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PubMed1988

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↗
PubMed1981

[Echocardiographic measurements of hemodynamic effects and pharmacokinetics of prenalterol (author's transl)].

The dose-dependent haemodynamic effects and pharmacokinetics and parenteral prenalterol (0.5-10 microgram/kg/min), a new cardioselective beta-1-adrenoceptor agonist, have been studied in 10 healthy volunteers by computed echocardiography. Prenalterol induced a dose-dependent strong and persistent increase in contractility (FV 46%, VCF70 64%, STI 12%), heart index (46%) and heart rate (27%) and a moderate not significant decrease in VED (14%). Afterload and mean arterial blood pressure was nearly unaltered. The hemodynamically effective threshold concentration of prenalterol in plasma was 20-30 nmol/l, the mean value of maximum concentration 493 nmol/l; 1 hour after stopping the infusion prenalterol plasma level was about 90 nmol/l. A strong linear correlation between the haemodynamic alterations and the logarithm of prenalterol plasma concentrations was not apparent.

Adolescent↗
PubMed1983

Acute effects of beta 1 agonism with prenalterol on catecholamine circulating levels in patients with congestive heart failure.

The effects of a single intravenous infusion of prenalterol, a beta 1 selective agonist, on haemodynamics (echocardiography) and venous plasma catecholamine concentration were studied in 8 patients with severe congestive heart failure. In these patients, age-adjusted plasma norepinephrine (NE) and epinephrine (E) levels before prenalterol infusion were higher compared to values found in 10 control healthy subjects (both P less than 0.01). In heart failure patients, circulating NE levels were not dissimilar in 2 samples drawn 60 and 0 minutes before commencing prenalterol infusion (772.0 +/- 131 ng/l [mean +/- SD] and 775.5 +/- 130.0 ng/l respectively). Prenalterol induced a significant improvement in the cardiac index, stroke index, ejection fraction and velocity of circumferential fiber shortening, associated with a moderate but significant decrease in peripheral vascular resistance. All these changes persisted for 60 minutes after the end of infusion. Circulating NE levels were 604.0 +/- 125 ng/l at 60 min. after start of infusion (P less than 0.01 vs pre-infusion levels) and 526.1 +/- 108 ng/l at 60 min. after the end of infusion (P less than 0.01 vs pre-infusion levels). Plasma E showed a slight decrease, which did not attain statistical significance. Heart rate and diastolic blood pressure remained unchanged during and after infusion, while systolic blood pressure increased by 10-15 mmHg during and after infusion. We conclude that a single 1-hour prenalterol infusion in patients with severe congestive heart failure induces an haemodynamic improvement associated with a reduction of previously elevated circulating NE levels. This reduction could indicate a lowering in the intensity of the afferent stimulus for the reflex sympathetic overactivity.

Adrenergic beta-Agonists↗
PubMed1983

[Beta-adrenergic stimulation with prenalterol in sick sinus syndrome].

The effect of beta-adrenergic receptor stimulation on sinus node function in patients with sick-sinus syndrome was investigated. Electrophysiological studies were performed in 14 patients (5 males and 9 females) aged 18-81 years before and after intravenous administration of 50 micrograms Prenalterol per kilogram body wt. Prenalterol decreased spontaneous cycle length by 26% (p less than 0.01), which corresponded to an increase in heart rate of 21 beats/min. The corrected sinus node recovery time was shortened by 23% (n.s.) in 10 patients, and was abnormal in 12 patients before and in 10 patients after Prenalterol. Secondary pauses occurred in 8 patients at control and in 9 patients after drug administration, in 2 of them for the first time after Prenalterol. In the sick-sinus syndrome the pronounced chronotropic response to beta-adrenergic receptor stimulation with Prenalterol doses not indicate improvement of impaired sinus node function.

Adolescent↗
PubMed1979

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↗
PubMed1984

Influence of long-term beta receptor stimulation with prenalterol on intrinsic heart rate in rats.

Previous studies have shown that the intrinsic heart rate (IHR) may undergo changes, e.g., decrease after long-term endurance training. The mechanism for this adaptation is not known. In this study, rats were subjected to long-term oral treatment with the beta receptor stimulating drug prenalterol. During the treatment period heart rates at rest and during submaximal exercise were measured. Heart rate after 30 min rest and also 2 min after exercise was higher in the treated animals, due to the beta stimulation. The treated rats had a significantly lower heart rate increase during exercise than untreated controls, consistent with a partial beta-blocking effect of the drug in states with a high endogenous sympathetic activity. Therefore, the animals were not trained but only exposed to the increased stimulation of cardiac beta receptors accomplished by the drug while at rest. After 25 weeks, prenalterol was withdrawn and the IHR was measured in situ after a denervation procedure. The treatment with prenalterol had not altered the IHR. Our previous results from training studies indicate that a heart rate increase above a certain level or the stimulation for a lower setting of the IHR as seen after endurance training. In this study chronic beta receptor stimulation with prenalterol did not influence the IHR, which supports that hypothesis.

