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Are the clinical benefits of oral prenalterol in ischaemic heart failure due to beta blockade? A six month randomised double blind comparison with placebo.

The clinical effects of the oral beta 1 partial agonist, prenalterol, were investigated in 37 patients (29 male, eight female; mean age 57 years) with chronic ischaemic left ventricular failure using a placebo controlled randomised double blind protocol over six months. All patients were limited by dyspnoea (New York Heart Association class III) despite treatment with digoxin and diuretics. Twenty eight patients completed the protocol. Moderate clinical improvement was seen in the prenalterol group, whereas there was little change in the placebo group. Bicycle exercise capacity increased over six months in the prenalterol and placebo groups but only achieved statistical significance for prenalterol when compared with baseline values. Maximum exercise heart rate was significantly reduced in the prenalterol group compared with placebo. Radionuclide left ventricular ejection fraction at rest and during exercise and cardiothoracic ratio showed no significant improvement in either group over six months. Prenalterol was well tolerated and produced no increase in frequency of angina or ventricular arrhythmias. Prenalterol produced clinical benefits and improved exercise tolerance while reducing exercise heart rate. A moderate placebo response was noted. The apparent beta blocking effect of prenalterol may be as important as the beta 1 agonist effect in producing these benefits. Prenalterol has, however, been withdrawn because of side effects in animals.

Adrenergic beta-Agonists

Effects of prenalterol on beta adrenergic responsiveness and receptors in the cerebral cortex of the rat.

The activity of the beta-adrenoceptor agonist, prenalterol, at beta adrenoceptors in the cerebral cortex of the rat and the effect of chronic intraperitoneal infusion of prenalterol on the biochemical responsiveness and density of cerebral cortical beta adrenoceptors was studied. Whereas isoproterenol caused a four-fold rise in the content of cyclic AMP in slices of cerebral cortex, prenalterol did not produce a significant increase in cyclic AMP. However, prenalterol inhibited the isoproterenol-stimulated increase in cyclic AMP in cortical slices in a concentration-dependent manner. Using an in vivo binding technique, prenalterol (3.8 mg/kg/hr) infused intraperitoneally through osmotic minipumps, penetrated the brain and significantly inhibited the binding of the beta adrenoceptor antagonist, [125I]iodopindolol (125I-IPIN), to cortical beta adrenoceptors. Infusion of prenalterol (3.8 mg/kg/hr) for 7 days resulted in a small (20%), but significant, reduction in the ability of isoproterenol to stimulate maximally the accumulation of cyclic AMP in slices of cerebral cortex. No alteration in the Bmax or KD of the binding of [125I]iodopindolol was observed in homogenates of cortex obtained from prenalterol-treated rats. Furthermore, no change was observed in the binding of the hydrophilic ligand [3H]CGP-12177 in homogenates of cortex. In this study, then, prenalterol exhibited properties in vitro of a beta adrenoceptor antagonist, but did cause modest desensitization of beta adrenoceptor responsiveness when administered continuously in vivo.

Animals

Changes in coronary haemodynamics and myocardial metabolism at rest and during exercise after a cardiotonic drug (prenalterol) in patients with coronary artery disease.

To elucidate the myocardial metabolic and haemodynamic effects of an inotropic drug in patients with coronary artery disease (CAD) without evident congestive heart failure (CHF), the acute effects of prenalterol were studied in nine patients. Patients with documented CAD by leftsided cardioangiography and end-diastolic pressure greater than 15 mm Hg were included in the study. They were examined at rest and during supine exercise at a level just below their anginal threshold before and after prenalterol. At rest, rate pressure product (RPP) increased by 40% (P less than 0.01), cardiac index rose 20% (P less than 0.01), cardiac venous flow (CVF) increased by 18% (P less than 0.05), and myocardial oxygen consumption (MVO2) increased by 20% (P less than 0.05) after prenalterol administration. Despite a decrease in mean pulmonary capillary venous pressure (PCV) of 40% (P less than 0.01), myocardial lactate extraction fell significantly (P less than 0.01) and lactate production was observed in three of nine patients compared to before prenalterol administration. During exercise, RPP increased by 20% (P less than 0.01), cardiac index remained unchanged, CVF increased by 25% (NS) and MVO2 showed a tendency to an increase (NS) after prenalterol administration. Mean PCV pressure decreased by 30% (P less than 0.01). Myocardial lactate extraction was markedly reduced during exercise (P less than 0.01) and five of nine patients showed lactate production compared to that before prenalterol administration. Thus, despite a decrease in left ventricular filling pressure, increased myocardial oxygen demand occurred after acute administration of prenalterol. Prenalterol and probably similar inotropic drugs should be used cautiously in patients with CAD without clinical evidence of congestive heart failure.

