Marianne Frisk-Holmberg

Plasma levels and effects of metoprolol on blood pressure, adrenergic beta receptor blockade, and plasma renin activity in essential hypertension

The effects of metoprolol, a selective beta adrenergic receptor antagonist, on blood pressure, beta receptor blockade (antagonist of isoproterenol and exercise tachycardia), and plasma renin activity (PRA) have been compared with those of placebo in 16 patients with essential hypertension. The dose of metoprolol was 25 mg three times daily for 1 wk and thereafter 100 mg three times daily for 5 wk. The mean decrease in blood pressure during treatment with metoprolol was 24 ± 3.8 (SEM)/10 ± 2.1 mm Hg in the lying position and 23 ± 4.419 ± 3.1 mm Hg after 1 min in the standing position. At a dose of 2.9 to 5.4 mg/kg, steady‐state plasma concentrations of metoprolol varied 17‐fold (from 20 to 341 ng/ml) between patients and correlated with the interindividual variability in isoproterenol antagonism (r = 0.58, p < 0.05) and decrease in exercise tachycardia (r = 0.65, p < 0.01). By contrast, neither of these variables correlated with the dose of metoprolol in mglkg. Metoprolol decreased PRA by 67 ± 1.9 and 71 ± 1.2% in the lying and standing positions, respectively. The decrease in the mean arterial blood pressure in the lying position was significantly correlated to the PRA during the placebo period (r = 0.61, p < 0.05) but not to the plasma steady‐state levels ofmetoprolol, the degree of beta receptor blockade, and the decrease in PRA.

The relationship between the lipophilic nature of tricyclic neuroleptics and antidepressants, and histamine release

Abstract The relative histamine-releasing activity of tricyclic psychoactive drugs, using rat mast cells, was determined. The presence of a halogen or a halogen-containing group at position 2 in the neuroleptics or at position 3 in the antidepressants, and/or carbon instead of nitrogen at position 10 in the neuroleptics or at position 5 in the antidepressants and an unsaturated bond in the aliphatic sidechain increased histamine-releasing activity when compared with unsubstituted homologues. Regarding substitutions of the sidechain the following conclusions for the neuroleptics can be drawn: the presence of a piperidine or piperazine ring in the sidechain increased histamine-releasing activity. From these substituted compounds, those having a methyl group at the terminal nitrogen were more active than homologues with an alcohol group at the nitrogen. For antidepressants, aliphatic tertiary amines were more active than secondary amines. Lipophilic nature was expressed as the partition coefficients of the drugs in a octanol-buffer and chloroform-buffer system. A significant correlation was found, between lipophilic nature and histamine-releasing activity.

Influence of alprenolol on hemodynamic and metabolic responses to prolonged exercise in subjects with hypertension

In 7 young men with essential hypertension, central and regional hemodynamics and leg metabolism were studied at rest, during and after a prolonged exercise, and with and without long‐term alprenolol treatment. Alprenolol (200 mg twice daily) lowered arterial blood pressure. Heart rate decreased in relation to plasma levels during and after exercise. Cardiac output was not significantly influenced, but leg blood flow was reduced at rest. Lipolysis was also attenuated by treatment both at rest and during exercise, and the increment in plasma insulin after exercise was decreased. A reduction in the release of leg muscle lactate was noted during exercise.

Steady-state plasma concentrations of alprenolol in man

SummaryPlasma concentrations of alprenolol during one inter-dose interval and steady-state plasma concentrations have been determined in 30 patients treated for a prolonged period. The latter varied 25-fold between patients who received identical doses. Peak plasma concentrations were achieved at similar times in different patients, but only the level 5–7 h after administration was well correlated (r=0.997) with the steady-state concentration. The type of pharmacokinetic analysis described here is recommended for studies of the relationships between plasma concentration and effects of drugs with short half-lives.