Adrenergic beta-Agonists↗
PubMed1983

Effects of prenalterol on cardiac performance and transmural myocardial perfusion in patients with chronic renal failure.

The acute haemodynamic effects of the beta-adrenoreceptor agonist, prenalterol, were studied in six patients with chronic end-stage renal failure. Prenalterol 0.8 mg, 1.6 mg, and 3.2 mg was administered i.v. as a bolus, and after the last dose the selective adrenergic beta-1-receptor antagonist metoprolol was administered i.v. in doses of 5 and 10 mg. The haemodynamic effects of the drugs were investigated using impedance cardiography and radionuclide angiocardiography. The main haemodynamic effects were a dose-related chronotropic effect, demonstrated by an increase in heart rate (26%; less than 0.05), and an inotropic effect, shown by an increase in stroke volume index (20%; p less than 0.05) and left ventricular ejection time (12%; p less than 0.05); the cardiac index was increased by 47% (p less than 0.05). Transmural myocardial perfusion (DPTI/SPTI ratio) was decreased by 22% (p less than 0.05) after prenalterol. It is concluded that prenalterol has positive inotropic and chronotropic effects in patients with chronic renal failure, that the improvement in left ventricular performance is at the expense of a decreased transmural myocardial perfusion, and that metoprolol is a specific antidote.

Aged↗
PubMed1987

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↗
PubMed1982

Prenalterol is an agonist at beta 2- as well as at beta 1-adrenoceptors.

Prenalterol exerted agonist activity in cat, but not guinea-pig, isolated atria, which contain predominantly beta 1-adrenoceptors. Prenalterol relaxed K+ -contracted rat uterus, but not histamine-contracted cat lung strips; both contain predominantly beta 2-adrenoceptors. The effect of prenalterol in rat uterus was antagonised by the selective beta 2-adrenoceptor antagonist ICI 118551 but not by the selective beta 1-adrenoceptor antagonist atenolol. Thus the ability of prenalterol to exert beta-adrenoceptor activity is tissue-dependent, rather than beta-adrenoceptor subtype-dependent.

Adrenergic beta-Agonists↗
PubMed1981

Determination of prenalterol in plasma and in urine by gas-liquid chromatography.

A description is given of a gas-liquid chromatographic method for the quantitative determination of unchanged prenalterol in plasma and for the total (free and conjugated) prenalterol in urine. After addition of an adequate internal standard, prenalterol together with the internal standard, is extracted with diethyl ether and derivatized with heptafluorobutyric anhydride-pyridine to form a tri-heptafluorobutyric derivative. This derivative has favourable properties for its estimation by gas-liquid chromatography using electron-capture detection. A large percentage of prenalterol is excreted as sulfate conjugate in man. Thus a hydrolysis step is added to the urine assay. The sensitivity of the method is about 2ng/ml.

Chromatography, Gas↗
PubMed1983

Prenalterol in primary dilated cardiomyopathy: hemodynamic and angiographic evaluation.

The hemodynamic effects of an acute infusion of prenalterol (PN), a new inotropic beta-adrenoceptor agonist, have been evaluated by cardiac catheterization in 10 patients with primary dilated (congestive) cardiomyopathy. A single dose of 20 micrograms/kg was administered over 5 min after basal hemodynamic and angiographic measurements. The administration of prenalterol caused a significant increase in mean cardiac index, from 2.3 to 3.3 l/min/m2 (P less than 0.01) and mean stroke volume, from 47 to 62 ml (P less than 0.01) without a change in heart rate. Mean left ventricular end-diastolic pressure was reduced from 19 to 13 mm Hg (P less than 0.05) and left ventricular dp/dt rose from 902 to 1089 mm Hg/s (P less than 0.01). Stroke work index increased from 27 to 40 g m/m2 (P less than 0.01) and ejection fraction from 31 to 36% (P less than 0.05). Mean blood pressure did not change and the systemic vascular resistance decreased from 24 to 17 RU (P less than 0.01). The favorable effect of prenalterol on left ventricular relaxation was shown by an increase of peak negative left ventricular dp/dt from 946 to 1159 mm Hg/s and by a decrease of the time constant of left ventricular pressure fall from 49 to 39 s. These results demonstrated a positive inotropic effect of prenalterol on patients with diffuse and severely reduced contractility.

