Beta 1-adrenoceptor Partial Agonist Research Articles

In Vitro Evidence That Carteolol Is a Nonconventional Partial Agonist of Guinea Pig Cardiac β1-Adrenoceptors: A Comparison with Xamoterol

The present study was designed to verify our previous hypothesis that carteolol, a beta1/beta2-adrenoceptor-blocking agent, is a nonconventional partial agonist of cardiac beta1-adrenoceptors. To this purpose, we characterized the effects of carteolol in guinea pig myocardial preparations and measured the affinities of carteolol for high- and low-affinity sites of beta1-adrenoceptors labeled by CGP12177 [(-)4-(3-t-butylamino-2-hydroxypropoxy)-2-benzimidazol-2-one]. All experiments were performed in comparison with xamoterol, a cardioselective beta1-adrenoceptor partial agonist. Both drugs caused cAMP-dependent positive inotropic and chronotropic effects, but carteolol was less effective and less potent than xamoterol, and its cardiac actions were not affected by conventional concentrations of the beta-blocker propranolol. Both carteolol and xamoterol antagonized the cardiac effects of isoprenaline, but although the antagonistic concentrations of xamoterol were almost equal to those producing cardiostimulation, the antagonistic concentrations of carteolol were 3 log units lower than those causing cardiostimulant effects. Both carteolol and xamoterol competed with (-)[3H]CGP12177 for a high-affinity site of beta1-adrenoceptors, but carteolol showed a higher affinity than xamoterol. Moreover, carteolol, unlike xamoterol, bound also to a low-affinity site of the receptors. The binding affinity constants of the drugs for the high-affinity site correlated well with the respective blocking potencies against isoprenaline, whereas the affinity constant of carteolol for the low-affinity site was well related to its agonist potency. In conclusion, our findings demonstrate that carteolol, unlike xamoterol, is a nonconventional partial agonist, which causes agonistic effects through interaction with the low-affinity propranolol-resistant site of beta1-adrenoceptors and antagonistic actions through the high-affinity site of the same receptors.

Glucocorticoid effects on memory retrieval require concurrent noradrenergic activity in the hippocampus and basolateral amygdala.

Previous findings indicate that administration of abeta-adrenoceptor antagonist systemically blocks glucocorticoid impairment of memory retrieval. Here, we report that beta-adrenoceptor activation in the hippocampus and the basolateral complex of the amygdala (BLA) is implicated in the impairing effects of glucocorticoids on memory retrieval. The specific glucocorticoid receptor (GR) agonist 11beta,17beta-dihydroxy-6,21-dimethyl-17alpha-pregna-4,6-trien-20yn-3-one (RU 28362) (15 ng) infused into the hippocampus of male Sprague Dawley rats 60 min before water maze retention testing, 24 hr after training, impaired probe trial retention performance, as assessed by quadrant search time and initial latency to cross the platform location. Because we found previously that RU 28362 infused into the hippocampus does not affect water maze acquisition or immediate recall, the findings suggest that the GR agonist-induced retention impairment was attributable to a selective influence on long-term memory retrieval. Likewise, systemic injections of the beta1-adrenoceptor partial agonist xamoterol (3.0 or 10.0 mg/kg, s.c.) 60 min before the probe trial dose-dependently impaired retention performance. The beta-adrenoceptor antagonist propranolol (2.0 mg/kg) administered subcutaneously before retention testing did not affect retention performance alone, but blocked the memory retrieval impairment induced by concurrent intrahippocampal infusions of RU 28362. Pretest infusions of the beta1-adrenoceptor antagonist atenolol into either the hippocampus (1.25 microg in 0.5 microl) or the BLA (0.5 microg in 0.2 microl) also prevented the GR agonist-induced memory retrieval impairment. These findings suggest that glucocorticoids impair retrieval of long-term spatial memory by facilitating noradrenergic mechanisms in the hippocampus, and additionally, that norepinephrine-mediated BLA activity is critical in enabling hippocampal glucocorticoid effects on memory retrieval.

