Inotropic Effect Of Isoprenaline Research Articles

Treatment with atorvastatin partially protects the rat heart from harmful catecholamine effects

Atorvastatin blunts the response of cardiomyocytes to catecholamines by reducing isoprenylation of G gamma subunits. We examined whether atorvastatin exerts similar effects in vivo and protects the rat heart from harmful effects of catecholamines. Rats were treated with atorvastatin (1 or 10 mg/kg x day) or H(2)O for 14 days per gavage. All three animal groups were subjected to restraint stress on day 10 and to infusions of isoprenaline (ISO; 1 mg/kg x day) or NaCl via minipumps for the last 4 days. Heart rate was measured by telemetry, left ventricular atrial natriuretic peptide (ANP) transcript levels by RT-PCR, and left atrial contractile function in organ baths. Heart rate was similar in all six study groups. In animals pre-treated with water, infusion of ISO induced an increase in heart-to-body weight ratio (HW/BW) by approximately 20%, an increase in ANP mRNA by approximately 350%, and a reduction in the inotropic effect of isoprenaline in left atrium by approximately 50%. In animals pre-treated with high-dose atorvastatin, the effects of ISO on HW/BW, ANP, and left atrial force were approximately 40, 50, and 40% smaller, respectively. Low dose atorvastatin had similar, albeit smaller effects. Atorvastatin treatment of NaCl-infused rats had only marginal effects. In cardiac homogenates from atorvastatin-treated rats (both NaCl- and ISO-infused), G gamma and G alpha(s) were partially translocated from the membrane to the cytosol. In the rat heart, treatment with atorvastatin results in translocation of cardiac membrane G gamma and G alpha(s) to the cytosol. This mechanism might contribute to protecting the heart from harm induced by chronic isoprenaline infusion without affecting heart rate.

Ontogeny of positive inotropic responses to sympathomimetic agents and of myocardial adrenoceptors in rats

Positive inotropic efficacies (maximal increase in contractile force) and potencies of the alpha-adrenoceptor agonist methoxamine and beta-adrenoceptor agonist isoprenaline were determined on electrically driven (1 Hz) ventricular strips from rats aged 0.5, 1, 2, 3, 6, and 10 (adult) weeks. The inotropic response to methoxamine significantly decreased after 2 weeks of age. The inotropic potency of isoprenaline was slightly but significantly lower at all ages than at 0.5 weeks of age. Up to 2 weeks of age, the maximal inotropic effect of methoxamine was comparable with that of isoprenaline, thereafter it was but markedly less. Phenylephrine behaved like methoxamine, and noradrenaline like isoprenaline. The effect of methoxamine was antagonized by prazosin but not by propranolol; the reverse was true for isoprenaline. Injections at birth of triiodothyronine and dexamethasone exerted minimal effects on the inotropic responses to methoxamine and isoprenaline. Chemical sympathectomy with 6-hydroxydopamine caused supersensitivity to the inotropic effects of isoprenaline but produced subsensitivity to responses to methoxamine at 1 week; effects of methoxamine at 3 and 6 weeks of age were not altered by sympathectomy. No significant differences in alpha 1- or beta 1-adrenoceptor densities or affinities in ventricular membranes from 7-day-old and adult rats were found. It is concluded that the positive inotropic responses to sympathomimetic amines decline with age, the decline is most marked in the case of alpha 1-adrenoreceptor- mediated effects, and these changes do not appear to be due to a decrease in the number or affinity of alpha 1- and beta 1-adrenoceptors.

Quantification of Gi alpha-proteins in the failing and nonfailing human myocardium.

