Inotropic Effect Of Adrenaline Research Articles

Effect of adrenaline on serum mid-regional pro-atrial natriuretic peptide and central blood volume.

New Findings What is the central question in this study? Atrial natriuretic peptide (ANP) is secreted in response to atrial wall distension and thus allows for evaluation, albeit indirect, of the central blood volume. Adrenaline has chronotropic and inotropic effects. We evaluated whether the chronotropic and inotropic effects of adrenaline were reflected in mid‐regional proANP. What is the main finding and its importance? Central blood volume remained stable with infusion of adrenaline and yet mid‐regional proANP increased. Thus, the chronotropic and inotropic state of the heart or adrenaline directly induces release of ANP variants from the myocytes. Atrial natriuretic peptide (ANP) has vasodilatory, natriuretic and diuretic properties. It is secreted in response to atrial wall distension and thereby provides an indirect evaluation of central blood volume (CBV). Adrenaline has chronotropic and inotropic effects that increase cardiac output. In the present study, we evaluated whether these effects were influenced by an increase in CBV and reflected in mid‐regional proANP (MR‐proANP) concentrations in the circulation, a stable proxy marker of bioactive ANP. Changes in CBV were evaluated by thoracic electrical admittance and haemodynamic variables monitored by pulse‐contour analysis during two intervals with graded infusion of adrenaline. Adrenaline infusion increased heart rate (by 33 ± 18%) and stroke volume (by 6 ± 13%), hence cardiac output (by 42 ± 23%; all P < 0.05). The increase in cardiac output did not result from an increase in CBV, because thoracic electrical admittance remained stable (−3 ± 17%; P = 0.230). Serum MR‐proANP concentrations were increased (by 26 ± 25%; P < 0.001) by adrenaline infusion and remained elevated 60 min postinfusion. We conclude that MR‐proANP in the circulation is affected not only by CBV, but also by increased chronotropy/inotropy of the heart, or that adrenaline directly induces release of ANP variants from the myocytes.

β1 Adrenoceptor Antagonistic Effects of ICI 118,551 on the Positive Inotropic Effect of Adrenaline in Murine Hearts

β1 Adrenoceptor Antagonistic Effects of ICI 118,551 on the Positive Inotropic Effect of Adrenaline in Murine Hearts

EC50 of adrenaline-atenolol: Functional agonist assay using Langendorff isolated rabbit heart tethered to powerLab data acquisition system

The purpose of this study was to determine the mean EC50 of adrenaline on heart rate and force of contraction of isolated New Zealand white rabbit hearts and to determine the concentration of atenolol that completely blocks the effect of adrenaline using one of modern physiological acquisition system, PowerLab, AD instrumnets. Twelve Isolated hearts from New Zealand white rabbits were perfused through aorta in a Langendorff mode. Heart rate and contractility were determined for 5 minutes after bolus injection of 5 different concentrations of adrenaline (1.0, 2.5, 5.0 and 10 µg/mL). The changes in heart rate and contractility after each treatment were compared with their baseline values. These data were used to calculate the mean EC50 of adrenaline on heart rate and force of contraction. This EC 50 was then used after perfusion of different concentrations of atenolol (1.0, 2.5, 5.0 and 10µg/mL). Data were collected with the help of PowerLab data acquisition and analyzed by Labchart pro7 software. Adrenaline resulted in a stimulatory effect on the heart rate and the amplitude of the heart contraction. The maximum increases in both heart rate and force of contraction were seen at adrenaline dose of 7.5 µg/mL and the plateau phase was achieved at a dose of 10 µg/mL. The average EC50 of adrenaline was 3.5 µg/mL. The positive inotropic effect of adrenaline was antagonized only at atenolol concentrations of 5.0 and 10 µg/mL and complete inhibition of adrenaline effect on heart rate was achieved at atenolol concentrations of 10 µg/mL. These data showed that atenolol must be used at a concentration no less than 7.5 µg/mL to demonstrate if β adrenergic receptors are involved in the mechanism of action of any newly tested positive inotropic or choronotroic drug. Key words: Adrenaline, atenolol, isolated hearts, rabbits.