Catheterization, Swan-Ganz

Different effects of acute intravenous administration of k-strophanthidin and prenalterol on the diastolic phase of left ventricular function in patients with coronary arterial disease.

In 21 patients with coronary arterial disease, and with maintained (or mildly depressed) systolic function, we studied the effects of two well-known inotropic agents, namely prenalterol and k-strophanthidin, on the diastolic phase. Selected variables of both systolic and diastolic function were assessed at controlled heart rate by cardiac catheterization and left ventriculography before and after acute intravenous administration of the beta 1 agonist prenalterol (35 micrograms/kg for 3 min) and of k-strophanthidin (0.008 mg/kg for 5-10 min). Ten patients received prenalterol, and 11 patients were injected with k-strophanthidin. Administration of prenalterol induced a remarkable diminution of end-systolic volume index (mean values from 41.8 +/- 11.9 to 32.2 +/- 10.4), while k-strophanthidin showed only a tendency towards a decrease (mean values from 43.4 +/- 13.2 to 40.7 +/- 15.1). After k-strophanthidin, we did not observe any significant changes in the peaks of maximal rate in volumetric increase during filling phase whereas, after prenalterol, a noteworthy increase of the first peak was accompanied by a significant decrease of the second peak. The lowest and end filling left ventricular pressures were decreased by prenalterol (mean values from -0.8 +/- 0.1 to -2 +/- 0.5 and from 10.6 +/- 4.6 to 4.1 +/- 1.1 respectively), whereas k-strophanthidin increased left ventricular end diastolic pressure (mean values from 11.6 +/- 4.3 to 17.1 +/- 9.1). Prenalterol induced a relevant increase of ejection fraction (mean values from 0.52 +/- 0.1 to 0.61 +/- 0.008), whereas k-strophanthidin produced only a nearly significant (P less than 0.06) mild increase (mean values from 0.51 +/- 0.06 to 0.54 +/- 0.09).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult

Increase of cyclic AMP in subcellular fractions of rat heart muscle after beta-adrenergic stimulation: prenalterol and isoprenaline caused different distribution of bound cyclic AMP.

Although prenalterol is a partial beta-agonist, it has been reported to produce only a marginal, non-significant increase of cAMP in rat hearts. We studied the effect of prenalterol and isoprenaline on free and bound cAMP content in subcellular fractions of perfused rat hearts to see whether prenalterol increased cAMP and whether there were differences in the subcellular distribution of the cAMP contents after stimulation with the drugs. The in situ binding characteristics of cAMP to the protein kinases at different degree of beta-adrenergic stimulation were elucidated. Prenalterol increased significantly both total cAMP content in homogenate, bound cAMP in a 100,000 g particulate fraction and bound, free and total cAMP contents in the resulting supernatant. While prenalterol increased bound cAMP in the particulate fraction and in the supernatant proportionally, isoprenaline caused a relatively greater increase of bound cAMP in the supernatant. At equieffective concentrations regarding inotropic and lusitropic effects, prenalterol and isoprenaline increased bound cAMP in the particulate fraction to the same degree, while the increase in the other fractions was greater after isoprenaline. Thus, the cAMP bound in the particulate fraction seemed to determine the inotropic state of the cell after beta-adrenergic stimulation, supporting a compartmentation of cAMP in myocardium. In controls 31 to 34% of the total binding capacity for cAMP in the particulate fraction was occupied, increasing to 77% after maximal beta-stimulation. The binding capacity in the supernatant was only 15 to 18% saturated in the basal situation and about half saturated after maximal beta-stimulation. cAMP bound in the particulate fraction is of special interest when cAMP and functional effects are studied.

