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At least 1,369 records · Page 76Linked to original sources
PubMed1978

Responses of the rat superior cervical ganglion in vitro to isoprenaline and bethanechol.

The effects of isoprenaline were studied in isolated rat superior cervical ganglia. Intracellularly recorded excitatory postsynaptic potentials were depressed by isoprenaline in concentrations of 10(-5) to 10(-4)M. In 13 out of 17 cells, isoprenaline caused ganglionic hyperpolarization (mean, 4mV). Changes in the amplitude and contour of antidromic action potentials caused by isoprenaline could be accounted for by the increased membrane potential. A slight increase in membrane input resistance from 44--50.2 megohms (mean values) occurred in about half of the cells. Activation of an ion pump by isoprenaline was suggested by the finding that the hyperpolarization did not occur when the bathing solution contained ouabain (10(-5)M) or lacked Na+ or K+. Characterization of the isoprenaline effects by the use of alpha and beta adrenergic blocking drugs was not possible because of the direct depressant effects of the antagonists. The muscarinic agonist bethanechol (2.5 X 10(-5) to 2.5 X 10(-4)M) caused ganglionic depolarization and increased input membrane resistance (42--52 megohms) during depolarization in each of the cells tested. The ganglionic responses to bethanechol were prevented by atropine.

Action Potentials↗
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↗
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↗
PubMed1985

Pharmacokinetics and plasma-concentration-effect relationships of prenalterol in cardiac failure.

Prenalterol was administered as an intravenous infusion at three incremental rates (60, 120 and 240 nmol/min) to five patients with severe cardiac failure. Haemodynamic, hormonal and metabolic variables were measured at the same time as plasma prenalterol concentrations, and the pharmacokinetics of the drug were studied by following plasma concentrations and urinary excretion during and after the infusion. Concentration-dependent increases in cardiac index, stroke index and stroke work index were observed without increases in arterial pressure, heart rate or myocardial oxygen demand. The reninangiotensin-aldosterone system was stimulated, although the extent of stimulation varied among patients. No strong correlations were found between the logarithm of the plasma prenalterol concentration and effect. Plasma clearance of the drug was lower in cardiac patients than in normal volunteers, but a large decrease in renal clearance was partially balanced by an increase in nonrenal clearance. Over the observed range of concentrations, no deviation from linearity was evident, and plasma concentrations of about 150 nmol/l were effective in improving cardiac function without significant side-effects.

Adrenergic beta-Agonists↗
PubMed1984

Lack of effect of prenalterol on dialysis-associated hypotension.

Prenalterol, a cardio selective beta adrenergic receptor antagonist was given perorally in doses from 20-150 mg/day in three patients with dialysis associated hypotension. No effect on blood pressure was seen over several months during this treatment.

Adrenergic beta-Agonists↗
PubMed1984

Dose-response relationship in normal subjects of prenalterol, a beta-adrenergic agonist with positive inotropic and resistance lowering effects.

The acute haemodynamic effects of increasing doses of parenterally administered prenalterol-a beta-adrenergic stimulating drug-were assessed in normal subjects by means of radionuclide ventriculography. Prenalterol induced dose-related increases in the left ventricular ejection fraction and the systolic pressure end-systolic volume ratio. Left ventricular end-systolic and end-diastolic volumes decreased to the same extent accounting for an unchanged stroke volume. Cardiac output increased due to a rise in the heart rate. Systolic blood pressure increased, whereas diastolic and mean blood pressure remained unchanged. Calculated total peripheral resistance decreased significantly. The maximum effect of prenalterol on cardiac performance occurred with a dose of 18 to 36 micrograms/kg. Plasma concentrations of prenalterol showed large interindividual variations. In conclusion, prenalterol improves the pump function of the normal heart and causes a fall in peripheral vascular resistance, implying a reduction of the load on the heart. These effects may prove beneficial in the treatment of acute heart failure.

Adrenergic beta-Agonists↗
PubMed1980

Metabolic and haemodynamic effects and pharmacokinetics of a new selective beta 1-adrenoceptor agonist, prenalterol, in man.

