Marked Positive Inotropic Effect Research Articles

Temperature-dependent inotropic action of A23187 on guinea-pig ventricular muscles

1. The effects of the Ca 2+ ionophore, A23187, on the contraction and membrane action potential of the isolated guinea-pig papillary muscle were examined at various temperatures (30–16°C) and compared to those of isoprenaline and a high calcium medium. 2. A23187 caused a marked positive ionotropic effect with a significant prolongation of the action potential duration at an early repolarization phase but not a late repolarization phase at normal temperature (30°C). 3. Such an inotropic effect was completely abolished at low temperature (16°C) where a marked positive inotropic effect of isoprenaline (5 × 10 −8 M) and a high calcium medium (6.2 mM) still remained. 4. These results suggest that the cardiac responsiveness to A23187 was sensitive to a low temperature at which a membrane lipid phase transition may occur.

In Vivo and In Vitro Assessment of the Cardiovascular Effects of 8-(Benzylthio)-N6-n-Butyl–Cyclic AMP

In the canine heart-lung preparation (HLP) and the anesthetized open-chest dog, both 8-(Benzylthio)-N6-n-butyl-cyclic AMP (BTB-cyclic AMP) (10 times more potent) and dibutyryl-cyclic AMP (DB-cyclic AMP) produced a definite positive inotropic effect (PIE) and an increase in the coronary blood flow with either no change (HLP) or a slight increase (anesthetized animal) (BTB-cyclic AMP) and a definite increase in the heart rate (DB-cyclic AMP). In the isolated atrial preparations of the guinea pig (AG), BTB-cyclic AMP produced a slight PIE at 3 X 10(-5) M and a negative chronotropic effect at 3 X 10(-4) M. Aminophylline reversed the latter to the positive one, while potentiating the former. At 10(-3) M marked positive inotropic and chronotropic effects were observed. DB-cyclic AMP was without effects. In the right ventricular papillary muscle preparations of the guinea pig (PMG), both compounds produced PIE. BTB-cyclic AMP initiated a contraction (AG) and a "slow" action potential (PMG) in partially depolarized preparations. Both of these effects were abolished by diltiazem. BTB-cyclic AMP (10(-3) M) suppressed the heart rate increase induced by isoproterenol in right AG. It was concluded that BTB-cyclic AMP was a cardiotonic agent with a relatively weak positive chronotropic effect and that the cardiotonic effect was ascribable to the initiation of slow action potentials and related contractions.

The interaction of ephedrine with beta-adrenoceptors in tracheal, cardiac and skeletal muscles.

Three beta-adrenoceptor mediated effects were measured in vitro on tissues from guinea-pig: (a) relaxation of the trachea (mainly beta 2), (b) increase in the force of contraction of the papillary muscle (beta 1), and (c) depression of the subtetanic contractions of the soleus muscle (beta 2). The relaxant effect of ephedrine on the trachea was weak but was resistant to reserpine pretreatment. There was no appreciable agonistic effect of ephedrine on the soleus muscle. Ephedrine per se had a marked positive inotropic effect on the papillary muscle with a pD2 of about 6.0. This effect disappeared completely after pretreatment with reserpine. Ephedrine inhibited the response to isoprenaline. The apparent pA2 was about 4.8 in all tissues studied.

Cardiovascular Effects and Plasma Levels of Denopamine (TA-064), a New Positive Inotropic Agent, in Chronically Instrumented Dogs

