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PubMed1982

Effect of prenalterol in asthmatic patients.

The bronchial effects of prenalterol, a selective inotropic beta-adrenoceptor agonist, were examined to see whether beta 1-adrenoceptor stimulation would produce bronchodilatation, or whether beta 2-adrenoceptor blockade could be demonstrated. In a first investigation 8 asthmatic patients were studied under standardized conditions in a double-blind, randomized, crossover comparison between i.v. doses of prenalterol and saline infusions. After the fourth dose of prenalterol/saline, 4 intravenous doses of terbutaline were given. All medication was given at 30 min intervals. In a second study in 7 of the previously studied patients, 5 increasing doses of prenalterol or saline were inhaled from a bird ventilator, and after the last dose 4 i.v. doses of terbutaline were given as before. Prenalterol and saline caused no change in FEV1 during the intravenous study. Terbutaline infusion produced a dose dependent increase in FEV1 which was not significantly altered after prenalterol treatment. In the inhalation study, in which a much larger dose was applied to the bronchial tree, there was no significant difference in FEV1, between the saline and prenalterol inhalations. However, prenalterol did show beta 2-blocking property, as the dose response curve of terbutaline was shifted to the right. The heart rate increased significantly and to the same degree during both the i.v. and inhaled prenalterol treatments. Thus, this study revealed no significant beta 2-blocking effect of therapeutic doses of i.v. prenalterol. However, when the drug was inhaled in a much higher dose, a beta 2-blocking effect on FEV1 was recorded. No significant beta 1-adrenoceptor-mediated bronchodilator effect of prenalterol could be demonstrated.

Adrenergic beta-Agonists↗

PubMed1999

Heart-rate variability effects of beta-adrenoceptor agonists (xamoterol, prenalterol, and salbutamol) assessed nonlinearly with scatterplots and sequence methods.

Full antagonists of the cardiac beta-adrenoceptor improve heart-rate variability (HRV) in humans; however, partial agonism at the beta2-adrenoceptor has been suggested to decrease HRV. We therefore studied the HRV effects of some partial agonists of the beta1- and beta2-adrenoceptors in normal volunteers. Under double-blind and randomised conditions (Latin square design), eight healthy volunteers received placebo; xamoterol, 200 mg (beta1-adrenoceptor partial agonist); prenalterol, 50 mg (beta1- and beta2-adrenoceptor partial agonist); salbutamol, 8 mg (beta2-adrenoceptor partial agonist); ICI 118,551, 25 mg (selective beta2-adrenoceptor antagonist); and combinations of each partial agonist with ICI 118,551. Single oral doses of medication (at weekly intervals) were administered at 22:30 h with HRV assessed from the overnight sleeping heart rates. HRV was determined by using standard time-domain summary statistics and two nonlinear methods, the Poincaré plot (scatterplot) and cardiac sequence analysis. On placebo, the sleeping heart rate decreased significantly, between 2 and 8 h after dosing. The heart rate with ICI 118,551 was unaltered. Xamoterol, prenalterol, and salbutamol increased the sleeping heart rate. ICI 118,551 blocked the heart-rate effects of salbutamol, attenuated those of prenalterol, but did not influence the xamoterol heart rate. The scatterplot (Poincaré) area was reduced by beta1-adrenoceptor (xamoterol), beta2-adrenoceptor (salbutamol), and combined beta1- and beta2-adrenoceptor (prenalterol) agonism. A reduction in scatterplot length followed salbutamol, prenalterol alone, and prenalterol in combination with ICI 118,551. The geometric analysis of the scatterplots allowed width assessment (i.e., dispersion) at fixed RR intervals. At higher heart rates (i.e., 25 and 50% of RR scatterplot length), dispersion was decreased after xamoterol, prenalterol, and prenalterol/ICI 118,551. Cardiac sequence analysis (differences between three adjacent beats; deltaRR vs. deltaRRn+1) assessed the short-term patterns of cardiac acceleration and deceleration; four patterns were identified: +/+ (a lengthening sequencing), +/- or -/+ (balanced sequences), and finally -/- (a shortening sequence). Cardiac acceleration or deceleration episodes (i.e., number of times deltaRR and deltaRRn+1 were altered in the same direction) were increased after salbutamol and prenalterol. In conclusion, partial agonism at either the cardiac beta1-adrenoceptor (xamoterol), beta2-adrenoceptor (salbutamol), and beta1- plus beta2-adrenoceptors (prenalterol) altered the autonomic balance toward sympathetic dominance in healthy volunteers; blockade of the beta2-adrenoceptor with the highly selective beta2-antagonist ICI 118,551 prevented the effects of salbutamol on HRV, attenuated the HRV effects of prenalterol, but had no effect on the actions of xamoterol. Agonism at both the beta1- and beta2-adrenoceptor reduced HRV in healthy subjects; the implications for the preventive use of the beta-adrenoceptor compounds in cardiovascular disease warrant further investigation.

