated with a decrease in the magnitude of the cytosolic Ca2+ concentration ([Ca2+]i) transient but not with changes in myofilament responsiveness to Ca2+. Spermidine induced a less pronounced negative inotropic effect, whereas putrescine did not modify myocyte contraction. In the unstimulated state, spermine did not alter resting [Ca2+]i. Superfusion of the cardiac myocytes with 10 mM alpha-difluoromethylornithine, an inhibitor of polyamine synthesis, did not modify cellular responses to isoproterenol (10(-9)-10(-7) M). beta-Adrenergic stimulation did not affect either ornithine decarboxylase activity or intracellular polyamine levels within a 10-s to 15-min period of treatment. In summary, only exogenously administered polyamines were able to influence myocyte contractility. Their negative inotropic effect resulted from changes in [Ca2+]i homeostasis and required cellular depolarization.

Pronounced direct inhibitory action mediated by adenosine A1 receptor and pertussis toxin-sensitive G protein on the ferret ventricular contraction

An adenosine A1 receptor agonist R-N6-phenylisopropyladenosine (R-PIA) elicited a pronounced negative inotropic effect with the EC50 value of 0.69 mumol/l in the presence of a beta-adrenoceptor blocking agent bupranolol (0.3 mumol/l) in the isolated ferret papillary muscle. The negative inotropic effect of R-PIA was not associated with changes in cyclic AMP level. Adenosine and other A1 receptor agonists also elicited a negative inotropic effect. DPCPX (1,3-dipropyl-8-cyclopentyl xanthine) antagonized the negative inotropic effect of R-PIA in a competitive manner (pA2 value = 8.4). The inhibitory action of R-PIA was markedly attenuated in the ventricular muscle preparation isolated from ferrets pretreated with pertussis toxin that caused ADP-ribosylation of 39 kDa proteins in the membrane fraction. In the membrane fraction derived from the ferret ventricle, [3H]-DPCPX bound to a single binding site in a saturable and reversible manner with high affinity (Kd value = 1.21 +/- 0.41 nmol/l; Bmax = 12.8 +/- 3.02 fmol/mg protein; n = 7). The binding characteristics of [3H]-DPCPX in the rat ventricle (Kd value = 1.51 +/- 0.09 nmol/l; Bmax = 12.7 +/- 1.47 fmol/mg protein; n = 5) were similar to those in the ferret. On the other hand, the content of G(o), a major pertussis toxin-sensitive G protein in the ferret heart, was much higher in the ferret than in the rat ventricle. The present results indicate that adenosine receptors may play an important role in the inhibitory regulation of ventricular contractility in the ferret in contrast to other mammalian species. The signal transduction process subsequent to agonist binding to A1 receptors including the pertussis toxin-sensitive G protein and ion channels may be responsible for the unique inhibitory action of adenosine in this species.

2‐Aryl‐substituted 4H‐3,1‐benzoxazin‐4‐ones as novel active substances for the cardiovascular system

Abstract4H‐3,1‐Benzoxazin‐4‐ones of the structural types 3 and 4 are accessible by cyclization reactions. The introduction of the phosphonate group was achieved by way of Wohl‐Ziegler bromination and subsequent Michaelis‐Arbuzow reaction with a trialkyl phosphite. Pharmacological investigations on isolated left atria, ileum specimens, and Langendorff hearts as well as in vivo circulatory studies on anesthetized rats revealed that the phosphonates 4 exert calcium antagonistic effects. Whereas 2‐(arylvinyl)benzoxazinones gave rise to pronounced negative inotropic effects, compound 3e exhibited relaxing effects on smooth musculature in particular and markedly increased the coronary flow through Langendorff hearts.

