Congestive heart failure model in rabbits: effects of digoxin and a drug containing toad venom.

A low-output-type heart failure model was established in rabbits by protease treatment of the surface of the left ventricular anterior wall. Heart rate, aortic blood flow (AoF), left ventricular pressure (LVP) and maximal rate of rise of LVP (max dP/dt) in this model were maintained at lower levels than in normal rabbits, while left ventricular end-diastolic pressure (LVEDP) and systemic vascular resistance (SVR) were maintained at higher levels, and mean blood pressure (MBP) remained at a normal level. Intraduodenal administration of digoxin and a drug containing toad venom (Kyushin:KY) improved the hemodynamic parameters by increasing the AoF, LVP and max dP/dt and by decreasing the LVEDP and SVR without a significant change in MBP. These results suggest that the beneficial effects of digoxin and KY on this heart failure model originate from their cardiotonic activity.     

Effect of inosine in the normal and reperfused rat heart.

Inosine is a positive inotropic agent and dilates coronary blood vessels. During ischemia, inosine infusion increases blood flow, resulting in decreased myocardial damage. We wished (a) to determine inosine's effect in isolated rat hearts and (b) to determine if inosine attenuates myocardial dysfunction after transient global ischemia. Developed left ventricular pressure (LVP), LV dP/dt, and coronary perfusion pressure were monitored in hearts receiving Krebs-Henseleit buffer (KHB) (n = 10) or KHB + 2 mM inosine (n = 4). KHB + 2 mM inosine significantly reduced coronary perfusion pressure by 21% but had no effect on developed LVP or LV dP/dt. Hearts receiving KHB (n = 6) or KHB + 2 mM inosine (n = 5) were subjected to 15-min global ischemia followed by 30-min reperfusion with KHB. Recovery of LVP, LV dP/dt, the incidence of arrhythmias, and the time to peak recovery of developed LVP was not different between groups. In two additional hearts, KHB + 2 mM inosine administered during reperfusion had no effect on developed LVP, LV dP/dt, or coronary perfusion pressure. Thus, unlike other preparations, inosine pretreatment did not significantly affect the time course of postischemic functional recovery of rat myocardium.     

左旋四氢巴马汀对麻醉大鼠血流动力学影响

L-THP 6mg/kg iv仅显著降低麻醉大鼠血压,LVP-过性降低。iv L-THP 18mg/kg在显著降低血压的同时伴有LVP,±(dP/dt)_(max),(dP/dt)P~(-1)降低及HR减慢。但血压下降程度比心室收缩性能下降为大。L-THP依剂量降低DAP,且降低程度大于SAP。表明L-THP能降低外周阻力,大剂量时对心脏收缩性能有抑制作用。     

Effects of 5-([2-(diethylamino)-ethyl]amino)-3-phenyl-1,2,4-oxadiazole dihydrochloride (DEPO) on cardiac functions and myocardial metabolism of the dog

Effects of 5-([2-(diethylamino)-ethyl]amino)-3-phenyl-1,2,4-oxadiazole (DEPO) on cardiac functions and myocardial metabolism were examined using the heart in vivo and the isolated perfused heart of dogs. In the heart in vivo DEPO i.v. produced dose-dependent decreases in coronary perfusion pressure (PP), heart rate (HR), left ventricular pressure (LVP), dP/dt max of LVP and coronary vascular resistance (VR). DEPO i.c. dose-dependently increased left circumflex coronary flow (LCCF) and decreased PP, LVP and dP/dt max of LVP, but did not change HR. In the isolated perfused heart, DEPO induced a marked increase in coronary blood flow (CBF) and depressed HR and myocardial contractile force. Myocardial oxygen consumption and myocardial redox potential were not significantly changed. DEPO could not modify the effects of isoproterenol, adenosine and reactive hyperaemia on the heart. The results suggest that DEPO may have a coronary vasodilating action and some direct inhibitory actions on the heart.     