Adrenergic beta-Agonists↗

PubMed1983

Intrinsic sympathomimetic activity of the partial agonist prenalterol in relation to beta adrenoceptor interaction in various tissues, in vitro.

The intrinsic sympathomimetic activity (ISA) of prenalterol was studied in isolated tissues from different species, including tissues containing predominantly beta-1 adrenoceptors (cardiac preparations from cat, rabbit, rat and guinea pig) and tissues characterized by beta-2 adrenoceptor predominance (cat skeletal muscle and rat uterus). The ISA of prenalterol, varying between 0 and 94% in the various tissues, was found to be positively correlated to the stimulatory potency (-log EC50) of isoproterenol and prenalterol. In the cardiac preparations from the rabbit there was an interindividual variation in the ISA of prenalterol, which was also positively correlated to the stimulatory potency of the beta agonists. The density of beta adrenoceptors in the tissues studied correlated neither to the variable ISA of prenalterol nor to the -log EC50 values of isoproterenol or prenalterol. The affinities of isoproterenol and prenalterol for the beta adrenoceptors were subject to less variation than were the stimulatory potencies of the agonists. The degree of separation between the concentration-effect curves for beta adrenoceptor occupancy and mechanical performance, expressed as the ratios Kd/EC50 for both agonists, were positively correlated to the corresponding ISA of prenalterol in various tissues. However, a considerably steeper relationship between occupancy/potency ratio and ISA was seen with prenalterol than with isoproterenol. The present data suggest that the level of ISA of the partial agonist, prenalterol, depends upon the efficiency of signal transmission from the activated receptor to the final end-organ response. The separation between the concentrations of the full agonist, isoproterenol, required for receptor occupancy and response serves as an index of the efficiency of coupling between the stimulus, elicited by activation of the receptor, and the response.

Adrenergic beta-Agonists↗

PubMed1983

Characterization of mechanical effects and beta-adrenoceptor binding of prenalterol in rat myocardium.

The partial beta-agonist prenalterol has been found to differ from the full agonist isoprenaline in some aspects of its cardiac action. We therefore studied in rat myocardium whether prenalterol elicited the same qualitative changes of the contraction-relaxation cycle as was previously found for isoprenaline. We also measured binding of prenalterol to beta-adrenoceptors. Prenalterol augmented relaxation more than contraction and thus evoked the same qualitative changes of the contraction-relaxation cycle as did isoprenaline. However, the response developed slower than that to isoprenaline, and the effect on relaxation followed a more protracted time course than the effect on contraction. Prenalterol bound non-selectively to beta 1- and beta 2-adrenoceptors in both heart and lung broken cell preparations. pKd for binding to beta-adrenoceptors and pD2 values for functional effects in heart were similar, i.e. prenalterol had to occupy half the amount of beta-adrenoceptors in order to evoke half-maximal functional effects. The non-selective alpha-blocker phentolamine potentiated the effects of prenalterol on contraction, but did not change the equilibrium binding of prenalterol to cardiac beta-adrenoceptors. Phentolamine did not change the potency and efficacy of isoprenaline. Thus, although prenalterol qualitatively evoked the same response as isoprenaline, it also exhibited some properties which differed.

