Chronic treatment with propranolol enhances the synthesis of prostaglandins E2 and I2 by the aorta of spontaneously hypertensive rats.

The effects of treatment with dl, d- or l-propranolol (subcutaneously for 1 week) on arterial blood pressure and on 6-keto prostaglandin (PG) F1 alpha (stable metabolite of PGI2) and PGE2 production by aorta, renal medulla and renal cortex were examined in spontaneously hypertensive rats. dl-Propranolol and l-propranolol significantly (P less than .05) lowered blood pressures from 148 +/- 9/113 +/- 5 (n = 6) and 133 +/- 4/100 +/- 2 (n = 12) mm Hg to 112 +/- 3/80 +/- 3 and 121 +/- 3/81 +/- 3 mm Hg, respectively. Comparable treatment of spontaneously hypertensive rats with inactive d-propranolol was without effect. Basal immunoreactive (i) i6-keto-PGF1 alpha and iPGE2 production by isolated aorta, renal medulla and cortex was not different in vehicle compared to the dl-propranolol-treated rats. In contrast, norepinephrine (1 microM)-stimulated synthesis of i6-keto PGF1 alpha and iPGE2 by the aorta in the dl-propranolol-treated group was significantly (P less than .05) enhanced compared with the vehicle-treated group. Aortic i6-keto-PGF1 alpha and iPGE2 synthesis stimulated by norepinephrine in l-propranolol-treated rats was also significantly (P less than .05) higher than that observed in vehicle and d-propranolol-treated rats. dl-Propranolol treatment did not alter norepinephrine-stimulated renal cortical or medullary i6-keto-PGF1 alpha or iPGE2 synthesis. Indomethacin (5 mg/kg i.p.) given on the last 2 days of dl-propranolol treatment, significantly inhibited aortic i6-keto-PGF1 alpha and iPGE2 production and blunted the antihypertensive effect of dl-propranolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics and metabolism of oral doses of a 4'-methylthio derivative of propranolol in man.

1. The objective of this study was to determine the oral dose pharmacokinetics and metabolism of 4'-methylthiopropranolol (MTP) in man and compare the results with observations for propranolol in previous studies. 2. Three women and five men received single oral doses of MTP, dose range 5-320 mg. Plasma concentration of MTP over time were measured by gas chromatography-mass spectrometry. MTP metabolites in urine were identified by comparative high-performance liquid chromatographic (HPLC) retention times and mass spectrometry with previously characterized reference compounds and quantified by HPLC. 3. The oral clearance of MTP of 1.2-1.4 l/min for the 80, 160 and 320 mg doses was about one third of the value previously reported for propranolol. The half-life for MTP (3.3-4.1 h) was, however, similar to that of propranolol. In contrast to propranolol, the peak (2.5 h) plasma concentrations of MTP increased linearly with dose (5-320 mg). 4. The oral clearance for MTP was about 2-fold higher in the men than in the women (P less than 0.01). In addition, the clearance of the (S)-enantiomer was about 30% higher than that of the (R)-enantiomer (P less than 0.05), which was a reversal of that seen with propranolol. 5. The metabolism of MTP resulted mainly in sulphur oxidation to sulphoxide and sulphone metabolites. These two metabolites accounted for 75% of the MTP dose. This switching from aromatic carbon oxidation for propranolol to sulphur oxidation for MTP is proposed as the basis of the lower oral clearance of MTP. 6. This study also demonstrated higher plasma binding of MTP (unbound fraction 3.7%) than of propranolol (10.5%; P less than 0.01), a factor probably contributing to decreased tissue distribution of MTP.

A stereoselective central hypotensive action of atenolol.

Previous studies have demonstrated that propranolol can lower arterial pressure through an action within the central nervous system. The purpose of this study was to determine 1) whether the hydrophilic beta blocking drug atenolol which is devoid of membrane stabilizing activity can reduce arterial pressure through a central action and 2) whether this action is stereoselective for the (-)-, or beta receptor blocking enantiomer. Studies were conducted in the anesthetized spontaneously hypertensive (SH) rats in which the cardiovascular effects of (-)- and (+)- atenolol were compared after i.v. or intracisternal administration. Intravenous injection of 100 micrograms/kg of (-)-atenolol reduced mean arterial pressure 25 +/- 5 mm Hg (P less than .02) and lowered heart rate 58 +/- 7 bpm (P less than .02). The same dose of (+)-atenolol i.v. produced no significant changes in either mean arterial pressure or heart rate. Similarly, intracisternal (-)-atenolol, 66 micrograms/kg, significantly (P less than .05) reduced mean arterial pressure and heart rate whereas the same dose of the (+)-isomer was without effect. When the i.v. dose of (-)-atenolol was lowered to 33 micrograms/kg, heart rate was decreased markedly but mean arterial pressure was not reduced. In contrast, 33 micrograms/kg of intracisternal (-)- atenolol significantly reduced mean arterial pressure 17 +/- 6 mm Hg and reduced heart rate. These results suggest that atenolol possesses a central hypotensive action that is selective for the (-)-, beta receptor blocking enantiomer.

