Inotropic Effect Of Noradrenaline Research Articles

The role of diadenosine pentaphosphate and nicotinamide adenine dinucleotide (NAD+) as potential nucleotide comediators in the adrenergic regulation of cardiac function

The functioning of the heart is under the tight control of the sympathetic division of the autonomous nervous system. The terminals of the postganglionary fibers release both noradrenaline (NA), which is the major sympathetic neurotransmitter, and comediators that can contribute to the fine “tuning” of the adrenergic control of cardiac function. Purine compounds, such as diadenosine pentaphosphate (Ар5А), as well as nicotinamide adenine dinucleotide (NAD+), can act as comediators. The distinctive features of the effects of these compounds on the heart have been incompletely characterized. It is not clear whether these compounds can act as comediators, i.e., to modulate the sympathetic (adrenergic) activity in the heart. Exogenous extracellular Ар5А was shown to reduce the contractility of the ventricular myocardium and to suppress conduction in the atrioventricular (AV) junction in a Langendorff-perfused isolated rat heart. Extracellular NAD+ had a weak effect on inotropy but induced a negative dromotropic effect in the AV junction, similarly to Ар5А. We found that Ар5А and NAD+ suppress both the positive inotropic effect of noradrenaline in the ventricular myocardium and the positive dromotropic effect of NA in the AV junction. The “inhibitory” effects of both purine compounds were more pronounced in the case of combined application with NA. In addition, the influence of Ар5А and NAD+ on the effects of noradrenaline was shown to depend on the timing of the application of these compounds. Our results suggest that the role of the sympathetic comediators NAD+ and Ар5А may consist of the limitation of noradrenaline effects and/or the effects of sympathetic stimulation in the heart.

Atomic Force Mechanobiology of Pluripotent Stem Cell-Derived Cardiomyocytes

We describe a method using atomic force microscopy (AFM) to quantify the mechanobiological properties of pluripotent, stem cell-derived cardiomyocytes, including contraction force, rate, duration, and cellular elasticity. We measured beats from cardiomyocytes derived from induced pluripotent stem cells of healthy subjects and those with dilated cardiomyopathy, and from embryonic stem cell lines. We found that our AFM method could quantitate beat forces of single cells and clusters of cardiomyocytes. We demonstrate the dose-responsive, inotropic effect of norepinephrine and beta-adrenergic blockade of metoprolol. Cardiomyocytes derived from subjects with dilated cardiomyopathy showed decreased force and decreased cellular elasticity compared to controls. This AFM-based method can serve as a screening tool for the development of cardiac-active pharmacological agents, or as a platform for studying cardiomyocyte biology.

Phosphodiesterase PDE3 blunts the positive inotropic and cyclic AMP enhancing effects of CGP12177 but not of noradrenaline in rat ventricle

1.--The cardiostimulant effects of CGP12177, mediated through a beta(1)-adrenoceptor site with low affinity for (-)-propranolol, are potentiated by the nonselective PDE inhibitor IBMX but the role of PDE isoenzymes is unknown. We studied the effects of the PDE3-selective inhibitor cilostamide (300 nM) and PDE4-selective inhibitor rolipram (1 microM) on the positive inotropic and cyclic AMP-enhancing effects of CGP12177 and noradrenaline in right ventricular strips of rat. 2.--CGP12177 (under (-)-propranolol 200 nM) only increased contractile force in the presence of either cilostamide or rolipram with -logEC(50)M 6.7 (E(max)=23% over basal) and 7.1 (E(max)=50%) respectively. The combination of cilostamide and rolipram caused CGP12177 to enhance contractile force with -logEC(50)M=7.7 and E(max)=178%. 3.--The positive inotropic effects of noradrenaline (-logEC(50)M=6.9) were potentiated by rolipram (-logEC(50)M=7.4) but not by cilostamide (-logEC(50)M=7.0). 4.--In the presence of rolipram and (-)-propranolol, noradrenaline (2 microM) and CGP12177 (10 microM) produced matching inotropic effects but failed to increase cyclic AMP levels. 20 microM (-)-noradrenaline increased cyclic AMP levels, a response further enhanced by rolipram. 5.--Both PDE3 and PDE4 of rat ventricle appear to hydrolyse cyclic AMP generated through the low-affinity beta(1)-adrenoceptor site, thereby preventing inotropic responses of CGP12177. When (-)-noradrenaline interacts with the beta(1)-adrenoceptor, the generated cyclic AMP is hydrolysed only by PDE4, thereby reducing cardiostimulation.