Animals

The selectivity of xamoterol, prenalterol, and salbutamol as assessed by their effects in the presence and absence of ICI 118,551.

The selectivity of single oral doses of xamoterol, 200 mg, prenalterol, 50 mg, and salbutamol, 8 mg, was compared in eight healthy male volunteers by measuring their effects on sleeping heart rate, supine heart rate, blood pressure, forearm blood flow, finger tremor, and exercise heart rate in the presence and absence of the specific beta 2-adrenoceptor antagonist ICI 118,551, 25 mg. Xamoterol, 200 mg, increased sleeping heart rate and systolic blood pressure, decreased exercise heart rate, and had no effect on diastolic blood pressure, forearm blood flow, or finger tremor. The concurrent administration of ICI 118,551, 25 mg, did not alter these results. Supine heart rate was increased by xamoterol and did not differ from that for xamoterol with ICI 118,551. Prenalterol, 50 mg, increased sleeping heart rate, supine heart rate, systolic blood pressure, forearm blood flow, and finger tremor, decreased diastolic blood pressure, and had no effect on exercise tachycardia. The concurrent administration of ICI 118,551 with prenalterol reduced the increase in sleeping heart rate, supine heart rate, and forearm blood flow, and reduced the fall in diastolic blood pressure caused by prenalterol alone. The increase in finger tremor following prenalterol with ICI 118,551 tended to be less than that following prenalterol. Salbutamol, 8 mg, increased sleeping heart rate, supine heart rate, systolic blood pressure, forearm blood flow, finger tremor, and exercise heart rate, and caused a fall in diastolic blood pressure. When salbutamol, 8 mg, was administered with ICI 118,551, 25 mg, the only changes detected were a small initial increase in finger tremor and a small rise in diastolic blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists

Prenalterol: a partial beta 1-adrenoceptor agonist or a beta-blocker with intrinsic activity?

Hemodynamic studies have demonstrated a significantly reduced beta 1-adrenoceptor stimulating effect of prenalterol compared to dobutamine suggesting a partial agonism on the receptor. In order to prove this hypothesis we administered 80 micrograms/kg of prenalterol within 5 minutes in 8 healthy volunteers during a continuous infusion of dobutamine (15 micrograms/kg/min). In addition to heart rate, blood pressure and the double product, the systolic time intervals QS2I, PEP and LVET and the echocardiographically determined parameters FS and Vcf were measured for evaluation of ventrical function. The injection of prenalterol caused a distinct attenuation of the cardiostimulating effects of dobutamine: there was a prompt fall in heart rate and systolic blood pressure and a typical negative inotropic effect on the parameters of left ventricular function. In the experimental conditions selected, the effects of prenalterol were those of a beta-sympatholoytic agent. Prenalterol should therefore be classified as a partial beta 1-adrenoceptor agonist or as a beta-blocking agent with pronounced intrinsic sympathomimetic activity. The beta 1-stimulating potency of prenalterol amounts to about 60% of a full agonist.

Adrenergic beta-Agonists

Decrease in beta-receptor density explaining the development of pindolol- and prenalterol-tolerance in orthostatic hypotension.

A 58-year-old woman with diabetic autonomic dysfunction was well treated for orthostatic hypotension with pindolol. After eight months however, symptoms recurred in spite of continued treatment with pindolol. Addition of prenalterol, a beta-blocking agent with very high intrinsic sympathomimetic activity, had a marked clinical effect on her orthostatic hypotension. Before treatment with prenalterol, stroke volume and left ventricular enddiastolic volume markedly decreased during tilt, as demonstrated by radionuclide angiography. After short-term prenalterol treatment, the orthostatic decreases of stroke volume and left ventricular end-diastolic volume were less pronounced. During continued prenalterol treatment, both symptoms and haemodynamic changes recurred in the erect position. Beta-receptor density in her lymphocytes decreased from elevated levels before prenalterol to subnormal levels, when the clinical effect had disappeared. The data suggest that the tolerance development to prenalterol may be explained by the decrease in beta-adrenergic receptor density.

