PI 3-kinase, protein kinase C, and protein kinase A are involved in the trigger phase of beta1-adrenergic preconditioning.

OBJECTIVE: Using an isolated non-working rat heart model, this study investigated the mechanisms of pharmacological preconditioning (PC) induced by transient beta1-adrenoreceptor (beta1-AR) stimulation with xamoterol (XA). METHODS: After 6-hydroxydopamine (6-OHDA) pretreatment and a 20-min stabilization period, hearts were perfused at constant pressure for 20 min then subjected to 40 min of global ischemia and 30 min of reperfusion (I/R, Ctrl); exposed to 0.01 microM XA for 5 min with or without 10 microM atenolol (ATE), a specific antagonist of beta1-AR, followed by a 15-min XA-free perfusion before I/R (PC, ATE-PC, respectively); treated during 20 min with either phosphoinositide (PI) 3-kinase inhibitors, LY-294002 (LY, 15 microM), or wortmaninn (WO, 0.1 microM); protein kinase C (PKC) inhibitor, GF-109203X (GF, 4 nM); or protein kinase A (PKA) inhibitor, H89 (H89, 1 microM), with an infusion starting 3 min before XA (LY-PC, WO-PC, GF-PC, and H89-PC, respectively). The main endpoints were the mean coronary flow (MCF), the left ventricular end-diastolic pressure (LVEDP), rate-pressure product (RPP), and creatine kinase (CK) release. RESULTS: XA induced an increase in the MCF after I/R (t 105 min) and a protective effect on the LVEDP, which were blocked by ATE and abolished with the different inhibitors. The transient increase in RPP following XA infusion was blocked by ATE and was not modified by the inhibitors except for H89. Recovery of RPP, measured 25 min after reperfusion, was improved by XA, blocked by ATE, and decreased with the different inhibitors. Fifteen minutes after the end of ischemia, CK release reached maximal values in all groups. XA provided significant protection whereas ATE and the four inhibitors suppressed XA-induced protection. CONCLUSION: The transient preischemic exposure to nanomolar concentrations of a beta1-AR agonist is protective against I/R. PI 3-kinase, PKC, and PKA are implicated in the trigger phase of PC. These observations were confirmed by Western blots.

Cardioselective beta-blockers for reversible airway disease.

BACKGROUND: Beta-blocker therapy has mortality benefit in patients with hypertension, heart failure and coronary artery disease, as well as during the perioperative period. These drugs have traditionally been considered contraindicated in patients with reversible airway disease. OBJECTIVES: To assess the effect of cardioselective beta1-blockers on respiratory function of patients with reversible airway disease. Reversible airway disease was defined as asthma or chronic obstructive pulmonary disease with a reversible obstructive component. SEARCH STRATEGY: A comprehensive search of EMBASE, MEDLINE and CINAHL was performed using the Cochrane Airways Group registry to identify randomized blinded placebo-controlled trials from 1966 to May 2001. The search was completed using the terms: asthma*, bronchial hyperreactivity*, respiratory sounds*, wheez*, obstructive lung disease* or obstructive airway disease*, and adrenergic antagonist*, sympatholytic* or adrenergic receptor block*. We did not exclude trials on the basis of language. SELECTION CRITERIA: Randomized, blinded, placebo-controlled trials of single dose or longer duration that studied the effects of cardioselective beta1-blockers on the forced expiratory volume in 1 second (FEV1), symptoms and use of short-acting inhaled beta2-agonists, in patients with reversible airway disease. Reversible airway disease was documented by response to methacholine challenge, by an increase in FEV1 of at least 15% to beta2-agonist administration, or the presence of asthma as defined by the American Thoracic Society. DATA COLLECTION AND ANALYSIS: Two independent reviewers extracted data from the selected articles, reconciling differences by consensus. Cardioselective beta1-blockers were divided into 2 groups, those with or without intrinsic sympathomimetic activity (ISA). Two interventions studied were the administration of beta1-blocker, given either as a single dose or for longer duration, and the use of beta2-agonist given after the study drug. MAIN RESULTS: Nineteen studies for single-dose treatment and 10 for treatment of longer duration met selection criteria. The patients had mild-moderate airways obstruction. For cardioselective beta1-blockers taken as a group, administration of a single dose was associated with a 7.98% (CI, 6.19 to 9.77%) reduction in FEV1, but with a 13.16% (CI, 10.76 to 15.56%) increase in beta2-agonist response, as compared to placebo. There was no increase in symptoms. After treatment lasting a few days to a few weeks, there was no decrement in FEV1 compared to placebo and no increase in symptoms or inhaler use. Regular use of cardioselective beta1-blockers without ISA produced a 13.13% (CI, 5.97 to 20.30) increase in beta2-agonist response compared to placebo, a response not seen with beta1-blockers containing ISA (-0.60% [CI, -11.7 to +10.5%]). REVIEWER'S CONCLUSIONS: Cardioselective beta1-blockers, given to patients with mild-moderate reversible airway disease, do not produce clinically significant adverse respiratory effects in the short term. It is not possible to comment on their effects in patient with more severe or less reversible disease, or on their effect on the frequency or severity of acute exacerbations. Given their demonstrated benefit in conditions such as heart failure, coronary artery disease and hypertension, cardioselective beta1-blockers should not be withheld from patients with mild-moderate reversible airway disease.