Coexistence of at least three distinct beta-adrenoceptors in human internal mammary artery.

The internal mammary artery (IMA) is currently the preferred conduit for myocardial revascularization. However, perioperative vasospasm and a hypoperfusion state during maximal exercise may limit its use as a bypass graft. The mechanism of spasm has not been clearly defined. Since beta-adrenoceptor activation plays a major role in vasorelaxation, the present study was carried out to investigate the beta-adrenoceptor responsiveness of human IMA smooth muscle. Isoproterenol produced a concentration-dependent relaxation in endothelium-denuded IMA segments, precontracted with phenylephrine (maximal relaxation 46.33+/-5.45%). Atenolol (10(-6)M) and propranolol (2x10(-7)M) inhibited isoproterenol-induced relaxation. While atenolol produced partial inhibition, propranolol caused a complete inhibition in a majority of the segments and a partial inhibition in a minority. BRL 37344, a selective beta 3-adrenoceptor agonist, produced a concentration-dependent relaxation in phenylephrine-precontracted rings of endothelium-denuded IMA (maximal relaxation 40.35+/-4.07%). Cyanopindolol, a beta-adrenoceptor partial agonist, produced a marked relaxation (58.65+/-6.2%) in endothelium-denuded IMA rings, precontracted with phenylephrine. Cyanopindolol-induced relaxation was resistant to blockade by propranolol (2x10(-7)M). Spontaneous contractions of IMA rings were also observed in some cases that were inhibited by isoproterenol and BRL 37344. This observation implies the important role of beta-adrenoceptor activation in prevention of human IMA spasm. The results obtained in present study indicate that human IMA smooth muscle possesses an atypical beta-adrenoceptor together with beta1- and beta2-adrenoceptors. Regarding the relaxation induced in IMA rings by adding BRL 37344, the possible identical entities of IMA atypical beta-adrenoceptors and beta 3-adrenoceptors are suggested.

Partial Agonistic Effects of Carteolol on Atypical β-Adrenoceptors in the Guinea Pig Gastric Fundus

The properties of the beta1-/beta2-adrenoceptor partial agonist carteolol were investigated in atypical beta-adrenoceptors on the guinea pig gastric fundus. Carteolol induced concentration-dependent relaxation in this tissue (pD2 = 5.55, intrinsic activity = 0.94). However, a combination of the selective beta1-adrenoceptor antagonist atenolol (100 microM) and the selective beta2-adrenoceptor antagonist butoxamine (100 microM) produced only small rightward shifts in the concentration-response curves of carteolol in the gastric fundus (pD2 = 4.91, intrinsic activity = 0.94). In the presence of both atenolol (100 microM) and butoxamine (100 microM), the non-selective beta1-, beta2- and beta3-adrenoceptor antagonist (+/-)-bupranolol (10-100 microM) caused a concentration-dependent right-ward shift of the concentration-response curves for carteolol in the guinea pig gastric fundus. Schild plot analyses of the effects of (+/-)-bupranolol against carteolol gave the pA2 value of 5.29 and the Schild slope was not significantly different from unity. Furthermore, carteolol (10 microM) weakly but significantly antagonized the relaxant responses to catecholamines ((-)-isoprenaline, (-)-noradrenaline and (-)-adrenaline), a selective beta3-adrenoceptor agonist BRL37344 ((R*,R*)-(+/-)-4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl)amino]propyl]phenoxy-acetic acid sodium salt) and a non-conventional partial beta3-adrenoceptor agonist (+/-)-CGP12177A ([4-[3-[(1,1dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one] hydrochloride) in the guinea pig gastric fundus. These results suggest that the partial agonistic effects of carteolol are mediated by atypical beta-adrenoceptors in the guinea pig gastric fundus.

Changes in intracellular Ca2+ mobilization and Ca2+ sensitization as mechanisms of action of physiological interventions and inotropic agents in intact myocardial cells.