Steroid-induced cardiac contractility requires exogenous glucose,glycolysis and the sarcoplasmic reticulum in rainbow trout

Recent data from our laboratory suggest that sex steroids promote contractile function in cardiac muscle of rainbow trout (Oncorhynchus mykiss Walbaum), and there are sex differences in hormone signaling and cardiac function. The current study investigated whether steroid-induced inotropism in electrically paced (0.5 Hz, 14 degrees C) ventricle strips at 90% Lmax (1) has a metabolic requirement for exogenous glucose and (2) is associated with enhanced intracellular Ca2+ storage and release from the sarcoplasmic reticulum (SR). We also explored whether sex differences exist in extracellular Ca2+ (Ca2+o) or cardiac sensitivity to Ca2+o. In the absence or at low concentrations (1 or 2 mmol l-)) of exogenous glucose, resting tension and relaxation time were increased selectively in cardiac tissue from females. Increasing glucose promoted twitch force in a bell-shaped manner, with 5 mmol l-1 representing the optimal concentration for both sexes. The positive inotropic effects of physiological concentrations of testosterone (T) and 17beta-estradiol (E2) in male and female trout ventricle strips, respectively, developed slowly (10-45 min) and were not apparent in glucose-free medium, in medium containing iodoacetate (IAA), an inhibitor of glycolysis, or medium containing 5 mmol l-) lactate or pyruvate. Male ventricle strips had increased inotropic responses to glucose and T compared with female strips exposed to glucose and E2. Furthermore, sexually maturing males showed a greater inotropic response than immature males or females. Pretreatment with ryanodine (a specific blocker of SR Ca2+ release) also eliminated the inotropic effects of sex steroids and exogenous glucose and reduced the post-rest potentiation of contractile force (a marker of SR Ca2+ storage). By contrast, the inotropic effects of epinephrine (Epi) or elevated Ca2+o were faster (developing within 1-3 min) and were not diminished by the presence or absence of glucose or by pretreatment with IAA or ryanodine. Sex differences were also found in responsiveness to caffeine (males>females) and the relationship between Ca2+ concentration and force development above baseline. The Ca2+50 was lower in female cardiac tissue than males, suggesting greater Ca2+ sensitivity, and although plasma albumin was higher in females, total and ionized plasma Ca2+ did not differ between the sexes. For the first time, our study highlights the importance of extracellular glucose, glycolytic activity and SR Ca2+ storage and release for sex steroid-induced inotropism in the trout ventricle. Conversely, the inotropes Epi and elevated [Ca2+o] do not require the presence or metabolism of exogenous glucose or the SR for signaling their positive effects on contractility. These results also demonstrate novel sex-related differences in cardiac reliance on exogenous glucose, Ca2+ sensitivity and SR function and thus should be considered in future studies.

Combined use of amrinone and high-dose epinephrine for postoperative low output syndrome (LOS) in pediatric patients

Low output syndrome (LOS) is one of the serious consequences following open-heart surgery, and high-dose catecholamines and/or mechanical assist devices are required to support failed myocardial function. As one of the pharmacological options to counteract this complication, epinephrine remains the most potent drug to treat LOS, especially in pediatric cases. Since the inotropic effect of epinephrine is dose-dependent, highdose epinephrine is sometimes necessary in patients with severe pump failure. However, the administration of high-dose epinephrine can interfere with peripheral circulation because of its strong vasoconstricting effects, resulting in severe acidosis and oliguria. Amrinone has become available as an inotrope and vasodilator with a suggested main mechanism of selective phosphodiesterase III inhibition. Its unique properties include inotropic support combined with pulmonary and systemic vasodilation [1], and this effect is maintained in the presence of exogenous catecholamines including dopamine (DOA), epinephrine and norepinephrine (NE) [2-4]. Therefore, the benefit of using amrinone and other inotropes in combination is the vasodilating action of amrinone to counteract the vasoconstricting effects of the strong inotropes, in addition to its inotropic support. We report on two pediatric patients who successfully recovered from life-threatening heart failure by the combined use of high-dose epinephrine and amrinone.