Negative inotropic effect of a CB2 agonist A-955840 in isolated rabbit ventricular myocytes is independent of CB1 and CB2 receptors

A-955840, a selective CB2 agonist, has been shown to elicit concentration-dependent decreases in cardiac contractility in the anesthetized dog (decreased maximal velocity of left ventricular pressure development [LV dP/dt max]). However, it is unknown whether this represents a direct effect or a response dependent on other factors (such as autonomic tone and neurohumoral factors) present in vivo. This study examined if A-955840 had a direct effect on contractility of isolated cardiac myocytes, and if so to determine the potential mechanisms. Contractility was assessed in vitro using percent changes in maximal shortening velocity of sarcomeres (dL/dt max) and fractional shortening of sarcomere length (FS) in rabbit left ventricular myocytes. L-type calcium current in myocytes was recorded using wholecell voltage-clamp techniques. A-955840 reduced dL/dt max and FS in a reversible and concentration-dependent manner with an IC50 of 11.4 μg/mL (based on dL/dt max) which is similar to the estimated IC50 value of 9.8 μg/mL based on the effects of A-955840 on LV dP/dt max in anesthetized dogs. A-955840 (4.1 μg/mL) reduced myocyte contractility (%FS) to a similar extent in the absence and presence of a CB2 antagonist, SR-2 (24.0 ± 3.4 vs 23.1 ± 3.0 %, n=5) or a CB1 antagonist, Rimonabant (18.8 ± 2.3 vs 19.8 ± 2.7 %, n=5). A-955840 (4.1 μg/mL) also reduced L-type calcium current of rabbit ventricular myocytes (1.05 ± 0.11 vs 0.70 ± 0.12 nA, n=5, P < 0.01). These results suggest that A-955840 exerts direct negative inotropic effects on isolated rabbit ventricular myocytes, which is mediated by neither CB2 nor CB1 receptors, and consistent with off-target negative inotropy mediated by inhibition of the cardiac L-type calcium current.     

Ca(2+)-sensitizing effect is involved in the positive inotropic effect of troglitazone

1. Troglitazone, an insulin sensitizing agent, has a direct positive inotropic effect. However, the mechanism of this effect remains unclear. Thus, we examined the inotropic effect of troglitazone while focusing on intracellular Ca2+ handling. 2. Troglitazone significantly increased peak isovolumic left ventricular pressure (LVP(max)), peak rate of rise of LVP (dP/dt(max)), peak rate of fall of LVP (dP/dt(min)) in isolated rat hearts perfused at a constant coronary flow and heart rate. This inotropic effect of troglitazone was not inhibited by pretreatment with carbachol (muscarine receptor agonist), H89 (protein kinase A inhibitor), U73122 (phospholipase C inhibitor), H7 (protein kinase C inhibitor), verapamil (L-type Ca2+ channel antagonist), thapsigargin (Ca(2+)-adenosine triphosphatase inhibitor) or ryanodine (ryanodine receptor opener). 3. Radioimmunoassay showed that the cyclic adenosine monophosphate concentration in the left ventricle was not increased by troglitazone. 4. Whole-cell patch clamp analysis revealed that troglitazone had no effect on inward Ca2+ currents in cardiomyocytes. 5. In fura-2 loaded perfused rat hearts, troglitazone exerted its positive inotropic effect without increasing Ca2+ concentration. 6. These results suggest that neither the inward Ca2+ currents nor Ca2+ handling in the sarcoplasmic reticulum was involved in the inotropic effect of troglitazone. Furthermore, troglitazone exerted its positive inotropic effect without affecting the intracellular concentration of Ca2+. 7. In conclusion, the positive inotropic effect of troglitazone is mediated by a sensitization of Ca2+.     

Inotropic selectivity of salbutamol and terbutaline in anaesthetised, areflexic dogs

The cardiovascular effects of the selective beta 2-adrenoceptor agonists salbutamol and terbutaline have been evaluated in anaesthetised, areflexic dogs. The preparation was designed to reduce the effects of changes in cardiac function mediated via reflex responses to changes in blood pressure. The effects of the selective beta 2-adrenoceptor agonists on heart rate, hindlimb blood flow, left ventricular pressure, max dP/dt and (dP/dt)/IIT (integrated isometric tension) were compared to those of isoprenaline, while blood pressure was held constant. All three drugs produced dose-dependent increases in heart rate, myocardial contractility and iliac blood flow. When equiactive inotropic doses of isoprenaline and salbutamol were compared, salbutamol produced a significantly lower chronotropic effect. A similar inotropic selectivity was found when terbutaline was compared to isoprenaline. beta 2-Adrenoceptor blockade abolished this selectivity. It is concluded that, in the absence of autonomic reflex activity, the beta 2-selective adrenoceptor agonists are relatively selective inotropic stimulants.     