The inotropic response of the isolated, perfused, working rat heart to norepinephrine is attenuated by inhibition of nitric oxide

Experiments on isolated, perfused, working left ventricular (LV) hearts of 66 female Wistar rats were done to examine whether nitric oxide (NO) influences the effects of norepinephrine (NE) on coronary flow as well as on contraction and relaxation. Functional parameters were monitored before and after application of NE at a concentration of 3 X 10(-8) M in the absence and presence of the nitric oxide synthase (NOS) inhibitor L-nitro-arginine (L-NA) at a concentration of 1 X 10(-4) M and of the spontaneous NO donor sodium (Z)-1-(N,N-diethylamino) diazen-1-ium-1,2-diolat (DEA/NO) at a concentration of 1 X 10(-7) M. In control experiments, heart rate was varied by electrical stimulation between 200 and 400 beats/min. Within this range of heart rates, coronary flow and cardiac output remained constant, while stroke volume, LV peak pressure and LV dP/dt(max) decreased with increasing heart rate. NE increased coronary flow from 7.6 +/- 0.4 to 9.8 +/- 0.7 ml/min and induced the well-known positive chronotropic and inotropic effects. DEA/NO increased coronary flow; however, the inotropic and lusitropic parameters were not affected. Simultaneous infusion of NE with DEA/NO further increased coronary flow from 9.8 +/- 0.7 to 12.1 +/- 0.8 ml/min without a significant effect on any other functional parameter. When NOS was inhibited by L-NA, the positive inotropic effect of NE was attenuated. Cardiac output, however, was increased, while coronary flow did not change significantly. Under these conditions, NE increased dP/dt(max) by 65.5 +/- 5.8% (from 2999 +/- 97 to 4929 +/- 230 mmHg/s) compared with an increase by 92.8 +/- 6.7% (from 3770 +/- 82 to 7234 +/- 211 mmHg/s) under control conditions. Application of DEA/NO reversed the attenuated inotropic response, but relaxation remained partially impaired. Thus, the presence of NO seems to be necessary for the inotropic effect of NE to become manifest.

Effect of ondansetron on the contractile responses to positive inotropic agents in electrically driven left atria of rats.

We studied the interaction of ondansetron with positive inotropic agents, including serotonin (5-hydroxytryptophane, 5-HT), noradrenaline, 4-aminopyridine (4-AP), calcium chloride, or with reserpine in isolated electrically driven rat atria. Concentrations of 5-HT ranging from 1 to 64 microg/ml increased atrial contractions in a dose-dependent manner. The inotropic effect of 5-HT in the right atria appeared to be weaker than that in the left atria. Ondansetron (30 microg/ml) depressed the positive inotropic effect of lower 5-HT concentrations . This effect was thought to be due to the local anesthetic action of ondansetron or its agonistic interaction with inhibitory imidazoline receptors on the sympathetic nerve endings that reduce noradrenaline release. The positive inotropic effect of 5-HT was abolished almost completely by cyproheptadine (2 microg/ml) and was reversed only partially by pretreatment with reserpine (1 or 3 mg/kg). This result was considered as evidence for the participation of pre- and post-junctional 5-HT2A receptors and the involvement of the sympathetic nervous system in the positive inotropic action of 5-HT in rat atria. Experiments with atropine (1 microg/ml) in atria from reserpine-pretreated rats revealed that the parasympathetic component of the autonomic nervous system is not involved in the inotropic action of 5-HT. Ondansetron (30 microg/ml) tended to increase the positive inotropic effects of noradrenaline, 4-AP, and calcium chloride, which were partially significant at certain concentrations. This result might be due to the activation of both pre- and post-junctional 5-HT2A receptors or due to the inhibition of noradrenaline reuptake into the sympathetic nerve endings through the activation of imidazoline receptors. From these findings, we conclude that the positive inotropic effect of 5-HT in the electrically driven rat atria seems to be mediated primarily by its interaction with 5-HT2A receptors, which are likely to be found on the pre- and post-junctional structures. Other mechanisms that might be involved in this relation are also discussed.

