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Interactions of sympathomimetic drugs, propranolol and phentolamine, on atrial refractory period and contractility

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... Wenzel and Su (1966) first reported the existence of a 1pha adrenoceptors in rat myocardial strips. In addition, Govier (1968) found that alpha adrenoceptors were present in guinea-pig atrium, while Benfey and Varma (1967) confirmed their existence in rabbit left atrium. , however, were unable to confirm the presence of alpha adrenoceptors in the atria of guinea-pigs and rabbits. ...
... The ability of a beta antagon i st to affect the inotropic response of phenylephrine is controversial. Benfey and Varma (1967) observed that propranolol (3x10 ''M) did not inhibit the effect of phenylephrine on the-contract!le force of rabbit atria. ...
... The adrenergic receptors of cardiac muscle have been generally cIassified as p receptors. A number of investigators (Benfey and Varma 1967; Berger and Mokler 1969; Govier 1968; Nakashima et al. 1971; Wenzel and Su 1966), however, have reported evidence supporting the existence of a-adrenergic receptors in the heart which were capable of mediating a positive inotropic effect in response to sympathomimetic agents. Two possibilities therefore exist. ...
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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.
Article
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Rabbit left atria were driven electrically at frequencies from 6 to 240/min or higher. The contractile tension-frequency curve was significantly moved upward by phenylephrine (10-6 and 10-5 M). The positive inotropic effect was not influenced by propranolol but was markedly attenuated by phentolamine. Theophylline in a concentration (10-4 M) sufficient to potentiate the effect of isoproterenol did not alter the positive inotropic effect of phenylephrine. Cardiac excitability studied in preparations driven at high frequencies was reduced by phenylephrine, the effect being inhibited by phentolamine and potentiated by propranolol. The excitability was enhanced by isoproterenol. Theophylline potentiated the effect of isoproterenol but inhibited the effect of phenylephrine in a high concentration (10-5 M). It may be concluded that an enhancement of the contractile force by stimulation of myocardial alpha-receptors is not due to increased formation of cyclic AMP. Theophylline does not appear to change the effect of alpha-receptor stimulation on cardiac excitability but rather to unmask the effect of beta-receptor stimulation when high concentrations of phenylephrine are applied.
Article
We determined the effect of alpha-adrenergic receptor stimulation on cyclic adenosine monophosphate (cyclic AMP) concentrations in isolated myocytes derived from adult rat hearts and in isolated perfused rat hearts. Activation of alpha-adrenergic receptors with either phenylephrine (10(-8) M to 10(-6) M) or epinephrine (10(-8) M to 10(-6) M) plus propranolol (10(-6) M) resulted in a reduction in cyclic AMP levels in isolated myocytes. The action of phenylephrine was antagonized by phentolamine (10(-6) M). Phenylephrine (10(-5)M attenuated cyclic AMP generation in response to isoproterenol (10(-8) M and 10(-5) M). However, this effect of phenylephrine was not antagonized by phentolamine. Elevation of cyclic AMP concentrations produced by glucagon and by theophylline in isolated myocytes was attenuated by phenylephrine and by epinephrine plus propranolol and the attenuation was antagonized by phentolamine. In isolated perfused rat hearts epinephrine (10(-6) M), when given with propranolol, diminished the rate of development of tension and also reduced tissue levels of cyclic AMP. Epinephrine alone, as well as isoproterenol, increased contractility and myocardial cyclic AMP concentrations as expected. These results indicate that catecholamines may increase or decrease cyclic AMP levels in rat myocardium, depending on the intensity of stimulation of receptor types. Increases are mediated by beta-adrenergic receptors, whereas decreases appear to by mediated by alpha-adrenergic receptors.
Article
We have tested the effect of some antiarrhythmic and some-receptor blocking drugs on the functional refractory period and the contractility of guinea-pig atria stimulated electrically with single (contractility I) and paired (contractility II) stimulation. 1. The most pronounced prolongation of functional refractory period was seen with quinidine (1.310–5 to 710–5 mol/l). There was no negative inotropic effect after single stimulation. Increased contractility after paired stimulation was depressed. 2. Procainamide and diphenylhydantoin (3.610–5 to 3.610–4 mol/l) prolonged the functional refractory period. Procainamide had no influence on cardiac contractility I and II, but diphenylhydantoin had a negative inotropic effect. 3. Sparteine (2.410–6 to 7.110–5 mol/l) prolonged the functional refractory period. It had a positive inotropic effect on cardiac contractility I and II. After pretreatment of guinea-pigs with 21 mg/kg reserpine the effects on contractility were no longer demonstrable. 4. Verapamil (210–7 to 6.110–6 mol/l) showed a great prolongation of the functional refractory period and the most pronounced negative inotropic effect of all drugs tested. 5. d-Alprenolol (2.510–7 to 2.510–5 mol/l) prolonged functional refractory period and depressed contractility after single stimulation. l-Alprenolol (3.510–7 to 3.510–5 mol/l) showed these effects only on the atria of guinea-pigs treated with reserpine. 6. dl-Propranolol (3.410–7 to 110–5 mol/l) increased the functional refractory period without changing contractility I or II.d-propranolol had no effect in the same range of concentrations. 7. Pretreatment of the animals with 21 mg/kg reserpine decreased the duration of the functional refractory period of the isolated atria but had no influence on cardiac contractility.
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Alpha-adrenoceptors mediating positive inotropic effects are well established in the heart of various species including human heart. The mechanism by which alpha-adrenoceptor stimulation increases force of contraction is not known. cAMP is unlikely to be involved as a mediator. Evidence has been presented that an increase in magnitude and duration of the slow Ca++ inward current may be partly responsible for the positive inotropic efffect. In addition, stimulation of alpha-adrenoceptors may increase Ca++ sensitivity of the contractile proteins. Stimulation of alpha-adrenoceptors by endogenous catecholamines may serve as a reserve mechanism under various conditions of impaired beta-adrenergic influence, e.g. hypothyroidism, bradycardia or ischemia. Furthermore, alpha-adrenoceptors may be involved in the genesis of reperfusion arrhythmias in ischemic heart.