Animals↗

PubMed1984

Acute intravenous and sustained oral treatment with the beta1 agonist prenalterol in patients with chronic severe cardiac failure.

Prenalterol, a beta1 agonist, was given in a single blind acute intravenous study to seven patients with cardiac failure (New York Heart Association class II and III). It was then given in a double blind crossover study of sustained oral prenalterol to six of them. As a result of dose titration studies the oral dose of prenalterol given was 100 mg twice a day in all patients. Erect bicycle sprint tests were performed to exercise tolerance before and after treatment had been started. Cardiac function was assessed at rest and during graded supine bicycle exercise by determining haemodynamic indices using a Swan-Ganz catheter and radionuclide left ventricular ejection fractions. In the intravenous study cardiac function was assessed at rest and during exercise after a control infusion of dextrose and after an infusion of 5 mg prenalterol. In the oral crossover study a placebo or prenalterol were given for two periods of two weeks; at the end of each period exercise tolerance was measured and cardiac function assessed at rest and during exercise. Throughout the study period there was no change in symptoms, medication, or exercise tolerance. Intravenous prenalterol significantly improved cardiac function; left ventricular ejection fraction and cardiac index increased and left ventricular filling pressure fell both at rest and during exercise. Sustained oral treatment with prenalterol, however, did not improve resting left ventricular filling pressure or left ventricular ejection fraction at rest or during exercise but did increase heart rate at rest, and mean blood pressure and peripheral vascular resistance at rest and during exercise; in fact, during exercise left ventricular filling pressure was significantly increased while cardiac index and stroke volume index were decreased by prenalterol. Sustained oral treatment with prenalterol did not have the beneficial effects on cardiac function produced by intravenous treatment and in fact had deleterious effect on the measured indices of cardiac function during exercise.

Administration, Oral↗

PubMed1985

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↗

PubMed1983

Prenalterol, an oral beta-1 adrenoceptor agonist, in the treatment of chronic heart failure.

The haemodynamic effects of prenalterol, a new beta-1 agonist, were studied in 10 patients with chronic heart failure. Following intravenous prenalterol infusions of 1 mg, 2.5 mg and 5 mg at 15 min intervals, oral slow release prenalterol 20 mg, 30 mg and 50 mg was given at 2 h intervals and then 50-100 mg bid for one month. There were no significant changes in heart rate or blood pressure. Cardiac output increased significantly from control of 4.4 +/- 0.91/min to a maximum of 5.8 +/- 1.81/min (p less than 0.01) following the 5 mg prenalterol infusion and this increase was maintained following oral prenalterol on Days 1 and 2 and at 1 month. Significant increases in stroke volume and stroke work indices and reduction in systemic vascular resistance were also observed. Maximum increases in cardiac output and stroke work index following intravenous prenalterol correlated significantly with maximum increases observed following oral prenalterol on Day 2. Non-invasive evaluation showed no change in echocardiographic left ventricular end-diastolic dimension but a significant reduction in left ventricular end-systolic dimension on Day 30. PEP/LVET was significantly reduced from control of 0.56 +/- 0.15 to 0.47 +/- 0.12 (p less than 0.05) on Day 2 and 0.49 +/- 0.09 (p less than 0.05) at 1 month. Treadmill exercise duration was significantly improved for the group at 1 month and no adverse effects were noted. Oral slow release prenalterol is a potentially useful new drug for patients with chronic heart failure.

Administration, Oral↗

PubMed1988

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↗

PubMed1983

Hemodynamics and leg muscle metabolism at rest and during exercise in young healthy men after prenalterol.