Adrenergic beta-Agonists

A comparison of the properties of prenalterol and corwin at beta 1- and beta 2-adrenoreceptors in vitro.

1. The affinities and efficacies (relative to isoprenaline) of prenalterol and corwin at beta 1- and beta 2-adrenoreceptors, have been determined in isolated cardiac and vascular tissues respectively. 2. Prenalterol and corwin have similar affinities for cardiac beta 1-adrenoreceptors. The affinity of prenalterol for beta 2-adrenoreceptors is approximately 10 times lower than for beta 1-adrenoreceptors; that for corwin is approximately 100 times lower than for beta 1-adrenoreceptors. 3. The efficacies of prenalterol and corwin, relative to isoprenaline, at beta 1 and beta 2-adrenoreceptors, are similar. 4. The greater selectivity of corwin compared with prenalterol, as an agonist at beta 1-adrenoreceptors, is a reflection of its lower affinity for beta 2-adrenoreceptors.

Adrenergic beta-Agonists

The immediate haemodynamic and electrophysiological response to prenalterol during fixed rate pacing in patients with chronic ischaemic heart disease.

The immediate haemodynamic and electrophysiologic effects of intravenous prenalterol 2.5-75 micrograms/kg in patients with coronary heart disease without clinical heart failure were investigated during fixed rate atrial pacing. Right ventricular peak dP/dt increased pronounced and serum concentration dependent after prenalterol concomitant with an increase in stroke volume and a moderate decrease in peripheral vascular resistance. The effects on haemodynamics after prenalterol were thus serum concentration dependent but with marked interindividual variation. AV nodal conduction velocity increased significantly. It is concluded that prenalterol possess pronounced inotropic properties. The haemodynamic response to prenalterol intravenously is to a lesser degree dependent on the chronotropic effects of the drug and it is often unpredictable.

Aged

Prenalterol in severe congestive heart failure. II. Long-term oral treatment. Results with comments on the methods for evaluation of drugs in congestive heart failure.

Nine patients with severe congestive heart failure were treated with a partial beta-1-agonist prenalterol for 9.6 months on average. Five of the nine patients improved with an increase in NYHA-functional capacity of one class. In four of these patients, the improvement was maintained for 12 months. Upon discontinuation, deterioration occurred only in one case; in the latter, improvement reoccurred on reinstitution of prenalterol treatment. Significant improvement on exercise testing, however, occurred only in two patients. Prediction as to which patients would benefit from oral prenalterol was not possible from the pretreatment haemodynamic variables; similarly, the effect of oral prenalterol treatment could not be predicted from the response to prenalterol given intravenously. A critical review of the methods for evaluation of therapeutic intervention in congestive heart failure concludes the article.

Administration, Oral

Cardiovascular effects of prenalterol (H133/22) in normal man.

1 Prenalterol, (S-(-)-1-(4 hydroxyphenoxy)-3-isopropylaminopropanol-2 hydrochloride) a cardio-selective beta-adrenergic receptor agonist, was infused intravenously into six normal male volunteers to determine the cardiovascular effects of this drug. 2 On different occasions, each volunteer received a placebo infusion, an infusion of 0.5 mg prenalterol and an infusion of 1 mg prenalterol. Cardiac output (impedance cardiography), arterial pressure (sphygmomanometry), heart rate and ECG were measured throughout. 3 Prenalterol produced a statistically significant increase in cardiac output and at the end of the infusion this increase was 24% with 0.5 mg and 29% with 1 mg, mainly due to an increase in stroke volume (18% and 17%) with a lesser change in heart rate (+2 and +7 beats/min). Pulse pressure increased but mean arterial pressure showed little change. Peripheral resistance fell by 18% and 20%. As indicated by systolic time indices myocardial contractility increased. 4 Prenalterol at plasma concentrations in excess of 20 nmol l-1 produced significant inotropic effects but did not markedly increase heart rate at concentrations of 60 nmol l-1.