Possible involvement of cyclic adenosine monophosphate-independent mechanism in the positive chronotropic effect of norepinephrine in the isolated guinea pig right atrium.

Although both positive chronotropic and inotropic effects of beta-adrenergic stimulation are thought to be mediated by cyclic adenosine 3'5'-monophosphate, phosphodiesterase III inhibitors such as amrinone and milrinone potentiate the positive inotropic effect of catecholamines with minimum influence on the heart rate in clinical setting. The aim of the current study was to compare the positive chronotropic effect of norepinephrine with that of forskolin to elucidate whether cyclic adenosine monophosphate is relevant to the chronotropic effect of norepinephrine. Concentration-response curves for the positive chronotropic effects of norepinephrine and forskolin on the spontaneously beating right atria of guinea pigs were determined in the absence and presence of phosphodiesterase inhibitors or ion channel inhibitors. In some experiments, the left atria driven electrically were used to determine the positive inotropic effect of norepinephrine. Norepinephrine and forskolin increased the beating rate in a concentration-dependent manner. The positive chronotropic effect of forskolin was potentiated by amrinone and 3-isobutyl-1-methylxanthine, whereas the positive chronotropic effect of norepinephrine was not potentiated by the phosphodiesterase inhibitors. In contrast, the positive inotropic effect of norepinephrine was potentiated by amrinone. The hyperpolarization-activated inward current inhibitor cesium chloride and L-type voltage-dependent Ca2+ current inhibitor verapamil suppressed the chronotropic effect of norepinephrine, whereas these inhibitors did not affect the chronotropic effect of forskolin. Norepinephrine increases the spontaneously beating rate by a different mechanism from that of forskolin, suggesting that cyclic adenosine monophosphate is causally unrelated to the positive chronotropic effect of norepinephrine in the guinea pig heart.

Temperature-dependence of the age-related difference in the inotropic effect of norepinephrine in the rat myocardium.

The influence of temperature on the myocardial inotropic response to norepinephrine was studied in rats of different ages. Right papillary muscles isolated from 3-, 12-, and 24-month-old rats were superfused at two temperatures (29 degrees C and 37 degrees C) with progressively larger doses of norepinephrine. At 29 degrees C, the contraction duration was longer and the inotropic effect of norepinephrine was significantly smaller in 24-month muscles than in 3- and 12-month preparations. In muscles superfused at 37 degrees C, these age-related differences in the contraction duration and in the response to norepinephrine disappeared. Analysis of variance and covariance showed that temperature, but not age, is responsible for the differences in the inotropic response to norepinephrine observed. These results show that experimental conditions, among which temperature may play a major role, deeply affect the responsiveness of cardiac preparations to beta-adrenergic agonists.

Effects of Volatile Anesthetics on Response to Norepinephrine and Acetylcholine in Guinea Pig Atria

The in vitro chronotropic and inotropic effects of norepinephrine and acetylcholine in isolated right and left guinea pig atria were examined in the absence and presence of halothane, isoflurane, and enflurane (0.6 and 1.2 MAC). All three anesthetics elicited dose-dependent reductions in contractile force and spontaneous pacemaker activity. The maximal developed tension observed in the presence of norepinephrine was not altered by the anesthetics and corresponding ED50 values increased only in the presence of 1.2 MAC halothane and 1.2 MAC isoflurane. The anesthetics did not affect (a) the maximal positive chronotropic effect of norepinephrine, (b) the ED50 values for its positive chronotropic effect, and (c) acetylcholine-induced negative inotropic and chronotropic actions and did not induce arrhythmic activity even in the presence of the maximally effective neurotransmitter concentrations. These findings indicate that in isolated guinea pig atria volatile anesthetics, in concentrations up to 1.2 MAC, do not alter the inotropic and chronotropic effects of norepinephrine or acetylcholine and do not induce arrhythmogenic action in the presence of the neurotransmitters. These data suggest that altered atrial responsiveness to adrenergic or muscarinic stimulation does not contribute to the development of anesthetic-induced cardiac arrhythmias.

