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PubMed1983

In vitro binding of propranolol and progesterone to native and desialylated human orosomucoid.

A comparison of propranolol and progesterone binding to native and desialylated human orosomucoid was studied by means of equilibrium dialysis. The association constants of propranolol and progesterone binding to native human orosomucoid under physiological conditions were 8.4 X 10(5) and 3.2 X 10(5) M-1, respectively. Enzymatic desialylation of human orosomucoid removed 95% of the sialic acid content and reduced the binding affinity of propranolol from 8.4 X 10(5) to 6.0 X 10(5) M-1, but the affinity of progesterone was not affected. In addition, desialylation reduced the percent binding for propranolol, indicating that electrostatic attraction of the positive charge on propranolol by sialic acid residues on human orosomucoid had some effect on the binding ability of purified orosomucoid for propranolol. The present data suggest that the electrostatic attraction between sialic acid and propranolol is partially responsible for the preferential binding of basic drugs to orosomucoid in plasma.

Dialysis↗
PubMed1986

Nonstereoselective aspects of propranolol pharmacodynamics.

Twenty years after its discovery, the beta-adrenergic blocking agent propranolol continues to interest pharmacologists and clinicians. Its therapeutic profile has extended to areas beyond the purview of the cardiovascular system, and its ocular and central nervous system effects have been well documented. In addition, it still remains a very good pharmacological tool to map out the adrenergic beta-receptors in the body, and stereoisomers of propranolol and other beta-blockers serve as valuable agents to distinguish between the effects related to beta-adrenoceptors and those which are not. The primary purpose of this review is to summarize the evidence indicating that beta-adrenergic blocking agents lack stereoselectivity in some of their effects, including several of considerable therapeutic importance. Because many pharmacological actions of propranolol followed a nonsteroselective pattern, the involvement of beta-adrenoceptors in them was questioned and this led to the search for alternate mechanisms to explain these effects. Studies with propranolol and some related drugs indicated the involvement of a cholinergic mechanism in their antiarrhythmic, ocular hypotensive and some central effects. Also, a presynaptic inhibitory effect at the skeletal neuromuscular junction has been suggested to explain the benefical effect of propranolol and other beta-blockers in tremor. Biochemical studies with these drugs revealed their inhibitory action on the cholinesterase enzyme in blood and other tissues like myocardium and brain. It is thus hypothesized that modulation of cholinergic neurotransmission by propranolol could explain some of its nonstereoselective actions and open new vistas in propranolol pharmacodynamics.

Animals↗
PubMed1985

Blood pressure and norepinephrine spillover during propranolol infusion in humans.

To determine whether a reflex increase of sympathetic nervous system activity contributes to maintenance of blood pressure during acute beta-adrenergic blockade, we measured plasma norepinephrine levels and norepinephrine kinetics during propranolol administration. During a 90-min infusion of propranolol (10 mg iv + 80 micrograms/min) in 12 normal subjects, heart rate fell from 56 +/- 2 to 49 +/- 2 (SE) beats/min (P less than 0.001), but there was no fall in mean arterial blood pressure (84 +/- 3 mmHg before and 86 +/- 3 mmHg after propranolol). Arterial plasma norepinephrine levels rose from 183 +/- 20 to 250 +/- 29 pg/ml during propranolol (P less than 0.001), suggesting increased sympathetic vasoconstrictor tone. However, isotope dilution studies using tritiated norepinephrine infusion showed that arterial plasma levels of tritiated norepinephrine rose from 743 +/- 78 to 1,002 +/- 101 dpm/ml during propranolol (P less than 0.001), indicating a reduction in the rate of norepinephrine clearance from plasma. The calculated fall in clearance from 1.90 +/- 0.13 to 1.42 +/- 0.11 1/min (P less than 0.001) entirely accounted for the rise in plasma norepinephrine, since the calculated rate of norepinephrine spillover into plasma remained at the base-line level of 340 +/- 40 ng/min during propranolol. In control studies on four subjects, arterial plasma norepinephrine levels and norepinephrine kinetics did not change from base line during the control period. We conclude that maintenance of blood pressure during propranolol infusion is not due to a reflex generalized increase of sympathetic vasoconstrictor tone.