Heterotrimeric Gi-proteins play an important role in the regulation of cardiac adenylate cyclase. Besides a downregulation of beta-adrenoceptors with an accompanying reduction of the positive inotropic effects of cAMP-dependent positive inotropic agents, an increase of pertussis toxin substrates (Gi alpha-proteins) has been observed. The increase of Gi alpha has been reported to be associated with a reduced adenylate cyclase activity in dilated cardiomyopathy from hearts with heart failure class NYHA IV. Since the quantification of Gi alpha-proteins with the pertussis toxin labeling method is hampered by a number of biological and technical factors, Gi alpha-proteins were quantified radioimmunologically using the iodinated C-terminus 125I-KENLKDCGLF as tracer, purified retinal transducin alpha as standard, and an antiserum (DS 4) raised against the same peptide. With this technique Gi alpha-proteins were increased by 118% in dilated cardiomyopathy and 48% in ischemic cardiomyopathy, although pertussis toxin substrates were only increased by 40% in dilated cardiomyopathy and no change was observed in ischemic cardiomyopathy. In cardiomyopathic tissue, an inverse relationship was observed between the increase of Gi alpha and the positive inotropic effects of isoprenaline or milrinone. These data provide evidence for a functional role of Gi alpha in the reduced positive inotropic effects of cAMP-dependent positive inotropic agents. In addition, results obtained with pertussis toxin labeling for quantification of Gi alpha-proteins do not necessarily reflect the expression of Gi alpha-proteins in the human myocardium.

Effects of Isomazole on Force of Contraction and Phosphodiesterase Isoenzymes I-IV in Nonfailing and Failing Human Hearts

The phosphodiesterase (PDE) inhibitor isomazole increased the force of contraction to 278.3 +/- 89.1% (n = 7) of the predrug value in ventricular trabeculae carneae isolated from nonfailing human hearts. This effect can be attributed mainly to a PDE III or a combined PDE III/IV inhibition since at the concentration of the maximal positive inotropic effect of isomazole, PDE III and PDE IV were completely inhibited. In explanted failing human hearts (end-stage myocardial failure, NYHA IV), isomazole increased the force of contraction only marginally to 110.1 +/- 10.7% of the predrug value. The lack of a distinct positive inotropic efficacy of isomazole in failing human hearts could not be explained by an impairment of PDE inhibition since the properties of the PDE I-IV isoenzymes separated by DEAE-Sepharose chromatography and the inhibitory effects of isomazole did not differ in both preparations. The positive inotropic effect of the beta-adrenoceptor agonist isoprenaline was also reduced in failing hearts. However, in the presence of isomazole, the diminished positive inotropic effect of isoprenaline was restored to values obtained with isoprenaline alone in nonfailing hearts. Thus, the decreased effect of inotropic drugs like isoprenaline or isomazole in preparations from failing human heart might be explained mainly by a diminished cAMP formation due to a defect in receptor-adenylate cyclase coupling.

Pharmacological characteristics of adenosine-induced inhibition of dog ventricular contractility: dependence on the pre-existing level of ?-adrenoceptor activation

Experiments were carried out to characterize the adenosine-induced negative inotropic effect in relation to the extent of beta-adrenoceptor activation in the isolated dog left ventricular myocardium. Adenosine and R-N6-phenylisopropyladenosine inhibited the positive inotropic effect of isoprenaline (10(-7) mol/l and lower) about 20% of its maximal response, which was antagonized by an A1 adenosine receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine in a concentration-dependent manner. The negative inotropic effect of adenosine disappeared and that of R-N6-phenylisopropyl-adenosine decreased when the isoprenaline concentration was elevated to the level higher than 10(-7) mol/l. Adenosine deaminase (1.5 U/ml) that abolished the negative inotropic effect of adenosine enhanced the effect of R-N6-phenylisopropyladenosine, indicating that endogenous adenosine released by high isoprenaline concentration (10(-6) mol/l) modulates the interaction. The maximal response to adenosine and R-N6-phenylisopropyladenosine determined in the presence of 10(-7) mol/l isoprenaline was 50% of that of carbachol which elicited the maximal inhibition even in the presence of 10(-6) mol/l isoprenaline. The negative inotropic effects of R-N6-phenylisopropyladenosine and carbachol were additive to the maximal response equivalent to that of carbachol. The difference in the efficiency between the adenosine and muscarinic receptor agonists may be partly ascribed to the difference in densities of the respective receptors in the dog ventricular myocardium. The negative inotropic effect of R-N6-phenylisopropyladenosine in the presence of isoprenaline was associated with decrease in cyclic AMP levels elevated previously by isoprenaline.(ABSTRACT TRUNCATED AT 250 WORDS)

Action of thyrotropin-releasing hormone in experimental hemorrhagic shock — cardiovascular mechanism