Cardiovascular effects of denopamine (TA-064), a new positive inotropic agent, in chronically instrumented dogs were investigated following intravenous and oral administration. In the conscious state, denopamine (0.5-4 micrograms/kg/min, i.v. infusion) increased LV dp/dtmax, cardiac output, stroke volume in a dose-dependent manner, and it decreased left ventricular end-diastolic pressure, total peripheral resistance and PQ interval. Denopamine produced an increase in LV dp/dtmax by 90% at a rate of 4 micrograms/kg/min with slightly increasing systemic blood pressure and heart rate. In the same dogs after anesthetizing with pentobarbital, denopamine in the same dose range showed more marked positive inotropic effects and less changes in cardiac output and total peripheral resistance than in conscious dogs. Other cardiovascular effects of denopamine were qualitatively similar to conscious dogs. These effects of denopamine were diminished by treatment with propranolol. Oral administration of denopamine to conscious dogs (0.1-0.4 mg/kg) produced a rise in LV dp/dtmax dose-dependently, and denopamine at a dose of 0.4 mg/kg increased LV dp/dtmax by 66%, this effect lasting for 7 hr. Heart rate and blood pressure were not affected significantly. Effects on other cardiovascular parameters were changed in the same direction as intravenous administration. The increase in LV dp/dtmax corresponded well with the changes in plasma levels of denopamine in conscious dogs by both intravenous and oral administration. Denopamine showed a selective positive inotropic effect in chronically instrumented dogs, and its positive inotropic action was more marked in the myocardium depressed with an anesthetizing dose of pentobarbital than in the conscious state.

Depression of the positive inotropic response to ouabain and noradrenaline by the myocardium of the ground squirrel ( Spermophilus richardsonii) during hibernation

1. 1. Seasonal variations in the positive inotropic response to both ouabain and noradrenaline were observed in the isolated papillary and atria muscles from the hibernating ground squirrel Spermophilus richardsonii. 2. 2. In the tissues of non-hibernating animals, a marked positive inotropic effect was observed over a narrow concentration range of ouabain (about 8 × 10 −9 M to 1 × 10 −7 M). 3. 3. Above 1 × 10 −7 M ouabain the magnitude of the inotropic effect declined and toxicity occurred above 5 × 10 −7 M. 4. 4. Strikingly different effects were obtained with tissues from hibernating animals. The magnitude of the positive inotropic response to ouabain was now greatly reduced; some animals failed to respond within the fiducial limits of our experiments. 5. 5. Toxic effects of ouabain could still be elicited by 5 × 10 −7 M or greater concentration of the drug when applied to tissues from hibernating animals. 6. 6. Similar depression of the inotropic response to noradrenaline during hibernation suggests that some common property of the pharmacological response mechanism is greatly depressed during hibernation at 5°C.

The effects of adenosine-und guanosine 3?,5?-phosphoric acid benzyl esters on guinea-pig ventricular myocardium

1. The inotropic effects of benzyl-and substituted benzyl triesters of cyclic AMP and cyclic GMP were studied in isometrically contracting guineapig papillary muscles driven at a rate of 0.2 Hz. 2. The triesters of cyclic AMP produced marked concentration-dependent positive inotropic effects. The maximum increase of contraction force (ΔFc) was 2.2 g (n=5) for p-MeBncAMP and 1.8 g for BncAMP and o-NO2BncAMP, respectively (n=5 for each ester). Total contraction time (t1+t2) was thereby shortened by 44 ms (n=15). Threshold and maximally effective concentrations for the positive inotropic effects were 1×10−4 M and 6×10−4M (BncAMP), 3×10−4 M and 3×10−3 M (p-MeBncAMP) and 1×10−5 M and 2×10−4 M (o-NO2BncAMP), respectively. 3. The phosphodiesterase inhibitor 1-methyl,3-isobutyxanthine (IBMX) (2×10−5 M) shifted the concentration-effect curves of all 3 triesters to the left, decreasing the concentrations required to produce a half-maximal increase of the force of contraction by a factor of 6. 4. The time necessary to produce a half-maximum inotropic effect was 2 min for p-MeBncAMP, 10 min for BncAMP and 66 min for o-NO2BncAMP. The inotropic effects could not be reversed upon washing the preparations for 1 h with a drug-free solution. 5. The concentration-effect curves of the triesters of cyclic AMP were not affected by previous blockade of the β-adrenoceptors with 5×10−6 M (±)-propranolol. 6. BncGMP at concentrations ranging from 1×10−5 to 2×10−3 M, produced no inotropic effects on 3 guinea-pig papillary muscles, while a decrease of the contraction force was detectable 30 min after the addition of 2×10−3 M p-MeBncGMP, reaching 75% of the control value within 1 h (n=3). At 3×10−3 M, both esters induced a positive inotropic effect (ΔFc) of 0.2 g which was completed in 3–4 min. The negative inotropic effect of 2×10−3 M p-MeBncAMP was immediately reversed upon washing the preparation while the positive inotropic effect was not affected. 7. Spontaneous hydrolysis of the benzyl triesters of cyclic AMP or cyclic GMP in Krebs-Henseleit buffer gave rise to cyclic AMP or cyclic GMP and to the respective benzyl alcohols. The electron donating substituent p-CH3 of the p-MeBncAMP or the p-MeBncGMP increased the hydrolytic reactivity by a factor of 14 when compared to the unsubstituted benzyl esters which in turn were 5 times more reactive than the triesters which contained the electron withdrawing substituent o-NO2. 8. Triesters of cyclic AMP and cyclic GMP (3×10−3 M) inhibited beef heart phosphodiesterase (PDE) by 17–29% and by 58–65%, respectively (n=4 for each ester). The specific PDE-inhibitor IBMX (2×10−5 M) blocked PDE by 52% (n=4). 9. The data presented in this study are in agreement with the hypothesis that benzyl triesters of cyclic AMP are simply a transport form of cyclic AMP across the cell membrane and, once inside, they are hydrolyzed with a characteristic time course to cyclic AMP which is responsible for the positive inotropic effects. Assuming that the benzyl triesters of cyclic GMP are also intracellularly converted to cyclic GMP, its postulated mediator role of a negative inotropic effect is not in accordance with the present results.