Cardiac Output↗
PubMed1988

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↗
PubMedDate not supplied

Comparative effects of prenalterol and dobutamine in a canine model of acute ischemic heart failure.

The hemodynamic effects of the inotropic agents prenalterol and dobutamine were compared in a canine model of acute ischemic heart failure following two-vessel coronary artery constriction. Intravenous infusions of both inotropic agents resulted in improvement of cardiac output, left ventricular maximum dP/dt, and contractile force in the nonischemic zone and in a decrease in systemic vascular resistance. No significant changes occurred in ischemic zone contractile force or left ventricular end-diastolic pressure following either inotropic agent compared to saline controls. Significant differences between the two inotropic agents consisted of prenalterol's markedly longer duration of action (hemodynamic half life of 3 hr after discontinuation compared to a value of 1.7 min after dobutamine discontinuation) and greater augmentation of cardiac output at high-dose dobutamine due to greater increases in heart rate. However, similar hemodynamic effects were noted with prenalterol and dobutamine at doses which increased nonischemic contractile force 50%. Both inotropic agents were associated with ventricular arrhythmias in the acute ischemic state. Implications regarding the use of prenalterol and dobutamine in clinical acute ischemic low-output states are discussed.

Animals↗
PubMedDate not supplied

Selectivity of prenalterol for adrenergic receptor subtypes: a potential mechanism of inotropic selectivity.

To address the hypothesis that myocardial adrenergic receptors mediating chronotropy may be distinguishable from receptors mediating inotropy on the basis of existing subtype classifications, the binding properties of the inotropically selective adrenergic agonist prenalterol to receptor populations of known subtype were characterized. In competitive binding assays, prenalterol exhibited higher affinity for beta 1- than for beta 2-receptors, and a low affinity for both alpha 1- and alpha 2-receptors, in comparison with non-subtype-selective agonists. In addition, log molar displacement curves for prenalterol binding to beta 1-receptors, but not to beta 2- or alpha 2-receptors, were steepened and shifted rightward by guanine nucleotide, suggesting that prenalterol is a beta 1-agonist, but may have antagonist properties at beta 2- and alpha 2-receptors. This receptor subtype profile is similar to that of dobutamine, another inotropically selective adrenergic agonist. This concordance lends further support to the hypothesis that chronotropic responses to exogenous adrenergic agonists may be mediated selectively through beta 2-receptors.

Adrenergic beta-Agonists↗
PubMedDate not supplied

Contractile, coronary, and metabolic effects of the acute and long-term treatment of cardiac failure with prenalterol.

Prenalterol was examined with regard to its acute intravenous effects on left ventricular function, coronary hemodynamics, and myocardial oxygen consumption, as well as for its long-term effects, by oral therapy, on left ventricular function and systemic hemodynamics. Intravenous prenalterol enhances myocardial contractility and left ventricular ejection function significantly. A decrease in total peripheral vascular resistance is effected. Myocardial oxygen consumption is only moderately increased, most probably because of the decrease in the systolic integrated wall stress of the left ventricle. The changes of coronary circulation (blood flow, resistance, arteriovenous, oxygen difference) indicate benign and metabolically induced coronary vasodilation. Long-term oral treatment of patients with severe cardiac failure by prenalterol effects significant enhancement in-left ventricular performance within the first 1-2 months of treatment; however, this effect is not present at longer therapy intervals (16-28 weeks). Tolerance development as well as the natural history of these patients may be responsible for this inotropic amelioration. There were no clinical side effects with either intravenous or oral application. It may be concluded that prenalterol is highly effective in acute cardiac failure (intravenous administration) and also in chronic heart disease (long-term oral application). However, the long-term effects are unpredictable, and tolerance development has to be considered.

Administration, Oral↗
PubMedDate not supplied

Role of cyclic AMP in cardiac beta-adrenoceptor desensitization: studies using prenalterol and inhibitors of phosphodiesterase.