Physiological and pharmacological interventions are used to regulate cardiac contractile functions via modulation of Ca2+ signaling. The relevant regulatory mechanisms have recently been assessed in detail by use of novel experimental procedures, which include simultaneous measurements of intracellular levels of Ca2+ ions and contractile force in intact myocardial preparations loaded with the intracellular Ca2+ indicator aequorin and fluorescent dyes, namely, fura-2, indo-1 and fluo-3. Association with or dissociation from intracellular Ca2+ transients of contractile activity is taken as evidence that reflects the primary mechanism of action of individual inotropic interventions. In addition, motility assays of actin-myosin interactions in vitro have made it possible to define the site of action of Ca2+ sensitizers as troponin C and the interaction of the troponin-tropomyosin complex with actin or the actin-myosin interface at crossbridges. Frank-Starling mechanism operates at the level of the binding of Ca2+ ions to troponin C and subsequent regulatory processes, while the force-frequency relationship is mainly ascribed to an alteration in the intracellular mobilization of Ca2+ ions. Cardiotonic agents can be classified as follows: 1) agents that act via a cyclic AMP-dependent or a cyclic AMP-independent mechanism; and 2) agents that facilitate the intracellular mobilization of Ca2+ ions or increase in myofibrillar sensitivity to Ca2+ ions. Regulatory mechanisms mediated via the phosphorylation of functional proteins induced by cyclic AMP, which is responsible for the actions of novel cardiotonic agents, beta 1-adrenoceptor partial agonist and selective inhibitors of phosphodiesterase (PDE) III, have currently been clarified in more detail. Ca2+ sensitizers are of extreme therapeutic interest because of their ability to increase myocardial contractility without an increase in activation energy; they are devoid of risks of arrhythmogenicity and myocardial cell death from intracellular Ca2+ overload; and they effectively reverse contractile dysfunction under pathophysiological situations, such as acidosis or myocardial stunning.

Evaluation of partial beta-adrenoceptor agonist activity.

A partial beta-adrenoceptor (beta-AR) agonist will exhibit opposite agonist and antagonist activity depending on the prevailing degree of adrenergic tone or the presence of a beta-AR agonist with higher intrinsic activity. In vivo partial beta-AR agonist activity will be evident at rest with low endogenous adrenergic tone, as for example with chronotropicity (beta 1/beta 2), inotropicity (beta 1) or peripheral vasodilatation and finger tremor (beta 2). beta-AR blocking drugs which have partial agonist activity may exhibit a better therapeutic profile when used for hypertension because of maintained cardiac output without increased systemic vascular resistance, along with an improved lipid profile. In the presence of raised endogenous adrenergic tone such as exercise or an exogenous full agonist, beta-AR subtype antagonist activity will become evident in terms of effects on exercise induced heart rate (beta 1) and potassium (beta 2) responses. Reduction of exercise heart rate will occur to a lesser degree in the case of a beta-adrenoceptor blocker with partial beta 1-AR agonist activity compared with a beta-adrenoceptor blocker devoid of partial agonist activity. This may result in reduced therapeutic efficacy in the treatment of angina on effort when using beta-AR blocking drugs with partial beta 1-AR agonist activity. Effects on exercise hyperkalaemia are determined by the balance between beta 2-AR partial agonist activity and endogenous adrenergic activity. For predominantly beta 2-AR agonist such as salmeterol and salbutamol, potentiation of exercise hyperkalaemia occurs. For predominantly beta 2-AR antagonists such as carteolol, either potentiation or attenuation of exercise hyperkalaemia occurs at low and high doses respectively. beta 2-AR partial agonist activity may also be expressed as antagonism in the presence of an exogenous full agonist, as for example attenuation of fenoterol induced responses by salmeterol. Studies are required to investigate whether this phenomenon is relevant in the setting of acute severe asthma.

Effects of (-)-RO363 at human atrial beta-adrenoceptor subtypes, the human cloned beta 3-adrenoceptor and rodent intestinal beta 3-adrenoceptors.