Stereoselective uptake of atenolol into storage granules isolated from PC12 cells.

Atenolol has been shown to be stored and secreted from PC12 cells by calcium-dependent and stereoselective mechanisms. The present study was designed to determine if the cytoplasmic amine storage granule was the site for storage and release of atenolol and if the drug was, in fact, an enantiomeric selective substrate for the vesicular amine transport protein. Uptake of racemic [3H]atenolol and (-)-[3H]norepinephrine was studied in a vesicular preparation of storage granules isolated from PC12 cells. Uptake of both molecules was found to be ATP-dependent (80%) and to reach steady state in approximately 10 to 15 min. Uptake and storage was inhibited (95%) by either reserpine, an inhibitor of the vesicular amine carrier, or by nigericin which dissipates the proton gradient across the membrane. Uptake of neither compound was inhibited by desipramine, an inhibitor of uptake 1, or oligomycin, an inhibitor of mitochondrial adenosine triphosphatase. Furthermore, uptake of the (-)-enantiomer of atenolol was found to be approximately 5-fold greater than the (+)-enantiomer. Kinetic studies revealed a Km of 184 microM for (+/-)-atenolol and 79 microM for (-)-norepinephrine and Vmax values of 750 and 503 pmol/min/mg of protein for atenolol and norepinephrine, respectively. The interaction of the two compounds with the transport process was found to be kinetically competitive. In separate experiments, atenolol was also found to be transported stereoselectively into bovine adrenal chromaffin granule ghosts and to be ATP dependent (85%) and reserpine sensitive (44%).(ABSTRACT TRUNCATED AT 250 WORDS)

Stereoselective secretion of atenolol from PC12 cells.

Stereoselective storage and release of the cardioselective beta adrenergic receptor antagonist atenolol was studied using cultured PC12 cells as a neural model. [3H]Atenolol efflux from preloaded PC12 cells was increased 4-fold in response to membrane depolarization by elevated extracellular potassium (50 mM). [3H]Norepinephrine release was enhanced 4.5-fold under the same conditions. Potassium-induced release of both [3H] atenolol and [3H]norepinephrine was inhibited completely in the absence of extracellular calcium. [3H]Atenolol release from PC12 cells was also reduced by the calcium channel antagonist nifedipine (IC50 = 1.6 +/- 0.5 nM). In addition, the calcium channel agonist BAY K8644 (1 microM) significantly enhanced potassium-induced [3H]atenolol efflux. After loading overnight, accumulation and storage of the (-)-enantiomer of atenolol by PC12 cells was found to be approximately 3-fold greater than that of the (+)-enantiomer. The (-)-enantiomer of atenolol was also preferentially released by 50 mM potassium with a (-)/(+)-enantiomer ratio of 3.6 to 1. The results support the existence within neurosecretory cells of storage and calcium-dependent release mechanisms which result in stereoselective secretion of the (-)-or active enantiomer of atenolol in response to membrane depolarization.

Inhibitors of prostaglandin synthesis reverse the effects of chronic beta-receptor blockade to attenuate adrenergic neurovascular transmission in dogs.