We examined the effects of prolonged exposure of cardiac cells in primary culture to the partial beta-adrenoceptor agonist prenalterol and inhibitors of phosphodiesterase on their subsequent ability to increase intracellular cyclic AMP during a 5-min exposure to 50 microM isoprenaline (receptor responsiveness). Although prenalterol possesses only 7% of the agonist activity of isoprenaline on adenylate cyclase, it induces extensive beta-adrenoceptor desensitization. Three hours after exposing the cells to 1 microM prenalterol, beta-adrenoceptor responsiveness was reduced by 40% (p less than 0.05), whereas after 12 h the reduction averaged 55%. Prolonging the incubation time to 48 h had no further effect on the magnitude of receptor desensitization. The magnitude of the desensitization was concentration dependent. On exposure of cells to 10(-8) M prenalterol for 16 h, receptor responsiveness was reduced by 19%, and at concentrations of 1 microM and higher responsiveness was reduced by 60% (p less than 0.01). Receptor desensitization appeared to be due to an inability of receptors to activate adenylate cyclase as well as to receptor loss. To investigate if beta-adrenoceptor desensitization as well as receptor loss could be mediated by cyclic AMP, the cells were exposed for 16 h to inhibitors of phosphodiesterase. Exposure of cells to the phosphodiesterase inhibitor isobutylmethylxanthine (0.1 mM) (which increased intracellular cyclic AMP by between 50 and 150%) also induced receptor desensitization. The reduction in receptor responsiveness averaged 62% (p less than 0.01). The loss in responsiveness could be accounted for by an inability of receptors to activate adenylate cyclase as well as by receptor loss.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗
PubMedDate not supplied

Hemodynamic and myocardial metabolic effects of the beta-agonist prenalterol in ischemic left ventricular dysfunction.

Hemodynamic and myocardial metabolic parameters in ischemic left ventricular (LV) dysfunction were evaluated in response to the beta-agonist prenalterol. Twenty micrograms/kg intravenous prenalterol increased resting heart rate and cardiac output and decreased LV filling pressure, systemic vascular resistance, and pulmonary artery pressure. Resting coronary blood flow and myocardial oxygen consumption increased but net myocardial lactate and oxygen extraction did not change significantly. During pacing induced tachycardia (121 +/- 4 beats/min), prenalterol improved cardiac index and stroke work index; whereas, LV filling pressure, systemic vascular resistance, and pulmonary artery pressure decreased. Coronary blood flow and myocardial oxygen extraction did not change significantly. Net myocardial lactate extraction during pacing decreased insignificantly; one patient developed overt lactate production. Thus, prenalterol improves cardiovascular function at rest and during pacing-induced tachycardia in ischemic LV failure, but at the cost of higher resting myocardial oxygen consumption. The majority of subjects had no adverse metabolic response.

Adrenergic beta-Agonists↗
PubMed1982

Haemodynamic effects of prenalterol in patients with severe congestive heart failure--NYHA III-IV.

In 12 patients with severe congestive heart failure due to ischaemic heart disease (n = 6) and due to congestive cardiomyopathy (n = 6) the haemodynamic effects of a new beta 1-agonist, prenalterol, were studied. Left ventricular (LV) function was studied before and 20 min after infusion of 12 mg prenalterol. Heart rate was kept constant by atrial pacing at a rate of 100 min-1 unless intrinsic heart rate exceeded it. As a sign of positive inotropic support, prenalterol enhanced peak rate of LV pressure development (dP/dt) from 1160 +/- 100 mm Hg/s to 1590 +/- 190 mm Hg/s (p less than 0.005). In the mean LV end-diastolic and end-systolic volume determined by cineventriculography and two-dimensional echocardiography decreased. LV stroke work index measured with both methods increased with 4 ml/m and 5 ml/m, respectively (p less than 0.02). LV ejection fraction was improved by 6% and 8% (p less than 0.005). Increase of peak fall of left ventricular pressure (dP/dt) (1050 +/- 60 mm Hg/s to 1270 +/- 100 mm Hg/s, p less than 0.005) and shortening of time constant (T) of pressure fall from 64.5 +/- 5.0 ms to 44.5 +/- 6.0 ms (p less than 0.005) demonstrated the improved LV relaxation. Analysis of LV volume and myocardial compliance revealed decrease of left ventricular stiffness. Thus, LV filling pressure was reduced from 22.1 +/- 4 mm Hg to 14 +/- 3.5 mm Hg (p less than 0.001). Pressure volume analysis showed a significant increase of LV power and work, as well as a slight decrease of wall stress. Our study could demonstrate, even in patients with severe heart failure, a sustained positive inotropic effect of prenalterol leading to an improved left ventricular contractility, relaxation and compliance. LV power and work was enhanced. The increase of oxygen demand seemed to be counterbalanced by an improved perfusion of particularly subendocardial layers indicated by an increased transmyocardial pressure gradient.

Adrenergic beta-Agonists↗