Increased exercise ejection fraction and reversed remodeling after long-term treatment with metoprolol in congestive heart failure: a randomized, stratified, double-blind, placebo-controlled trial in mild to moderate heart failure due to ischemic or idiopathic dilated cardiomyopathy.

BACKGROUND: the effects of long-term administration of beta-blockers on left ventricular (LV) function during exercise in patients with ischemic heart disease (IHD) and idiopathic dilated cardiomyopathy (DCM) are controversial. PATIENTS AND METHODS: patients with stable congestive heart failure (CHF) (New York heart association [NYHA] class II and III) and ejection fraction (EF) < or =0.40 were randomized to metoprolol, 50 mg t.i.d. or placebo for 6 months. Patients were divided into two groups: ischemic heart disease (IHD) and idiopathic dilated cardiomyopathy (DCM). The mean EF was 0.29 in both groups and 92% were taking angiotensin-converting enzyme (ACE) inhibitors. In the IHD group, 84% had suffered a myocardial infarction (MI) and 64% had undergone revascularization at least 6 months before the study. LV volumes were measured by equilibrium radionuclide angiography. Mitral regurgitation was assessed by Doppler echocardiography. All values are changes for metoprolol subtracted by changes for placebo. RESULTS: metoprolol improved LV function markedly both at rest and during sub-maximal exercise in both groups. The mean increase in EF was 0.069 at rest (P<0.001) and 0.078 during submaximal exercise (P<0.001). LV end-diastolic volume decreased by 22 ml at rest (P=0.006) and by 15 ml during exercise (P=0.006). LV end-systolic volume decreased by 23 ml both at rest (P=0.001) and during exercise (P=0.004). Exercise time increased by 39 s (P=0.08). In the metoprolol group, mitral regurgitation decreased (P=0.0026) and only one patient developed atrial fibrillation vs. eight in the placebo group (P=0.01). CONCLUSION: metoprolol improves EF both at rest and during submaximal exercise and prevents LV dilatation in mild to moderate CHF due to IHD or DCM.

Combination therapy with metoprolol and nifedipine versus monotherapy in patients with stable angina pectoris. Results of the International Multicenter Angina Exercise (IMAGE) Study.

OBJECTIVES: This study was designed to investigate whether combination therapy with metoprolol and nifedipine provides a greater anti-ischemic effect than does monotherapy in individual patients with stable angina pectoris. BACKGROUND: Combination therapy with a beta-adrenergic blocking agent (which reduces myocardial oxygen consumption) and a dihydropyridine calcium antagonist (which increases coronary blood flow) is a logical approach to the treatment of stable angina pectoris. However, it is not clear whether, in individual patients, this combined therapy is more effective than monotherapy. METHODS: Two hundred eighty patients with stable angina pectoris were enrolled in a double-blind trial in 25 European centers. Patients were randomized (week 0) to metoprolol (controlled release, 200 mg once daily) or nifedipine (Retard, 20 mg twice daily) for 6 weeks; placebo or the alternative drug was then added for a further 4 weeks. Exercise tests were performed at weeks 0, 6 and 10. RESULTS: At week 6, both metoprolol and nifedipine increased the mean exercise time to 1-mm ST segment depression in comparison with week 0 (both p < 0.01); metoprolol was more effective than nifedipine (p < 0.05). At week 10, the groups randomized to combination therapy had a further increase in time to 1-mm ST segment depression (p < 0.05 vs. placebo). Analysis of the results in individual patients revealed that 7 (11%) of 63 patients adding nifedipine to metoprolol and 17 (29%) of 59 patients (p < 0.0001) adding metoprolol to nifedipine showed an increase in exercise tolerance that was greater than the 90th percentile of the distribution of the changes observed in the corresponding monotherapy + placebo groups. However, among these patients, an additive effect was observed only in 1 (14%) of the 7 patients treated with metoprolol + nifedipine and in 4 (24%) of the 17 treated with nifedipine + metoprolol. CONCLUSIONS: The mean additive anti-ischemic effect shown by combination therapy with metoprolol and nifedipine in patients with stable angina pectoris is not the result of an additive effect in individual patients. Rather, it may be attributed to the recruitment by the second drug of patients not responding to monotherapy.

Selection of medical treatment in stable angina pectoris: results of the International Multicenter Angina Exercise (IMAGE) Study.