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The functional role of -adrenoceptors was investigated in different parts of the rabbit heart. Phenylephrine (PE) caused a marked increase in force of contraction (Fc) and a prolongation of the action potential (AP) in preparations from the left atrium and the right ventricle. The response was less pronounced in the right atrium and in the left ventricle, whereas APs of spontaneously beating sinoatrial preparations remained completely unchanged. Phentolamine as well as the diesters phorbol 12,13 dibutyrate (PDBu) or 12-O-tetradecanoylphorbol-13-acetate (TPA) eliminated the effects of PE. The contribution of a-adrenoceptors to the effects of adrenaline (Adr) and noradrenaline (NA) on Fc was determined in preparations from the right ventricle. Phentolamine and the phorbol diesters reduced the effects of Adr and NA by about 30 to 60%; the remaining response was abolished by propranolol. It can be derived from our experiments that, in some parts of the rabbit heart, a considerable amount of the effects of Adr and NA is due to the stimulation of a-adrenoceptors. The present findings therefore support the view that, in the rabbit heart, the maximally effective drive of the heart requires the stimulation of both - and -adrenoceptors. The inhibitory effects of phorbol diesters on the -adrenoceptor-mediated response indicate that the activation of protein kinase C (PKC) specifically uncouples -adrenoceptors from the effector system, whereas the response to -adrenoceptor stimulation remains unchanged.
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On the isolated papillary muscle of the rabbit experiments were performed in order to study whether -and/or -adrenoceptors mediate the positive inotropic effect of phenylephrine and, for comparison, of other sympathomimetic drugs.1. The positive inotropic effect of phenylephrine in concentrations of up to 310–6M was antagonized by the -adrenolytic drug phentolamine, while that evoked by higher concentrations was inhibited by the -adrenolytic drug pindolol. The intrinsic activity of phenylephrine amounted to 0.6 compared with that of isoprenaline. 2. Pretreatment with reserpine altered neither the pD2-value for phenylephrine nor its intrinsic activity. 3. The inhibitors of phosphodiesterase, theophylline (10–4M) and papaverine (10–5M) enhanced the effect of higher concentrations of phenylephrine—mediated mainly by stimulation of -adrenoceptors, whereas that of lower concentrations—mediated by stimulation of -adrenoceptors—was not affected. Papaverine strongly increased the intrinsic activity of phenylephrine, which then reached that of isoprenaline. 4. The -adrenoceptor stimulating drugs, methoxamine, naphazoline and oxymetazoline did not cause positive inotropic effects but, on the contrary, negative ones. The positivei notropic effect of noradrenaline was not changed by phentolamine, whereas that of adrenaline in concentrations of up to 10–5 M was inhibited. 5. From these results it is concluded that in the rabbit papillary muscle not only - but also -adrenoceptors are of functional importance for the mediation of the positive inotropic effect of some sympathomimetic drugs. The nature of these -adrenoceptors is apparently distinct from those of other organs since these receptors were stimulated only by phenylephrine and adrenaline but not by noradrenaline, methoxamine, naphazoline and oxymetazoline.
Article
Myocardial α-adrenoceptors are similar to vascular α-adrenoceptors; therefore the drugs which are used to study myocardial α-adrenoceptors can affect the heart indirectly by acting on vascular α-adrenoceptors. High concentrations of α-adrenoceptor stimulant and α-adrenoceptor blocking drugs can exert cardiac effects that do not result from action on α-adrenoceptors; therefore relatively low concentrations of these drugs must be used to obtain specific effects.An α-adrenoceptor mediated positive inotropic effect has been observed in relatively slow beating isolated heart preparations; it is not associated with shortening of the duration of systole or an increase in myocardial cyclic AMP concentration and is probably accompanied by an increase in Ca2+ influx. Usually α-adrenoceptor stimulation has no effect on heart rate.Myocardial α-adrenoceptor mediated ventricular arrhythmias have been caused in animals by high concentrations of catecholamines, and a transient increase in α-adrenoceptor concentration has been found in ischemic myocardium. We do not know how myocardial α-adrenoceptor stimulation causes arrhythmias. In isolated heart preparations low concentrations of epinephrine and norepinephrine prolong refractory period and action potential duration by α-adrenoceptor stimulation, and higher concentrations of the catecholamines shorten refractory period and action potential duration by α-adrenoceptor stimulation. In isolated specialized conducting fibers low concentrations of catecholamines reduce automaticity by α-adrenoceptor stimulation and higher concentrations increase automaticity by β-adrenoceptor stimulation. In partially depolorized ventricle preparations α-adrenoceptor stimulation has been reported both to depress and to restore electrical and mechanical activity. Clearly, much remains to be done before we understand α-adrenoceptor mediated cardiac effects.
1. Neural mechanisms in teleost cardioregulation were investigated through physiological and pharmacological characterization of autonomic receptors in the isolated heart of goldfish.2. Acetylcholine decreases cardiac frequency and force of contraction in the isolated, saline-perfused heart, a response abolished by atropine.3. The relative potency of sympathomimetic agonists in producing cardioacceleration is: isoproterenol > norepinephrine > phenylephrine; the effect is antagonized by propranolol but not phentolamine.4. Propranolol decreases heart rate dose-dependently, while atropine and phentolamine elicit no change.5. Vagal stimulation in situ produced bradycardia, reversed by atropine to tachycardia.6. The presence of inhibitory, cholinergic-muscarinic and excitatory, β-adrenergic receptors in goldfish heart is indicated; functional cardioacceleratory fibers reach the β-adrenoceptors via the vagus nerve.
1. The cardiac adrenoceptors of the frog and the trout have been characterized as β2-types over the physiological temperature ranges for these species.2. In contrast to mammals, the neuronal uptake of the frog was found to remove adrenaline, whereas the extraneuronal uptake was specific for noradrenaline. Accordingly, in each species the neuronal and extraneuronal uptake mechanisms were selective towards the naturally occurring catecholamine in the sympathetic nerves and in the circulation respectively.3. The present results do not indicate a temperature-dependent transformation of the cardiac β-receptor tto an α-type at low temperature in the homeothermic or the poikilothermic animals. In the rat atria, nno evidence was obtained to indicate functionally important subpopulations of α-receptors at normal or llow temperature.4. The β2-adrenoceptors have now been termed “adrenaline” receptors as opposed to the β1-receptors of mammals which are “noradrenaline” receptors. The limitations of the earlier classification of β1- as “innervated” and β2- as “humoral” adrenoceptors as a general pattern for the vertebrates, are discussed on the basis of the observed species differences with respect to the nature of the catecholamines as neurotransmitters and circulating hormones in mammals and lower vertebrates.
1.1. α-adrenergic effects were demonstrated in the spontaneously beating right and the electrically driven left atrium of the rat by phentolamine blockade of the inotropic and chronotropic responses to phenylephrine at 38°C.2.2. At 21°C, no α-effects of phenylephrine could be detected. The results are inconsistent with the postulated conversion of the cardiac β-adrenoceptors to an α-type at low temperature.3.3. At normal temperature the α-receptor differed from the α-receptor types in the ventricle and the vasculature by lack of response to noradrenaline, adrenaline, naphazoline, oxymetazoline, xylometazoline and clonidine.