The metabolic and haemodynamic effects of three intravenous doses (0.5, 1.0 and 4.0 mg) of prenalterol, a selective beta 1-adrenoceptor agonist, were studied in 10 healthy male subjects. Plasma levels of prenalterol during the experiments were related to the haemodynamic effects. Prenalterol induced a dose-dependent increase in systolic blood pressure and heart rate. The maximal effects amounted to about 30 mm Hg and 15 beats/min, respectively, after the highest dose (4.0 mg). The diastolic blood pressure fell by a maximum of about 15 mm Hg. The effect of prenalterol on systolic blood pressure and heart rate persisted for about 3 h after the end of the last infusion, whereas that on diastolic blood pressure only lasted for 60 min. Compared with placebo, there was a moderate increase in plasma FFA and glycerol. A small rise in insulin level was also recorded, but no significant change was seen in other metabolic variables--triglycerides, glucose, lactate pyruvate. Serum potassium tended to decrease and serum sodium was unchanged. The initial distribution of prenalterol was rapid (half-life 7 min) and the overall elimination rate corresponded to a plasma half-life of 2 h. A linear relationship was found between the plasma level of prenalterol and its effects on systolic blood pressure and heart rate.

Adrenergic beta-Agonists↗
PubMed1980

Immediate haemodynamic effects of prenalterol, a new adrenergic beta-1-receptor agonist, in healthy volunteers.

The acute haemodynamic effects of prenalterol, a selective adrenergic beta-1-receptor agonist, were studied in eight healthy male volunteers. Prenalterol was administered i.v. in five increasing doses to a cumulative dose of 5.55 mg. After the last dose of prenalterol, three doses of the selective adrenergic beta-1-receptor antagonist metoprolol were administered i.v. to a cumulative dose of 17.5 mg. After each dose, cardiac output (CO), stroke volume (SV), blood pressure (BP), heart rate (HR), systolic time intervals (STI) and forearm blood flow (FBF) were determined. Prenalterol had the following effects: CO was significantly increased by 21.0% after the fourth dose, but the fifth dose did not further change CO. SV was unchanged after the first four doses, but after the fifth dose a significant decrease in SV of 7.0% was seen. Mean BP was increased significantly by 7.7%, but diastolic BP remained unchanged. HR was increased by 28.4%. Total peripheral resistance was reduced by 8.8%. STI were reduced significantly after the second dose, which indicates that prenalterol has a positive inotropic action. FBF was increased significantly after the fourth dose. After the third dose of metoprolol, the CO, SV, means BP, HR, STI and FBF had returned to their control values. It is concluded that prenalterol has positive inotropic and chronotropic effects on the myocardium, and that metoprolol is a specific antidote.

Adolescent↗
PubMed1981

Pharmacokinetic studies in man of the selective beta 1-adrenoceptor agonist, prenalterol.

The pharmacokinetics of prenalterol, a selective beta 1-adrenoceptor agonist, has been studied in healthy subjects, by following the plasma concentration and urinary excretion of the unchanged compound and its total radioactive metabolites after oral and intravenous administration. Each of six healthy subjects received a single i.v. dose (2.5 mg) and three oral doses (2.5, 5.0 and 10 mg) of prenalterol. The oral dose was administered as a solution. Three of the subjects received the intravenous and oral doses of 2.5 mg as tritiated drug. Prenalterol was rapidly and completely absorbed after oral administration. The peak plasma concentration was attained after about 0.5 h. About 25% of prenalterol reached the systemic circulation. Prenalterol was extensively distributed to extravascular tissues with a half-life of the distribution phase close to 7 min. About 90% of the dose was excreted in urine within 24 h irrespective of the route of administration, indicating complete absorption of the drug. On average 60% of the i.v. and 13% of the oral doses were excreted as unchanged drug. The elimination half-life of the compound was 1.8 h, and the decline in the plasma concentration of the metabolites indicated a slower elimination rate than for the unchanged drug. Dose-dependent kinetics were not observed after the oral doses examined.