Thyrotropin-releasing hormone (TRH) could improve mean arterial pressure (MAP), myocardial contractile parameters (+/- dp/dtmax, Vpm and Vmax) and increase plasma epinephrine level significantly at 10 min after TRH administration in hemorrhagic shock rabbits, but the action of TRH on MAP and the myocardial contractility did not appear in rabbits pre-treated with reserpine (4 mg/kg, 24 h pre-treatment, i.v.). TRH had no effects on myocardial contractility and MAP at 20 and 30 min after administration to rabbits pre-treated with beta-adrenergic blocker propranolol (1 mg/kg, 1 h before TRH injection i.v.), but it did exert effects on these parameters in rabbits pre-treated with alpha-adrenergic blocker phenoxybenzamine. Experiments in vitro showed that, although TRH (10(-4) M/L) had no direct effect on heart, left atrium and aortic strip, it did potentiate the inotropic effects of isoprenaline and dopamine on the left atrium. These results suggested that antishock effect of TRH is related to adrenergic system. TRH stimulates sympathomedullary system to secrete epinephrine and sensitize the beta-receptors, but not alpha-receptors. Thus, TRH improves cardiac contractility, cardiac output and hemodynamics during hemorrhagic shock. The sensitization of the beta- and dopamine receptors played an important role in producing direct peripheral actions of TRH.

Receptor reserve for positive inotropic effects of isoprenaline in the human heart: alterations with increasing degree of cardiac failure

Receptor reserve for positive inotropic effects of isoprenaline in the human heart: alterations with increasing degree of cardiac failure

β‐Adrenoceptor blocking effects of a selective β2‐agonist, mabuterol, on the isolated, blood‐perfused right atrium of the dog

1. Effects of (+/-)-1-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-tert.- butylamino-ethanol hydrochloride (mabuterol) on pacemaker activity and atrial contractility were investigated in the isolated and blood-perfused right atrium of the dog. 2. Mabuterol, injected into the sinus node artery of the isolated atrium, dose-dependently increased atrial rate and contractile force at doses of 0.01-10 nmol but the responses to over 10 nmol of mabuterol gradually decreased and mabuterol at higher doses induced biphasic cardiac responses, i.e., negative followed by positive cardiac responses. 3. The maximal increases in atrial rate and contractile force induced by mabuterol were 41.4% and 12.9%, respectively, of the maximal chronotropic and inotropic effects of isoprenaline. 4. Positive chronotropic and inotropic responses to mabuterol were dose-dependently inhibited by a selective beta 2-adrenoceptor antagonist, ICI 118,551. These responses were only slightly attenuated by atenolol. 5. Mabuterol (1-300 nmol) dose-dependently inhibited both dobutamine- and procaterol-induced positive chronotropic and inotropic responses. 6. These results indicate that mabuterol causes weak positive chronotropic and inotropic effects on the perfused canine right atrium by activating beta 2-adrenoceptors, and that higher concentrations non-selectively block both beta 1-and beta 2-adrenoceptors.

Positive Inotropic Effect of DPI 201-106 in Spontaneously Hypertensive Rats

The positive inotropic effect of DPI 201-106 has been studied in isolated, electrically driven papillary muscles of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WK). The positive inotropic effect of isoprenaline (Iso) and Ca2+ was studied for comparison. The maximal positive inotropic effect of Iso was less in SHR than in WK. In SHR, DPI 201-106 more effectively increased force of contraction than Iso. The positive inotropic effects of DPI 201-106 and Ca2+ were not different in SHR and WK. The EC50 values of DPI 201-106, Iso, and Ca2+ did not differ in either group. Furthermore, adenosine and carbachol reduced the positive inotropic effect of Iso but failed to exert a negative inotropic action when force of contraction has been increased with DPI 201-106. The isoprenaline-antagonistic effect of adenosine and carbachol was not different in SHR and WK. We conclude that DPI 201-106 might be an effective positive inotropic agent in states in which adrenergic function is compromised. The lack of inhibition by adenosine or m-cholinoceptor agonists could contribute to the effectiveness of the compound to increase myocardial force of contraction.