Relative inotropic and chronotropic activity of beta-adrenoceptor stimulants in anaesthetised, areflexic dogs

The use of different methods of measuring contractility and the effects of cardiovascular reflexes are among the factors which complicate the assessment of selective inotropic activity of beta-adrenoceptor agonists. The effects of dobutamine, prenalterol, noradrenaline and isoprenaline on heart rate, iliac blood flow, left ventricular pressure, max dP/dt and (dP/dt) divided by IIT (integrated isometric tension) were evaluated in anaesthetised dogs in which the hearts were denervated and blood pressure held constant. All the drugs caused dose-dependent increases in heart rate and contractility. The relative chronotropic and inotropic activity of each agonist was evaluated. At most doses studied the agonists exerted similar chronotropic and inotropic activity when compared to the non-selective agonist isoprenaline. It is likely that the inotropic selectivity observed with prenalterol and dobutamine in previous studies depends on factors other than direct drug action.     

The haemodynamic effect of intravenous flecainide acetate in patients with coronary artery disease

Flecainide acetate has been shown to be a potent antiarrhythmic agent which is active for more than 8 h, whether given intravenously or orally. However, the negative inotropic effect demonstrated in animal studies could hamper the potential clinical utility of the drug. Ten patients with coronary artery disease but without cardiac failure were given intravenous flecainide (2 mg/kg). Stroke index (SI), left ventricular systolic pressure (LVP), end diastolic pressure (EDP) and LV contractility indices (max dP/dt, VCE 40 mm Hg, peak VCE, Vmax from total pressure (TP] were measured immediately before and 10 min after flecainide, under resting conditions and during atrial pacing with heart rates up to 133 +/- 4.2 beats/min (mean +/- s.e. mean). It is demonstrated that flecainide has a negative inotropic effect, not only under resting conditions, but also less apparently during pacing-induced tachycardia. The effect appears to be dose-related and may result in a reduction of cardiac performance.     

Effects of platelet-activating factor on myocardial contraction and myocardial relaxation of isolated perfused guinea pig hearts.

Platelet-activating factor (PAF) is an important mediator of cardiovascular shock owing to immunologic reactions, including anaphylaxis and endotoxaemia. Previous studies have shown that PAF is a potent cardio-depressive agent causing a marked coronary constriction and a sustained impairment of myocardial contractility. In this study, we attempted to characterize further the prolonged PAF effects on coronary circulation and myocardial contractile force in isolated guinea pig hearts perfused at constant pressure (60 cm H2O) or constant flow which was adjusted to a level of 100% above basal flow. In addition, the PAF-induced changes of ventricular systolic and diastolic function were distinguished. In the hearts perfused at constant pressure, PAF induced a dose-dependent (0.57, 5.7, and 57 pmol/min) decrease of coronary flow rates, left ventricular pressure (LVP), LV contraction (peak positive dP/dt) and LV relaxation (peak negative dP/dt). The decrement of peak negative dP/dt was more pronounced than that of peak positive dP/dt. Maintenance of coronary flow rates only attenuated, but did not suppress, the PAF-induced ventricular malfunction, and it improved ventricular relaxation less than it did ventricular contraction. Pretreatment with the PAF antagonist WEB 2086 (19.7 nmol/min) almost completely abolished the effects of the highest PAF dose on coronary circulation and ventricular contractile parameters. We conclude that the cardiodepressive effects of PAF are due to coronary constriction and direct contractile events. Furthermore, PAF impairs ventricular diastolic function more than ventricular systolic function.     

Cardiovascular actions of prostaglandin C in the cat and dog

1 Prostaglandin C(2) causes a prolonged fall in arterial blood pressure in the cat.2 At constant heart rate this fall in arterial pressure is accompanied by falls in stroke volume, left ventricular end diastolic pressure, and left ventricular dP/dt max.3 If mean aortic pressure and left ventricular end diastolic pressure are held constant as well as heart rate, prostaglandins C(2) and E(2) do not affect dP/dt max in the cat.4 In the dog, under similarly controlled conditions, prostaglandins C(2) and E(2) raise dP/dt max.5 We conclude that prostaglandins E(2) and C(2) have no direct inotropic action in the cat, but both have a direct positive inotropic action in the dog.     