The effect of contrast media on the isolated perfused canine heart.

The intravascular injection of contrast medium produces a rise of ventricular filling pressure which may reflect blood volume expansion, a negative inotropic effect on the myocardium, and/or a decrease in ventricular diastolic compliance. This phenomenon was studied by randomly infusing three substances, Renografin-76, 1% saline and 38% sucrose, into the aortic root of the isolated perfused canine heart. The preparation was modified by having an inflated ballon within the left ventricular cavity so that the end diastolic ventricular volume and afterload were fixed. A dose-related depression of left ventricular systolic pressure and peak dP/dt due to contrast media occurred, without a significant change in the left ventricular diastolic pressure. This decrease in ventricular contractility due to Renografin-76 could not be attributed entirely to either a saline or an osmotic effect. No significant changes were observed in left ventricular diastolic compliance. Sucrose was found to exhibit a marked positive inotropic effect.

Inotropic action of hydroxylated chlorpromazine metabolites and related compounds

Effects of several hydroxylated chlorpromazine metabolites and related compounds on cardiac contractile force were studied using electrically stimulated left atrial preparations of guinea pig hearts. 7,8-Dihydroxychlorpromazine and 7,8-dioxochlorpromazine produced marked positive inotropic effects in μM concentrations. 7,8-Dihydroxyperphenazine and 7-hydroxychlorpromazine had relatively weak inotropic actions. 2-Hydroxydesmethylimipramine also had a weak inotropic action. Other compounds, such as chlorpromazine, 8-hydroxychlorpromazine, 2-hydroxy- or 3-hydroxy-promazine, and 2-hydroxyimipramine, failed to significantly alter cardiac contractile force. The positive inotropic effects of 7,8-dihydroxychlorpromazine or 7,8-dioxochlorpromazine were markedly reduced by pretreatment with (±)-propranolol, indicating the involvement of β-adrenergic mechanisms in the inotropic action of these agents.

Direct positive chronotropic and inotropic effects of ouabain in the isolated and blood-perfused canine atrium.

Using isolated, blood-perfused canine atrial preparations the effects of ouabain on sinus rate and contraction were investigated in 20 preparations. A continuous infusion of ouabain (1 microgram/min) usually induced a significant increase in sinus rate but occasionally a slight but no significant decrease followed by a clear increase, and then finally decrease followed by atrial arrest. On the inotropy, ouabain induced only distinct positive inotropic effect from the earlier stage, and the time to the maximum positive inotropic effect was much earlier than that to the maximum chronotropic effect. The positive chronotropic effect of norepinephrine was not affected by ouabain in the dose for inducing marked positive inotropic effect. On the other hand, the positive inotropic effect of norepinephrine was suppressed in percent changes by ouabain but not abolished. The negative chronotropic and inotropic effects of ACh were not significantly affected by ouabain in the dose for inducing marked positive inotropic effect. During atrial arrest by ouabain infusion, distinct staircase phenomenon disappeared. In this condition, atrial muscle responded more readily to higher frequencies of electric pacing (above 2 Hz) than to lower frequencies (under 1 Hz).