Postnatal development of β-adrenergic response in ventricular muscle of the rat heart

In adult mammalian, heart responses to beta- and alpha-adrenergic stimulation are different: the beta-type effect exhibits a larger increase of relaxation than of contraction, while the alpha-stimulation has no selective influence on relaxation. The present results show that the effect of isoprenaline (ISO) on the neonatal rat heart during the 1st postnatal week is not a typical beta-effect in that the relaxant influence of beta-stimulation is lacking. During the 2nd and 3rd postnatal weeks the typical beta-response, with improved relaxation, gradually appears. The absence of the typical beta-effect is not caused by the lack of beta-receptors or cAMP-dependent phosphorylation reactions because in other respects, the positive inotropic effect of ISO is well developed at the moment of birth. In addition to these qualitative changes, also prominent quantitative changes occurred in the ISO response. The dose-response curves were shifted to the right with advancing age, suggesting reduced beta-agonist potency of the maturing tissue. The developed tension (Tmax) abruptly increased between the 12th and 17th postnatal days and then steeply declined during the next 2 weeks. Changes in Tmax correlated fairly well with the general ability of the tissue to generate extra force, as expressed by rest-dependent potentiation of twitch. However, during the 2nd postnatal week cardiac tissue seemed to be subsensitive to ISO, since all contractile parameters except T''max were depressed. The results suggest that the postnatal changes in beta-response are primarily determined by alternations in the electromechanical coupling process of the developing tissue, and less by the proper adrenergic mechanisms.

Does an impaired adenosine mediated feedback control play a role in the development of hereditary dystrophic cardiomyopathy?

A study was carried out to investigate whether or not an impairment of the adenosine mediated negative inotropic effect in the presence of beta adrenoceptor stimulation plays a role in the pathogenesis of the hereditary cardiomyopathy of the Syrian hamster. In electrically driven papillary muscles isolated from the hearts of cardiomyopathic (strain BIO 8262) and age matched healthy control Syrian hamsters the effects of isoprenaline, adenosine, and adenosine in the presence of isoprenaline were studied within the first 30 days of life (the prenecrotic stage of the disorder). In both cardiomyopathic and control hamsters adenosine antagonised the positive inotropic effect of isoprenaline, whereas adenosine alone had no or, only a weak, inhibitory effect on the force of contraction. The effects in both groups were similar. The effect of isoprenaline on the force of contraction also did not differ in the two groups. The data show that in both cardiomyopathic and control hamsters adenosine reduces the force of contraction during beta adrenergic stimulation. The potency or efficacy of adenosine did not differ in the two groups. An impaired adenosine mediated feedback control of the heart does not therefore seem to play a role in the pathogenesis of the hereditary dystrophic cardiomyopathy of the Syrian hamster.

Increased sensitivity to alpha-adrenoceptor stimulation but intact purinergic and muscarinergic effects in prehypertensive cardiac hypertrophy of spontaneously hypertensive rats.

The effects of phenylephrine, isoprenaline and adenosine, (-)-N6-phenylisopropyladenosine (PIA) or carbachol alone and in the presence of isoprenaline on force of contraction were studied in isolated electrically driven papillary muscles of spontaneously hypertensive rats (SHR) and age-matched Wistar control rats. In SHR an increased heart to body weight ratio was observed when blood pressure was not yet elevated. During this stage of the syndrome (i.e. between the 27th and 35th day of life) phenylephrine was about 3.4 times more potent to increase force of contraction in SHR (mean EC50: 2.8 mumol l-1) than in control rats (mean EC50: 9.4 mumol l-1). The positive inotropic effect of isoprenaline was similar in SHR and control rats. Also no difference could be detected in the isoprenaline-antagonistic effect of adenosine, the adenosine receptor agonist PIA or carbachol. We conclude that an increased sensitivity to cardiac alpha-adrenoceptor stimulation might be related to prehypertensive cardiac hypertrophy in SHR.

Influences of age on the positive inotropic effect mediated by alpha- and beta-adrenoceptors in rat ventricular strips.

The positive inotropic effect of phenylephrine (in the presence of atenolol) and isoprenaline was studied in isolated right ventricular strips obtained from Wistar rats aged 2 weeks, 3 months, and 26 months. The positive inotropic effects induced by phenylephrine and isoprenaline were higher in the 2-week-old than in the 3- or 26-month-old rats. The typical 'alpha-type' or 'beta-type' responses were induced by phenylephrine (plus atenolol) or isoprenaline, in all the age groups. The EC50 values for the alpha-mediated positive inotropic effect decreased with age, while the EC50 value for the positive inotropic effect of isoprenaline increased in the senescent heart. These results suggest an enhanced alpha-adrenergic sensitivity in the senescent heart.