The effects of acute and chronic treatment with beta-adrenergic receptor blocking drugs on peripheral adrenergic neurovascular transmission were investigated. Experiments were performed using the blood perfused gracilis muscle preparation in control dogs and in animals treated with single or repeated doses of beta-receptor antagonists. After 7 days of d,l-propranolol, l-propranolol, or atenolol administration, the arterial pressor response to sympathetic nerve stimulation was significantly reduced in treated dogs (p less than 0.05) when compared with control- or d-propranolol-treated animals. In comparison, acute beta blockade produced by a single intravenous dose of propranolol had no effect on the pressor response to nerve stimulation. Inhibition of fatty acid-cyclooxygenase activity by indomethacin or piroxicam enhanced the vasoconstrictor response to sympathetic nerve stimulation in chronic d,l-propranolol-, l-propranolol-, and atenolol-treated dogs, but had no effect on vascular neurotransmission in control-, chronic d-propranolol-, or acutely d,l-propranolol-treated animals. The vasoconstrictor response to intraarterial phenylephrine was not significantly altered by chronic propranolol treatment, and measurement of norepinephrine overflow during sympathetic nerve stimulation failed to reveal any difference in neurotransmitter release between control- and propranolol-treated dogs. The results indicate that chronic but not acute beta-adrenergic receptor blockade alters signaling at the neurovascular synapse to diminish adrenergic transmission. This effect does not appear to result from a change in postsynaptic alpha 1 receptors or from a decrease in norepinephrine release.(ABSTRACT TRUNCATED AT 250 WORDS)

C1 area of the rostral ventrolateral medulla as a site for the central hypotensive action of propranolol.

Previous studies suggest that the hypotensive response to centrally administered propranolol results from a drug-induced release of norepinephrine which then stimulates central alpha adrenergic receptors and, as a consequence, arterial pressure is lowered. Inasmuch as the C1 area of the rostral ventrolateral medulla is known to contain noradrenergic nerve terminals and participate in arterial pressure regulation, we determined whether this medullary region is a site mediating the hypotensive response to centrally administered propranolol. Bilateral microinjections (0.1 microliter) of dl-propranolol (0.25-2 nmol) into the C1 area of urethane-anesthetized rats resulted in a gradual reduction in mean arterial pressure which was sustained throughout the 120-min experimental period. The injection site was verified pharmacologically at the end of each experiment by bilateral microinjection of 10 nmol of tyramine and observing a further decrease in mean arterial pressure and a reduction in heart rate. Pretreatment of the C1 area bilaterally with reserpine 24 hr earlier significantly reduced the hypotensive responses to microinjections of both propranolol and tyramine whereas the hypotensive response to the direct acting agonist clonidine was unchanged. These results demonstrate that the C1 area of the rostral ventrolateral medulla is a site for a central hypotensive action of propranolol. Moreover, the data provide further evidence that the hypotensive action of centrally administered propranolol results from a drug-induced release of norepinephrine from central noradrenergic neurons.

Stereoselective delivery and actions of beta receptor antagonists.

These studies have revealed that the delivery and actions of beta receptor antagonist drugs are controlled by a cascade of stereoselective processes involving multiple enzymes, transport proteins and receptors. In essence, the free concentration of the pharmacologically active (-)-enantiomer species of these drugs presented to cell surface beta receptors appears to be a function of the stereoselective clearance by hepatic cytochrome P-450 isoenzymes, enantiomer selective binding to alpha 1-acid glycoprotein and albumin and perhaps predominantly by stereoselective sequestration (and release) by the vesicular amine transport protein within adrenergic neurons. Stereoselectivity in the clearance of beta blocking drugs, which can favor either the (+)- or (-)-enantiomer, only appears to be important for the lipophilic drugs which are cleared by hepatic metabolism. Such stereoselectivity is due to differential stereochemical substrate requirements of individual hepatic cytochrome P-450 isoenzymes. Interindividual variations in the stereoselectivity can occur as a result of differences in the amount and expression of cytochrome P-450 isoenzymes due to genetic predisposition or other factors. In the same context, we have observed a significant correlation between the extent and stereoselectivity of binding of beta blocking drugs to plasma proteins. This is another finding which suggests that variability in the expression of individual proteins involved in the beta blocking drug-protein cascade determines the free concentration of the pharmacologically active enantiomer. However, since most observations have been made in young normal subjects, the extent of stereoselectivity in metabolism, binding and other processes is unknown in the general population where steady-state plasma concentrations can vary widely due to multiple biological factors. The observations from neural studies support the concept that adrenergic nerve endings provide a depot for the stereoselective storage and release of the active enantiomer of beta receptor antagonists. The mechanism of this release appears to involve exocytotic secretion of drug that has been stereoselectively accumulated by the neurotransmitter storage vesicles. In terms of this idea, beta receptor antagonists released during nerve stimulation may achieve concentrations of the (-)-enantiomer within the adrenergic synapse greatly in excess of those found in plasma. Such a mechanism could significantly influence both the intensity and duration of beta receptor blockade in the heart, blood vessels, brain and other target tissues.(ABSTRACT TRUNCATED AT 400 WORDS)

Selective induction of propranolol metabolism by smoking: additional effects on renal clearance of metabolites.

