Influence of propranolol on catecholamine concentration in blood of normotensive man during physical exercise and dependence of the drug effect on dosage intervals.

Physical exercise on a bicycle ergometer caused in normotensive subjects an overshooting increase of plasma noradrenaline and adrenaline concentration, when exercise test was performed during acute or chronic treatment with propranolol both 2 hours after the last intake of the beta receptor blocking agent. At the same time heart rate and blood pressure during exercise were significantly reduced by the drug. But 8 hours after intake of the drug there was a dissociation between the drug effect on plasma catecholamine concentration and its effect on heart rate and blood pressure. While heart rate and blood pressure still were effectively lowered, the influence on plasma catecholamine concentration had already disappeared. The results demonstrate that an increase of plasma catecholamine concentration caused by the adrenergic beta receptor blocking agent propranolol, is strongly dependent on the time interval between measurement of drug effect and the last intake of the drug.

Dopamine-beta-hydroxylase, adrenaline, noradrenaline and dopamine in the venous blood of adrenal gland of man: a comparison with levels in the periphery of the circulation.

In 10 human subjects plasma dopamine-beta-hydroxylase activity was found in the adrenal vein blood to be as high as in the periphery of the circulation. Adrenaline concentration in the adrenal vein blood was in the mean 170 times, noradrenaline concentration 11 times and dopamine concentration little higher than levels in the periphery.

[Increase of renal failure after treatment of malignant hypertension by captopril (author's transl)]. / Zunehmende Niereninsuffizienz nach Blutdrucksenkung mit Captopril bei maligner Hypertonie.

In a 25-year-old woman with malignant hypertension based on primary nephrosclerosis, captopril, an oral inhibitor of angiotension I-converting enzyme, lowered blood pressure effectively, which had been resistant previously to other oral antihypertensive drugs. Concomitantly with the decrease of the high blood pressure, an increase of creatinine from 2.1 mg% to 8.5 mg% occurred. There is evidence that this increase of renal failure is a consequence of blood pressure reduction and is not caused by a toxic effect of captopril.

[Clonidine-diuretic combination in patients with essential hypertension. Modification of sympathetic activity and blood pressure as well as the reaction following sudden withdrawal]. / Clonidin-Diuretikum-Kombination bei Patienten mit essentieller Hypertonie. Beeinflussung von Sympathikusaktivität und Blutdruck sowie Reaktion nach plötzlichem Absetzen.

In ten patients with essential hypertension, 6 weeks of treatment with a clonidine/diuretic combination (1 retard capsule/day, 75 micrograms or 150 micrograms clonidine, and 15 mg chlortalidon) was suddenly discontinued. The blood pressure, heart rate and sympathetic tone were monitored via the noradrenaline level (NA) in the blood. The six-week treatment with an average of 97.5 micrograms clonidine and 15 mg chlortalidon/day, reduced the NA blood level from 0.48 to 0.37 ng/ml, the blood pressure from 167/102 to 142/86 mmHg, and the heart rate from 73 to 69 bpm. On the second day after termination of therapy, the NA level had increased, on average, 35% above the initial value in 4 out of the 10 patients. In the remaining six patients, the NA level was increased only slightly, and remained markedly below the pre-treatment levels. The blood pressure, however, remained below its initial levels throughout the whole of the two-week observation period. During the phase of increased sympathetic activity, the patients experienced no symptoms. The results show that even after discontinuation of a very low dose of clonidine, some patients can be expected to show a mild increase in sympathetic tone which however would seem to have no clinical significance.

Plasma catecholamine concentration in hypertensive subjects with chronic renal failure before and during treatment with the beta-receptor blocking drug metipranolol.

In seven male hypertensive patients with chronic renal failure (serum creatinine level 6.9 +/- 4.1 mg%) plasma catecholamine levels were in the same range as in five normotensive healthy volunteers. Treatment with the beta-receptor blocker metipranolol (2 x 20 mg/day orally for 2 weeks) significantly elevated plasma catecholamine levels in the hypertensive patients with chronic renal failure, but not in the healthy volunteers. Blood pressure and heart rate were reduced in both groups.