Adverse effects on rat cardiac function ex vivo after repeated administration of the benzodiazepine partial inverse agonist, FG7142

1. The Langendorff preparation was used to investigate functional changes in rat heart one week after the last of a course of repeated injections of the benzodiazepine inverse agonist, FG7142 (20 mg kg-1 i.p; three times weekly for five weeks). 2. Under these conditions, FG7142 caused a statistically significant reduction in both cardiac basal tension and the inotropic effect of noradrenaline at doses giving 50 and 100% of the maximum response. 3. Basal heart rate, basal coronary perfusion pressure and the effects of noradrenaline ex vivo on these parameters were all unaffected by repeated administration of FG7142. 4. FG7142 had no intrinsic effects on cardiac function when administered in vitro. 5. We discuss mechanisms which could underlie the effects of FG7142 on cardiac tension ex vivo and consider the possibility that this action may be related to the anxiogenic or proconvulsant actions of this drug.

Adrenoceptors in myocardial regulation: concomitant contribution from both alpha- and beta-adrenoceptor stimulation to the inotropic response

The studies presented deal with the alpha 1-adrenoceptor mediated inotropic effects of noradrenaline obtained by exclusive ("pure") alpha 1-adrenoceptor stimulation or by concomitant stimulation of alpha 1- and beta-adrenoceptors in myocardium. The pure beta-adrenergic effects of noradrenaline were also quantified. Interactions between the two receptor systems were studied. The pure alpha 1- and beta-adrenergic effects of noradrenaline, respectively, were achieved separately in the presence of high concentrations of appropriate receptor blockers. The experiments were performed on isolated ventricular myocardium from rat, rabbit, and man. The pure alpha 1-adrenergic inotropic effects were about 35-50% of control (basal) and half the pure beta-adrenergic effects both in rat and rabbit myocardium. Ventricular myocardium from man exhibited an alpha 1-adrenergic inotropic effect of the same magnitude (50% of control [basal]) as did rabbit papillary muscle. Determination of the alpha 1-adrenergic inotropic component during concomitant beta-adrenoceptor stimulation was associated with difficulties. Several experimental approaches on rat and rabbit myocardium are presented and discussed. Some types of experimental approaches obviously underestimate the alpha 1-adrenergic component. The methods regarded as reliable revealed an alpha 1-adrenergic inotropic effect of about 20-30% during combined adrenoceptor stimulation by noradrenaline. Concomitant beta-stimulation reduced the alpha 1-adrenergic effect by about 50%, while alpha 1-stimulation attenuated the beta-effect to a lesser degree (about 20-25%). A model is presented on a mutual attenuation of the functional expression of the two receptor systems.(ABSTRACT TRUNCATED AT 250 WORDS)

Temperature-dependence of the age-related difference in the inotropic effect of norepinephrine in rat papillary muscle

Temperature-dependence of the age-related difference in the inotropic effect of norepinephrine in rat papillary muscle

Different antagonism of the positive chronotropic and inotropic responses of the isolated, blood-perfused dog atrium to Bay k 8644 by nicardipine and verapamil