Article
The mechanism of adrenergic effects on ventricular vulnerability, appearing in the form of a decrease in the ventricular fibrillation threshold, reduction of the electrical diastolic threshold, shortening of the refractory period as well as an increased asynchrony of recovery of excitability, was analysed in dogs under chloralose-urethane anesthesia. All these alterations of the electrophysiological parameters of the heart seem to be closely related to stimulation of the adrenergic beta receptors; this was shown by the fact that the selective beta receptor blocking agent 1-INPEA which is without any notable quinidine-like action effectively prevented these changes whereas the alpha-receptor blocking agent phenoxybenzamine did not. This was so irrespective of whether ventricular vulnerability was increased by direct stimulation of the cardiac sympathetic nerve (stellate ganglia) or by reflex sympathetic stimulation (by means of temporary bilateral carotid occlusion) or by infusions of adrenaline or noradrenaline.
Article
The effects of phenylephrine on the shape of the contraction curve and on the cyclic adenosine 3',5'-monophosphate (c-AMP) content were studied in electrically driven (frequency 0.2 Hz) cat papillary muscles. All experiments were done in the presence of 1 micron propranolol in order to minimize interference from beta-adrenoceptors. 1. Phenylephrine increased the force of contraction in a concentration-dependent manner. Maximal effects (about 200% of control) occurred at 30 micron phenylephrine. 2. The positive inotropic effect (PIE) of phenylephrine was antagonized by phentolamine. Phentolamine, 5 micron, produced a parallel shift of the concentration-response curve for the PIE of phenylephrine by about two log units to the right. 3. The PIE of 30 micron phenylephrine occurred without any detectable increase in the c-AMP levels of the preparations. 4. The PIE of 30 micron phenylephrine developed about three times more slowly than the PIE of an equieffective concentration of isoprenaline. 5. The PIE of phenylephrine was accompanied by significant, concentration-dependent increases in both time to peak force and relaxation time. 6. It is concluded that the PIE of phenylephrine in the presence of propranolol is mediated mainly by a stimulation of alpha-adrenoceptors. It is unlikely to be related to an increase in c-AMP. With respect to time course and influence on the shape of the contraction curve it is qualitatively different from the effects of beta-adrenoceptor stimulation. These data are taken to support the hypothesis that the mechanical effects of alpha- and beta-adrenoceptor stimulating agents on the heart are produced by different mechanisms.
Article
Abstract If β- and -adrenergic inotropic effects are cyclic AMP dependent and cyclic AMP independent, respectively, they may be qualitatively different. The inotropic effects of β-receptor stimulation (isoprenaline) and -receptor stimulation (phenylephrine combined with propranolol) were characterized in isolated perfused rat hearts, rat atria and rat papillary muscles. The β-effect reached its maximum before the -effect. The -effect followed a three-phasic time-course indicating both stimulatory and inhibitory components. The aortic pressure wave (perfused heart) indicated a shorter contraction phase after β-stimulation than after -stimulation. The time to peak tension (atrium, papillary muscle) was relatively shorter after isoprenaline than after -stimulation, which tended to prolong it. The contraction-relaxation cycles (atrium, papillary muscle) were examined by recording the isometric tension (T), its first (T′) and second (T″) derivatives, - and β-stimulation both increased Tmax, T′max (maximal rate of tension rise), T′min, (maximal rate of tension decline) and T″min (maximal rate of transition from rise to decline of tension). Isoprenaline increased Tmin, (papillary muscle) and T″min (atrium, papillary muscle) relatively more than did -stimulation, i.e. the relaxing processes were activated relatively more by β-stimulation. The results indicate different mechanisms for the two adrenergic inotropic effects. The relatively larger activation of relaxation by β-stimulation is assumed to be caused by cyclic AMP.
Article
The order of affinity for catecholamine agonists was obtained for the spontaneously beating auricles of as a function of temperature, pH and glucose in the medium. At 15°C a β2-adrenoceptor mediated the inotropic and chronotropic responses (isoprenaline > salbutamol > adrenaline ⩾ noradrenaline). Xylometazoline and Hässle had no effect, and blockers of α- or β1-adrenoceptors were without inhibiting effects on the responses to the natural neurotransmitter, adrenaline. Absence of glucose or lowered pH in the medium did not unmask an α-adrenoceptor either at 25 or at 15°C. The adrenoceptor mediating the responses to adrenaline at 15°C appeared therefore identical to the β2-adrenoceptor previously shown to dominate at 25°C in the frog heart (.,. and .).
Article
Previous experiments suggested that the positive inotropic response to α–adrenergic stimulation was unrelated to cyclic AMP in contrast to the inotropic effect of β–adrenergic stimulation. In order to elucidate this question further we perfused hearts from rats made hypothyroid by treatment with propyl–thiouracil, since this treatment is known to augment the myocardial α–adrenergic effects. α–stimulation (phenylephrine in the presence of propranolol) caused a marked inotropic response and no increase in cyclic AMP. In contrast β–stimulation (isoprenaline) increased the cyclic AMP content. The time–courses of the inotropic responses to α– and β–stimulation were different. The aortic pressure waves indicated a shorter duration of each contraction phase after isoprenaline than after phenylephrine in the presence of propranolol. This difference is probably due to the cyclic AMP accumulated after isoprenaline. The findings support the hypothesis that the positive inotropic effect of α–adrenergic stimulation is caused by mechanisms independent of cyclic AMP, while the β–adrenergic inotropic effect involves cyclic AMP mediated processes. Such a dual mechanism of action for adrenergic agents might serve to maintain responsiveness of the heart under various conditions.