The underreporting of results and possible mechanisms of 'negative' drug trials in patients with chronic heart failure.

Large drug trials have become very important to determine which drugs should be used in the treatment of patients with chronic heart failure (CHF). When these trials showed "positive" results, publication of the data soon followed, leading to a substantial impact on prescription patterns. In the case of "negative" results, many times they were not published, or were reported as an abstract or as short paper disclosing only the main findings. In this article we will discuss some of these trials that were conducted in the last 10 years, since we believe they may provide insight into the pathophysiology and treatment options in CHF.

Cardioselective beta-blocker use in patients with reversible airway disease.

BACKGROUND: Beta-blocker therapy has mortality benefit in patients with hypertension, heart failure and coronary artery disease, as well as during the perioperative period. These drugs have traditionally been considered contraindicated in patients with reversible airway disease. OBJECTIVES: To assess the effect of cardioselective beta-blockers on respiratory function of patients with reversible airway disease. Reversible airway disease was defined as asthma or chronic obstructive pulmonary disease with a reversible obstructive component. SEARCH STRATEGY: A comprehensive search of EMBASE, MEDLINE and CINAHL was performed using the Cochrane Airways Group registry to identify randomized blinded placebo-controlled trials from 1966 to February, 2000. The search was completed using the terms: asthma*, bronchial hyperreactivity*, respiratory sounds*, wheez*, obstructive lung disease* or obstructive airway disease*, and adrenergic antagonist*, sympatholytic* or adrenergic receptor block*. We did not exclude trials on the basis of language. SELECTION CRITERIA: Randomized, blinded, placebo-controlled trials of single dose or longer duration that studied the effects of cardioselective beta-blockers on the forced expiratory volume in 1 second (FEV1), symptoms and use of short-acting inhaled beta-agonists, in patients with reversible airway disease. Reversible airway disease was documented by response to methacholine challenge, by an increase in FEV1 of at least 15% to beta-agonist administration, or the presence of asthma as defined by the American Thoracic Society. DATA COLLECTION AND ANALYSIS: Two independent reviewers extracted data from the selected articles, reconciling differences by consensus. Cardioselective beta-blockers were divided into 2 groups, those with or without intrinsic sympathomimetic activity (ISA). Two interventions studied were the administration of beta-blocker, given either as a single dose or for longer duration, and the use of beta-agonist given after the study drug. MAIN RESULTS: Nineteen studies for single-dose treatment and 10 for treatment of longer duration met selection criteria. The patients had mild-moderate airways obstruction. For cardioselective beta-blockers taken as a group, administration of a single dose was associated with a 7.98% (CI, 6.19 to 9.77%) reduction in FEV1, but with a 13.16% (CI, 10.76 to 15.56%) increase in beta-agonist response, as compared to placebo. There was no increase in symptoms. After treatment lasting a few days to a few weeks, there was no decrement in FEV1 compared to placebo and no increase in symptoms or inhaler use. Regular use of cardioselective beta-blockers without ISA produced a 13.13% (CI, 5.97 to 20.30) increase in beta-agonist response compared to placebo, a response not seen with beta-blockers containing ISA (-0.60% [CI, -11.7 to +10.5%]). REVIEWER'S CONCLUSIONS: Cardioselective beta-blockers, given to patients with mild-moderate reversible airway disease, do not produce clinically significant adverse respiratory effects in the short term. It is not possible to comment on their effects in patient with more severe or less reversible disease, or on their effect on the frequency or severity of acute exacerbations. Given their demonstrated benefit in conditions such as heart failure, coronary artery disease and hypertension, cardioselective beta-blockers should not be withheld from patients with mild-moderate reversible airway disease.