Adrenergic beta-Agonists

Effect of the partial beta-agonist prenalterol on plasma renin activity in patients with left ventricular failure.

Beta agonist therapy for heart failure has been disappointing, perhaps because of renin induced aldosteronism. To investigate this possibility we measured plasma renin activity (PRA) in 23 patients (17 male, 6 female, age 41-70) with New York Heart Association stage III heart failure due to ischaemic heart disease in a placebo controlled trial over one month. All patients received constant doses of digoxin and diuretics throughout the trial. Compliance was confirmed in all patients by digoxin and prenalterol assay. In a preliminary (dose titration) study of 9 patients there was a progressive, but non-significant rise of mean PRA from 14.8 to 17.6 and 27.7 ng/ml per h with doses of 20, 50 and 100 mg of prenalterol, respectively. After one month of treatment with prenalterol (n = 11), PRA was 12.8 +/- 2.4 (SEM) ng/ml per h which was not significantly different from the initial level of 14.4 +/- 2.3 ng/ml per h (n.s.). The placebo group (n = 12) results were 13.8 +/- 4.2 ng/ml per h at entry and 14.4 +/- 5.2 ng/ml per h at one month (n.s.). These results indicate that PRA is elevated by acute treatment with the partial beta agonist prenalterol but stimulation of renin secretion does not appear to occur with chronic therapy.

Adult

Effects of prenalterol on renal function in patients after major vascular surgery.

Hemodynamic and renal effects of prenalterol were studied in 13 mechanically ventilated patients on the first day after major vascular surgery. Prenalterol (1-[4-hydroxyphenoxy]-3-isopropylamino-2 propanol hydro-chloride), a partial beta-agonist with a predominant beta-1 and a weak beta-2-adrenoceptor activity, was infused into seven patients at rates of 0.5 and 1.0 microgram/kg.min (group A), and at a dose of 2.0 micrograms/kg.min in six patients (group B). Although no hemodynamic changes were observed in group A, systolic BP, mean BP, heart rate, and cardiac output increased significantly in group B. Catecholamine levels and plasma renin activity were unaltered in both groups, as was glomerular filtration rate. Renal blood flow did not change in group A but it increased by 25% in group B. Urine flow, fractional free water clearance, fractional sodium excretion, and fractional chloride excretion were unaltered in both groups. Fractional potassium excretion decreased by 20%, 22%, and 26% at the three infusion rates of prenalterol, respectively. We conclude that prenalterol does not directly influence renal function in the postoperative setting.

Aged

Effects of prenalterol on central hemodynamics and myocardial metabolism in experimental propoxyphene-induced shock.

The hemodynamic and cardiometabolic effects of prenalterol were evaluated in propoxyphene-induced circulatory shock in 10 pentobarbital-anesthetized pigs. Circulatory shock (i.e. a systolic arterial blood pressure below 60 mmHg (8 kPa) and/or a cardiac index of less than 2.0 1 X min-1 X m-2) was induced by intravenous propoxyphene chloride 15 mg X min-1. Circulatory shock occurred after 26 +/- 3 mg X kg-1 of propoxyphene. During continuous infusion of propoxyphene, consecutive doses of prenalterol 0.5, 1.0, 2.0 and 4.0 mg i.v. were injected with an interval between increments of 8 min. The maximum effect of prenalterol was seen following the 2 mg dose. Increases were observed in mean arterial blood pressure, cardiac index, stroke volume index, left ventricular stroke work index, right ventricular stroke work index, maximum rate of rise of ventricular pressure, and total body oxygen consumption. Decreases were observed in pulmonary artery occlusion pressure, mean right atrial pressure and systemic vascular resistance, whereas heart rate and pulmonary vascular resistance remained unchanged. The cardiometabolic parameters: coronary sinus flow, coronary vascular resistance, myocardial oxygen consumption and extraction, remained low. Due to profound vasodilation, normal perfusion pressures were not reestablished. In conclusion, prenalterol improved cardiac performance by a significant positive inotropic action. However, pure inotropic stimulation was not sufficient to counteract the circulatory shock state during severe propoxyphene intoxication.

