The Influence of Beta-Blocking Agents on Plasma Volume and Extracellular Volume in Ischaemic Heart Disease

Plasma volume and extracellular volume (sodium space) were found to be unchanged during treatment with propranolol (nine patients) and practolol (four patients) for well-compensated ischaemic heart disease. The volumes were determined before treatment and 2 days and 3 months after optimal dose for each patient was reached.     

普萘洛尔致犬急性心衰模型的方法学研究

目的探讨普萘洛尔对比格犬诱导急性心力衰竭模型的可行性。方法静脉推注普萘洛尔诱导急性心力衰竭,静脉滴注普萘洛尔维持心衰,股动脉插管监测血流动力学指标变化,电磁流量计测量心输出量。结果与造模前基础值相比,普萘洛尔造模后心率、动脉收缩压、动脉舒张压、平均动脉压、左室内压下降速度和左室收缩压均下降(P<0.05~0.01),左室舒张末期压上升(P<0.01),左室内压上升速度和心输出量分别下降51.7%、41.1%(P<0.01),达到心衰标准,且上述指标在2 h内保持稳定。结论普萘洛尔建立急性心力衰竭模型稳定可行。     

Effects of high ambient temperature on parasympathetically mediated cardiovascular reflexes in normal man

AIMS: To examine the effects of high ambient temperature ('heat stressor') on parasympathetically mediated cardiovascular reflexes (power of respiratory sinus dysrhythmia; change in heart rate elicited by change in posture from lying to standing ['30 : 15 ratio']). METHODS: Twelve healthy male volunteers participated in four weekly sessions, each of which was associated with one treatment condition (placebo at an ambient temperature of 22 degrees C; propranolol 40 mg at 22 degrees C; placebo at 40 degrees C; propranolol 40 mg at 40 degrees C), according to a balanced double-blind design. Heart rate was recorded by ECG, finger tremor (7-12 Hz) with an accelerometer strapped to the middle finger of the nondominant hand, and sublingual temperature by a mercury thermometer. Power of finger tremor and the variations of the R-R intervals of the ECG were obtained from Fourier transformations of the data. Data were analysed by analysis of variance, with repeated measures using a significance criterion of P < 0.05; individual comparisons of active treatment with placebo and of data obtained at 40 degrees C with those obtained at 22 degrees C were made with Fisher's Least Significant Difference test. RESULTS: Heart rate was increased by the heat stressor, and this increase was abolished by propranolol. The heat stressor reduced the power of respiratory sinus dysrhythmia and the 30 : 15 ratio, and increased the power of physiological finger tremor. Propranolol did not affect heat stressor-induced changes in the parasympathetic cardiac reflexes, but reduced the heat stressor-induced enhancement of finger tremor. CONCLUSIONS: The increase in the power of physiological finger tremor at high ambient temperature is consistent with sympathetic activation, whereas the reduction in the power of respiratory sinus dysrhythmia and 30 : 15 ratio indicates a decrease in parasympathetic activity. These results demonstrate that high ambient temperature may induce vagal withdrawal in the heart.     

PLASMA PROPRANOLOL CONCENTRATION IN PATIENTS WITH ANGINA AND ACUTE MYOCARDIAL INFARCTION

1. Plasma levels of propranolol were measured fluorometrically in patients with angina pectoris and in patients admitted to the Coronary Care Unit with acute myocardial infarction. 2. In thirty patients with stable angina pectoris, plasma propranolol levels varied almost linearly with doses between 10 and 120 mg during 6-hourly chronic oral administration. Plasma levels greater than 100 ng/ml produced 70–80% reduction in the tachycardia induced by strenous exercise on a treadmill. 3. In nineteen patients with acute myocardial infarction given oral propranolol, 20 mg 6-hourly, peak as well as trough plasma levels of the drug increased progressively but remained below 100 ng/ml in all except two patients during the first 24 h after their admission to the Coronary Care Unit. 4. The data suggest that the use of low and fixed doses of propranolol may not produce adequate plasma levels or significant β-adrenoceptor blockade in the early stages of acute myocardial infarction in man.     

Effects of atenolol,labetalol and propranolol on the peripheral circulation in hypertensive patients without obstructive vascular disease

Summary In an observer-blind, randomised cross-over trial, in 12 patients, the effects on the peripheral circulation of antihypertensive doses of atenolol, labetalol and propranolol and placebo were compared. After a placebo period of at least 4 weeks, patients were allocated at random to one of the three active drug treatments. After active treatment for at least 6 weeks and a fall in diastolic pressure (DP) to less than 90 mmHg subjects were switched to the next medication. At the end of each period, photoelectric plethysmography (PHELP) was done on all fingers of one hand cooled over 4 min in water in steps of 3°C from 33° to 12°C, and subsequently warmed in room air (20°C) for a period of 10 min. Blood flow changes during cooling were expressed as a percentage of the initial PHELP value (% PHELP). Areas under the curves, representing the % PHELP/cooling period and % PHELP/warming-up period, showed that within the temperature range normally encountered in daily life, labetalol preserved finger blood flow significantly better than propranolol and marginally better than placebo. With atenolol, finger blood flow was not significantly different from that during the three other regimens, but there were significantly fewer other side-effects. It is concluded that labetalol may be the drug of choice for hypertensive patients treated with beta-blocking agents whose peripheral arterial circulation seems inadequate at low temperatures.     