OBJECTIVES: The present study was designed to investigate which characteristics of anginal symptoms or exercise test results could predict the favorable anti-ischemic effect of the beta-adrenergic blocking agent metoprolol and the calcium antagonist nifedipine in patients with stable angina pectoris. BACKGROUND: The characteristics of anginal symptoms and the results of exercise testing are considered of great importance for selecting medical treatment in patients with chronic stable angina pectoris. However, little information is available on how this first evaluation may be used to select the best pharmacologic approach in individual patients. METHODS: In this prospective multicenter study, 280 patients with stable angina pectoris were enrolled in 25 European centers. After baseline evaluation, consisting of an exercise test and a questionnaire investigating patients' anginal symptoms, the patients were randomly allocated to double-blind treatment for 6 weeks with either metoprolol (Controlled Release, 200 mg once daily) or nifedipine (Retard, 20 mg twice daily) according to a parallel group design. At the end of this period, exercise tests were repeated 1 to 4 h after drug intake. RESULTS: Both metoprolol and nifedipine prolonged exercise tolerance over baseline levels; the improvement was greater in the patients receiving metoprolol (p < 0.05). Multivariate analysis revealed that low exercise tolerance was the only variable associated with a more favorable effect within each treatment group. Metoprolol was more effective than nifedipine in patients with a lower exercise tolerance or with a higher rate-pressure product at rest and at ischemic threshold. None of the characteristics of anginal symptoms or exercise test results predicted a greater efficacy of nifedipine over metoprolol. CONCLUSIONS: The results of a baseline exercise test, but not the characteristics of anginal symptoms, may offer useful information for selecting medical treatment in stable angina pectoris.

Use of beta-adrenoceptor blockers in patients with congestive heart failure.

The beneficial effect of chronic beta-blockade in patients with congestive heart failure has been repeatedly shown since its introduction into treatment for this condition in 1975. Still this kind of therapy remains controversial, it is sometimes regarded as a therapeutic paradox, and its use is mainly limited to specialist centers. Various favorable effects of beta-blockers in patients with heart failure due to idiopathic dilated cardiomyopathy and ischemic heart disease have been demonstrated, the principal among them being reduction in energy requirements and ischemia, antiarrhythmogenic effect, improvement of diastolic function, protection of myocytes against catecholamine overload, centrally mediated increase in vagal tone, upregulation of beta-adrenergic receptors, and possible blockade of autoantibodies against beta 1-receptors. Although most of the studies used metoprolol, these effects may be relevant to certain other beta-blockers. Despite very solid pathophysiological and pharmacological rationales for the use of beta-blockade, a major obstacle for a general acceptance of this therapeutic concept is the striking contrast between hemodynamic changes during the acute effect and long-term treatment. When titrated carefully from very low doses and used with a true commitment to long-term treatment, beta-blockers have been shown to prevent further deterioration of heart failure and to improve hemodynamics, exercise tolerance, quality of life, and prognosis.

Developmental changes in the acetylcholine influence on heart muscle of Rana catesbeiana: in situ and in vitro effects.

The influence of acetylcholine (ACh) on cardiac performance of larval (Taylor Kollros [TK] stages II-XVIII) and postmetamorphic (3-609 g) Rana catesbeiana was analyzed in situ (circulatory system intact) and in vitro (isolated heart or ventricular strip preparations). Topical application of ACh to the heart in situ resulted in a dose-dependent decrease in heart rate and in a slight decrease in systolic ventricular pressure in all developmental stages. Injection of acetylcholine into the ventricle lumen in situ caused a dose-dependent transient decrease in systolic ventricular pressure, with little heart rate effect. Intraventricular ACh injection also changed the hemodynamic coupling between ventricle and conus arteriosus, generating a biphasic pressure profile in the conus due to sequential contractions of the ventricle and of the conus. In situ the sensitivity of the ventricle to ACh decreased during larval development, with the lowest sensitivity in small postmetamorphic adults. ACh applied in vitro to cardiac muscle strips or small hearts produced a negative inotropic effect. The ACh dose necessary to induce a 50% reduction in muscle strip contraction force in vitro decreased substantially during larval development, indicating an increase in ACh sensitivity with development. The effects of ACh both in vitro and in situ were diminished or eliminated by topical application or injection of atropine, suggesting the presence of muscarinic cholinergic receptors. After preincubation with the acetylcholinesterase blocker eserine, injection of ACh into the conus arteriosus decreased systolic ventricular pressure with a delay of 4-10 seconds, probably representing the minimum blood circulation time.(ABSTRACT TRUNCATED AT 250 WORDS)

Transient myocardial ischemia during daily life in rest and exertional angina pectoris and comparison of effectiveness of metoprolol versus nifedipine.