Effects of beta receptor antagonists on left ventricular function in patients with clinical evidence of heart failure after myocardial infarction. A double-blind comparison of metoprolol and xamoterol. Echocardiographic results from the Metoprolol and Xamoterol Infarction Study (MEXIS).

Two hundred and ten patients with clinical evidence of heart failure, developing after an acute myocardial infarction, were randomized to treatment with the beta 1-receptor antagonist metoprolol 50-100 mg b.i.d. (n = 106) or the beta 1-receptor partial agonist xamoterol 100-200 mg b.i.d. (n = 104). Left ventricular systolic and diastolic function were assessed with echocardiography and transmitral Doppler cardiography before and after 3 and 12 months of double-blind treatment. E-point septal separation and percent left ventricular fractional shortening were used as indices of systolic function. The ratio between peak early and late mitral diastolic flow (E/A ratio) and isovolumic relaxation time were used as indices of diastolic function. In the xamoterol group, there was a deterioration in E-point septal separation (P < 0.05). A difference between the treatment groups was present both at 3 months (E-point septal separation 11.4 vs 13.0 mm, P < 0.01, fractional shortening 27.1 vs 25.2%, P < 0.05) and 12 months (E-point septal separation 11.1 vs 13.2 mm. P < 0.005, fractional shortening 26.9 vs 25.0%, P < 0.05). E/A ratio increased in the metoprolol group (P < 0.05) but not in the xamoterol group. At 3 months there was a significant difference (0.85 vs 0.67, P < 0.005) between the groups but not at 12 months. In comparison with the beta 1-receptor antagonist metoprolol, the beta 1-receptor partial agonist xamoterol impaired left ventricular systolic function in patients with clinical evidence of heart failure after an acute myocardial infarction.

Xamoterol improves right ventricular systolic and diastolic function in pulmonary heart disease.

OBJECTIVE: Abnormal right ventricular function in patients with pulmonary heart disease (PHD) may contribute to their reduced exercise capacity. We have evaluated the effect of subacute dosing with xamoterol, a beta-1 adrenoreceptor partial agonist with inotropic properties, on right ventricular function in patients with PHD. PATIENTS: Twelve patients with advanced chronic obstructive pulmonary disease and clinical evidence of PHD received xamoterol 200 mg twice daily or placebo for 7 days in a randomised double-blind crossover study. Right heart krypton-81m radionuclide ventriculography was used to derive right ventricular ejection fraction (RVEF) both at rest and during submaximal exercise, and indices of right ventricular systolic and diastolic function at rest. RESULTS: During treatment with placebo, mean RVEF was 0.53 at rest and was unchanged during exercise. After xamoterol, mean RVEF was 0.55 at rest and increased to 0.59 during exercise. Xamoterol increased right ventricular peak ejection rate from 3.04 to 3.45 EDV.s-1 and mean early diastolic filling rate from 1.00 to 1.20 EDV.s-1. CONCLUSION: Subacute treatment with xamoterol in patients with PHD improves right ventricular systolic and diastolic function at rest and results in a favourable augmentation in right ventricular function during submaximal exercise.

Left ventricular volume in thrombolysed patients with acute anterior myocardial infarction: the effect of captopril and xamoterol.