Positive inotropic effect of adrenaline on potassium contractures in tonic skeletal muscle fibres of the frog.

K+ contractures were elicited in small bundles of tonic skeletal muscle fibres of the frog. Adrenaline (1 microM) increased the amplitude of K+ contractures in a [K+]o-dependent manner: maximal effects were produced between 20 and 60 mM [K+]o. In contrast, we found no effect of adrenaline on K+ contractures of twitch fibres. The potentiating effect of adrenaline depended on [Ca2+]o. Increasing [Ca2+]o from 1.8 to 10 mM doubled the positive inotropic effect of adrenaline. In a nominally Ca2+ free saline, adrenaline had no potentiating effect. The Ca2+ channel blockers nifedipine (20 microM) and Ni2+ (1.8 mM) reversibly reduced the amplitude of the tonic phase of K+ contractures and blocked the potentiation by adrenaline. The mechanical effects of adrenaline cannot be explained by changes in the membrane potential, as revealed by intracellular recordings at several [K+]o. It was concluded that the potentiating effect of adrenaline in tonic muscle fibres of the frog may be mediated through Ca2+ channels.

Extracellular calcium and the inotropic effect of epinephrine on frog skeletal muscle.

The purpose of these experiments was to determine if extracellular calcium plays an important role in mediating the inotropic effect of epinephrine in isolated frog sartorius muscle. Initial experiments indicated that epinephrine potentiated the muscle twitch in a concentration-dependent manner with concentrations of 10 microM to 1 mM, increasing peak tension by approximately 33%. To inhibit the influx of extracellular calcium, muscles were incubated for 20 min in media containing epinephrine in which calcium had been removed and replaced by magnesium or EDTA, or in experimental media containing epinephrine and the calcium channel blockers D-600 or diltiazem (5 microM). Each experimental condition was found to antagonize the effects of epinephrine such that peak twitch tensions were not significantly different from the control. When muscles were returned to normal Ringer's solution containing epinephrine, twitches exhibited progressive potentiation. Muscles were also incubated for 20 min in epinephrine without stimulation. Once stimulation was resumed, twitches were not immediately potentiated but rather gradually increased over time. These results suggest that the inotropic effects of epinephrine are influenced by the influx of extracellular calcium, an event that is dependent on muscle activation.

Negative inotropic effects of ATP on the isometric contractions of isolated rat heart muscle.

The effects of ATP on the isometric contractions of isolated rat left ventricular papillary muscle were studied. Exogenously administered ATP had an immediate onset, an abrupt response, progressive recovery and produced dose-related depression in the peak developed tension, maximum rate of tension development and relaxation, which were statistically significant. There were no significant changes in the resting tension, time to peak tension and relaxation time, except for a significantly prolonged relaxation time at the highest concentration of ATP. In the studies of interactions of ATP and either epinephrine or Ca(++), we observed that ATP seemed to interfere with the inotropic effect of epinephrine, while Ca(++) antagonized the negative inotropic action of ATP. We conclude that the site of negative inotropic action of ATP is most likely on the cell membrane, where ATP interferes with Ca(++) flux, and that ATP interferes with the positive inotropic action of epinephrine.

Altered cardiovascular responsiveness to adrenaline in endurance-trained subjects.