Article
The time course of changes of the level of 3′,5′-cyclic AMP (cAMP) and of the tension developed under stimulation of α- and β-adrenoceptors by phenylephrine was investigated in the isolated rabbit papillary muscle. Furthermore the doseresponse relationships for increases of cAMP and of developed tension elicited by phenylephrine were determined.1. A submaximally effective concentration of phenylephrine (10−5 M) increased significantly the level of cAMP of the papillary muscle at 15 and 30 s by 45 and 36%, respectively; the level of cAMP returned to the control value at 60 s after the administration. The developed tension increased significantly not before 45 s and reached its maximal level at 180 s. 2. When α-adrenoceptors were blocked by phentolamine (10−6 M), the positive inotropic effect of phenylephrine was decreased significantly but the increase of cAMP induced by phenylephrine was not reduced. In the presence of phentolamine the increase of cAMP induced by phenylephrine lasted longer than in the control experiments. 3. The effects of phenylephrine (10−5 M) both on the level of cAMP and the developed tension mediated via stimulation of β-adrenoceptors in the presence of phentolamine were enhanced by the phosphodiesterase inhibitor papaverine throughout the course of responses. 4. Phenylephrine produced an increase in developed tension as well as in cAMP. The corresponding dose-response curves run parallel to each other but differed by about 1.5 log units whereby the developed tension was evoked by lower concentrations. Phentolamine (10−6 M) shifted the curve for the positive inotropic action by about 1.5 log units but did not affect that for increase in cAMP. Therefore, in the presence of the α-adrenolytic drug phentolamine the difference between both curves became smaller so that both curves were superimposed. Papaverine (10−5 M) shifted the whole curve for cAMP upwards and enhanced the maximal contractile response to phenylephrine mediated by stimulation of β-adrenoceptors. 5. The present results indicate that the positive inotropic action of phenylephrine in lower concentrations (<10−5 M) induced by stimulation of α-adrenoceptors is independent of the level of cAMP. The positive inotropic action of the higher concentrations of phenylephrine induced via stimulation of β-adrenoceptors was preceded by an accumulation of cAMP; the inhibition of the cAMP phosphodiesterase activity by papaverine enhanced the actions of phenylephrine both on the level of cAMP and on the contractile force.
Article
In isolated, electrically driven right auricular strips of the human heart the inotropic effect of phenylephrine was studied. 1. First, the influence of the driving rate on the tension developed (i.e., the frequency-force relationship) was determined by stimulation of the preparations at 0.1, 0.5, 1, 2 and 3 Hz. The force of contraction was lowest at a stimulation rate of 0.1 Hz (36.9 g/g dry weight). The maximally developed force of contraction observed at frequencies of 0.5, 1, and 2 Hz amounted to about 200 g/g dry weight. The values did not significantly differ from each other. 2. The negative log of the EC50(−log EC50) for the positive inotropic effect of phenylephrine determined at a frequency of 0.5 and 1.0 Hz amounted to 5.28±0.08 and 5.34±0.11, respectively. The α-adrenolytic drug phentolamine (3×10−6 M) diminished significantly the −log EC50 to 5.01±0.04 and 4.89±0.10, respectively. 3. At a frequency of 1 Hz a shift of the concentration-response curve to the right was observed after treatment with the β-adrenolytic drug pindolol (3×10−8 M); the −log EC50 of phenylephrine decreased significantly to 4.08±0.07. 4. From these results it is concluded that α-adrenoceptors are present in human atria; they mediate positive inotropic effects and are stimulated by phenylephrine.
Article
Summary The presence and distribution of myocardial α-adrenoceptors in different parts of the heart of various mammalian species was investigated. For this reason experiments were performed in isolated cardiac preparations of rats, guinea pigs and cats. In order to obtain more information about the nature of the cardiac α-adrenoceptors additional experiments were undertaken at different temperatures. These studies were aimed to show whether or not a conversion of β-to α-adrenoceptors or vice versa takes place. Moreover, we analyzed the influence of hypothyroidism on the sensitivity of α- and β-adrenoceptors of preparations from rats fed with propylthiouracil. Finally, we tried to find out whether stimulation of these α-adrenoceptors leads to the formation of the cyclic nucleotides cAMP and cGMP.
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The effects of adrenergic and cholinergic receptor agonists and antagonists on single and clustered mouse cardiocytes in culture have been studied. Cardiocytes were obtained from mice, ranging in ages from 9 days in utero to 1 day postpartum, and were grown in culture for 2–14 days. Single isolated cells of every age tested possessed the ability to respond both via a muscarinic cholinergic receptor to the cholinergic agonist, carbamylcholine, and via α- and β-adrenergic receptors to norepinephrine and epinephrine. Thus, cholinergic and adrenergic receptors are simultaneously present on the same cell. Cardiocyte clusters had considerably higher sensitivity to both autonomic agents, but, because of the extensive functional specializations between cells, the localization of functional receptors to specific cells could not be made. [3H]Alprenolol, a potent β-adrenergic receptor antagonist, and [3H]quinuclidinyl benzilate ([3H]QNB), a potent muscarinic cholinergic receptor antagonist, were used to localize β-adrenergic and muscarinic cholinergic receptors by autoradiography. Quantitation of the muscarinic ACh receptor gave ∼800 sites/μm2, a value comparable to that for the nicotinic ACh receptor on primary skeletal muscle in culture. Electrophysiological and fine-structural studies confirmed the myocardial nature of these cells.
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A theoretical model is presented to describe the interaction between an agonist and two functionally opposite receptor populations in a pharmacological test system. It is suggested that the total effect in the system can be obtained by the algebraic summation of the two effects resulting from the activation of the two opposing receptor populations. Five cases of agonist action are distinguished on the basis of the relationship between the affinities and intrinsic activities of the agonist at the opposing receptors. Each case of drug-receptor interaction is described by a theoretical concentration-effect curve of characteristic shape: (1) no observed effect; (2) bell-shaped curve; (3) monophasic saturation curve; (4) monophasic curve which has a peak, and then declines to a plateau; (5) biphasic curve. It is proposed that a drug acting as a competitive antagonist at either or both of the receptors changes the relationship between the two opposing concentration-effect curves, resulting in potentiation, antagonism or reversal of the observed effect. The applicability of the model is supported by experimental examples from the pharmacological literature.
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Direct membrane effects and beta-adrenergic blocking action of pindolol were studied comparatively on isolated perfused cardiac fibers of dogs. In Purkinje fibers, the duration of transmembrane action potential decreased in concentrations higher than 0.5 mg/L. Maximum rate of depolarization also decreased in higher concentrations (5.0 mg/L or more). The functional refractory period decreased to a lesser degree compared with the decrease of the action potential duration. Nevertheless, slow-rising action potentials could not be abolished in premature responses, probably because of membrane depressant effects of this drug. In ventricular muscle fibers, these changes were minimum in the same range of concentrations. On the other hand, 0.05 mg/L of pindolol which was close to the therapeutic plasma concentrations and had no effect on action potentials of both Purkinje and ventricular muscle fibers, minimized the increase in automaticity of Purkinje fibers induced by 0.2 mg/L of isoproterenol. It is rationally speculated that the mechanism of antiarrhthmic action of pindolol is mainly due to its beta-adrenergic blocking action.