The value added by measuring myocardial contractility 'in vivo' in safety pharmacological profiling of drug candidates

INTRODUCTION: The objective of this study was to define the normal LVdP/dt (an index of myocardial contractility)-heart rate relationship in telemetered conscious dogs, primates and mini-pigs in our laboratory and to use these data as the basis for an additional parameter useful in drug safety evaluation. METHODS: Trained dogs, Rhesus monkeys, Cynomolgus monkeys and mini-pigs (Goettinger) were equipped with radiotelemetry transmitters (ITS). Aortic pressure (AP), left ventricular pressure (LVP), a lead II ECG and body temperature could be continuously monitored. The contractility index LVdP/dtmax was derived from the LVP signal. Notocord HEM 4.1 software was used for data acquisition. For each species an LVdP/dt-heart rate relationship was evaluated using spontaneous heart rates (HR) throughout the observation period. A validation compound with positive inotropic effects (pimobendan) was then used to investigate the LVdP/dt-heart rate relationship. RESULTS: There was a clear LVdP/dt-HR relationship in the animals tested. The inotropic agent pimobendan demonstrated the expected shift in this relationship. DISCUSSION: Contractility of the myocardium is regulated by autonomic input activating primarily myocardial beta1-adrenoceptors, but it is also affected by the "force-frequency" relationship. Compounds can therefore either directly or indirectly affect the contractility of the heart. The chronotropic effects are routinely measured in preclinical studies; however, the inotropic effects are not routinely analysed in cardiovascular safety studies. Our experience strongly recommends including this evaluation for drug candidate selection. The evaluation of LVdP/dtmax, as an index of myocardial contractile state must, however, take into account its HR-dependency.     

Pharmacology of LY195115, a potent, orally active cardiotonic with a long duration of action

Compound LY195115 is a novel cardiotonic with both inotropic and vasodilator activities. In cat papillary muscles, LY195115 increased contractility in a concentration-dependent manner; its actions were not blocked by either prazosin or propranolol. An intravenous dose of 7.0 micrograms/kg LY195115 resulted in a 50% increase in contractility in anesthetized dogs; comparable inotropic responses were observed in anesthetized cats receiving 10 micrograms/kg i.v. These doses of LY195115 increased heart rates of both dogs and cats by less than 10%. Oral administration of 25 micrograms/kg to conscious dogs was associated with a selective inotropic response that was maximal at 3 h and maintained in excess of 23 h. This effect was not accompanied by gross behavioral changes or emesis. The hemodynamic profile of LY195115 was evaluated in anesthetized beagle dogs. A 60-min infusion of 1.0 microgram/kg/min LY195115 followed by a 5-min infusion of 10 micrograms/kg/min resulted in dose-dependent increases in contractility (LV dP/dt60) and heart rate; doses that increased LV dP/dt60 by 50% increased heart rate by less than 10%. Doses of greater than 5.0 micrograms/kg decreased left ventricular end-diastolic pressure and systemic vascular resistance; mean arterial blood pressure and cardiac output were unchanged. Estimated myocardial oxygen consumption (heart rate times either systolic or mean arterial blood pressure) was not altered by doses as high as 110 micrograms/kg. This balance of inotropic/vasodilator activities may provide a means of improving cardiac function while maintaining myocardial oxygen supply/demand.     

Influence of autonomic blockade on the reduction in myocardial performance produced by clonidine

Clonidine (15 μg/kg, i.v.) induced an increase followed by a long-lasting decrease in blood pressure and reduced heart rate and cardiac output of dogs. All the indices of myocardial performance were decreased: maximal rate of rise in left ventricular pressure, max dP/dt/I.P. (I.P. = ventricular pressure at max dP/dt), pressure time index. The left ventricular end diastolic pressure was increased even when stroke work was decreased. The curve relating dP/dt to the developed pressure was flattened. These facts indicate that clonidine decreased myocardial contractility. Ventricular volumes were not altered. Pacing of the heart after clonidine did not lead to a recovery of cardiac output and myocardial contractility.To analyze the role of the sympathetic and vagal tones on these factors, 5 groups of dogs were used: (1) reserpinized, (2) reserpinized with both vagus nerves cut, (3) with β-adrenoceptor (S 2395, 50 μg/kg) and muscarinic receptor (atropine, 50 μg/kg) blockade, (4) with both vagus nerves cut, and (5)_with both carotid sinus nerves cut.Heart rate was markedly reduced in group 1 but not change in group 2 and 3 3; in groups 4 and 5, heart rate was decreased but to a smaller extent than in control dogs. Therefore the decrease in sympathetic tone and the increase in vagal tone were responsible for the bradycardia. The increase in the vagal tone was apparently due to potentiation of the influence of baroreceptor impulses.The maximal rate of rise in left ventricular pressure did not change in groups 1,2, and 3, but was decreased in groups 4 and 5, indicating that the loss of the sympathetic tone was responsible for the reduction in myocardial contractility.Cardiac output was not changed significantly in groups 2,3 and 4, but decreased in groups 1,3 and 5. The loss of the sympathetic tone and the bradycardia when very marked appear to reduce cardiac output.Left ventricular end diastolic pressure rose in groups 1 and 2, and was increased only transiently in groups 4 and 5. The decrease in myocardial contractility, the changes in blood pressure, the bradycardia and possibly the reduced venous return appear to be the factors influencing this parameter.Blood pressure shows the usual biphasic changes, an increase followed by a decrease in groups 3,4 and 5, did not change in group 1, and was only increased in group 2. The loss of the sympathetic tone was therefore responsible for this effect.     