We measured left ventricular volume in 70 asymptomatic patients after first Q-wave anterior myocardial infarction in order to determine whether ventricular dilatation occurs and whether there is evidence for its attenuation or prevention by treatment with captopril or xamoterol--PRevention Of VEntricular Dilatation?: the PROVED? study. 77% of patients received thrombolytic treatment. Patients were randomised a mean of 11 days after infarction to receive either captopril 25 mg three times daily, xamoterol 200 mg twice daily or matching placebo. After 6 months of treatment, 6 patients from the placebo group (n = 24), 1 from the captopril group (n = 23) and 3 from the xamoterol group (n = 23) had been withdrawn from the study because of clinical complications. Left ventricular volume was measured using magnetic resonance imaging, before randomisation and after 6 months of treatment. Changes in left ventricular end-diastolic and end-systolic volume after 6 months of treatment were defined prospectively as the primary endpoints. Mean initial end-diastolic volume index was 85 (S.D. 19) ml/m2, mean end-systolic volume index was 45 (S.D. 18) ml/m2, and mean ejection fraction was 48 (S.D. 11)% for the whole group. There was no significant change in left ventricular volume index in the placebo or either treatment group after 6 months of treatment. Only minimal left ventricular dilatation was evident at 11 days. No further increase in left ventricular volume occurred after six months and there was no additional benefit from treatment with either captopril or xamoterol.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of beta receptor antagonists in patients with clinical evidence of heart failure after myocardial infarction: double blind comparison of metoprolol and xamoterol.

OBJECTIVE: To evaluate whether xamoterol, a partial agonist, would improve exercise time more than metoprolol in patients with mild to moderate heart failure after a myocardial infarction. DESIGN: Single-centre double blind randomised parallel group comparison of metoprolol 50-100 mg and xamoterol 100-200 mg twice daily. PATIENTS: 210 patients aged 40-80 years (173 men) with clinical evidence of heart failure early after a myocardial infarction. 106 were given metoprolol and 104 xamoterol. MAIN OUTCOME MEASURES: Exercise test results and performance at three months; the exercise test, quality of life, and clinical assessments at baseline (5-7 days after the infarction) and after 3, 6, and 12 months. RESULTS: Exercise time increased at three months by 22% in the metoprolol group and 29% in the xamoterol group, but with no significant difference between the groups. Patients taking xamoterol showed overall non-significantly higher mean values of exercise time achieved with higher heart rates at rest and exercise. Improvements in quality of life, clinical signs of heart failure, and New York Heart Association functional class were seen in both treatment groups over one year, with minor benefits of xamoterol on breathlessness, peripheral oedema, and functional class. Eighteen patients taking metoprolol and 22 taking xamoterol withdrew from the study during one year, with a low mortality, reinfarction rate, and progress of heart failure in both treatment groups. Mean dose from baseline to 3 months was 135 mg metoprolol and 347 mg xamoterol. CONCLUSION: beta 1 Receptor antagonists with or without partial agonist activity are safe to use in mild to moderate heart failure after a myocardial infarction. Exercise tolerance, quality of life, and clinical signs and functional class of heart failure improve, and few patients show deterioration in their condition. Exercise tolerance is no better with xamoterol than metoprolol.

Xamoterol improves the control of chronic atrial fibrillation in elderly patients.

Twenty digitalized elderly patients with chronic atrial fibrillation were randomized into a double-blind cross-over study. None was in overt heart failure and all were taking < 80 mg frusemide daily. They received xamoterol 200 mg b.d. for 2 months with their usual dose of digoxin for 1 month and placebo digoxin for the other month. Twenty-four-hour heart rate analysis was done at baseline and at the end of each treatment period. Compared with baseline digoxin, xamoterol alone significantly increased nocturnal minimum heart rate [85 +/- 17 vs. 62 +/- 9 (mean +/- SD), p < 0.0001] without affecting daytime maximum heart rate (132 +/- 18 vs. 122 +/- 20, p = NS). Compared with baseline digoxin, xamoterol plus digoxin significantly increased nocturnal minimum heart rate (68 +/- 8, p < 0.05) and reduced daytime heart rate (114 +/- 17, p < 0.05). The mean number of pauses > 1.5 s was significantly reduced by xamoterol alone. Walking distance in 6 minutes was 406.1 +/- 27.1 m (mean +/- SE) at baseline and improved significantly on both treatments (450.3 +/- 19.8 on xamoterol; p < 0.02 and 453.7 +/- 19.2 on xamoterol plus digoxin; p < 0.01). No significant change was found in subjective measurements of palpitations, breathlessness and well-being using visual analogue scales. Xamoterol combined with digoxin improves effort tolerance and heart-rate control by reducing diurnal tachycardia and nocturnal bradycardia and pauses.