Article
A high incidence of sudden death due to ventricular fibrillation (VF) has been observed in dogs under chronic treatment with probucol, a new hypocholesterolemic agent. The present study describes the cardiac electrophysiologic properties of probucol-treated dogs and characterizes the electrophysiological response of these animais to manipula-tion of the autonomic nervous system. There was no significant difference in the spontaneous sinus cycle length, the QT interval, refractory period of the atrium, ventricle or A-V junction between normal and probucol-treated dogs. Epinephrine produced VF with few and sometimes no preceding premature ventricular extra-systoles. Electrical stimulation of the left stellate ganglion induced VF in 16/19 dogs whereas stimulation of the right stellate ganglion induced VF in 1/19 dogs. Phenyl-ephrine induced VF in 0/19 dogs, isoproterenol in 5/19 dogs, but phenylephrine + isoproterenol induced VF in 9/11 dogs in which isoproterenol did not produce VF. α(phentolaminej or β (propranolol) blockade prevented initiation of VF by epi-nephrine, phenylephrine + isoproterenol, and left stellate stimulation but a blockade did not prevent induction of VF by isoproterenoJ when isoproterenol alone produced VF. In this nonischemic model, we conclude that left stellate stimulation is a far more potent initiator of VF than right stellate stimulation and that induction of VF appears to require both α and β adrenergic receptor stimulation.
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Studies have been carried out on the effect of phenylephrine hydrochloride, at various concentrations (2×10−6, 5×10−6, 1×10−5 g/ml), on transmembrane action potentials and effective refractory period in the Purkinje fibres of sheep heart. The amine, at all three concentrations, increased the duration of the action potential and effective refractory period in electrically driven preparations.When applied at the higher concentration, phenylephrine induced a positive chronotropic effect in spontaneously beating preparations; this effect was associated with an increased steepness of the pacemaker potential.The results may be interpreted according to the point of view that myocardial alpha receptors contribute to the modulation of the repolarization phases of the action potential.
Chapter
Der pharmakologische Receptorbegriff hat eine lange Vorgeschichte. Paul Ehrlich entwickelte die Vorstellung, daß jede pharmakologisch wirksame Substanz wenigstens zwei getrennte funktionelle Strukturanteile besitzt, eine haptophore Gruppe, bestimmend für die Verteilung des Pharmakons im Körper und die selektive Bindung an die jeweiligen Erfolgsorgane, und eine pharmakophore Gruppe, der die spezifischen Wirkungen des Pharmakons auf die Erfolgsorgane zuzuordnen sind. Die Annahme eines haptophoren Strukturanteils am Pharmakon setzt entsprechende spezifische Empfänger bzw. Receptoren am jeweiligen Erfolgsorgan voraus. Von Langley wurde 1905 der Receptorbegriff zur Deutung der Curarewirkung an der quergestreiften Skelet-Muskulatur entwickelt. Auch für ihn waren die „receptiven Substanzen“bestimmte Komponenten der Zellen, mit denen sich pharmakologisch wirksame Substanzen verbinden müssen, um ihre spezifischen Wirkungen auslösen zu können.
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In absence of β-receptor blocking agents, α-adrenergic inotropic effects could be demonstrated in the rat myocardium for the synthetic α-agonists phenylephrine and methoxamine, but not for the naturally occurring catecholamines, adrenaline and noradrenaline. Other synthetic α-agonists were without effects. In the presence of the β-receptor blocking agent, propranolol or timolol, marked α-effects were demonstrated for adrenaline and noradrenaline in both the right and left atria and the right ventricle. The results indicate that α-receptors may be functionally important in the β-blocked myocardium.
Article
Electrocardiographic changes caused by electrical stimulation of individual cardiac sympathetic nerves were observed with Frank's corrected orthogonal lead system and Frank's vetorcardiogram. The effects of drugs on nervous stimulation and the electrocardiographic changes after the resection of the cardiac nerves were investigated in 45 closed chest dogs. The following results were obtained: 1. The amplitude of the T wave decreased in Y lead and increased in Z lead in 20 out of 34 cases in which the right stellate ganglion [R. S. G. (A)] had been stimulated and in all cases in which the right recurrent cardiac nerve (R. Rec. C. N.) and the left ventromedial cervical cardiac nerve (L. V. M. C. N.) had been stimulated. Spatial maximum T vector displaced anteriorly and superiorly. The magnitude of spatial maximum T vector increased in all cases. 2. An increase in the amplitude of T waves in Y lead was seen in all cases in which the left stellate ganglion (L. S. G.), and the left ventrolateral cervical cardiac nerve (L. V. L. C. N.) had been stimulated, and in 14 out of 34 cases in which the right stellate ganglion [R. S. G. (B)] had been stimulated. The spatial maximum T vector was displaced inferiorly. The magnitude of the spatial maximum T vector increased in all cases. 3. The amplitude of the T wave increased in Y lead with simultaneous stimulation of both right and left stellate ganglia. The spatial maximum T vector was displaced inferiorly and the magnitude of the spatial maximum T vector increased in all cases. These electrocardiographic changes were similar to the changes which occurred with single L. S. G. stimulation. 4. Rotation of the T loop in the left saggital plane was clockwise in more than 80% of cases with R. S. G. stimulation. However, rotation of the T loop in left saggital plane was counter clockwise in more than 75-80% of cases with L. S. G. and simultaneous stimulation of both right and left stellate ganglia. These results suggest that right and left cardiac sympathetic nerves innervate different myocardial areas and affect the local myocardial action potentials to cause these electrocardiographic changes. 5. In more than 40% of cases with stimulation of left cardiac sympathetic nerves (L. S. G., L. V. L. C. N.). arrythmias such as A-V dissociation and A-V junctional rythm were recognized. In more than 90% of cases with stimulation of right cardiac sympathetic nerves (R. S. G., R. Rec. C. N.), marked increase of sinus rythm occurred. 6. These electrocardiographic changes resulting from nervous stimulation decreased or disappeared after the use of propranolol. These results suggest that these electrocardiographic changes were caused by β-effects of catecholamines. 7. The QT ratio corrected by the formula of Bazett increased in all cases of right and left cardiac sympathetic nervous stimulation. 8. Long term observations after right or left stellate ganglionectomy revealed no significant changes in electrocardiographic patterns and a tendency to decrease in the QT ratio corrected by the formula of Bazett.
Article
Electrocardiographic and vectorcardiographic changes in Frank's corrected orthogonal lead system were studied stimulating electrically the right stellate ganglion (RSG), the left stellate ganglion (LSG) and both stellate ganglia (LSG+RSG) in anesthetized closed-chest dogs. The effects of propranolol on arrhythmias induced by the stimulation of the cardiac sympathetic nerve were also investigated. The following results were obtained: (1) The amplitude of T wave increased in Y lead with simultaneous stimulation of both right and left stellate ganglia. The spatial maximum T vector was displaced inferiorly and increased in the magnitude in all cases. These electrocardiographic changes were similar to those which occurred with LSG stimulation alone. (2) The rotation of the T loop, in the left sagital plane, was clockwise in more than 80% with RSG stimulation, while the T loop following the stimulation of LSG alone and LSG+RSG rotated counterclockwise in more than 75% of all cases. (3) In more than 40% of cases with stimulation of left cardiac sympathetic nerves (LSG, left ventrolateral cervical cardiac nerve), arrhythmias such as A-V dissociation and A-V junctional rhythm were recognized. Stimulation of right cardiac sympathetic nerve (RSG, right recurrent cardiac nerve) markedly increased the rate of sinus rhythm in more than 90% of cases. These arrhythmias resulted from the stimulation of nerves decreased or disappeared after the intravenous injection of propranolol.