1. Chronic treatment of patients with beta-blockers causes atrial inotropic hyperresponsiveness through beta 2-adrenoceptors, 5-HT4 receptors and H2-receptors but apparently not through beta 1-adrenoceptors despite data claiming an increased beta 1-adrenoceptor density from homogenate binding studies. We have addressed the question of beta 1-adrenoceptor sensitivity by determining the inotropic potency and intrinsic activity of the beta 1-adrenoceptor selective partial agonist (-)-RO363 and by carrying out both homogenate binding and quantitative beta-adrenoceptor autoradiography in atria obtained from patients treated or not treated with beta-blockers. In the course of the experiments it became apparent that (-)-RO363 also may cause agonistic effects through the third atrial beta-adrenoceptor. To assess whether (-)-RO363 also caused agonistic effects through beta 3-adrenoceptors we studied its relaxant effects in rat colon and guinea-pig ileum, as well as receptor binding and adenylyl cyclase stimulation of chinese hamster ovary (CHO) cells expressing human beta 3-adrenoceptors. 2. beta-Adrenoceptors were labelled with (-)-[125I]-cyanopindolol. The density of both beta 1- and beta 2-adrenoceptors was unchanged in the 2 groups, as assessed with both quantitative receptor autoradiography and homogenate binding. The affinities of (-)-RO363 for beta 1-adrenoceptors (pKi = 8.0-7.7) and beta 2-adrenoceptors (pKi = 6.1-5.8) were not significantly different in the two groups. 3. (-)-RO363 increased atrial force with a pEC50 of 8.2 (beta-blocker treated) and 8.0 (non-beta-blocker treated) and intrinsic activity with respect to (-)-isoprenaline of 0.80 (beta-blocker treated) and 0.54 (non-beta-blocker treated) (P < 0.001) and with respect to Ca2+ (7 mM) of 0.65 (beta-blocker treated) and 0.45 (non-beta-blocker treated) (P < 0.01). The effects of (-)-RO363 were resistant to antagonism by the beta 2-adrenoceptor antagonist, ICI 118,551 (50 nM). The effects of 0.3-10 nM (-)-RO363 were antagonized by 3-10 nM of the beta 1-adrenoceptor selective antagonist CGP 20712A. The effects of 20-1000 nM (-)-RO363 were partially resistant to antagonism by 30-300 nM CGP 20712A. 4. (-)-RO363 relaxed the rat colon, partially precontracted by 30 mM KCl, with an intrinsic activity of 0.97 compared to (-)-isoprenaline. The concentration-effect curve to (-)-RO363 revealed 2 components, one antagonized by (-)-propranolol (200 nM) with pEC50 = 8.5 and fraction 0.66, the other resistant to (-)-propranolol (200 nM) with pEC50 = 5.6 and fraction 0.34 of maximal relaxation. 5. (-)-RO363 relaxed the longitudinal muscle of guinea-pig ileum, precontracted by 0.5 microM histamine, with intrinsic activity of 1.0 compared to (-)-isoprenaline and through 2 components, one antagonized by (-)-propranolol (200 nM) with pEC50 = 8.7 and fraction 0.67, the other resistant to (-)-propranolol with pEC50 = 4.9 and fraction 0.33 of maximal relaxation. 6. (-)-RO363 stimulated the adenylyl cyclase of CHO cells expressing human beta 3-adrenoceptors with pEC50 = 5.5 and intrinsic activity 0.74 with respect to (-)-isoprenaline (pEC50 = 5.9). (-)-RO363 competed for binding with [125I]-cyanopindolol at human beta 3-adrenoceptors transfected into CHO cells with pKi = 4.5. (-)-Isoprenaline (pKi = 5.2) and (-)-CGP 12177A (pKi = 6.1) also competed for binding at human beta 3-adrenoceptors. 7. We conclude that under conditions used in this study, (-)-RO363 is a potent partial agonist for human beta 1- and beta 3-adrenoceptors and appears also to activate the third human atrial beta-adrenoceptor. (-)-RO363 relaxes mammalian gut through both beta 1- and beta 3-adrenoceptors. (-)-RO363, used as a beta 1-adrenoceptor selective tool, confirms previous findings with (-)-noradrenaline that beta 1-adrenoceptor-mediated atrial effects are only slightly enhanced by chronic treatment of patients with beta-blockers. Chronic treatment with

Regulation of beta-adrenoceptors in the guinea-pig sinoatrial node.