In eight young healthy men the effects of short-term treatment with prenalterol, a new beta-adrenergic agonist, on peripheral hemodynamics and leg muscle metabolism were studied at rest and during exercise at a moderate and a heavy workload. At rest prenalterol treatment significantly increased pulmonary oxygen uptake, heart rate, rate pressure product, and leg blood flow and decreased leg arteriovenous oxygen content difference. During exercise fewer hemodynamic effects of prenalterol were observed. At the moderate workload there was a slight increase in heart rate, but at the heavy workload heart rate fell. Prenalterol raised the arterial concentrations of free fatty acids and glycerol at rest by 70% and 40%, but during exercise these alterations were not present. The plasma levels of epinephrine and dopamine in subjects at rest decreased significantly during influence of prenalterol, but these differences were also abolished during exercise. The leg exchange of metabolites and the concentrations of endogenous muscle metabolites were not influenced by prenalterol, although the lactate concentrations in muscle tended to be lower at rest and during exercise. The results at rest demonstrate that prenalterol in this situation acts predominantly as a stimulator of beta 1-adrenoceptors. During heavy exercise, however, when the endogenous sympathetic tone is high, the beta-stimulating effects are no longer overt and instead reduced heart rate indicates a blocking effect on beta-adrenoceptors. The hemodynamic and metabolic results are concordant with the hypothesis that prenalterol acts as a partial beta-receptor agonist.

Adult↗

PubMed1981

Central and peripheral haemodynamic effects of prenalterol in patients with coronary heart disease.

The acute haemodynamic effects of prenalterol, a selective adrenergic beta-I-receptor agonist were studied in eight patients with coronary heart disease. Prenalterol was administered intravenously in four increasing doses to a cumulative dose of 5.6 mg. Fifteen minutes after the last dose of prenalterol two doses of the selective adrenergic beta-I-receptor antagonist metoprolol were administered intravenously to a cumulative dose of 17-5 mg. Ten minutes after each dose cardiac output, heart rate, arterial blood pressure, pulmonary artery pressure, systolic time intervals and forearm blood flow were determined. Haemodynamic effects of prenalterol: cardiac index and heart rate increased maximally by 38% and 39% respectively. Stroke index was increased by 6-9% after the first and second dose. Mean blood pressure was increased by 9.8 mmHg. Total peripheral resistance index was reduced by 19%. The mean pulmonary artery pressure decreased by 3.8 mmHg and pulmonary resistance index was reduced by 48%. Systolic time intervals were all reduced significantly after the second dose, which reflected the positive inotropic effects of prenalterol. Forearm blood flow increased by 29% and forearm vascular resistance was decreased by 20%. Haemodynamic effects of metoprolol: the haemodynamic changes induced by prenalterol were stepwise counteracted by metoprolol. After the second dose all the haemodynamic variables had returned to the control levels. It is concluded that prenalterol possesses a considerable positive inotropic as well as positive chronotropic effect on the myocardium. Both the chronotropic and inotropic effect of prenalterol was counteracted by metoprolol.

Blood Pressure↗

PubMed1988

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↗

PubMed1980

The lack of a pronounced preference of prenalterol for the beta-l-adrenoceptor subtype.

The beta-sympathomimetic effect of prenalterol was investigated on the electrically driven left atrium as well as on the tracheal chain of the guinea pig. 1. On the atrium driven at 2 Hz prenalterol caused a positive inotropic effect with a pD2-value of 7.0 +/- 0.08 (N = 4). Compared to isoprenaline (1.0) its intrinsic activity amounted to 0.3. 2. On the tracheal chain prenalterol caused very little relaxation. Its intrinsic activity was virtually negligible when compared with those of fenoterol (1.0) or noradrenaline (1.0); it amounted to 0.07 only. 3. On the atrium the positive inotropic effect of prenalterol vanished after 1 hour of incubation. At this time the concentration-response curve for isoprenaline was shifted dose-dependently to the right. The pD2-value for isoprenaline was significantly diminished (P less than 0.001) by prenalterol, 10(-6)M, from 8.36 to 7.14. 4. Likewise, on the trachea prenalterol caused a pronounced, dose-dependent shift of the concentration-response curves for fenoterol as well as for noradrenaline to the right. 5. The results presented here show that on beta-adrenoceptors of the guinea pig prenalterol is acting like a partial agonist in the left atrium, but as full antagonist in the trachea.