Chapter
The importance of the adrenergic system in the electrical activity of the heart can be briefly summarized by stating that the endogeneous catecholamines liberated by sympathetic excitation may substantially affect those electrophysiologic parameters of the heart which have been shown to play a significant role in the regulation of cardiac rate and rhythm and in the genesis of cardiac arrhythmias. Increased tone of the sympathetic nervous system as well as administration of catecholamines or other sympathomimetic agents closely resembling in structure the naturally occurring adrenergic activators may produce a variety of arrhythmias, from simple extrasystoles to lethal ventricular fibrillation. If the concentration of the adrenergic activators is high enough as in the case of pheochromocytoma, neuroblastoma, or overdosage of these agents, this may alone account for their arrhythmogenic action. On the other hand sensitivity to catecholamines can also be increased as in hyperthyroidism or when some hydrocarbon anesthetics are applied. Sometimes other potentially arrhythmogenic situations such as hypoxia of the heart, local myocardial ischemia due to coronary occlusion, ionic changes, (e.g., hypo- or hyperpotassemia) and high level of free fatty acids may produce manifest arrhythmias, if the cardiac sympathetic tone is increased or adrenergic activators are given. Since the term “cardiac arrhythmia” denotes the irregular activity of the whole cardiac syncitium, none of the electrophysiologic effects alone, even the most impressing changes determined by intracellular recordings or membrane current measurements, can account directly for the arrhythmic action of the adrenergic activators.
Chapter
Since alpha-adrenoceptors perform many physiological roles in the nervous and cardiovascular systems it is inevitable that, theoretically, their activation or blockade will impinge on any dysrhythmogenic process. Empirical observation also clearly shows that activation of the sympathetic nervous system can be dysrhythmogenic (Chap. 12), either when it is excessive or when some defect of cardiac function already exists, and that drugs which are known to be alpha-adrenoceptor antagonists can alleviate this. At present the fundamental basis of this phenomenon is not entirely clear. Consequently an opportunity may exist, by clarifying this, to increase the rational basis of antiarrhythmic therapy. To this end, this chapter reviews the roles of alpha-adrenoceptors in the heart or with a bearing on cardiac function, with particular emphasis on possible influences on normal or abnormal cardiac rhythm.
Chapter
An analysis of the influence of current strength and length of basic drive on atrial refractoriness has not been performed sistematically in the human atrium. We studied 29 patients (24 males and 5 females), ranging in age from 23 to 78 yrs. Atrial effective (ERP) and functional (FRP) refractory periods were measured during atrial pacing (100/min) using: a) variable current strengths (2, 3, 4, 5, 7, 10, 15 mA) and introducing extrastimuli after the eight paced complex of the basic drive; b) a constant current strength (5 mA) and introducing extrastimuli after 8 beats, 1 minute and 3 minutes of the basic drive. A bipolar stimulation, with the distal pole as cathode was performed. In all patients the increase of both current strength and basic drive length produced a reduction of ERP and FRP. At current strengths higher than 7 mA ERP and FRP became nearly fixed. We conclude that: 1. as stimulation occurs earlier in the cardiac cycle, more current and/or a longer previous basic drive are required to initiate a response. This is noteworthy considering that the ability to initiate or terminate reentrant arrhythmias by programmed stimulation is dependent on the refractoriness of the limbs of the reentrant circuit; 2. the relation between stimulus strength and atrial refractoriness is non linear. This could imply that if refractoriness is determined at a single current strength, it would be more appropriate to do so at a current strength (> 7 mA) at which minimal changes in refractoriness are observed; 3. 8 beats of atrial pacing are not sufficient to achieve a steady state of atrial refractoriness.
Chapter
Adrenaline and noradrenaline increase the force of contraction of the heart (positive inotropic effect) and the heart rate (positive chronotropic effect). They also lead to an increase in the rate of relaxation and, hence, to an abbreviation of the contraction (relaxant effect). The physiological relevance of the relaxant effects of the sympathomimetic agents has been fully recognized only recently; it permits adequate ventricular filling in the face of the increased heart rate.
Chapter
A wide variety of tissues undergo a change of functional state on exposure to noradrenaline or adrenaline. Those molecular constituents of the effector cells of a tissue with which molecules of these catecholamines must first interact in order to produce a change of state — or response — of the tissue, are the so-called adrenoceptors (also commonly called adrenergic receptors). For convenience, we refer to noradrenaline, adrenaline and other agents which produce responses in tissues by interacting with adrenoceptors, as adrenergic agonists. An agent which specifically inhibits a response produced by an adrenergic agonist is referred to as adrenergic blocking agent or adrenergic antagonist.
Chapter
The modulation of cardiac K+ channels by the cholinergic and adrenergic divisions of the autonomic nervous system is central to regulating chronotropy and inotropy in the heart. Interaction of drugs with autonomic receptors in cardiac tissues represents an important intervention in the control of arrhythmias, heart failure, hypertension, hypotension, and shock. The effects of adrenergic and cholinergic stimulation on cardiac K+ currents have been well described. More recent advances in molecular biology have also allowed us to better understand the signal transduction and effector mechanisms underlying these effects at a subcellular level and can provide a unifying approach to understanding the seemingly diverse effects of autonomic stimulation on cardiac K+ currents and function. Furthermore, there is substantial overlap between the effects of cholinergic and adrenergic responses. Finally, activation of one population of autonomic receptors may accentuate or antagonize the effects of another. This complex cross talk allows a finer control over cardiac K+ channel function and may arise at any level of the signal transduction pathways, including receptors, G-proteins, second messengers, downstream effectors, or even the channel proteins themselves.
Chapter
It has been known for decades that stimulation of the sympathetic nerves to the heart (von Bezold, 1863; Gaskell, 1884), injection of suprarenal extracts (Oliver and Schäfer, 1895) or addition of adrenaline (Elliott, 1905) increase the force of contraction of the heart and the heart rate. These changes are now generally accepted to be primarily due to stimulation of β-adrenergic receptors (β-adrenoceptors). However, recent evidence suggests that α-adrenoceptors are also present in the myocardium and that positive inotropic effects may be produced by stimulation of these receptors.