Metabolic effects in muscle during antihypertensive therapy with β1‐ and β1/β2‐adrenoceptor Blockers

The hemodynamic and metabolic consequences of long‐term antihypertensive treatment with β1‐and β1/β2‐andrenoceptor blockade was investigated in five young men with mild essential arterial hypertension (World Health Organization stages I and II) at rest and during submaximal exercise in a single‐blind crossover study. The drugs (atenolol and alprenolol) were given in equipotent doses as estimated from their effects on blood pressure. Leg blood flow and oxygen uptake were the same during both treatment periods. Muscle glycogen decreased by 40% during exercise, irrespective of the drug. There was a positive relationship between muscle lactate release and concentration, but for a given muscle lactate concentration the release tended to be lower during treatment with alprenolol. A negative correlation was observed between the percentage of slow‐twitch fibers versus lactate release and muscle lactate concentration. The results demonstrate that during exercise muscle glycogen breaks down despite beta blockade and is neither reduced when both β1‐ and β2‐receptors are blocked, nor when only the β1‐receptors are blocked. It is also shown that beta blockade impairs the translocation of lactate from the muscle cell to the blood and this is greater with alprenolol than with atenolol, probably due to a membrane effect.

Pharmacokinetics and pharmacodynamics of alprenolol in the treatment of hypertension

SummaryMean steady-state plasma concentrations of alprenolol were studied in relationship to the degree of beta-blockade, in sixteen patients receiving 600 mg daily in divided doses. Steady-state alprenolol concentrations were determined from the area under the plasma concentration-time curve during one eight-hour dosage interval after treatment for six weeks. Beta-blockade during alprenolol treatment was assessed from the chronotropic response to intravenous isoprenaline compared to the response after six weeks of placebo therapy. Although there was interindividual variability in the mean steady-state alprenolol concentration (range 11 — 141 ng/ml), and in the degree of beta-blockade (7-fold), the correlation between the two variables was highly significant (r=0.80, p<0.001). The prescribed dose of alprenolol (mg/kg) was not significantly correlated with the plasma level of alprenolol or the β-blockade. The chronotropic effects of isoprenaline during placebo and alprenolol were significantly interrelated (r=0.79, p<0.001).

Metabolic changes in muscle on long-term alprenolol therapy.

Muscle biopsies from the vastus muscle were taken at rest and immediately after upright bicycle exercise at 50% of the individual VO2max. before and during 6 wk of alprenolol treatment (200 to 400 mg twice daily) in 6 untrained patients with essential hypertension. Resting muscle concentrations (mmole · kg−1 · wet weight) of glycogen, glucose, lactate, and high‐energy phosphates [adenosine triphosphate (ATP) and creatine phosphate (CP)] were not affected by alprenolol treatment, but after 10 min of exercise the glycogenolysis increased and depletion of ATP and CP was enhanced. The relationship between blood and muscle lactate was altered by alprenolol, indicating that alprenolol prevents lactate translocation from the muscle to the blood. The results show that during moderate exercise, leg muscle metabolism is influenced by long‐term antihypertensive therapy.

Lipolysis in canine subcutaneous adipose tissue following release of endogenous histamine

Abstract Compound 48/80 and tubocurarine, which are known to release mast cell histamine in vitro , increased the outflow of histamine from blood-perfused canine subcutaneous adipose tissue in situ . Histamine release was always accompanied by increased lipolysis. Histamine by itself evoked lipolysis both in vitro and in vivo . Second and subsequent injections of either compound 48/80 or tubocurarine were much less effective in releasing histamine and lipolytic products, indicating tachyphylaxis; cross tachyphylaxis between compound 48/80 and tubocurarine also occurred. the results suggest that adipose tissue mast cells might be of importance in the regulation of lipid mobilization by virtue of their histamine content.

Chlorpromazine-induced histamine release and lipolysis in canine adipose tissue in situ

Abstract Chlorpromazine injections, 200–700 μg, and infusions released histamine, free fatty acids and glycerol from blood-perfused canine subcutaneous adipose tissue; concomitantly there was vasodilatation. In addition, chlorpromazine inhibited vasoconstriction induced by sympathetic nerve stimulation. The results demonstrate that chlorpromazine is lipolytic in adipose tissue and suggest that release of endogenous histamine is one mechanism of action.