The clinical characteristics of 65 patients with mixed angina were classified by means of (1) a questionnaire investigating the proportion of symptoms occurring at rest and on effort, (2) an exercise stress test, (3) 24-hour ambulatory Holter monitoring, and (4) coronary arteriography. According to the questionnaire, the proportion of effort-induced anginal episodes ranged from 1 to 99%. The ischemic threshold during exercise testing ranged from 110 x 10(2) to 350 x 10(2) mm Hg x beats/min. At least 1 episode of ST-segment depression was observed in 29 of the 65 patients during Holter monitoring. Ischemic episodes during Holter monitoring were more frequent (p less than 0.05) in patients reporting greater than or equal to 50% of anginal attacks on effort, with moderate to severe limitation of exercise capacity and with multivessel coronary artery disease. The effect on ambulatory ischemia of a 6-week treatment with a beta blocker (metoprolol CR, 200 mg once daily) or a dihydropyridine calcium antagonist (nifedipine retard 20 mg twice daily) were then compared according to a double-blind, parallel group design. Metoprolol significantly reduced the number and duration of the ischemic episodes during daily life (p less than 0.05) irrespective of the patients' clinical characteristics. Nifedipine was ineffective, particularly in patients with angina predominantly on effort and with a moderate to severe reduction in exercise tolerance. It is concluded that in patients with mixed angina, ischemic episodes during daily life are more likely to occur in patients with a clinical presentation suggesting poor coronary reserve.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular regulation in the mudpuppy Necturus maculosus at rest and during short term exercise.

Prebranchial blood pressure (Pva), heart rate (fH) and plasma catecholamine concentration were measured in the mudpuppy Necturus maculosus at rest and during exercise. During exercise, both fH and Pva increased, as did the plasma noradrenaline concentration. There was no significant effect on Pva after injection of the adrenergic neuron blocker, bretylium, in resting animals, neither did bretylium affect the exercise-induced increase in Pva. This suggests that there is no adrenergic nervous tone on the vasculature at rest or during exercise. The alpha-adrenoceptor antagonist yohimbine had no effect on the resting Pva in the bretylium-treated animals, but it abolished the increase in Pva during exercise. This is compatible with the view of no influence on Pva by the plasma catecholamines at rest, while during exercise the increase in plasma noradrenaline concentration is responsible for the increase in Pva. Injection of atropine elevated resting fH, and reduced or abolished cardiac arrythmia, indicating an inhibitory cholinergic tone on the heart at rest, and that variations in this tone are responsible for the intrinsic variation seen in untreated animals. After the atropine treatment, there was still an increase in fH during exercise. The beta-adrenoceptor antagonist sotalol decreased fH in resting atropinized animals, and inhibited the exercise-induced tachycardia, implying that there is an additional beta-adrenoceptor-mediated adrenergic tone, affecting the heart both at rest and during exercise. The cholinergic tone decreased during exercise with a concomitant increase in adrenergic tone. Falck-Hillarp fluorescent histochemistry was used to study the presence of adrenergic nerve fibres and other catecholamine-storing cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Autonomic influences on heart rate and blood pressure in the toad, Bufo marinus, at rest and during exercise.

Blood pressure (PA) and heart rate (HR) were measured in the conscious, resting toad, Bufo marinus. Treatment with bretylium (an adrenergic neurone blocking agent), alone or in combination with phentolamine and propranolol (adrenoceptor antagonists) did not alter PA or HR significantly. Atropine caused a small but significant increase in HR but had no effect on PA. The experiments indicate a cholinergic cardio-inhibitory tone but give no evidence for an adrenergic pressor tone at rest. Treadmill exercise caused a rapid increase in PA and HR which was sustained throughout the exercise period. This response was partly psychogenic. The concentration of plasma catecholamines increased during exercise and was high enough to affect organs that were included in an extracorporeal blood circuit with the exercising animal. Bretylium treatment revealed an initial hypotension, presumably due to work hyperaemia, followed by a hypertension which was reduced compared to controls. The tachycardia was delayed but HR eventually reached control levels. Additional treatment with phentolamine and propranolol did not further affect the PA response, but significantly reduced the tachycardia reached during exercise. It is concluded that the cardiovascular responses to exercise involve adrenergic nerve fibres causing hypertension and an initial rapid tachycardia. Circulating catecholamines seem to be the major cause of the sustained tachycardia.