The objective of this study was to examine the effect of cigarette smoking on the activities of the three primary pathways governing propranolol metabolism in human subjects, i.e., glucuronidation, side-chain oxidation and ring oxidation. A single 80-mg dose of propranolol p.o. together with 40 muCi of 4-[3H]propranolol was given to six smoking and seven nonsmoking, young, white, male subjects and the oral clearance of propranolol and the partial clearances through these pathways were determined. The oral clearance of propranolol was increased by 77% (P less than .02) in smokers compared with nonsmokers. This apparent induction of propranolol metabolism was due to a 122% increase in side-chain oxidation (P less than .001) and a 55% increase in glucuronidation (P less than .01). There was no significant effect of smoking on aromatic ring oxidation. Smokers had a 30% greater renal clearance of total metabolites (P less than .05), due mainly to a 53% greater renal clearance of the acidic propranolol metabolite naphthoxylactic acid (P less than .001). These data show a selective effect of smoking on propranolol metabolism and suggest that side-chain oxidation and glucuronidation are mediated by isoenzymes inducible by aromatic hydrocarbons. The selective effect of smoking on the renal clearance of the major propranolol metabolite naphthoxylactic acid may be due to induction of a renal transport protein.

Increased clearance of propranolol and theophylline by high-protein compared with high-carbohydrate diet.

The objective of this study was to determine whether changes in dietary protein and carbohydrate influence the oral clearance of propranolol, a high-clearance drug, and theophylline, a low-clearance drug. Six normal subjects studied in a clinical research center each received a single oral dose of propranolol, 80 mg, and theophylline, 5 mg/kg, after having been on each of two well-defined diets for a period of 10 days. When the diet was altered from high carbohydrate/low protein to low carbohydrate/high protein, the oral clearance of propranolol increased by 74% +/- 20% (mean +/- SE; range 9% to 156%; P less than 0.01) with no change in plasma half-life or plasma binding. This dietary change resulted in an increase in theophylline clearance of 32% +/- 6% (range 18% to 50%; P less than 0.02) and a corresponding decrease in plasma half-life of 26% +/- 6% (range 6% to 42%; P less than 0.05) with no alteration in the apparent volume of distribution. These observations reemphasize the importance of diet in drug disposition and suggest that the clearance of high-clearance drugs like propranolol is more susceptible than the clearance of low-clearance drugs to dietary manipulations, effects that may have to be considered in drug therapy.

Postprandial alterations in hemodynamics and blood pressure in normal subjects.

The effects of a standardized mixed meal, a self-selected meal and a sham meal on heart rate, arterial pressure, cardiac output, total systemic resistance and echocardiographic indexes of left ventricular performance were examined in normal volunteers. Supine heart rate and cardiac output increased after the meals (p less than 0.07 to 0.001), but not after the sham meal. Supine diastolic blood pressure and total systemic resistance decreased after the meals but not after the sham meal (p less than 0.05 to 0.001). Ejection fraction and mean velocity of circumferential fiber shortening increased after the standard meal (p less than 0.01) and tended to increase after the self-selected meal, but did not increase after the sham meal. Meals of normal size may induce splanchnic vasodilation and a decrease in total systemic resistance. Ingestion of food also significantly affects heart rate, blood pressure, cardiac output and echocardiographic indexes of left ventricular performance. Patients should not eat during short-term evaluation of cardiovascular interventions because the cardiovascular effects of a meal may compromise interpretation of the cardiovascular effects of the primary intervention. The hemodynamic effects of food may also interact with the effects of cardiovascular disease processes.

Acute hypotensive effects of oral and intravenous propranolol: early alterations in peripheral resistance.

The effects of single oral and intravenous doses of propranolol on blood pressure and hemodynamics were measured in normal volunteers. Systolic and diastolic blood pressure decreased 10% within 3 hours after the oral dose and by 3%-5% after the intravenous dose. Cardiac output decreased 16% after the intravenous dose and 10% after the oral dose. Total peripheral resistance transiently increased by 23% after the intravenous, but not after the oral dose. Change in mean arterial pressure was positively correlated with change in total peripheral resistance after both the oral and intravenous doses. In contrast, change in mean arterial pressure was negatively correlated with change in cardiac output after the intravenous dose. Single oral and intravenous doses of propranolol lowered blood pressure within 3 hours after administration, and the reduction was correlated with change in total peripheral resistance and not with change in cardiac output. At least part of the adaptation in peripheral resistance occurs within the first 3 hours after both oral and intravenous single doses of propranolol.