Preliminary study of the efficacy of xamoterol in bradycardia-tachycardia syndrome.

Following 4 weeks on placebo, eighteen patients with bradycardia-tachycardia syndrome (BTS) were treated with 100 mg xamoterol twice daily for 2-4 weeks. Ambulatory 24 h Holter electrocardiogram recordings showed that xamoterol decreased maximum heart rate from 140 +/- 5.1 to 107 +/- 6 beats min-1 (P < 0.001) during exercise, increased minimum heart rate from 43 +/- 1.7 to 51 +/- 2.4 beats min-1 (P < 0.005) at night and shortened maximum duration of sinus arrest from 3438 +/- 484 to 1767 +/- 202 ms (P < 0.005) in BTS. Symptomatically, patients reported that palpitations were improved and syncopal attacks disappeared. Although the study has the limitation of an open design, effects of treatment were objectively evaluated using Holter monitoring by investigators who reviewed the recordings in a blinded manner. The findings suggest that xamoterol may be useful in the treatment of BTS. Further studies are needed to evaluate fully its therapeutic potential in this condition.

Safety of concomitant potassium-sparing diuretics in angiotensin-converting enzyme inhibitor therapy in severe congestive heart failure. Xamoterol in Severe Heart Failure Study Group.

The safety of concomitant use of angiotensin-converting enzyme (ACE) inhibitors and potassium-sparing diuretics (PSD) in severe heart failure remains a controversial issue. The database of the recently reported double-blind international trial, "Xamoterol in Severe Heart Failure," was investigated to elucidate this question. Of 516 patients with New York Heart Association (NYHA) class III-IV, despite diuretics and ACE inhibitor therapy, 352 were randomized to xamoterol, a beta 1 partial agonist, and 164 were randomized to placebo. During the 13-week study, 28% of all patients (xamoterol, 104; placebo, 42) received potassium-sparing diuretics. All groups were comparable in hemodynamics and dose of other diuretics. At study end, patients with or without PSD showed no significant differences in serum K+ or creatinine, independent of xamoterol or placebo therapy. Mortality rate was consistently lower: 4.6% in patients with PSD and 8.5% in patients without PSD, although statistical significance was not reached. As compared with baseline, K+ values of 6 patients with and 17 patients without PSD had increased by > 5.0 mM at study end (p = NS); 1 patient with and 11 patients without PSD had a creatinine level > 180 microM (p = NS). For 3 patients receiving PSD, and 2 patients not receiving PSD because of renal impairment, study was discontinued because of hyperpotassemia. No significant differences were noted in long and short action or different dosages of ACE inhibitors. PSD may be administered concomitantly with ACE inhibitors, but serum K+ should be monitored as with other diuretics.

In vivo regulation of human cardiac beta-adrenoceptors by a partial agonist as compared with a full antagonist: selective differences in coupling to adenylate cyclase.

Chronic therapy with the beta 1-selective adrenoceptor partial agonist xamoterol is not associated with the tolerance observed with other beta-adrenoceptor agonists. A possible explanation is that xamoterol therapy does not desensitise human cardiac beta-adrenoceptors in vivo. beta-Adrenoceptor density and adenylate cyclase activities were determined in right atrial appendages obtained from 40 patients randomised in a double-blind fashion to receive either xamoterol or atenolol for at least 5 weeks before coronary artery bypass surgery. There was no significant difference in total or subtype beta-adrenoceptor densities, but basal and isoproterenol stimulated adenylate cyclase activity were significantly greater in the atenolol-treated group, as was the intrinsic activity of the beta 2-adrenoceptor partial agonist procaterol, suggesting that chronic therapy with xamoterol does not downregulate human cardiac beta-adrenoceptors in vivo. Coupling of beta-adrenoceptors to adenylate cyclase, predominantly mediated by the beta 2 subtype, is enhanced, however, after therapy with atenolol relative to therapy with xamoterol.

Xamoterol in sinus node disease.