The effects of Bay k 8644, a dihydropyridine calcium agonist, on sinoatrial (SA) node pacemaker activity and atrial contractility and its interaction with the calcium antagonists, nicardipine and verapamil, were investigated in the isolated, blood-perfused dog atrium. Bay k 8644 (0.03–30 μg) increased sinus rate and atrial contractility dose dependently. Norepinephrine (NE) and CaCl 2 dose dependently increased the sinus rate and contractility but the positive chronotropic effect of CaCl 2 was much less than that of the other drugs. The positive chronotropic effect of Bay K 8644 (0,3-1 μg) was dose dependently depressed by nicardipine at doses of 1–10 μg but the inotropic effect was depressed only by a large dose of 10 μg. After sinus arrest induced by nicardipine (10–30 μg), SA node pacemaker activity was readily restored by Bay k 8644 or NE. Verapamil (1–3 μg) also depressed the positive chronotropic effect of Bay k 8644 more effectively than the inotropic effect although it did not attenuate the chronotropic effect of NE. The inotropic interaction could not be evaluated at higher doses of antagonists because of sinus arrest. Propranolol (3 μg) suppressed both positive chronotropic and inotropic effects of NE but did not depress the Bay k 8644-induced responses. These results show that the antagonism between Bay k 8644 and calcium antagonists is predominant on SA node pacemaker activity in cardiac tissues.

Inotropic and chronotropic activity of a new cardiotonic agent, DM 9278 (1,2,3,4,8,9,10,12-octahydro[2,1-b]pyrido[2,3-f]quinazolin-9-one ), on isolated dog atrial and ventricular muscles.

The cardiac effects of DM9278 were studied in isolated and blood-perfused atrial and ventricular preparations from mongrel dogs. In spontaneously beating isolated right atria, DM9278 caused positive chronotropic and inotropic responses in a dose-related manner (1-100 micrograms). DM9278 produced relatively larger positive inotropic than positive chronotropic effects as compared with effects of aminophylline or papaverine. DM9278 increased the developed tension in left ventricles electrically driven at 1.5-2.0 Hz. Positive inotropic and chronotropic responses to DM9278 in both atrial and ventricular preparations were suppressed slightly but not significantly by 1-3 micrograms of propranolol, which completely blocked the positive chronotropic and inotropic effects of norepinephrine (0.01-0.1 micrograms). From these results, it is concluded that DM9278 has direct cardiotonic properties in isolated dog heart tissues, showing relatively selective positive inotropic activity.

Bisoprolol (EMD 33512), a Highly Selective β1-Adrenoceptor Antagonist: In Vitro and In Vivo Studies

The properties of the newly developed selective beta 1-adrenoceptor antagonist bisoprolol (EMD 33152) were investigated by in vitro and in vivo studies. Binding studies with (-)-[125I] iodocyanopindolol (ICYP) revealed that the affinity of (+/-)-bisoprolol to beta 1-adrenoceptors was approximately 100 times higher than to beta 2-adrenoceptors. This high beta 1-adrenoceptor selectivity of bisoprolol could be confirmed in binding studies with the tritiated compound (-)[3H] bisoprolol, which labelled in rabbit lung membranes--a tissue known to contain 80% beta 1- and 20% beta 2-adrenoceptors--exclusively beta 1-adrenoceptors. In physiological studies, (+/-)-bisoprolol was found to be devoid of any intrinsic sympathomimetic activity (ISA), since it had no positive chronotropic effects on spontaneously beating right atria of reserpinized rats. On isolated electrically driven human right atria, (+/-)-bisoprolol was approximately 30 times more potent in antagonizing the beta 1-adrenoceptor-mediated positive inotropic effect of noradrenaline (pA2-value, 8.42) than the beta 2-adrenoceptor-mediated positive inotropic effect of procaterol (pA2-value, 6.99). To test the beta 1-adrenoceptor selectivity in vivo, the effects of bisoprolol administration (1 X 10 mg/day for 9 days) on lymphocyte beta 2-adrenoceptor density [assessed by (-)-ICYP binding] in healthy volunteers were compared with those of the nonselective beta-adrenoceptor antagonists propranolol (4 X 40 mg/day for 9 days) without ISA, and pindolol (2 X 5 mg/day for 9 days) with ISA.(ABSTRACT TRUNCATED AT 250 WORDS)

Interaction between [formula omitted] and [formula omitted] inotropic effects of noradrenaline in rabbit papillary muscles : H. Aass, T. Skomedal & J.-B. Osnes, Department of Pharmacology, University of Oslo, P.O.Box 1057, Blindern, Oslo 3, Norway

Interaction between [formula omitted] and [formula omitted] inotropic effects of noradrenaline in rabbit papillary muscles : H. Aass, T. Skomedal & J.-B. Osnes, Department of Pharmacology, University of Oslo, P.O.Box 1057, Blindern, Oslo 3, Norway