The influence of physical training on responses to i.v. adrenaline infusions and to exercise were investigated in 10 endurance-trained men (mean age: 35 y; VO2max: 61.9 ml kg-1 min-1) and 10 age-matched and sedentary controls (36 y, 37.5 ml kg-1 min-1). The untrained subjects were reinvestigated after a 4 month training period which increased their VO2max by 18%. Resting heart rate and diastolic blood pressure were significantly lower in the trained state. The venous plasma adrenaline concentrations attained during infusions (4 dose levels, 8 min each) were lower in the well-trained than in the untrained subjects (2.15 vs. 3.59 nmol l-1 at the highest dose level, P less than 0.01). The adrenaline-induced increases in heart rate and in plasma cAMP and decreases in pre-ejection period (PEP) and PEP/LVET ratio were not dependent on the training state. The adrenaline-induced decrease in diastolic blood pressure was more pronounced (P less than 0.05) in the well-trained than in the untrained group and tended (0.05 less than P less than 0.1) to be enhanced by training in the latter group. The increases in systolic blood pressure were greater in the well-trained subjects (P less than 0.01) but training did not alter this response in the untrained subjects. The plasma noradrenaline response to maximal cycle ergometer exercise (VO2max test) was significantly greater in the well-trained than in the untrained subjects, while no difference was seen for adrenaline. The submaximal exercise systolic blood pressure was similar in all training conditions when related to the absolute rate of work. In summary, the present results indicate that both the vasodilator and systolic pressor responses to adrenaline are enhanced in endurance-trained subjects. The cardiac chronotropic and inotropic effects of adrenaline seem, however, to be independent of the training state.

Cyclic nucleotide regulation of the contractile proteins in mammalian cardiac muscle.

The contractile system of rat cardiac muscle that has been made hyperpermeable by soaking the tissue in EGTA (McClellan and Winegrad. 1978. J. Gen. Physiol. 72:737-764) can be probed directly with Ca buffer from the bathing solution without significant interference from either sarcoplasmic reticulum or mitochondria on the Ca concentration. Changes in Ca-activated force are due therefore to changes in the properties of the contractile system itself and not to regulation of Ca concentration. The addition of cAMP, cGMP, and GTP, guanylyl imidodiphosphate (GMP-PNP), or epinephrine to the bath does not alter maximum Ca-activated force, but when these drugs are added with 1% nonionic detergent to the bath, contractility increases by as much as 180%. An inhibitor of phosphodiesterase must be present for the inotropic effect of cAMP but not cGMP, GTP, GMP-PNP, or epinephrine. The inotropic response to cAMP is independent of the Ca sensitivity of the contractile system, but guanine nucleotides enhance contractility only when Ca sensitivity is not high. The inotropic effect of epinephrine is inhibited to a large extent by cGMP but not by GMP-PNP. These data can be explained by a model in which contractility is enhanced by a cAMP-regulated phosphorylation that can be controlled through the beta-receptor adenylate cyclase complex in the sarcolemma. The regulation involves two reactions, one a phosphorylation and a second that occurs in the presence of detergent. Phosphorylation of neither the myosin light chain nor the inhibitory subunit of troponin appears to be involved in this mechanism for regulating contractility.

Phosphorylation of troponin I and the inotropic effect of adrenaline in the perfused rabbit heart.

THE regulation of contractile activity in cardiac muscle by changes in the intracellular Ca2+ concentration involves the regulatory protein system, consisting of tropomyosin and the troponin complex that is located in the I filament. Although the regulatory protein system of cardiac muscle is essentially similar in function to that of skeletal muscle, the components differ in the two tissues. Cardiac tropomyosin consists principally of α subunits, whereas the skeletal protein is composed of α and β subunits1. Troponin I, troponin C and troponin T are all specific for cardiac muscle in that they have different chemical and immunochemical properties from the corresponding skeletal muscle proteins2–4. In addition, cardiac troponin I and cardiac troponin C have been shown to have different amino acid sequences from their skeletal muscle counterparts3,5.

Adrenaline, DB-c-AMP and myocardial 45Ca exchange. Comparative studies in rat and guinea-pig auricles.