A pharmacological alternative to pace-maker implantation would be useful in some patients with sinoatrial disorder particularly since the single lead ventricular system usually fitted has disadvantages. Xamoterol, a cardioselective beta-receptor partial agonist, has been shown to increase heart rate both in animals and in man. We, therefore, studied the effects of Xamoterol in patients with sinoatrial disease in a double blind, cross-over trial in 10 patients. Mean heart rates and number and duration of pauses were compared during the treatment phases of the trial with Holter monitoring. Mean heart rates were significantly increased between 01:00 h and 05:00 h (P < or = 0.02) and between 05:00 h and 09:00 h (P < or = 0.01) on Xamoterol. The number of sinus pauses were eliminated or reduced on Xamoterol in six patients, but there was an increased frequency in three patients. Xamoterol, therefore, does increase the heart rate and reduce the number of pauses in sinoatrial disorder, but only in some patients.

The xamoterol experience in the treatment of heart failure.

Beta blockers may benefit patients with dilated cardiomyopathy but low output failure can be a problem. Thus a beta 1-selective beta blocker with about 45% intrinsic sympathomimetic activity (ISA), such as xamoterol, was thought to have a desirable pharmacologic profile. Long-term studies of xamoterol in patients with idiopathic dilated cardiomyopathy have shown improved cardiac performance and exercise tolerance, while exercise heart rate, left ventricular ejection fraction, and pulmonary artery wedge pressure were decreased. This improvement in exercise capacity and overall quality of life in patients treated with xamoterol has been confirmed in further controlled trials of patients with mild-to-moderate heart failure (NYHA class I and II). However, in patients with moderate-to-severe heart failure (NYHA class III and IV), mortality was unfavorably influenced by xamoterol. The therapeutic role of xamoterol in patients with heart disease needs further refinement.

Role of the circulating and tissue-based renin-angiotensin system in the development of heart failure: implications for therapy.

The renin-angiotensin system (RAS) is believed to play a central role in the pathophysiology of heart failure. However, there is a wide variability in plasma renin levels in patients with heart failure, and normal plasma renin activity has been documented in patients with mild or compensated disease. Recent evidence has demonstrated the existence of endogenous RAS in a number of tissues associated with cardiovascular homeostasis. It is possible that these tissue RAS are activated in the early stages of heart failure when plasma renin activity is normal, and therefore contribute to the progression of this condition. Angiotensin-converting enzyme (ACE) inhibitors reduce both circulating and tissue RAS activity. They are of symptomatic benefit and reduce the mortality associated with heart failure. A number of large studies initiated to investigate the effects of the ACE inhibitor enalapril in patients with all degrees of heart failure have been published recently. These studies show that addition of this drug to therapy significantly decreases patient morbidity and mortality, an effect which is most likely due to the suppression of circulating and tissue RAS activity this agent affords. The relationship of the profile of hormonal suppression seen with enalapril and drug dosage to observed beneficial effects on morbidity or mortality is unclear. Given the large range of alternative ACE inhibitors available, their variable structure, potency and duration of action, the potential for differences between agents needs further consideration. Although direct comparative studies are rare, there is a body of work suggesting that such differentiation may be present and may be of clinical significance.

Differential effects of beta-adrenoceptor partial agonists in patients with postural hypotension.

The central haemodynamic effects of pindolol and xamoterol have been investigated in patients with postural hypotension. Pindolol is a non-selective beta-adrenoceptor partial agonist, whereas xamoterol is beta 1-selective and possesses a higher degree of agonist activity. The study comprised 16 patients with postural hypotension of different aetiologies. Blood pressure, heart rate and stroke volume were measured in the supine and head-up tilted positions. Left ventricular ejection fraction (LVEF) was measured in the supine position, and vascular resistance, left ventricular volume, and left ventricular contractility were derived. Pindolol and xamoterol were administered intravenously in incremental doses to reach total doses of 0.02 and 0.20 mg.kg-1, respectively. Pindolol showed beta-adrenoceptor antagonistic effects in the supine position through decrements in heart rate from 70 to 66 beats.min-1 and LVEF from 0.57 to 0.52, and reduced mean arterial blood pressure from 103 mm Hg to 93 mm Hg. Xamoterol showed beta-adrenoceptor agonistic effects in the supine position through increments in heart rate from 72 to 90 beats.min-1 and LVEF from 0.58 to 0.66, and raised mean arterial blood pressure from 108 to 123 mm Hg. It is concluded that the degree of agonist activity of a beta-adrenergic agent is of importance if it is given to a patient with postural hypotension.