Adrenergic beta-Agonists↗

PubMed1991

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↗

PubMed1983

Cardioselectivity of prenalterol and isoproterenol.

We examined the hemodynamic effects and kinetics of prenalterol, a new beta-adrenoceptor agonist, in 10 normal subjects. There is some doubt whether prenalterol is selective for beta 1 adrenoceptors in animals; therefore, we also compared its cardioselectivity with that of the nonselective agonist, isoproterenol, with respect to heart rate (HR) and blood pressure (BP) responses after inhibition of cardiovascular reflexes with atropine, clonidine, and phentolamine. After intravenous (2.5 mg) and oral (10 mg and 100 mg) dosing, t 1/2 beta was 2 to 3 hr. Oral bioavailability averaged 33% and was independent of dose. Oral prenalterol, 10 mg and 100 mg, increased resting HR, systolic BP, and cardiac index by up to 27% but had no significant effects during graded exercise. Prenalterol infusions were calculated to attain steady-state plasma concentrations of 10, 20, and 40 ng/ml. HR and BP effects of the levels (10.8, 23.6, and 47.4 ng/ml) were compared with those of 0.5, 1.5, and 2.5 micrograms isoproterenol. Before autonomic block, prenalterol increased HR by 10 bpm at the highest dose and mean arterial pressure (MAP) by 10 mm Hg. In contrast, HR rose and MAP fell after isoproterenol. After block, at the highest doses of prenalterol and isoproterenol, there was an average rise in HR of 42 and 27 bpm; BP was almost maintained after the former but fell by 33 mm Hg after the latter. Prenalterol is an inotropic drug that has the effects of a full cardioselective beta-adrenoceptor agonist. Its inotropic effects are evident at doses that have little effect on HR because of the modifying effect of cardiovascular reflexes. The hemodynamic effects are most obvious at rest when sympathetic tone is low.

Administration, Oral↗

PubMedDate not supplied

Effects of a beta 1-adrenoceptor agonist, prenalterol, on renal function and renin secretion rate in anesthetized dogs.

Experiments were conducted to examine the effects of prenalterol on renal function and renin secretion in anesthetized dogs. Specifically, we tested whether prenalterol alters renal function directly, or only indirectly as a consequence of a systemic action of the drug. Accordingly, prenalterol was infused into one renal artery for five consecutive 15-min periods, at incremental rates of 0.1, 0.3, 0.9, 2.7, and 8.1 micrograms X kg-1 X min-1. Heart rate and mean arterial blood pressure were recorded, and renal functions and renin secretion rates were measured bilaterally. Direct intrarenal prenalterol infusion caused a 60 bpm increase in heart rate and resulted in marked increases in renin secretion rates from both kidneys. Intrarenal prenalterol infusion also reduced urinary sodium and potassium excretions bilaterally and equally. There were no consistent changes in mean arterial blood pressure, or in glomerular filtration rate or renal blood flow, during prenalterol infusion. We conclude that although prenalterol increases renin secretion rate markedly and may alter renal electrolyte excretion, these effects are not mediated by a direct intrarenal action of the drug.

Adrenergic beta-Agonists↗

PubMed1982

The haemodynamic effects of intravenous prenalterol and ouabain in conscious dogs.