This study examined the changes of beta-adrenoceptors in the guinea-pig sinoatrial nodal region following 7 day (-)-isoprenaline (400 micrograms/kg/h s.c.) infusion and the relationship between beta-adrenoceptor desensitization and receptor down-regulation. Changes in beta 1- and beta 2-adrenoceptor density were measured using quantitative autoradiography and function in organ bath studies. (-)-Isoprenaline treatment produced a marked decrease in total (from 57.5 to 33.9 fmol/mg protein), beta 1- (from 49.4 to 32.8 fmol/mg protein), and beta 2-adrenoceptor density (from 8.1 to 1.05 fmol/mg protein) in the sinoatrial node. In adjacent right atrium, treatment produced no change in total (39.5 and 36.7 fmol/mg protein) or beta 1-adrenoceptors (35.9 and 36.4 fmol/mg protein) but did decrease beta 2-adrenoceptors (from 3.7 to 0.3 fmol/mg protein). Chronotropic effects were measured in spontaneously beating right atrium. Procaterol, a selective beta 2-adrenoceptor agonist, caused a biphasic chronotropic response in control right atria, the first part of which was abolished in the tissue from treated animals. The maximum increase in right atrial rate to RO363, a beta 1-adrenoceptor selective partial agonist, was reduced from 114 bpm in control to 43 bpm in treated animals. In electrically driven right atrium with the sinoatrial node removed procaterol failed to produce a positive inotropic response via beta 2-adrenoceptors, but the maximum response to RO363 was reduced from 0.75 g in the control tissue to 0.12 g in the treated tissue. This study showed that changes in beta 2-adrenoceptor density following 7 day (-)-isoprenaline infusion are compatible with reduced functional responsiveness in the SA node. The reduction of beta 1-adrenoceptor number in the SA node was also compatible with the reduced chronotropic response in this tissue. However the lack of effect on beta 1-adrenoceptor density in the right atrium was not consistent with the decrease in beta 1-adrenoceptor mediated inotropic response in this tissue. This suggests that beta-adrenoceptor desensitization is not always associated with receptor down-regulation but depends also on the changes in the cell signalling system beyond the level of the receptor which differ according to the cardiac location.

O-404 - Regulation of calcium transients and isometric contractions by beta-1 adrenoceptor partial agonist denopamine in aequorin-injected dog right ventricular trabeculae

O-404 - Regulation of calcium transients and isometric contractions by beta-1 adrenoceptor partial agonist denopamine in aequorin-injected dog right ventricular trabeculae

Selective beta‐adrenoceptor partial agonist effects of pindolol and xamoterol on skeletal muscle assessed by plasma creatine kinase changes in healthy subjects [see comments

1. The effects of selective beta-adrenoceptor partial agonist activity on plasma creatine kinase (CK) and skeletal muscle symptoms were studied in normal volunteers. 2. A drug with beta 1-selective partial agonist activity (xamoterol) and one with partial agonist activity acting mainly through beta 2-adrenoceptors (pindolol) were each given for 3 weeks in a randomised double-blind crossover study in 10 subjects. Five additional subjects received only one drug. Plasma CK levels were monitored during a baseline placebo run-in phase, the active treatment period and a placebo washout phase which continued until CK levels returned to baseline. 3. The degree of beta-adrenoceptor antagonism was determined by the inhibition of exercise-induced tachycardia and was similar for the two drug doses used. 4. During pindolol administration plasma CK levels rose compared with pretreatment baseline levels and with levels during xamoterol administration which did not rise. After pindolol was withdrawn CK levels reached higher peaks in some subjects after 1-5 days. 5. Muscle cramps were reported by five subjects during pindolol administration and by one of these subjects but to a lesser extent during xamoterol administration. 6. Pindolol may produce this effect, which was not seen with xamoterol, because of its specific beta 2-adrenoceptor partial agonist activity. Elevations in plasma CK produced by this type of drug or its withdrawal may cause confusion in the diagnosis of muscle disease or myocardial infarction unless the myocardial isoenzyme is measured.