Synthesis of 4'-hydroxypropranolol sulfate, a major non-beta-blocking propranolol metabolite in man.

4'-Hydroxypropranolol sulfate was recently identified as a major metabolite of propranolol (Inderal). In order to confirm the structure and to further study disposition and biological activity, we have synthesized 8 with use of 1,4-naphthoquinone as the starting material. Reduction and alkylation with benzyl iodide gave 4-(benzyloxy)naphthol. Sulfation and chlorosulfuric acid in N,N-dimethylaniline gave potassium 1-(benzyloxy)-4-naphthol sulfate. Catalytic hydrogenation, alkylation with [[[(trifluoromethyl)sulfonyl]oxy]methyl]oxirane, and amination in isopropylamine gave 8. Racemic 8 was found to be 100-1000 times less potent than racemic propranolol as a beta-adrenergic receptor blocking agent in the dog.

Depolarization-induced release of propranolol and atenolol from rat cortical synaptosomes.

The accumulation and release of [3H]-propranolol and [3H]-atenolol were examined in synaptosomes from rat cerebral cortex. Synaptosomes accumulated 20 pmol propranolol and 0.6 pmol atenolol mg-1 protein when incubated at 30 degrees C with radiolabelled drugs (0.1 microM). Exposure of propranolol-loaded synaptosomes to elevated K+, Rb+ or Cs+ evoked a concentration-dependent increase in propranolol efflux. The action of these ions in releasing propranolol was highly correlated with their ability to produce synaptosomal membrane depolarization, as estimated with the voltage-sensitive dye diS-C3-(5). Elevated K+ also promoted atenolol release from synaptosomes in a concentration-dependent manner. Veratridine (10 microM) released propranolol and atenolol from synaptosomes and these effects were antagonized by tetrodotoxin (1 microM). Under Ca2+-free conditions, K+-induced release of propranolol was reduced by 37% and atenolol release was diminished by 68%. The results support the concept that both polar and non-polar beta-adrenoceptor blocking drugs may be accumulated by nerve endings for release by membrane depolarization and suggest that neural storage and release of these molecules may influence their concentrations at localized sites of action.

Stereoselective ring oxidation of propranolol in man.

The objective of this study was to elucidate stereoselective mechanisms of propranolol metabolism in man. Five normal subjects were given single 80 mg oral doses of deuterium-labeled pseudoracemates of propranolol, and the stereochemical composition of propranolol and its major metabolites in urine was determined by GC/MS. The (-)/(+)-enantiomer ratios for unchanged propranolol, 1.50 +/- 0.10 (mean +/- s.e. mean), and propranolol glucuronide, 1.76 +/- 0.10, were similar to previous findings in plasma. All products of side-chain oxidation also consisted mainly of the (-)-enantiomer, with an overall (-)/(+) ratio of 1.61 +/- 0.11. A (-)/(+) ratio of 1.04 +/- 0.17 for 4-hydroxypropranolol did not indicate stereoselectivity in ring oxidation. However, the ratio for its glucuronic acid conjugate of 1.78 +/- 0.19 and for its sulphate conjugate of 0.27 +/- 0.03 suggested stereoselectivity in either the glucuronidation or sulphation of 4-hydroxypropranolol, or both. When the stereoselectivity in these secondary pathways was taken into consideration, the overall ring oxidation strongly favoured (+)-propranolol with a (-)/(+)-enantiomer ratio of 0.59 +/- 0.09. The composite observations of the stereochemistry of propranolol metabolism in man are consistent with stereoselective ring oxidation of (+)-propranolol, leading to a greater bioavailability of the pharmacologically more active (-)-propranolol and subsequent preferential side-chain oxidation and glucuronidation of this enantiomer.

Stereoselective clearance and distribution of intravenous propranolol.