Article
: α-And β-adrenergic inotropic effects have been shown to be qualitatively different. In order to further characterize these differences we compared the mechanical responses to α- and β-adrenoceptor stimulation, respectively, in electrically driven left ventricular papillary muscles from rat heart. The muscles were stimulated by either isoprenaline (β-adrenoceptor stimulation), phenylephrine in the presence of propranolol (α-adrenoceptor stimulation) or phenylephrine alone (combined α- and β-adrenoceptor stimulation). Isometric tension (T), rate of rise and decline of tension (first derivative = T′) and rate of transition from tension rise to tension decline (negative part of second derivative = T″) were recorded. These recordings disclosed qualitative differences between the α- and β-inotropic response both in dose-response and time course experiments. Maximal β-adrenoceptor stimulation caused a small increase in Tmax (18%), intermediate increases in T′max (45%) and T′min (68%) and a considerable increase in T″min (145%) (“β-type” effect). Maximal α-adrenoceptor stimulation increased all qualities by about the same degree (23–24%) (“α-type” effect). While β-adrenoceptor stimulation gave a dose-dependent and pronounced increase in the ratio T″min/T′max (relaxation-onset index), α-adrenoceptor stimulation decreased it to subcontrol values and phenylephrine alone gave a small dose-dependent increase at higher doses. The time course of the α-adrenoceptor stimulation was characterized by a transient decrease in all qualities followed by an increase which reached maximum at 4–5 min. β-Adrenoceptor stimulation gave a monophasic response which reached maximum after 1–2 min. Phenylephrine alone gave mainly an “α-type” effect although T″min increased significantly more in the absence than in the presence of propranolol and T″min/T′max showed a small increase which developed slowly. Thus β-adrenoceptor stimulation activated relaxation compared to contraction by a higher degree than did α-adrenoceptor stimulation. This probably reflects different mechanisms of action. While the α-effect may rely primarily on an increased calcium influx, the β-effect probably is the final result of several subcellular effects of cyclic AMP.
Article
: Dibutyryl cyclic AMP, and α- and β-adrenoceptor stimulators are all able to elicit inotropic effects, α- and β-Adrenoceptor stimulation are known to change each myocardial contraction-relaxation cycle differently. In order to elucidate the myocardial function of cyclic AMP the effects of dibutyryl cyclic AMP on the contraction-relaxation cycle of isolated rat heart papillary muscle were examined and compared to the effects of α- and β-adrenoceptor stimulation, respectively. Dibutyryl cyclic AMP (in the presence of propranolol) increased developed tension (Tmax) by 18%, rate of tension rise (T′max) by 46%, rate of tension fall (T′min) by 62% and onset-rate of relaxation (T″min) by 136%. These changes in the contraction-relaxation cycle were strikingly similar to those produced by isoprenaline (β-adrenoceptor stimulation). The response to dibutyryl cyclic AMP, however, developed much slowlier than did the response to isoprenaline. The latter effect was associated with cyclic AMP elevation in a way indicating a trigger function for cyclic AMP. The α-adrenoceptor stimulation (by phenylephrine combined with propranolol), however, increased measures both for contraction and for relaxation by about the same degree, and the effects occurred without changes of cyclic AMP contents. Phenylephrine alone (combined α- and β-adrenoceptor stimulation) elicited a substantial cyclic AMP elevation but gave mechanical effects only slightly different from the pure α-adrenergic response. Thus cyclic AMP effects did not seem to be fully expressed in this case. As a whole, the results indicate that the effects of both dibutyryl cyclic AMP and of isoprenaline are mediated by the cyclic AMP-system while α-adrenoceptor stimulation involves other mechanisms.
1.1. The inotropic responses to phenylephrine and methoxamine were compared in isolated left and right atria, ventricles and papillary muscles from rat, guinea-pig and rabbit. The responses were not consistent to both alpha-adrenoceptor agonists and depended on the type of preparation.2.2. The positive inotropic effect of phenylephrine was much greater than that of methoxamine in most of the preparations. However, in the rat atria, the inotropic effect of both agonists was equivalent.3.3. Phenolamine treatment (10−6M) shifted the dose response curve for phenylephrine to the right in all the preparations except for guinea-pig ventricles and papillary muscles. However, after combined treatment with phentolamine and propranolol (both 10−6M), the maximum tension increase produced by phenylephrine was inhibited.4.4. On the other hand, phentolamine nearly abolished the methoxamine-induced positive inotropic effect in rat ventricles and papillary muscles and reversed the methoxamine response to a negative inotropic effect in rabbit left atria. Even in the absence of phentolamine, methoxamine was able to elicit a negative inotropic effect in guinea pig ventricles and papillary muscles.5.5. Propranolol (10−6M) did not have apparent effect on any of the methoxamine responses.6.6. In the atria from the different animals, methoxamine could elicit the positive inotropic effect at different frequencies of stimulation (0.5–2.0 Hz).7.7. These results suggested that the existence of the regional and species differences should be considered in a study of the nature of myocardial adrenoceptors and that the alpha receptor is capable of eliciting an inotropic effect.
Article
Ontogeny of inotropic responses of the left atria and chronotropic responses of the right atria of rabbits was studied in vitro. The maximal inotropic effect (efficacy) of isoproterenol on atria from neonatal (1.5 weeks old) rabbits was significantly less than that of norepinephrine and epinephrine. The inotropic efficacy of isoproterenol increased with age and reached adult levels at 6 weeks. There was no difference in the potency and efficacy of inotropic effects of epinephrine and norepinephrine on neonatal and adult (∼40 weeks old) rabbit atria. At threshold concentrations, phenylephrine synergistically potentiated the inotropic effects of isoproterenol on atria from neonatal but not on atria from adult rabbits. The potentiation of the inotropic effects of isoproterenol by phenylephrine on neonatal rabbit atria was abolished by prazosin. There was no difference in the chronotropic effects of isoproterenol on atria from neonatal and adult rabbits. It is speculated that α1- and β1-myocardial adrenoceptors are functionally linked in early life and a full expression of inotropic responses requires a concomitant activation of both receptor types.