Experiments were performed on 5 resting conscious dogs supplied with an electromagnetic flow probe on the ascending aorta and a chronic aortic catheter for pressure recording. The animals were used repeatedly in four different types of experiment involving i.v. administration of 1. saline (controls), 2. prenalterol 45 nmol/kg (approximately 10 micrograms/kg) followed by an additional dose of 135 nmol/kg 20 min later, 3. ouabain 50 nmol/kg (approximately 30 micrograms/kg) and 4. a combination of protocols 2. and 3. Ouabain and the low dose of prenalterol exerted clear-cut positive inotropic effects as reflected in increased stroke volume and max dF/dt without significant changes in heart rate or arterial pressure. The PQ interval increased with ouabain but decreased with prenalterol. The higher dose of prenalterol caused a further rise in max dF/dt, a further shortening of the PQ time, increased heart rate and reduction in systemic vascular resistance. Higher doses of ouabain could not be given due to side-effects (vomiting). The combined treatment with ouabain and prenalterol showed their inotropic responses to be additive. Arrhythmias did not occur in any of the animals at the applied dose levels of the drugs. The experiments show that prenalterol through its beta 1-adrenoceptor stimulating action exerts a positive inotropic effect which surpasses that of emetic doses of ouabain. The inotropic response at moderate doses occurs without a change in heart rate. This fact and the apparent lack of influence of prenalterol on vascular alpha- and beta 2-adrenoceptors make the substance potentially useful clinically as an inotropic agent in cardiac failure, particularly in view of its relatively long duration of action.

Adrenergic beta-Agonists↗

PubMed1982

Inotropic, chronotropic and dromotropic effects of prenalterol, a new cardiostimulant drug.

Prenalterol (H 133/22) is an adrenergic beta-receptor stimulator which unlike isoproterenol is both orally active and has a long duration of action. The inotropic, chronotropic and dromotropic effects of prenalterol were investigated in pentobarbital anaesthetized dogs. Prenalterol was found to increase left ventricular maximum dP/dt in a dose-dependent manner up to a dose level of 50 micrograms/kg. Additional doses resulted in only small further increases in cardiac contractility. Electrophysiological studies were done to compare the effects of prenalterol and isoproterenol on sinus node and ventricular pacemaker function. Complete AV block was produced by electrocauterization of the His bundle. Prenalterol accelerated both ventricular and sinus node pacemakers at doses up to 50 micrograms/kg. The increase in ventricular rate was greater than the increase in sinus rate following supramaximal inotropic doses of prenalterol yet no ventricular extrasystoles were ever observed. Similar acceleration of the ventricular and sinus node pacemakers were observed by infusion of isoproterenol. Prenalterol and isoproterenol accelerated AV nodal conduction and ventricular conduction but had little effect upon His-Purkinje conduction. Sinus node reset time was abbreviated as was the functional and effective refractory periods of the atrium and AV nodes.

Animals↗

PubMed1982

Pharmacodynamic effects of prenalterol in healthy subjects.

1. Prenalterol induces a dose-dependent effect on different variables reflecting myocardial contractility and heart rate. A clearcut effect can be demonstrated after an oral dose of 2.5 mg. The duration of the effect increases considerably when prenalterol is administered as a controlled release preparation partly due to an increased bioavailability. 2. Prenalterol induces a lipolytic effect manifested as a rise in free fatty acids and glycerol. Also a slight increase of plasma insulin is recorded while plasma potassium decreases somewhat. 3. When prenalterol is administered together with therapeutic doses of a selective or non-selective beta-adrenoceptor blocker it induces the same haemodynamic effects as before the beta-blocker but the dose has to be increased ten-fold. These results suggest that prenalterol might be a useful drug to counteract unwanted haemodynamic effects of a beta-blocker. 4. In animal studies it has been shown that prenalterol has affinity for both beta 1- and beta 2-adrenoceptors. However, it has a stimulating effect mainly on beta 1-adrenoceptors. Therefore, theoretically it might act as a beta 2-adrenoceptor antagonist. Preliminary results from studies in patients with chronic asthma indicate that prenalterol only has an insignificant beta 2-blocking effect when the drug is administered in doses which induce a significant beta 1-adrenoceptor stimulating effect.

Administration, Oral↗