CARDIOVASCULAR EFFECTS OF NEUROMUSCULAR BLOCKADE DURING INDUCED HYPOTHERMIA

Young lambs were used to study the effects of progressive cooling and rewarming on cardiovascular function during neuromuscular blockade induced by gallamine. Initially, it was shown that gallamine exerted no immediate, direct haemodynamic effect in normothermic or hypothermic lambs (cooled by 10 degrees C). By comparison with hypothermic controls, neuromuscular blockade was associated with increases in left ventricular (LV) max dP/dt (153%; P less than 0.02) as cooling progressed, and even greater increases (232%; P less than 0.001) during rewarming. It was concluded that these changes seem likely to represent enhanced myocardial contractility since preload did not closely follow LV max dP/dt (heart rate and mean aortic pressure fell gradually during cooling but values were restored in the rewarming phase). LV max dP/dt in lambs given gallamine only after cooling also showed a similar response during rewarming. Results of this study may have clinical relevance relating to the mechanical recovery of the hypothermic heart in patients receiving neuromuscular blockade during cardiac surgery, and they argue against using gallamine as such an agent.     

Negative inotropic and lusitropic effects of intravenous amiodarone in conscious rats

1. The acute effect of amiodarone on haemodynamics (mean arterial pressure and heart rate) and ventricular function (+dP/dt(max) and -dP/dt(max)) was investigated in conscious rats. In addition, the effects of amiodarone on dobutamine stress were determined. 2. Catheters were inserted in rats into the left ventricle and femoral artery and vein. Three groups of rats received 25 or 50 mg/kg, i.v., amiodarone or vehicle (a 1:1:8 mixture of Tween 80:99.5% ethanol:distilled water), followed by dobutamine (10 microg/kg). 3. The hypotensive effect of 50 mg/kg amiodarone was combined with marked bradycardia and attenuation of +dP/dt(max) and -dP/dt(max). A slight, but significant, hypotension was caused by 25 mg/kg amiodarone, without affecting heart rate, +dP/dt(max) and -dP/dt(max). However, although both doses of amiodarone attenuated the tachycardia caused by dobutamine, neither 25 nor 50 mg/kg amiodarone affected the increase in mean arterial pressure or the enhanced response of +dP/dt(max) and -dP/dt(max). 4. In conclusion, amiodarone caused hypotension, bradycardia, negative inotropic (+dP/dt(max)) and lusitropic (-dP/dt(max)) effects in conscious rats. In addition, amiodarone attenuated the tachycardia without affecting the hypertensive, contractile (+dP/dt(max)) and lusitropic (-dP/dt(max)) responses to dobutamine stress.     

Upregulation of bradykinin B1-receptor expression after myocardial infarction

To determine the influence of the myocardial infarction (MI) on bradykinin B1-receptor (B1R) regulation, we studied its expression in the left ventricle (LV) after MI. Rats were submitted to a permanent occlusion of the left coronary artery. Six hours, 24 h and 6 days after MI or after sham operation, left ventricular pressure (LVP) and dP/dt(max) were measured. LV-total RNA was extracted and B1R expression was analysed by a RNase-protection assay (each group n = 6). LVP and dP/dt(max) were impaired at all time points after MI. Basal B1R expression was not detectable in controls. Six hours after MI, the B1R expression was upregulated and reached a maximum 24 h after MI (4 fold vs. 6 h). Six days post-MI, B1R expression returned to levels found 6 h after MI. These data are the first demonstration for an induced myocardial B1R expression in an in vivo model of MI.     