Pharmacokinetics of epanolol after acute and chronic oral dosing in elderly patients with stable angina pectoris.

1. Epanolol is a novel anti-anginal agent which is a beta 1-adrenoceptor partial agonist exhibiting selective beta 1-adrenoceptor antagonist and selective beta 1-adrenoceptor agonist activity. It is mainly metabolised to conjugates prior to excretion in urine and it was of interest to determine if any accumulation occurred in elderly patients. 2. The pharmacokinetics of epanolol have been studied over 72 h after a single oral dose of 200 mg and then over 24 h after 12 consecutive daily oral doses in 13 elderly patients with stable angina pectoris. 3. The peak plasma concentrations (mean +/- s.d.) after the single dose (25.7 +/- 17.0 ng ml-1) were not significantly different (P = 0.35) from those at steady state (32.4 +/- 20.9 ng ml-1). There was wide inter-individual variation on both occasions. The time to peak did not alter significantly during the study with mean values of 1.5 and 1.2 h on acute and chronic dosing respectively. 4. Plasma concentrations declined biphasically with a mean terminal phase half-life of 17 h and 5 fold inter-individual variation. 5. The mean area under the curve to 24 h was not significantly different (P = 0.26) after the single dose (59.0 +/- 29.8 ng ml-1 h) from that at steady state (78.4 +/- 55.0 ng ml-1 h). There was also wide inter-individual variation in these values. 6. In conclusion, the lack of significant accumulation of epanolol indicates that no alteration of dose is necessary when using epanolol in elderly patients with normal renal and hepatic function.

Selective Beta-1-Adrenoceptor Partial Agonist Treatment for Congestive Heart Failure

Xamoterol is a beta-adrenoceptor partial agonist which selectively acts at the beta 1-receptors of the heart. The partial agonist effect modestly increases myocardial contractility and appears also to improve diastolic function and cardiac output without an increase in myocardial oxygen demand. Improved myocardial performance is maintained during exercise while increased heart rate is attenuated. Partial agonist activity protects against tachyphylaxis and arrhythmogenicity. With chronic treatment, exercise duration and work capacity increase and clinical manifestations of heart failure are reduced.

Lack of Tolerance Development after Long-Term Administration of the Partial Beta-Adrenoceptor Agonist Xamoterol

Xamoterol is a selective partial beta-adrenoceptor agonist. In a double-blind randomized placebo-controlled study, 30 patients (1 female, 29 male) with mild to moderate heart failure were treated with 200 mg of xamoterol twice daily or placebo during 3 months. At baseline and 72 h after the last tablet intake, the hemodynamic and humoral effects of a single intravenous dose of xamoterol (0.2 mg/kg) were assessed by right heart catheterization. At baseline, intravenous xamoterol raised resting heart rate by 3% (NS) in the placebo and by 6% (NS) in the xamoterol group. On exercise, heart rate was reduced by 10% (p = 0.015) and 7% (p = 0.016), respectively. Pulmonary capillary wedge pressure (PCWP) dropped in both groups: at rest by 4 mm Hg (p = 0.0004) in the placebo group and by 6 mm Hg (p = 0.0002) in the xamoterol group; on exercise by 1 mm Hg (NS) in the placebo and by 6 mm Hg (p = 0.0001) in the xamoterol group. Similar changes of all variables were obtained after long-term therapy in both groups. Mean arterial blood pressure, cardiac index and systemic vascular resistance did not change importantly. Norepinephrine levels did not change, but plasma renin activity decreased at baseline as well as after long-term therapy in both groups by similar amounts. Thus, no signs of tolerance development were observed after an oral treatment with 200 mg of xamoterol twice daily during 3 months. However, xamoterol as a partial agonist exerted only weak changes of cardiac index and PCWP compared to full beta-adrenoceptor agonists. The drug was well tolerated, and serious side effects were absent.