The positive inotropic effect of adrenaline has been assumed to result from an increase in the intracellular level of c-AMP which, in turn, might enhance the permeability of the cardiac cell membrane to Ca2+. In order to further test this hypothesis, the effects of cyclic N6-2′-O-dibutyryl-adenosine-3′,5′-monophosphate (DB-c-AMP; 10−3 M) on mechanical performance, 45Ca uptake and total tissue calcium concentration were investigated in electrically stimulated (120 beats/min) left auricles isolated from female rats weighing 180–220 g. The experiments were performed in Tyrode solution containing 0.9 mM CaCl2; the duration of 45Ca exposure was 3–60 min. In this study, DB-c-AMP markedly enhanced contractile force but the drug failed to detectably increase 45Ca exchange (Figs. 1 and 2). This finding seemed to indicate that the effects of DB-c-AMP on myocardial 45Ca exchange were completely different from those of adrenaline which previously (and in this study; Fig. 4) has been shown to accelerate 45Ca exchange in auricles obtained from guinea-pigs of “normal” size. However, under the conditions used, adrenaline (2.2–5.5×10−6 M) also failed to significantly enhance 45Ca exchange not only in rat auricles (Fig. 3) but also in small auricles isolated from very light guinea-pigs (body-weight 75–150 g; Fig. 4). From these findings it is concluded that druginduced changes in membrane calcium fluxes, which possibly occur, only might have escaped detection under the present experimental conditions. The “pool saturation phenomenon” previously described by Grossman and Furchgott (1964b; 1964c) is discussed to be the underlying mechanism. Thus, substantial conclusions on the effects of DB-c-AMP on myocardial Ca fluxes can as yet not be drawn. They must await experiments in which an adrenaline induced increase in cardiac 45Ca exchange becomes detectable.

Analysis of the adrenergic receptors of pacemaker and myocardial cells

Chronotropic and inotropic dose-response curves for epinephrine and phenylephrine were determined in rabbit atria spontaneously beating and electrically-driven. The curves were obtained in the absence and in the presence of propranolol, 10 −7 M, or phentolamine, 2 × 10 −6 M. Propranolol antagonized the chronotropic effects of epinephrine and phenylephrine, and the inotropic effects of epinephrine. This antagonist reduced the inotropic responses to high doses of phenylephrine, but left unaltered the effects of low doses. Phentolamine antagonized the inotropic effects of low doses of phenylephrine which were unaffected by propranolol. The inotropic curve for epinephrine was shifted 2.5-fold to the right by phentolamine. In contrast, phentolamine did not modify the chronotropic responses to these amines. The ability of α- and β-blocking agents of antagonizing the inotropic effects of adrenergic amines suggest that the receptors mediating these effects possess pharmacological characteristics which are common to both types of receptors. Thus, a two-receptor system appears to operate in the production of inotropic responses to adrenergic stimuli. In addition, the results confirm the role played by β-receptors in the cardiac actions of adrenergic amines.

High Pressure Anion Exchange Chromatographic Measurement of Cyclic Adenosine 3′,5′-Monophosphate and Cyclic [14C]Adenosine Monophosphate Specific Activity in Myocardium Prelabeled with [14C]Adenosine

Abstract A 10-min high pressure pellicular anion exchange chromatographic method coupled to a new sensitive ultraviolet flow cell has been used to measure picomole amounts of cyclic adenosine 3',5'-monophosphate (cyclic AMP) in biological materials after previous purification of the samples. Tissue extracts in trichloroacetic acid are previously purified by anion exchange chromatography, zinc-barium precipitation, and thin layer chromatography. High specific activity cyclic [3H]AMP is used to determine purification recovery for each sample. The method has also been used to determine cyclic AMP and cyclic [14C]AMP specific activity in perfused frog ventricles prelabeled with [14C]adenosine. In addition, this method has been used to demonstrate that the positive inotropic effects of epinephrine and norepinephrine could not be dissociated from increased myocardial levels of cyclic AMP in the presence of the glycogenolytic blocking agent, N-isopropylmethoxamine.

Mechanism of action of epinephrine and glucagon on the canine heart. Evidence for increase in sarcotubular calcium stores mediated by cyclic 3',5'-AMP.