Effect of Isradipine on Left Ventricular Relaxation and Diastolic Filling

The effect of two calcium antagonists on left ventricular (LV) relaxation and diastolic filling was evaluated in 16 randomized patients. Isradipine and nifedipine were administered intravenously in a maximum dose of 60 micrograms/min for isradipine and 63 micrograms/min for nifedipine. Heart rate was increased significantly (p less than 0.01) by both study agents. LV end-diastolic pressure remained unchanged whereas peak systolic pressure decreased significantly (p less than 0.01). The reduction in systolic pressure was significantly greater (p less than 0.05) after isradipine (delta P of 30 mm Hg) than after nifedipine (delta P of 13 mm Hg). The time constant decreased from 65 to 56 ms (p less than 0.05) after isradipine and from 62 to 59 ms (NS) after nifedipine. LV filling remained unchanged. It is concluded that both calcium antagonists are associated with a significant reduction in LV afterload accompanied by a reflex increase in heart rate. Isradipine is a more potent vasodilator than nifedipine at the same infusion rate. A beneficial effect on LV relaxation with isradipine, but not nifedipine, may be due to its less pronounced negative inotropic effect or its more potent afterload-reducing action.

Poisoning Due to Class IA Antiarrhythmic Drugs Quinidine, Procainamide and Disopyramide

Quinidine, procainamide and disopyramide are antiarrhythmic drugs in the class 1A category. These drugs have a low toxic to therapeutic ratio, and their use is associated with a number of serious adverse effects during long term therapy and life-threatening sequelae following acute overdose. Class 1A agents inhibit the fast inward sodium current and decrease the maximum rate of rise and amplitude of the cardiac action potential. Prolonged Q-T interval and, to a lesser extent, QRS duration may be observed at therapeutic concentrations of quinidine. With increasing plasma concentrations, progressive depression of automaticity and conduction velocity occur. 'Quinidine syncope' (a transient loss of consciousness due to paroxysmal ventricular tachycardia, frequently of the torsade de pointes type) occurs with therapeutic dosing, often in the first few days of therapy. Extracardiac adverse effects of quinidine include potentially intolerable gastrointestinal effects and hypersensitivity reactions such as fever, rash, blood dyscrasias and hepatitis. Procainamide produces electrophysiological changes that are similar to those of quinidine, although Q-T interval prolongation with the former is less pronounced at therapeutic concentrations. Hypersensitivity reactions including fever, rash and (more seriously) agranulocytosis are associated with procainamide, and a frequent adverse effect requiring cessation of therapy is the development of systemic lupus erythematosus. Of the 3 drugs, disopyramide has the most pronounced negative inotropic effects, which are especially significant in patients with pre-existing left ventricular dysfunction. As with quinidine, unexpected 'disopyramide syncope' at therapeutic concentrations has been described. Anticholinergic side effects are common with this drug and may require cessation of therapy. Disopyramide therapy may unpredictably induce severe hypoglycaemia. Severe intoxication with the class 1A agents may result from acute accidental or intentional overdose, or from accumulation of the drugs during long term therapy. Acute overdose can result in severe disturbances of cardiac conduction and hypotension, frequently accompanied by central nervous system toxicity. Decreased renal function can cause significant accumulation of procainamide and its active metabolite acecainide (N-acetyl-procainamide), resulting in severe intoxication. Mild to moderate renal dysfunction is less likely to lead to quinidine or disopyramide intoxication, unless renal failure is severe or concurrent hepatic dysfunction is present. Management of acute intoxication with class 1A drugs includes gut decontamination with provision of respiratory support and treatment of seizures as needed. Hypertonic sodium bicarbonate, by antagonising the inhibitory effect of quinidine on sodium conductance, may reverse many or all manifestations of cardiovascular toxicity.(ABSTRACT TRUNCATED AT 400 WORDS)

Myocardial contractility, blood flow, and oxygen consumption in healthy dogs during anesthesia with isoflurane or enflurane