The pharmacokinetics of xamoterol in liver disease.

The pharmacokinetics of xamoterol, a beta 1-adrenoceptor partial agonist, have been studied in patients with liver disease and a group of age- and sex-matched normal controls. No significant differences were observed after the oral administration of xamoterol 200 mg. The low bioavailability of xamoterol was confirmed (6.1% in patients, 6.9% in controls). After i.v. xamoterol 0.2 mg kg-1, no significant differences between the groups were observed. A small increase in the terminal plasma elimination half-life (t1/2) was observed in patients when compared with controls (15.3 +/- 6.4 vs 8.4 +/- 2.8 h, mean +/- s.d., P = 0.08). Renal clearance accounted for about 50% of total clearance in patients and about 30% in controls. It is suggested that in patients with heart failure, hepatic dysfunction would probably not influence xamoterol disposition.

Modulation of the autonomic control of the failing heart

The failing heart operates with an abnormal combination of heart rate, stroke volume, and enddiastolic volume. This mismatch becomes more evident during exercise of patients with heart failure, when an increase in cardiac output is achieved with higher heart rate, a lower stroke volume and a higher enddiastolic volume. Using the beta 1-adrenoceptor partial agonist xamoterol which lacks beta 2-adrenoceptor agonism the response of the heart to sympathetic stimulation can be modulated. At rest and low levels of exercise xamoterol provides an inotropic support of the heart, whereas it reduces inappropriate tachycardia at higher levels. Thereby, xamoterol tends to normalize the balance of the inotropic and chronotropic control of the failing heart, because cardiac output is increased with a more normal combination of heart rate, stroke volume, and filling pressure. The beneficial effects of xamoterol are discussed as being especially important for failing ischemic hearts, because the balance between energy supply and energy demand may be improved by xamoterol.

Effects of long-term xamoterol therapy on the left ventricular mechanical efficiency in patients with ischemic heart disease

Myocardial oxygen uptake and an index of mechanical left ventricular efficiency were determined in basal conditions or during prolonged therapy with the new beta 1-adrenoceptor partial agonist xamoterol in 16 patients with mild to moderate ischemic heart failure. During xamoterol therapy, left ventricular end-diastolic pressure decreased from 24.4 +/- 6.5 to 17.8 +/- 8.6 mm Hg (P less than 0.01) and the isovolumic index of inotropic state (dP/dt)/DP40 increased by 14% (P less than 0.01). The heart rate increased slightly and the mean systolic and peak systolic wall stress also tended to increase (+ 7%; NS) but myocardial oxygen uptake (14.1 vs 14.7 ml/min; NS) and the index of efficiency (8.77 +/- 3.44 to 8.82 +/- 4.27; NS) were not significantly modified. In conclusion, prolonged therapy with xamoterol was not accompanied by a deterioration in the mechanical efficiency of the ventricle, even in patients with ischemic heart disease.

Xamoterol, a beta 1‐adrenoceptor partial agonist: review of the clinical efficacy in heart failure.

1. Xamoterol (Corwin, Carwin, Corwil, Xamtol, ICI 118,587), a beta 1-adrenoceptor partial agonist, improves both systolic and diastolic function in heart failure patients. 2. Double-blind, randomised studies comparing xamoterol with placebo showed that the beneficial haemodynamic effects of xamoterol produced significant improvements in exercise capacity and symptoms in patients with mild to moderate heart failure. These studies formed the basis for a large European multicentre study programme which recruited over 1000 patients, randomised to xamoterol (200 mg twice daily, n = 617), digoxin (0.125 mg twice daily, n = 135) or placebo (n = 300) for 3 months. 3. Efficacy was assessed by measuring exercise capacity and symptoms. The xamoterol group improved exercise capacity by 37% compared with an 18% improvement in the placebo group. Differences in the symptom scores measured by visual analogue scales and Likert scores indicated significant improvements by xamoterol in the cardinal symptoms of heart failure, dyspnoea and fatigue. 4. Analyses of data from subsets of patients in the study showed that elderly patients, patients on no other heart failure therapy and patients with cardiomegaly all had similar improvements in exercise and symptoms to those seen in the whole study population. In the subset which included digoxin treatment, xamoterol produced significantly greater improvements in exercise capacity than digoxin (33% vs 17%, P less than 0.05) and was associated with fewer side-effects. 5. Xamoterol is therefore a promising addition to heart failure therapies currently available.