The relationship between contractile tension and intracellular cyclic AMP level in frog atrium: An analysis by using NAF, verapamil and ouabain

1. The relationship between contractile tension and intracellular cyclic AMP level was studied in bullfrog atrium, modifying the external Ca ion concentration and using NaF, verapamil and ouabain. 2. Withdrawal of Ca led to a decrease of contractile tension and a significant increase of cyclic AMP level. 3. Likewise, application of verapamil (8 μg/ml) reduced contractile tension and enhanced the level of cyclic AMP. 4. NaF showed a marked positive inotropic effect on the muscles at a concentration of 10 −5 M, but a negative inotropic effect at 10 −2 M. 10 −5 M of NaF produced a transient increase and afterwards a later decrease of the intracellular cyclic AMP. Conversely, on the addition of 10 −2 M, the level of cyclic AMP remained elevated. The level of cyclic AMP was decreased with time of incubation with ouabain, while an augmentation in the contractile tension was observed. 5. These results are interpreted as indicating that the intracellular free Ca ions may regulate the intracellular level of myocardial cyclic AMP.

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.

Effects of an inotropic agent, RO 2-2985 (X-537A), on regional blood flow and myocardial function in chronically instrumented conscious dogs and anesthetized dogs.

RO 2-2985 produced a marked positive inotropic effect in unanesthetized, chronically instrumented dogs, measured as an increase in left ventricular dP/ dt and an increase in maximum velocity of myocardial fiber shortening. Similar changes produced in dogs in hemorrhagic shock lasted for 2-3 hours. RO 2-2985 increased peripheral blood flow and caused marked increases in both coronary and renal blood flows. The drug altered the response of the renal vascular bed to subsequent norepinephrine administration. After administration of a single dose of RO 2-2985, norepinephrine produced sustained increases in renal blood flow, and this altered responsiveness to norepinephrine persisted for periods ranging from 1 to 3 weeks.

Effects of dobutamine on myocardial mechanics.

In the intact circulation in man and dog dobutamine ( (±)-4-[2-[[3-(p-hydroxyphenyl)-1 -methylpropyl] amino]ethyl] pyrocatechol hydrochloride), a new synthetic catecholamine (Eli Lilly and Co., Indianapolis, Ind.) exerted marked positive inotropic effects (1–4). Since these effects were obtained with little change in heart rate and mean arterial pressure it has been suggested that dobutamine is potentially of clinical value in the enhancement of myocardial contractility and may have advantages over other frequently used catecholamines such as noradrenaline and isoproterenol (1–4). In view of the potential clinical value of dobutamine, and to exclude effects on the vascular system, this study was undertaken of characterize the direct effects of dobutamine on myocardial mechanics of the isolated cat papillary muscle.

Effect of guanethidine and bretylium on the dog heart-lung preparation.

Inotropic and chronotropic effects of guanethidine and bretylium have been observed in heart-lung preparations made from normal and chronically reserpinized dogs. Guanethidine (0.3 to 30 mg.) in the untreated preparation had marked positive inotropic and chronotropic effects, whereas after pretreatment with reserpine it had a striking negative inotropic effect and no effect on heart rate. Guanethidine given to preparations made from animals pretreated with guanethidine had a negative inotropic effect smaller than that seen after reserpine pretreatment. Bretylium (0.3 to 30 mg.) in the untreated preparation had both positive inotropic and positive chronotropic effects. In the chronically reserpinized animal, the positive inotropic effect of bretylium persisted though it was reduced to about one-quarter of the original size. The positive chronotropic effect of bretylium in this circumstance was reversed to a negative chronotropic effect. These effects are interpreted as indirect but strong evidence that: (1) guanethidine and bretylium exert at least part of their initial positive inotropic and chronotropic effects by a release of catecholamines; and (2) in the amine-depleted heart, guanethidine has an intrinsic negative inotropic effect, whereas bretylium has an intrinsic positive inotropic effect.