Myocardial inotropic responses and adrenoceptors in protein-deficient rats.

Inotropic effects of isoprenaline, phenylephrine and calcium were studied in left atria of 5 weeks old rats fed a low (5%) or a normal (21%) protein diet for 3 weeks. Rats maintained on a low (5%) protein diet consume about half the amount of food eaten by the same rats maintained on a normal (21%) protein diet and thus suffer from protein-calorie malnutrition (PCM). Body weight did not increase in PCM, but heart weight adjusted to body weight was slightly increased compared to normal rats. Atrial resting tension and peak developed tension in response to isoprenaline, phenylephrine or calcium were not diminished by PCM. The number of alpha and beta-adrenoceptors and the receptor affinity in ventricular membranes were not reduced by PCM.

Actions of alinidine and AQ-A 39 on rate and contractility of guinea pig atria during beta-adrenoceptor stimulation.

We studied two new agents, alinidine (St 567, 2-[N-allyl-N-(2,6-dichlorophenyl)-amino]-2-imidazoline) and AQ-A 39 (5,6-dimethoxy-2-[3[[alpha-(3,4-dimethoxy)-phenylethyl] methylamino]propyl]phthalimidine), in isolated guinea pig atria with respect to their specificity to decrease heart rate but not contractility during beta-adrenoceptor stimulation. Spontaneous electrical activity in sinoatrial node preparations was increased by perfusion with isoprenaline (0.1 micrograms/ml); addition of alinidine (3 micrograms/ml), AQ-A 39 (3 micrograms/ml), or propranolol (0.03-0.3 micrograms/ml) reduced sinus rate to the control values. The same concentrations of these drugs were tested in electrically driven (1 Hz) left atria. The positive inotropic effect of isoprenaline was not affected by alinidine and AQ-A 39; however, it was markedly reduced or abolished by propranolol. The experiments, therefore, demonstrated the bradycardic specificity of alinidine and AQ-A 39 under conditions of beta-adrenoceptor stimulation. A cumulative concentration-response curve for the positive chronotropic effect of isoprenaline was established in spontaneously beating atria. AQ-A 39, 1 and 10 micrograms/ml, reduced the control sinus rate but did not affect the following concentration-response curve of isoprenaline. A similar result was published earlier for alinidine and excludes an interaction of both drugs with isoprenaline on a possible subgroup of selective beta-adrenoceptors in the sinoatrial node.

Effects of trifluoperazine on beta-adrenergic responses of rat papillary muscle: related to calmodulin?

The beta-adrenergic stimulation of cardiac contraction and relaxation is related to an augmented Ca++ oscillation mediated by cAMP. This Ca++ mobilization may secondarily involve calmodulin in a way modulating the mechanical responses. We tested this possibility by studying interferences of trifluoperazine (which is able to block Ca++-calmodulin) with beta-adrenergic responses in rat heart papillary muscles. Trifluoperazine up to 10(-5) mol/l did not change the basal function. 10(-5) mol/l trifluoperazine augmented the contractile response to isoprenaline above 10(-7) mol/l. The inotropic effects of isoprenaline below 10(-7) mol/l and of the partial beta-agonist prenalterol were not influenced by trifluoperazine. 10(-5) mol/l trifluoperazine attenuated the stimulation of initial relaxation by isoprenaline in the entire concentration range. Thus this beta-adrenergic response was more sensitive to trifluoperazine than the contractile response. But trifluoperazine only slightly and non-significantly attenuated the stimulation of initial relaxation by prenalterol. From experiments on broken cell preparations the present results can be explained in terms of calmodulin blockade and thus inhibition of Ca++ efflux across the sarcolemma and of Ca++ uptake by the sarcoplasmic reticulum. Trifluoperazine effects unrelated to calmodulin can hardly account for the results. Thus a full beta-agonist can apparently mobilize enough Ca++ to activate calmodulin systems important for the final effects on the contraction-relaxation cycle.

Electrophysiological and antiarrhythmic properties of propafenon in isolated cardiac preparations.