Article
The role of a,-adrenergic receptors (adrenoceptors) on cardiac contractility was investigated in human subjects. The effect of methoxamine, a selective a-adrenoceptor agonist, and angiotensin II, on cardiac contractility was determined by means of noninvasive assessment of the slope of the end-systolic pressure (ESP)/end-systolic dimension (ESD) relationship. The slope (m) of this ratio was significantly higher with methoxamine (17.0; SD = 9.0 mm Hg/mm) than with antiotensin II (4.8; SD = 1.9 mm Hg/mm) (p < 0.05). Slopes with methoxamine were higher when heart rates (HRs) were reflexly reduced, and were significantly diminished when reflex bradycardia was prevented by atropine (p < 0.05) or atrial pacing (p < 0.01). Previous treatment with propranolol did not modify m values with methoxamine (m = 15.5; SD = 4.4 mm Hg/mm). Phentolamine, given at peak methoxamine effect, did not consistently modify m values, resulting in an average slope not significantly different from that obtained with methoxamine alone. However, the addition of phentolamine did cause an increase in ESDs at each level of ESP with respect to methoxamine. In the same subjects, infusion of phentolamine after angiotensin did not modify ESDs at comparable ESP levels.These findings suggest the existence of a positive inotropic effect mediated by [alpha]1 adrenoceptors in the in-tact human heart. (C) Lippincott-Raven Publishers.
Article
1. In pithed rats, yohimbine (1 mg/kg i.v.) enhanced the positive chronotropic responses to spinal stimulation of cardiac sympathetic nerves with eight pulses delivered at 2 or 4 Hz, indicating that auto-inhibition was operating, but did not increase responses to shorter lengths of trains of 8 pulses at 8, 16 or 32 Hz which did not allow sufficient time for auto-inhibition to come into effect. 2. The positive chronotropic response to cardiac sympathetic nerve stimulation with eight pulses at 8 Hz of about 60 beats/min was not affected by prazosin (1 mg/kg) or diltiazem (0.2 mg/kg), but was reduced to about 20% of the control value by propranolol (1 mg/kg). 3. In the presence of propranolol, the residual positive chronotropic responses to cardiac sympathetic nerve stimulation were virtually abolished by prazosin (1 mg/kg) or diltiazem (0.2 mg/kg). 4. The positive chronotropic response to tyramine (0.1 mg/kg i.v.) was reduced from 100 to 12 beats/min by propranolol (1 mg/kg), and the residual response was abolished by prazosin. 5. The findings indicate that noradrenaline released from cardiac sympathetic terminals by nerve stimulation or by tyramine acts on α1-adrenoceptors to produce a positive chronotropic response that is revealed when β-adrenoceptors are blocked.
Article
α1-Adrenoceptors (α1AR) are G protein-coupled receptors and include α1A, α1B, and α1D subtypes corresponding to cloned α1a, α1b, and α1d, respectively. α1AR mediate several cardiovascular actions of sympathomimetic amines such as vasoconstriction and cardiac inotropy, hypertrophy, metabolism, and remodeling. α1AR subtypes are products of separate genes and differ in structure, G protein-coupling, tissue distribution, signaling, regulation, and functions. Both α1AAR and α1BAR mediate positive inotropic responses. On the other hand, cardiac hypertrophy is primarily mediated by α1AAR. The only demonstrated major function of α1DAR is vasoconstriction. α1AR are coupled to phospholipase C, phospholipase D, and phospholipase A2; they increase intracellular Ca2+ and myofibrillar sensitivity to Ca2+ and cause translocation of specific phosphokinase C isoforms to the particulate fraction. Cardiac hypertrophic responses to α1AR agonists might involve activation of phosphokinase C and mitogen-activated protein kinase via Gq. α1AR subtypes might interact with each other and with other receptors and signaling mechanisms.Key words: cardiac hypertrophy, inotropic responses, central α1-adrenoreceptors, arrythmias.
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.
Article
1. There are α(1A)- and α(1B)-adrenoceptors in mammalian myocardium but no α2-adrenoceptors. 2. There are no agents that act selectively on myocardial α1-adrenoceptors, and because actions on vascular α1-adrenoceptors will interfere, it is difficult to show an effect on contractility by systemic administration of α1-adrenoceptor agonists or antagonists. In isolated heart preparations, the positive inotropic effect of α1-adrenoceptor stimulation, and, in most animal species, is accompanied by prolongation of action potential duration due to inhibition of outward K+ currents. Unlike β-adrenoceptor stimulation, α1-adrenoceptor stimulation has no significant effect on the voltage-activated Ca2+ current. 3. α1-adrenoceptor stimulation can cause cardiac arrhythmias and may be responsible for life-threatening events in myocardial ischaemia and re-oxygenation. 4 α1-adrenoceptor stimulation can cause cardiac hypertrophy.
Article
1 The effects of thyroid state on the properties of adrenoceptors mediating inotropic and chronotropic responses of the rat heart were assessed on the basis of the relative potencies of alpha- and beta-adrenoceptor agonists, the effects of alpha- and beta-adrenoceptor antagonists and the tissue uptake of [3H]-phenoxybenzamine ([3H]-PB). 2 In isolated, electrically driven left atria the ratio of the inotropic potencies of isoprenaline and phenylephrine and the inhibitory potency of propranolol (40nM-4 muM) were significantly reduced after thyroidectomy and were moderately increased after thyroxine treatment of control rats. 3 Block of inotropic responses to noradrenaline and to phenylephrine by PB (7.3 nM-7.3 muM) and the tissue uptake of [3H]-PB were significantly greater in preparations from thyroidectomized than in those from control or from thyroxine treated rats. alpha-Adrenoceptor inhibition by phentolamine (0.26-2.6 muM) also increased after thyroidectomy, and phentolamine effectively protected alpha-adrenoceptors from block by and binding of [3H]-PB. 4 The beta1-receptor antagonist H 93/26 (0.1 muM) significantly potentiated alpha-adrenoceptor blockade by PB in hypothyroid but not in control preparations. 5 In spontaneously beating right atria the chronotropic potency of agonists and the effects of antagonists were altered in the same way as were inotropic responses and the slope of the agonist concentration-response curves were significantly reduced after thyroidectomy. Effects of agonists and antagonists were not significantly influenced by thyroxine treatment. 6 Changes in the effects and tissue uptake of sympathomimetic drugs observed after thyroidectomy were reversed to or beyond control levels by thyroid hormone treatment of thyroidectomized animals. 7 The results presented are interpreted as indicating a thyroid hormone-dependent interconversion of myocardial alpha- and beta-adrenoceptors. It is suggested that this interconversion is similar to that observed earlier in frog hearts at different temperatures, and that both effects may reflect an allosteric transition between two forms of a single basic structure.
In the isolated guinea-pig atrium, phenoxybenzamine and other antagonists of sympathomimetic drugs and the adrenergic nerve blocking agent guanethidine inhibited the action of butyrylcholine and tyramine and potentiated the action of noradrenaline. Also in the isolated guinea-pig atrium, phenoxybenzamine and cocaine abolished the parasympathetic, and potentiated the sympathetic, effects of vagus stimulation.