Administration, Oral↗
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↗
PubMed1983

Ventilatory and haemodynamic effects of prenalterol and terbutaline in asthmatic patients.

In 8 asthmatic patients a comparative study was performed of the ventilatory and haemodynamic effects of the beta 1-receptor stimulator prenalterol and the beta 2-receptor stimulator terbutaline infused in increasing doses after a placebo. Terbutaline caused a dose-dependent decrease in diastolic blood-pressure (BP) and an increase in systolic BP and heart-rate (HR), while mean arterial pressure (MAP) did not change. Prenalterol produced a dose-dependent increase in MAP and systolic BP, while diastolic BP was unaffected. HR was increased only by the largest dose of prenalterol. The haemodynamic effects of the terbutaline infusion can be explained by a reflex response to the vasodilatation induced by stimulation of the vascular beta 2-receptors, while the effects of prenalterol can mainly be accounted for by a direct action on beta 1-receptors in the heart. These observations show that the cardiac side-effects of beta 2-agonists cannot be avoided by producing more selective agonists. Terbutaline caused a dose-dependent increase in the ventilatory indices. Prenalterol in larger doses caused a limited but significant increase in the ventilatory indices, comparable to the decrease in ventilation caused by the beta 1-selective blocker metoprolol. These findings suggest that the ventilatory effects of metoprolol and prenalterol are mediated via beta 1-receptors in the airways, which apparently play a functional role in asthma.

Adrenergic beta-Agonists↗
PubMed1986

Curve-fitting in pharmacokinetics--a comparison between gamma- and biexponential fits.

Seven sets of plasma concentration-time data were fitted to both a conventional biexponential equation and a gamma equation. The values of clearance (CL) and mean residence time (MRT) were calculated from the fitted parameters and compared with the values calculated by the trapezoid rule. Both the biexponential and gamma equations provided adequate fits to the data. The values of CL and MRT calculated from the biexponential fits correlated very closely with the values calculated by the trapezoid rule, but there were large discrepancies between the values calculated from the gamma fits and the trapezoid rule. The biexponential model appears to be less sensitive to scatter in the data.

Heart Failure↗
PubMed1985

The influence of molecular structure on the affinity and efficacy of some beta-adrenoceptor agonists.

The affinity and efficacy of a number of sympathomimetic amines structurally related to prenalterol and the selective beta 1-adrenoceptor agonist RO363 were determined using a combination of radioligand binding and organ bath techniques. Affinity of the molecules (pKD) was calculated from their ability to displace the radioligand [125I]iodocyanopindolol ([125I]CYP) from beta-adrenoceptor sites in left atrial (beta 1) and uterine (beta 2) membrane homogenates. These pKD values were used to calculate efficacy from the positive inotropic and uterine relaxant responses elicited by the drugs in organ bath experiments. The drugs studied were either arylethanolamines i.e., (-)-isoprenaline (ISO), p-hydroxyisoprenaline (pOH-ISO), compounds XIV and XVI or aryloxypropanolamine-derivatives, i.e., oxymethylene-isoprenaline (OM-ISO), prenalterol and Compound XI which possessed a p-phenol or catechol ring and an isopropyl or a homoveratryl amine substituent. Only ISO, OM-ISO, pOH-ISO and Compound XVI were active as agonists in both tissue preparations. These drugs were partial agonists which exhibited a wide range of pD2 values and did not display any marked selectivity for either beta-adrenoceptor subtype. Compound XI and prenalterol were inactive as agonists and together with the partial agonists behaved as competitive antagonists to ISO in the two preparations. All drugs tested displaced [125I]CYP from beta-adrenoceptor sites, however, there was also a wide range of potency amongst the drugs. Analysis of the structure-affinity and structure-efficacy relationships indicated that removal of the 3-hydroxyl group from the catechol ring reduces both affinity and efficacy without altering the selectivity of the drug for either beta-adrenoceptor subtype.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Agonists↗