Our objective was to determine the kinetics of (+)- and (-)-propranolol after intravenous doses of racemic drug. Five normal subjects received 0.1 mg/kg of a pseudoracemate of propranolol that consisted of deuterium-labeled (+)-propranolol and unlabeled (-)-propranolol. Plasma concentrations of (+)- and (-)-propranolol as measured by gas chromatography-mass spectrometry demonstrated enantiomeric differences in systemic clearance (Cls) [(+)-propranolol, 1.21 +/- 0.15 l/min; (-)-propranolol, 1.03 +/- 0.12 l/min; P less than 0.01] and apparent volume of distribution (Vd) [(+)-propranolol, 4.82 +/- 0.34 l/kg; (-)-propranolol, 4.08 +/- 0.33 l/kg; P less than 0.001], but no difference in distribution or elimination t1/2s (t1/2 beta 3.5 hr). The higher Cls of (+)-propranolol suggests stereoselective hepatic elimination. The higher apparent Vd of (+)-propranolol is mainly related to its lower plasma binding [(+)-propranolol, 20.3 +/- 0.8% unbound; (-)-propranolol, 17.6 +/- 0.7% unbound; P less than 0.001]. There was no stereoselective uptake by red blood cells. These findings demonstrate that multiple stereoselective mechanisms are involved in the disposition of propranolol and determine the access of the drug to active sites.

Accumulation, subcellular localization and release of propranolol from synaptosomes of rat cerebral cortex.

Propranolol is accumulated at several adrenergic neuroeffector junctions after chronic oral administration in the dog, and is released subsequently during sympathetic nerve stimulation. In the present study, the accumulation, subcellular localization and release of propranolol was examined in rat cortical synaptosomes. Synaptosomal propranolol accumulation was rapid and attained equilibrium within 1 min. Propranolol uptake increased in a nonlinear manner with increasing drug concentration in the medium, but could not be fully saturated over the concentration range studied (10(-7) - 10(-3) M). Uptake was unaffected by cocaine or ouabain and showed no stereoselectivity. Subsynaptosomal fractionation of propranolol-loaded synaptosomes revealed that the drug was concentrated principally in fractions enriched in synaptic plasma membranes and synaptic storage vesicles. Exposure of propranolol-loaded synaptosomes to elevated potassium evoked a concentration-dependent increase in propranolol overflow, which was not seen in mitochondrial fractions, myelin fractions or in freeze-thawed synaptosomal preparations. Veratridine was also effective in promoting propranolol overflow in a concentration-dependent manner. The increase in propranolol overflow induced by elevated potassium was significantly reduced, but not completely inhibited, in a calcium-free, ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid-supplemented medium. These results indicate that propranolol may be accumulated by neuronal tissue and stored at sites from which release may occur in response to depolarizing stimuli. The data further suggest that propranolol release in the synaptosome preparation may occur by both calcium-dependent and calcium-independent processes.

Exercise-induced increments in plasma levels of propranolol and noradrenaline.

Exercise-induced changes in the plasma levels of propranolol and noradrenaline were determined in nine volunteers. Total plasma propranolol levels were increased during submaximal treadmill exercise, with exercise-induced increments of 13 +/- 4% at 4 h after the last dose, 18 +/- 7% at 9 h and 41 +/- 5% at 16 h. Exercise-induced increments in plasma propranolol were observed after single as well as repeated doses. During exercise, increments in plasma propranolol were correlated temporally with changes in plasma noradrenaline. Exercise-induced increments in plasma noradrenaline were greater during propranolol administration than during placebo periods. The changes in plasma propranolol concentration during exercise may reflect a redistribution of propranolol at its site(s) of action.

Time course of development of the antihypertensive effect of propranolol.

Ten patients with essential hypertension were hospitalized and treated with placebo, followed by their usual dose of propranolol. Systolic and diastolic blood pressure decreased significantly after the first dose of propranolol, and by the third day of propranolol treatment reached 84% to 92% of the maximum decrease achieved during the 6 days of treatment. Mean maximum falls in blood pressure were 13/12 mm Hg supine and 12/13 mm Hg standing. This development of the decrease in heart rate and blood pressure over 48 hours occurred in parallel with cumulation of propranolol to steady state in plasma. The decrease in diastolic, but not systolic, arterial pressure was directly related to pretreatment blood pressure, but not significantly related to pretreatment plasma renin activity (PRA) or change in PRA. Thus, single doses of propranolol lowered blood pressure in patients with essential hypertension, and with continued therapy, near maximum antihypertensive effects were achieved within 48 hours.