Response of plasma catecholamines and blood pressure to clonidine and to sudden withdrawal of the drug in subjects with essential hypertension.

In this retrospective study in ten patients with essential hypertension a short-time treatment of 3 days with 0.15 mg clonidine 2 times/day orally, as well as a second short-term treatment period with the slow-release oral preparation (.025 mg clonidine once/day) significantly lowered blood pressure, heart rate, and plasma concentration of norepinephrine in the supine and standing subject. After sudden withdrawal of clonidine all these parameters returned to pretreatment levels within 2-3 days. No rebound or overshoot phenomenon was observed.

Antihypertensive effects, plasma levels and beta-adrenergi blocking activity of racemic and dextrorotatory propranolol in man.

In hypertensive patients, whose blood pressure was decreased by racemic propranolol, the dextrorotatory isomer had no antihypertensive effect. The differences in antihypertensive activity of racemic and dextrorotatory propranolol cannot be explained by different plasma levels. The data indicate that the hypotensive effect of propranolol is due to beta-receptor blockade.

Plasma catecholamines in children.

Plasma catecholamine concentrations in 46 children of various ages were determined by a sensitive radioenzymatic assay. Noradrenaline levels were found to be in the same range as in adults, whereas adrenaline levels in a few of the children were abnormally high.

Studies on the effects of propanolol on plasma catecholamine levels in patients with essential hypertension.

The influence of the beta receptor blocking agent propranolol on plasma catecholamine concentrations was studied in eight patients with essential hypertension. The study was of single blind crossover design. Propranolol given in oral doses ranging from 60 to 240 mg daily for a period of 3 weeks decreased blood pressure and heart rate. The beta-adrenergic blocking agent caused plasma catecholamine levels to increase both at rest and during bicycle exercise. Chromatographical analysis showed that concentrations of noradrenaline as well as of adrenaline rose during treatment with propranolol. However, dopamine-beta-hydroxylase activity in plasma was not altered. Furthermore, the urinary excretion of noradrenaline, adrenaline and 4-hydroxy-3-methoxy mandelic acid did not change during beta receptor blockade. The results are compatible with the assumption that antihypertensive doses of propranolol by decreasing cardiac output cause an activation of the sympatho-adrenal system.

Excretion of norephedrine by man after oral administration of oxyfedrine.

After oral administration of oxyfedrine to healthy volunteers, norephedrine was identified in the urine by thin layer chromatography and gas liquid chromatography and mass spectrography. 30 hours after single oral doses of 8, 16 or 24 mg of oxyfedrine, about 4, 8 and 9 mg, respectively, of norephedrine were found in the urine, i.e. on a molar base 75-100% of the dose was excreted as norephedrine. The peak of excretion occurred within 2-4 hours after administration of the drug. No accumulation of oxyfedrine and/or its metabolite was observed after administration of 16 mg of oxyfedrine t.i.d. for three days. It could not be decided whether oxyfedrine was metabolized to norephedrine by liver enzymes, as in rats, or was spontaneously degraded to norephedrine, e.g. in duodenal fluid before absorption. 30-150 min after oral oxyfedrine (24 mg) norephedrine was demonstrable in duodenal fluid. Thus, in addition to the direct beta-sympathomimetic effects of oxyfedrine, it may also have indirect sympathomimetic effects because of the noradrenaline-releasing properties of its metabolite norephedrine.

Correlation between increased dopamine-beta-hydroxylase activity and catecholamine concentration in plasma: determination of acute changes in sympathetic activity in man.