Propafenon, a new antiarrhythmic drug, caused a 30% decrease in maximal driving frequency and a 65 ms net increase in functional refractory period of isolated guinea pig atria at a concentration as low as 0.5 microgram/ml. The spontaneous rate of isolated atria and the contractility of electrically driven ventricular strips were reduced after treatment with propafenon 1 microgram/ml. Propafenon 0.5 microgram/ml also altered action potentials of sheep Purkinje fiber. It reduced the action potential and overshoot amplitudes, decreased the maximum rate of depolarization of the action potential upstroke in a frequency-dependent fashion, shortened the action potential and effective refractory period, and depressed the membrane responsiveness. Moreover, propafenon antagonized the chronotropic and inotropic effects of isoprenaline in isolated guinea pig heart preparations; the pA2 value was about 6.4. Finally, propafenon possessed very weak calcium antagonist properties, being about 100 times less potent than verapamil in this respect. We conclude that propafenon is an antiarrhythmic drug with beta-adrenoceptor blocking and "membrane stabilizing" activities in the same range of concentrations and that it has a calcium antagonistic activity only at much higher concentrations.

Effects of tetramethylpyrazine on isolated atria of the guinea-pig.

The chronotropic and inotropic effects of tetramethylpyrazine (TMPZ) obtained from the stem of JATROPHA PODAGRICA H OOK (Euphorbiaceae) have been investigated on guinea-pig isolated atria. TMPZ caused negative chronotropic and inotropic responses on the isolated atria of guinea-pigs. These TMPZ - induced negative chronotropic and inotropic responses were resistant to the action of atropine. Prior administration to the bath fluid of TMPZ also antagonized the positive chronotropic and inotropic effects of isoprenaline, noradrenaline and calcium on the tissue preparations. It is concluded that TMPZ probably exerts a non-specific inhibitory effect on the isolated cardiac muscles examined, and that this non-specific depressant action on the myocardium might have contributed, at least in part, to the observed IN VIVO depressor (blood pressure lowering) effects of the amide alkaloid reported earlier.

Quantitative changes in beta-adrenergic responses of isolated atria from hyper- and hypothyroid rats.

Concentration-response curves for the chronotropic and inotropic effects of isoprenaline, in the absence and presence of propranolol, were obtained on heart atria isolated from normo- or dysthyroid rats. Hyperthyroidism increased the chronotropic potency and efficacy of the beta-adrenergic agonist. The results are compatible with the view that thyroid hormone increases the density of functional beta-adrenoceptors in cardiac pacemaker tissue.

Effects of several phosphodiesterase-inhibitors on guinea-pig myocardium

1. The inotropic effects of (±)-isoprenaline and several phosphodiesterase (PDE)-inhibitors were studied in isometrically contracting guinea-pig papillary muscles driven at a rate of 0.2 Hz. The maximal positive inotropic effect of isoprenaline (ΔFc=2.2 g;n=7) corresponded to that of 1-methyl, 3-isobutylxanthine (IBMX) and theophylline (ΔFc=2.1 and 2.2 g, respectively;n=7 each). Papaverine produced only a slight increase in contractile force (ΔFc=0.38 g;n=7), which in some preparations was completely absent. 2. The positive inotropic effects of IBMX, theophylline, and papaverine were not due to release of noradrenaline from adrenergic nerve endings. Blockade of the β-adrenoceptors with 5×10−6 M (±)-propranolol did not prevent the positive inotropic effect of IMBX. 3. The relaxation time,t2, was shortened by isoprenaline (36 ms) more than by IBMX (28 ms) while the time to peak force,t1, was reduced by 12 ms by isoprenaline and by 24 ms by IBMX. Isoprenaline and IBMX abbreviated the total contraction time,t1+t2, to nearly the same extent (48 and 52 ms, respectively). Theopylline and papaverine prolongedt1+t2 by 68 and 30 ms, respectively, due to a lengthening oft2. 4. IBMX, theophylline, and papaverine shifted the isoprenaline concentration-effect curve to the left, decreasing the concentration of isoprenaline required to produce a half-maximal increase in the force of contraction from 1×10−8 M to 2×10−9 M for IBMX and papaverine and to 3.2×10−9 M for theophylline. IBMX enhanced the inotropic effect of dibutyryl cyclic AMP by a factor of 7. 5. Among several PDE-inhibitors, IBMX was found to mimic the effects of isoprenaline with regard to its maximum inotropic effect and its shortening oft1+t2. Isoprenaline-like effects of theophylline and papaverine were probably masked by the involvement of additional factors discussed in this study.