Animals

Analysis of the inotropic effect of prenalterol in papillary muscles from guinea-pig hearts.

The inotropic effects of prenalterol were studied in papillary muscles isolated from the right ventricle of guinea-pig hearts. Force production and action potential were recorded. The preparations were paced at 0.4 Hz (at 31-32 degrees C) under isometric conditions. Prenalterol, in concentration 0.1 microM did not change the action potential duration whereas the peak force and the maximum rate of force development increased by 40.3 and 36.3%, respectively. Time to peak force was slightly shortened (-3.0%) and so was the time from peak force to half relaxation (-5.2%). A predetermined stimulus protocol was used for assessment of the recirculation fraction of activator calcium. At selected times an extra contraction was introduced in order to obtain contractile potentiation. Force of the subsequent two test contractions (after fixed intervals) was analysed. Prenalterol slightly reduced the decay of the postextrasystolic potentiation measured in the two test contractions. It is suggested that the inotropic effect of prenalterol is due to an intensified calcium influx during the action potential, and to some extent to more efficient re-utilization of released calcium. There seems to be a more rapid release of calcium from troponin C giving rise to a shortened time to peak force and an enhanced relaxation.

Action Potentials

Effects of clenbuterol and prenalterol on behavior maintained under a multiple fixed-interval, fixed-ratio schedule.

The results of a number of studies have implicated beta adrenergic receptors in the brain in the actions of proven antidepressant drugs. This suspected involvement of central beta adrenergic receptors made it of interest to characterize the behavioral effects of centrally acting beta adrenergic agonists. Clenbuterol and prenalterol, unlike most beta adrenergic agonists, penetrate into the central nervous system after peripheral administration. In the present study, the effects of these agonists on behavior maintained under a multiple fixed-interval 5-min, fixed-ratio 30-response schedule were determined. Both compounds, in a dose-dependent manner, reduced response rate under both components of the multiple schedule. Under the fixed-interval component, clenbuterol and prenalterol altered the temporal pattern of responding. At no dose tested was there evidence for any stimulant action of either of the drugs. The effects of clenbuterol and prenalterol on behavior maintained under the multiple schedule appeared to be a result of an interaction of the agonists with beta adrenergic receptors. This was evidenced by the ability of the beta adrenergic antagonist propranolol to block the effects of the agonists. The behavioral effects of clenbuterol and prenalterol appear, in general, to be similar to effects reported previously for tricyclic and monoamine oxidase inhibiting antidepressant drugs.

Adrenergic beta-Agonists

Prenalterol in severe congestive heart failure. I. The immediate haemodynamic effects as compared to nitroglycerine.

The immediate haemodynamic effects of prenalterol and nitroglycerine were examined in 15 patients, with severe chronic heart failure. Prenalterol was given intravenously in increasing doses of 2, 4, and 8 mg. Cardiac index increased significantly by 16%, 24%, and 32%, respectively. Heart rate increased by 16%, 19%, and 24%. Stroke volume index, systemic artery pressure, pulmonary artery pressure, and right atrial pressure did not change. Prenalterol reduced systemic vascular resistance by 15%, 17%, and 24%, respectively. Forearm blood flow and forearm vascular resistance was unchanged. Cardiac index and heart rate were not changed by 0.5 mg nitroglycerine, administered sublingually. Systolic and diastolic blood pressure were on average reduced by 14% and 12%, respectively. Systolic and diastolic pulmonary artery pressure and right atrial pressure were similarly reduced by 17%, 31%, and 39%, respectively. Nitroglycerine lowered calculated systemic vascular resistance by 11%, whereas forearm blood flow and forearm vascular resistance was unchanged. The conclusion is that prenalterol acutely increased cardiac index and improved haemodynamics in 14 out of 15 patients, mainly due to an increased heart rate. Nitroglycerine did not change cardiac index in the same group of patients.

Aged