Cyclic AMP and the positive inotropic effect of norepinephrine and phenylephrine

Time-response studies of the effects of norepinephrine and phenylephrine revealed that both agonists caused an increase in cyclic AMP levels before increases in contractile force in either the electrically stimulated left atria or spontaneously beating right atria of the rat. Norepinephrine caused a nearly sixfold increase in cyclic AMP, whereas phenylephrine produced only a 50% increase in the nucleotide. Pretreatment with reserpine did not affect the norepinephrine cyclic AMP response; however, the phenylephrine cyclic AMP response was abolished. Reserpine pretreatment did not significantly affect the contractile responses of either amine. In the presence of propranolol, norepinephrine was found to have the ability to produce an increace in contractile force in which cyclic AMP was apparently not involved. The time course of the contractile response induced by adrenergic amines was found to be remarkably influenced by the chronotropic response in spontaneously beating preparations while the cyclic AMP response was not greatly affected. This difference in the contractile response may be due to the ability of the chronotropic response to influence the flux of calcium through the cell membrane.

Blockade of cardiac histamine receptors by promethazine.

The inotropic and chronotropic effects of histamine on the isolated perfused guinea pig heart were antagonized by promethazine over a concentration range 4 × 10−6 – 16 × 10−6 M. Promethazine (4 × 10−6 M) decreased the ability of histamine (1 μg) to elevate cardiac cyclic AMP. A higher dose of histamine could not overcome the promethazine blockade. Promethazine (4 × 10− 6 M) did not block the inotropic effect of noradrenaline. Higher concentrations of promethazine, particularly 16 × 10−6 M did decrease the noradrenaline response. The data indicate that promethazine can interact with cardiac histamine receptors but the interaction is either noncompetitive or competitive non-equilibrium in nature.

Antisympathomimetic Effects of Kö 1313 and Kö 1366 in Guinea-Pig Atria

The antagonistic effects of two new β-receptors blocking agents Kö 1313 Kö 1366 against the chronotropic and inotropic responses to noradrenaline and tyramine were studied on the isolated right left atria of guinea-pigs. From the KB values estimated by means of three different methods it was found that the potencies of Kö 1366 were 5 to 10 times and 5 to 7 times those of Kö 1313 in the antagonism against chronotropic and inotropic effects of noradrenaline respectively. From the depression of maximum chronotropic inotropic effects of tyramine in the presence of these agents Kö 1366 was demonstrated to be approx. three times more potent than Kö 1313 in the antagonism against both effects of tyramine.

Studies on the sensitization to cardiovascular effects of catecholamines.

Wistar rats were given 20 daily injections of either isoproterenol (ISO) (30 μg/100 g/day), nor-adrenaline (NA) (30 μg/100 g/day), guanethidine (G) (15 mg/kg/day), or NA plus G together. Guanethidine, alone or in association with NA, increased the blood pressure and heart rate response to NA in the whole animal. Guanethidine alone had no effect on the inotropic effects of NA in isolated hearts. Beta receptor responses to NA were potentiated in the whole animal by chronic treatment with NA and in isolated hearts by chronic treatment with NA or ISO. Responses to ISO were also potentiated by treatment with guanethidine, noradrenaline, and isoproterenol. It was found also that guanethidine treatment reduced 3H-NA uptake by 50% but had no effect on 3H-ISO uptake and that NA and ISO treatments had no effect on the uptake of 3H-NA and 3H-ISO. Prolonged treatments with NA or ISO increased the sensitivity of the beta receptors, possibly as a result of the repeated stimulations by large doses of these stimulants. The sensitization of adrenergic receptors by guanethidine could result from both a reduced NA uptake and a direct action on smooth muscle fibers.

Modification by Ca Removal and Mg of the Membrane Effect and the Inotropic Effect of Noradrenaline in the Rabbit Left Atrium

Modification by Ca Removal and Mg of the Membrane Effect and the Inotropic Effect of Noradrenaline in the Rabbit Left Atrium