In 11 healthy untrained volunteers the increase in plasma dopamine-beta-hydroxylase (DBH) activity during graded physical exercise has been examined as a true measure of increased activity of the sympathetic nervous system. The correlation between DBH activity, catecholamine concentration (CA) in plasma and heart rate was studied. When work on an electrically braked bicycle ergometer was gradually increased from 12.5 to 100, 200 and 300 watts there was a linear increase in DBH activity and heart rate; the increase in CA concentrations followed an exponential function. The peak values for DBH activity and CA concentration in plasma after the 300 watt work load (as percentages of the resting levels) were 130+/-3% and 820+/-71%, respectively; the adrenaline concentration in plasma increased only to 150+/-19% (p less than 0.05). There were significant correlations between heart rate and work load, DBH and work load and log CA and work load. The data imply direct correlations between heart rate and DBH, heart rate and log CA and DBH and log CA. The exponential increase in noradrenaline concentration in plasma might be due either to a greater net ""overflow'' from sympathetic nerve endings, and/or to increased secretion by the adrenal medulla. In the latter case, the release of noradrenaline would not be accompanied by secretion either of adrenaline or DBH. After work ceased there were sharp falls in heart rate and CA concentration, which indicate an immediate drop in sympathetic activity. DBH activity in plasma returned to normal very slowly; it reached half maximum values after 20-22 min. It is concluded that increased sympathetic activity in man can be estimated in vivo as changes in DBH and/or CA concentration in plasma. In contrast, a rapid decrease in sympathetic activity is directly reflected only by a rapid fall in the plasma concentrations of CA.

[Number and kinds of drug side-effects in a medical clinic (author's transl)]. / Zahl und Art von Arzneimittelnebenwirkungen in einer Medizinischen Klinik

All drug side-effects - definite, probable and suspected - were noted during one year in 1592 patients. The severity of the side-effects was classified into mild (15%), moderate (6.5%), and severe (1%) forms. Fatal side-effects occurred without exception only in those patients who were severely ill so that any risk of treatment had been fully justified. Among patients with renal failure, malignant haematological diseases or Hodgkin's disease there was a particularly high incidence of side-effects. Although the proportion of the latter patients was only 15% of all in-patients, they accounted for 35% of patients with side-effects.

A comparison of catecholamine concentrations and dopamine-beta-hydroxylase activities in plasma from normotensive subjects and from patients with essential hypertension at rest and during exercise.

In 8 normotensive subjects and in 8 patients with essential hypertension total catecholamine content and dopamine-beta-hydroxylase (DBH) activity in plasma were measured at rest and during physical exercise. Catecholamine levels at rest were significantly higher in the hypertensive than in the normotensive persons whereas the 2 groups of subjects did not differ in DBH activity at rest. At a work load of 150 watts there was a more pronounced increase of the catecholamine concentrations and of the DBH activity in the hypertensive patients than in the normotensives. One may conclude from the data that there is an increased sympathetic nerve activity in patients with essential hypertension.

[Specific and non-specific effects of beta-adreno-receptor blocking drugs in man (author's transl)]. / Spezifische und unspezifische Wirkungen von beta-Sympatholytika am Menschen

The effect of tyramine infusion or exercise on catecholamine concentration and dopamine-beta-hydroxylase activity in plasma of normal volunteers has been studied. Whereas the increase in plasma catecholamine concentrations by tyramine infusion was not changed 90 min after oral application of a single dose of beta-adrenoceptor blocking drugs (penbutolol, practolol, I.C.I. 66082), the increase in blood pressure was diminished. However, the increase in plasma catecholamine, concentration, i.e. the adrenergic response to exercise was significantly enhanced during beta-adrenoceptor blockade. On the other hand, dopamine-beta-hydroxylase activity was not further increased during beta-adrenoceptor blockade. - The non-specific membrane activity of the beta-adrenoceptor blocking drugs wass assessed by the degree of inhibition of serotonin uptake by human platelets in vitro. Their order of potency, according to IC 50 values estimated from the dose response curves was: propranolol less than penbutolol less than practolol less than I.C.I. 66082. The inhibitory activity of these drugs in vivo was also studied by measuring serotonin uptake by platelets isolated 90 min after oral administration. Due to the high dose only propranolol showed a marked membrane activity.