Nervous control of the blood pressure in the Atlantic cod, Gadus morhua.

Dorsal (PDA) and ventral aortic blood pressure (PVA) and heart rate (HR) were measured in conscious resting cod, Gadus morhua L., which has been allowed 24 h recovery from surgery. Plasma adrenalin and nonadrenalin concentrations in these fish were 3.4 and 2.2 nmoll-1 respectively, and thus lower than previously reported values from partially recovered cod. Twenty-four hours after treatment with the adrenergic neurone blocking agent bretylium, PDA was significantly reduced by 17% compared to sham-injected controls, although PVA and heart rate were unaltered. Subsequent alpha-adrenoceptor blockade by phentolamine produced no further fall in PDA and no changes in PVA or HR, provided a 5-h period was allowed to overcome the acute toxic side effects of phentolamine. The effectiveness of the bretylium or phentolamine blockade was confirmed by noting the absence of any vasoconstrictor response during sympathetic nerve stimulation in perfused tails from fish used in the in vivo experiments. Bretylium had no significant effect on the sensitivity of the isolated coeliac artery to adrenalin, but effectively blocked the adrenergic innervation of this artery or the vasculature of the tail. Evidence for a non-selective blockade of non-adrenergic nerves to the heart was also obtained. It is concluded that the adrenergic tonus affecting the dorsal aortic blood pressure in resting cod that have recovered for 24 h following surgery is due solely to an adrenergic nervous tone.

Physiological evidence for peripheral ganglionic synapses in adrenergic pathways to the swimbladder of the Atlantic cod, Gadus morhua.

Effects of sympathetic and vagosympathetic nerve stimulation on the swimbladder of the cod (Gadus morhua) were studied in situ. Adrenergic nerves mediated vasoconstriction in the saline-perfused gas gland and opening of the oval. Chlorisondamine was used to locate ganglionic synapses in the adrenergic pathways. Ganglionic relays in most sympathetic vasoconstrictor pathways lay in the coeliac ganglion. A few sympathetic and all vagosympathetic vasoconstrictor pathways had peripheral relays, probably in the swimbladder nerve ganglion. Vagosympathetic pathways causing oval opening had central relays, probably in the sympathetic chain.

Ultrastructure and adrenergic innervation of preglomerular arterioles in the euryhaline teleost, Salmo gairdneri.

The opisthonephric kidney of the rainbow trout was investigated by light- and electron microscopy and a fluorescent-histochemical technique for biogenic amines was used. Preglomerular sphincters at the origin of afferent arterioles are present in this euryhaline teleost. The branching point of the afferent arteriole is characterized by (i) the formation of a right angle with the parent vessel, (ii) circularly arranged smooth muscle cells of the tunica media, (iii) additional circularly arranged smooth muscle cells intercalated between endothelium and tunica media, and (iv) a collar-like arrangement of several large endothelial cells with elaborate marginal folds and abundant myoendothelial junctions. A dense adrenergic innervation displaying specific fluorescence was found along the terminal arterioles and afferent arterioles, and conspicuously at the preglomerular sphincters. These results are suggestive of a neural participation in kidney function. They are discussed on the basis of recent evidence from pharmacological and physiological experiments for neural involvement in glomerular intermittency.

Effects of hypophysectomy and cortisol on the catecholamine biosynthesis and catecholamine content in chromaffin tissue from rainbow trout, Salmo gairdneri.

The in vitro activities of dopamine beta-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT) were determined in the chromaffin tissue of hypophysectomized and cortisol-treated rainbow trout, Salmo gairdneri. In addition, the content of adrenaline and noradrenaline was estimated. DBH activity increased after both hypophysectomy and cortisol administration. The increased activity after hypophysectomy was restored with administration of pituitary extract, ADP. The PNMT activity seemed to increase slightly after hypophysectomy, while the activity remained unchanged after cortisol administration. A small decrease in catecholamine content was seen after hypophysectomy or treatment with cortisol but the A/NA ratio was not changed. A regulation of the biosynthesis of catecholamines in trout chromaffin tissue is suggested and discussed in relation to mammalian conditions.