The Pharmacology of a New Hypoglycaemic Agent N-[4-(2-(2,3-dihydrobenzo (b) furan-7-carboxamido)-ethyl)- benzenesulphonyl]-N′-cyclohexylurea (NOVO CS 476). II. Pharmacological Studies on the Mechanism of Action

Abstract The new sulphonylurea CS 476 does not potentiate the effect of insulin on plasma glucose levels in diabetic dogs in which an oral glucose load does not cause insulin release. In normal dogs propranolol 0.3 mg/kg intravenously inhibites the insulin release and the hypoglycaemia due to CS 476 suggesting involvement of β-adrenergic receptors in its action on the pancreas. Pretreatment of dogs with phentolamine leads to an augmentation of the insulin response to CS 476.     

Effect of Propranolol and Related Drugs on Transmembraneous pH Differences in Liposomes

Abstract Propranolol (1-isopropylamino-3-(1-naphtoloxy)-propan-2-ol) a β-adren-ergic receptor blocking agent was found to cause changes of transmembraneous pH in liposomes prepared from Soy-lecithin and cardiolipin. When the external pH was neutral and the internum of the liposomes acidic, the drug decreased the pH gradient. When the externum was acidic and the internum neutral, the gradient was increased by the drug. The effect of butacaine was similar to that of propranolol, while procaine, timolol and practolol were ineffective. It is suggested that the charged form of propranolol is bound to the membrane and dislocates protons from binding sites in the membrane and that the uncharged form of propranolol penetrates the membrane. After penetration it could associate with protons in the intraliposomal compartment and hence increase the pH of the interior. Depending on the direction of the pre-existing proton gradient propranolol would thus be able to increase or decrease the pH difference across the liposomal membrane.     

The effect on plasma prolactin,growth hormone and luteinising hormone concentrations of single oral doses of propranolol and tolamolol in normal man

Summary In a placebo controlled double-blind study in six healthy male volunteers the effects of single oral doses of 100 mg and 200 mg of tolamolol on plasma concentrations of prolactin, growth hormone and luteinising hormone were investigated. In a second placebo controlled single-blind study in a further six healthy male volunteers the effects of single oral doses of 200 mg tolamolol and 160 mg propranolol on the same plasma hormone concentrations were compared. A dose dependent increase in plasma prolactin concentration was demonstrated after tolamolol. The increase in plasma prolactin concentration was not evident after propranolol. Plasma growth hormone and luteinising hormone concentrations were not significantly changed by either propranolol or tolamolol.Report prepared by Pfizer Central Research, Europe     

The Effect of Propranolol and Phentolamine on Serum Gastrin Concentration in Response to Respiratory Acidosis in Normal Man

Abstract. Serum gastrin concentration and basal acid secretion were studied in normal subjects under the influence of respiratory acidosis induced by CO2 rebreathing. During the intragastric instillation of 100 ml/h 0. 5 M bicarbonate a significant increase of gastrinaemia from 130 to 158 pg/ml (p < 0. 01) occurred in ten subjects during respiratory acidosis (pCO₂ 62 torr, pH 7. 25). Under, the intragastric instillation of 100 ml/h 0. 1 N HC1 the rise of gastrin concentration in response to CO2 rebreathing (pC02 68 torr, pH 7. 20) was not significant. The relationship between the decrease of pH and the increase of the gastrin concentration was shifted in the direction of a greater systemic acidosis compared to the results performed in the presence of a neutral intragastric pH. 50 μg/kg propranolol intravenously produced a decrease of gastrin concentrations from 145 to 127 pg/ml (p < 0. 01) and a total suppression of hyper-gastrinaemia in respons'e to CO₂ rebreathing, suggesting activation of beta-cell receptors in respiratory acidosis. The infusion of phentolamine in a dose of 0. 6 to 1. 8 mg/min. resulted in a rise of gastrin concentration from 140 to 165 pg/ml (p < 0. 01) which was not further elevated during respiratory acidosis. The basal acid secretion showed a significant rise in response to CO2 rebreathing, which was abolished by the administration of propranolol.     

Mean time and first-pass metabolism

Summary The theoretical principles are outlined for estimating the fraction of a drug undergoing first-pass metabolism using only the plasma levels found after a single oral dose. Data for 3 drugs are used to illustrate the method. It involves analysis of the parent drug and the metabolite formed during the first passage through the gut wall and liver and evaluation of their total mean times. The mean time characteristics of molsidomine, nortriptyline and propranolol are considered and they confirm the theoretically deduced dependency of the mean time of the parent drug and the metabolite. Whether the results are more precise than those obtained from comparison of areas after oral and intravenous administration is discussed. From the data presented it is clear that the mean time method depends on the scatter inherent in the data. In order to estimate the true first-pass effect, greater scatter requires an increased number of data pairs, i.e. subjects. If intravenous data are not available, however, the method described provides a rough but worthwhile estimate of the first pass effect.Dedicated to Professor Dr. H.J. Dengler, Bonn, on the ocassion of his 60th birthday