Comprehensive evaluation of cardiovascular function in the anesthetized rat.

The present report describes methods and procedures which have been developed and used in the intact, anesthetized rat for cardiovascular functional evaluation. Integrative hemodynamic mechanisms are ascertained under resting conditions by measuring arterial blood pressure, cardiac output and heart rate. Stroke volume and total peripheral resistance are derived from the above measurements. In addition, left ventricular pressure is determined by direct cardiac puncture. Derived rates of left ventricular pressure development (+dP/dt) and left ventricular pressure decline (-dP/dt) provide estimates of myocardial contractility and cardiac relaxation, respectively. Hemodynamic responses to isoproterenol infusion test the functional adequacy of the beta-adrenergic receptor, adenylate cyclase, cyclic AMP system. Ventricular function curves relating stroke volume and end-diastolic pressure during rapid volume infusion provide useful indices of cardiac pump performance in the intact heart. Peak left ventricular +dP/dt in response to brief aortic occlusion provides an index of cardiac contractile performance. Cardiac cellular/subcellular mechanisms relating (a) myofibrillar ATPase with heart contractility and (b) sarcoplasmic reticulum calcium handling properties with myocardial relaxation can be assessed. Thus, the methods and procedures described represent an experimental animal preparation which should prove useful for comprehensive evaluation of cardiovascular function.     

低浓度毒毛旋花子苷元的强心作用及其与心肌细胞膜Na~＋，K~＋-ATP酶的关系

目的:观察低浓度的毒毛旋花子苷原(Strophanthidin,Str)对离体豚鼠心脏是否有强心作用,及其与心肌细胞膜Na~+,K~+-ATP酶活性的关系。方法:采用Langendorff离体灌流装置经主动脉逆行灌流心脏;八道生理记录仪记录心率(HR),左室内压(LVP)及其最大变化速率(±dP/dt_(max));无机磷法测定心肌细胞膜Na~+,K~+-ATP酶活性。结果:Str 0.1nmol/L可兴奋Na~+,K~+-ATP酶活性(P<0.05)但不影响心脏的收缩功能,Str 1nmol/L仅能升高+dP/dt_(max)(P<0.05)并兴奋Na~+,K~+-ATP酶活性(P<0.01),Str 10和100 nmol/L可升高LVP和+dP/dt_(max)(P<0.05或P<0.01),对Na~+,K~+-ATP酶活性无明显作用,Str 1-100μmol/L虽能短暂升高LVP和±dp/dt_(max)(P<0.01),但随后出现不规则收缩并使LVP和±dP/dt_(max)降低,其对Na~+,K~+-ATP酶活性则表现为剂量依赖性抑制作用(P<0.01)。结论:高浓度Str的正性肌力作用是通过抑制Na~+,K~+-ATP酶活性实现的,而低浓度Str的强心作用似与Na~+,K~+-ATP酶抑制作用无关。     

Hemodynamic effects of different calcium antagonists in the heart-lung preparation of the guinea pig

The present study was performed with the aim to demonstrate and quantify the influence of several different calcium antagonists (CA) on hemodynamic parameters in the guinea pig heart lung preparation (HLP). In paced HLP the following parameters were recorded: dp/dt max; cardiac output (CO); left ventricular pressure (LVP), and aortic pressure (AoP). In separate experiments the influence of the CA on heart rate (HR) was established in spontaneously performing HLP. All CA studied reduced or depressed dp/dt max, CO, LVP, AoP and HR. Nifedipine and verapamil showed the strongest depressant influence on dp/dt max and CO, whereas diltiazem caused a moderate reduction of these parameters. Lidoflazine, flunarizine and bepridil proved considerably less potent than nifedipine, verapamil and diltiazem. Bepridil proved least potent with respect to the influence on LVP and AoP. The strongest reduction on HR was caused by nifedipine greater than verapamil greater than diltiazem, and to a lesser degree by lidoflazine. Bepridil and flunarizine only caused a mild reduction of HR. From the calculated ratio EC20(HR)/EC20(dp/dt max) it is obvious that nifedipine, verapamil and bepridil display a much stronger influence on contractility than on HR. dp/dt max proved the most sensitive indicator for contractility in the HLP as used in our experiments.