Effect of beta‐adrenoceptor agents on the blood flow in carotid arteries in normal volunteers.

The effects on carotid artery blood flow of atenolol (a selective beta 1-adrenoceptor antagonist) and xamoterol (a beta 1-adrenoceptor partial agonist with 43% agonist activity) were measured using a Doppler technique in eight healthy volunteers. Atenolol produced a decrease in blood pressure and blood velocity flow, and tended to reduce volume flow. In contrast, there were no changes with xamoterol or placebo. Beta 1-adrenoceptor blockade may reduce cerebral blood flow but the partial agonist xamoterol does not appear to reduce carotid blood flow.

Focus on diastolic dysfunction: a new approach to heart failure therapy.

1. Although heart failure is commonly associated with depressed systolic function, there is increasing evidence that impaired diastolic performance is also universally present and might be a key determinant of symptoms, physical capacity and even survival in some subsets of patients. 2. Reduced diastolic distensibility increases cardiac filling pressure not only at rest, but even more during exercise when diastolic filling time is reduced. The increases in filling pressure and diastolic wall stress lead to pulmonary congestion and subendocardial ischaemia, it also triggers myocardial hypertrophy and a detrimental remodelling of the ventricular cavity. Perhaps even more importantly, impaired ventricular distensibility limits the use of the Frank-Starling mechanism, impairing systolic pump function and cardiac output adaptation during exercise. Therapies able to improve the distensibility of the ventricle are, therefore, desirable in heart failure. 3. Nitrates, angiotensin converting enzyme (ACE) inhibitors and diuretics may indirectly increase left ventricular chamber compliance by their effects on the right side of the heart. Cardiac glycosides do not improve myocardial relaxation and may even cause diastolic contracture at toxic doses. The new beta 1-adrenoceptor partial agonist, xamoterol, on the other hand, consistently lowers left ventricular filling pressure at rest and during exercise, and produces an increase in left ventricular dynamic compliance through the direct lusitropic effect of beta 1-adrenoceptor stimulation. These beneficial effects are maintained during prolonged therapy and also appear sufficient to slow the remodelling of the ventricular cavity. The improvement in symptoms and in exercise tolerance observed during xamoterol (Corwin, Carwin, Corwil, Xamtol, ICI 118,587) therapy might, therefore, be related to the improvement in left ventricular diastolic distensibility induced by this drug.

Long‐term studies with xamoterol in heart failure.

1. Xamoterol (Corwin, Carwin, Corwil, Xamtol, ICI 118,587) is a beta 1-adrenoceptor partial agonist which, unlike full beta-adrenoceptor agonists, does not down-regulate beta-adrenoceptors in the rat ventricle during chronic administration. 2. Improvements in myocardial performance have been demonstrated following acute administration of xamoterol to patients with mild or moderate heart failure, and these are sustained during at least 1 year of continued treatment. 3. Exercise duration is increased by xamoterol in patients with left ventricular dysfunction and benefit is still apparent after at least 1 year of therapy. 4. Despite sustained cardiac stimulation, xamoterol does not appear to affect adversely mortality in patients with mild or moderate heart failure. 5. Few adverse events directly attributable to xamoterol were reported during 3 month efficacy studies in more than 600 patients, and the laboratory safety profile over 1 year of treatment is good. 6. Xamoterol is a promising, well-tolerated addition to established therapies for chronic mild or moderate heart failure.