Left ventricular contractility (V max), myocardial blood flow (MBF), and oxygen consumption (O 2C) were determined together with systemic hemodynamic parameters in a total of 21 mongrel dogs. Baseline recordings were obtained under basal anesthetic conditions with a narcotic (piritramid, IV). In the control group (n = 7), recordings were obtained during a three-hour observation period with infusion of piritramid. In experimental groups measurements were repeated with equi-anesthetic concentrations of isoflurane (0.7 and 1.4 vol%; n = 8) and enflurane (1.1 and 2.2 vol%; n = 6). Dose-dependent reductions of arterial pressure, cardiac output (CO) and peripheral vascular resistance were observed with isoflurane and enflurane. CO at the higher anesthetic level was depressed significantly more with enflurane. This difference was obviously due to a more severe depression of myocardial contractility with enflurane; V max was decreased by 18% and 26% with enflurane, but only by 10% and 17% with isoflurane ( P < 0.01). MBF and the fraction of CO received by the heart were increased above their baseline values with both concentrations of isoflurane. In contrast, the fraction of CO remained constant with enflurane while MBF decreased. O 2C was reduced due to decreases of afterload and left ventricular contractility. The reduction was greater with enflurane than with isoflurane. All parameters remained unchanged in the control group. The results of this study indicate that the most striking difference in the actions of isoflurane and enflurane on cardiac parameters is on myocardial vascular resistance; MBF is increased with isoflurane, but is decreased with enflurane although myocardial perfusion pressure is reduced by almost identical amounts. The stronger depression of systemic hemodynamic parameters with enflurane is due to its more pronounced negative inotropic effects.

Simultaneous Evaluation of Left Ventricular End-systolic Pressure-volume Ratio and Time Constant of Isovolumic Pressure Decline in Dogs Exposed to Equivalent MAC Halothane and Isoflurane

The effects of 1.5, 2.0, and 2.5 MAC halothane (N = 8) and isoflurane (N = 6) upon systolic performance and isovolumic relaxation were evaluated in open chest dogs. Left ventricular internal volume was determined using piezoelectric crystals. Left ventricular end-systolic pressure-volume points were determined for a series of normal sinus beats during transient venae caval occlusions. The slope of the line formed by those points is a load-independent inotropic index (EES). Left ventricular pressure points during isovolumic relaxation were plotted for computing the time constant of isovolumic pressure decline (T). Both drugs dose-dependently decreased mean arterial blood pressure with no change in heart rate, end-diastolic pressure, or end-diastolic volume. Increasing halothane concentration decreased the values of EES, the maximum rate of rise of left ventricular pressure (dP/dtMAX), and systolic ejection fraction (SEF). Total systemic resistance was unchanged by halothane. Increasing isoflurane concentration decreased EES and dP/dtMAX. The EES was significantly larger (P less than 0.05) with 2.5 MAC isoflurane than 2.5 MAC halothane. The SEF was unchanged by increasing isoflurane. Total systemic vascular resistance was decreased by increasing isoflurane. Isovolumic relaxation was prolonged and became more load-dependent with increasing halothane concentration. Isoflurane did not alter T, but the load-dependency of T was increased by 2.5 MAC isoflurane. There were no differences in T or its load-dependency between drug groups. These results indicate that both anesthetics evoke load-independent negative inotropic effects. Systolic ejection fraction is maintained during isoflurane anesthesia by decreased systemic vascular resistance and less pronounced negative inotropic effects than equivalent MAC halothane.(ABSTRACT TRUNCATED AT 250 WORDS)

Functional antagonism between calcium-antagonists and noradrenaline on isolated guinea-pig atria.

In the isolated electrically driven guinea-pig atrium the influence of D 600 and nifedipine on the action of noradrenaline was investigated. 1. The calcium-antagonists caused a dose-dependent negative inotropic effect. 10(-7) M of D 600 or nifedipine inhibited the contractile amplitude by 75 and 55%, respectively. 2. In spite of the pronounced negative inotropic effect evoked by the two calcium-antagonists, the maximal response to noradrenaline was not changed. The sensitivity of the myocardium to noradrenaline was only slightly diminished i.e. by a factor of 4.6 and 3 as calculated from the pD2-values. 3. The functional antagonism between noradrenaline and calcium-antagonists, therefore, offers the possibility to overcome cardiac side-effects of calcium-antagonists.