The mechanisms by which the catecholamines and glucagon increase myocardial contractility were investigated by studying the effects of cyclic 3', 5'-AMP, epinephrine, and glucagon on calcium accumulation by a microsomal fraction of canine myocardium thought to represent sarcoplasmic reticulum, and by assaying the microsomal fraction for adenyl cyclase activity. Each agent produced a concentration-dependent increase in calcium accumulation. Moreover, adenyl cyclase, an enzyme activated by epinephrine and glucagon and responsible for the production of cyclic 3', 5'-AMP, was present in the microsomal fraction. Its specific activity and responsiveness to epinephrine and glucagon were similar to that previously found in sarcolemmic fractions. The beta-receptor blocking agent propranolol abolished the activation of adenyl cyclase and increase in microsomal calcium accumulation produced by epinephrine, but was without effect when these same changes were produced by glucagon. These findings are consistent with the hypotheses that: (1) the positive inotropic effects of epinephrine and glucagon may occur as a result of an augmentation of the sarcotubular calcium pool(s); and (2) this effect is mediated, at least in part, by an elevation of cyclic 3', 5'-AMP levels produced by activation of an adenyl cyclase localized to the sarcoplasmic reticulum.

�ber den Einflu� von Mangan-Ionen auf die positiv inotrope Wirkung von Adrenalin, Theophyllin und Digitoxigenin an isolierten Meerschweinchenvorh�fen

The influence of bivalent manganese ions (Mn++) on the positive inotropic effect of adrenaline, theophylline, and digitoxigenin was studied in isolated, electrically driven left guinea-pig auricles in phosphate-free Tyrode's solutions with different extracellular calcium concentrations ([Ca]e; 0.45; 1.8; 7.2 mM).

The effect of adrenaline on the tension developed in contractures and twitches of the ventricle of the frog.

1. The effect of adrenaline on contracture and twitch tension in frog's ventricle has been examined, using the superfused preparation.2. In 1 mM-Ca Ringer, contractures induced with excess KCl concentrations from 50 to 200 mM, are reduced by 1 x 10(-6) g/ml. adrenaline to an average of 0.62 of control values, in marked contrast to the well known positive inotropic effect of adrenaline on the heart twitch. This effect of adrenaline is directly dose dependent. Increasing [Ca](o) diminishes the effect of adrenaline on contracture tension, and on the twitch tension.3. Adrenaline has a significantly greater effect on the KCl contracture tension than noradrenaline or isoprenaline.4. In 1 mM-Ca Ringer, Na-free contractures are reduced to 0.72 of controls by 1 x 10(-6) g/ml. adrenaline. Adrenaline also significantly reduces tension in contractures induced by 50 c/s alternating current.5. The action of adrenaline on contracture tension is largely complete in 1-2 min at various rates of stimulation and calcium concentrations. A similar time course has been found for the effect of adrenaline on membrane potential.6. Pronethalol blocks the action of adrenaline on both twitch and contracture. The action on the contracture can also be blocked by ouabain (1 x 10(-5)M), and exposure of the tissue to K-free or Na-free Ringer solution.7. Adrenaline hyperpolarizes the membrane potential with a range of [K](o) from 0 to 200 mM. This effect is blocked by pronethalol and ouabain. After exposure to ouabain, adrenaline causes a significant decrease in the membrane potential. This may be due to an increase in the sodium permeability.8. At low values of the [Ca]/[Na](2) ratio, adrenaline takes a relatively constant number of beats for full action, but at high values of the ratio the development of full effect is largely time dependent.9. The time course of the effect on the twitch of changing from 0.5 to 2 mM-Ca Ringer has been studied at various rates of stimulation. The equilibration time has been found to depend on the heart rate.10. The effect on the contracture suggests that adrenaline decreases the calcium permeability. It is further suggested that the development of twitch tension is not due to direct Ca entry but is due to the release of Ca from a local store within or between the cells. The inotropic action of adrenaline is explained in terms of this store.