Adult↗
PubMed1989

Effect of propranolol on ischemic myocardial damage and left ventricular hypertrophy following permanent coronary artery occlusion or occlusion followed by reperfusion.

This study was designed to assess the effect of propranolol for limiting myocardial damage and hypertrophy in rats with permanent coronary artery occlusion or occlusion followed by reperfusion. Rats were subjected to occlusion of the left main coronary artery for 48 h (MI) or 0.5 h of occlusion followed by reperfusion for 47.5 h (MI/R). Myocardial injury was determined by measuring the depletion of creatine phosphokinase (CK) levels from the left ventricular free wall. In comparison to sham-occluded animals, myocardial CK levels were significantly decreased by 40% in MI + vehicle animals and 30% in MI/R + vehicle animals. Propranolol (0.3 mg/kg 1 min before occlusion followed by 1 mg/kg at 4 and 24 h after occlusion) significantly reduced the loss of myocardial CK-specific activity in MI animals, but failed to prevent the loss of CK-specific activity in animals subjected to coronary artery reperfusion. Left ventricular hypertrophy developed to a similar extent in both vehicle-treated MI and MI/R groups. Propranolol had no effect on the myocardial hypertrophy in MI or MI/R animals. Likewise, in MI/R animals no diminution of polymorphonuclear leukocyte infiltration was seen with propranolol. These data indicate that propranolol had a significant cardioprotective effect in rats with permanent coronary artery occlusion but failed to salvage ischemic tissue, reduce myocardial hypertrophy or mitigate neutrophil infiltration in animals with early reperfusion of the ischemic myocardium. These results suggest that propranolol may afford a significant protection of the ischemic myocardium, but the combination of reperfusion and propranolol may not result in any greater reduction in infarct size than reperfusion alone.

Animals↗
PubMed1987

Altered S(--)-propranolol disposition in bilateral ureter-ligated rats.

Previous clinical studies indicate that the metabolic clearance of oral (+/-)-propranolol is reduced in end-stage renal failure patients. Animal models are needed to explore the mechanism(s) underlying the observed metabolic inhibition in man. The disposition kinetics of S(-)-propranolol were characterized after intravenous and peroral administration in rats with acute renal failure induced by bilateral ureteral ligation (BUL). No alteration in either the systemic clearance or the apparent volumes of distribution of S(-)-propranolol was observed in renal failure animals after a single intravenous dose of 1.5 mg/kg. In contrast, acute uremia did elicit a change in the bioavailability of orally administered S(-)-propranolol. At 36 h after ureteral ligation, the area under the serum concentration-time curve after a 6 mg/kg oral dose of S(-)-propranolol was significantly elevated in renal failure animals, which corresponded to an approximate two fold increase in its systemic availability (from 7.7 to 20.5%). Such an effect could not be demonstrated at times earlier than 36 h after ureteral ligation. Additional experiments were performed to evaluate whether concomitant changes in gastrointestinal absorption or serum protein binding of S(-)-propranolol could have contributed to the apparent increase in oral availability. The results lead to the hypothesis of an inhibited first-pass hepatic metabolism of S(-)-propranolol in acute renal failure and suggest a significant time delay in the onset of inhibition.

Acute Kidney Injury↗
PubMed1976

Effect of timolol versus propranolol on hypertension and hemodynamics.

The effect of timolol versus propranolol on hypertension, hemodynamics, and plasms renin activity was evaluated in 20 men. After two weeks of placebo, 11 men received timolol 30 to 60 mg daily, and nine men received propranolol, 240 to 480 mg daily, for five weeks in a double-blind randomized study. The 20 men then received placebo again for two weeks. Right heart catheterization was performed in all 20 patients after two weeks of the first placebo and after five weeks of timolol or propranolol. Equipotent doses of timolol and propranolol were equally effective in significantly lowering supine and upright systolic and diastolic blood pressure and heart rate recorded on an outpatient basis. Equipotent doses of timolol and propranolol caused similar hemodynamic effects including similar significant depression of cardiac index. Equipotent doses of timolol and propranolol caused similar marked depression of plasma renin activity. The hypotensive action of timolol and of propranolol was unrelated to their effect on plasma renin activity.

Adrenergic beta-Antagonists↗
PubMed1977

Infarct size reduction by propranolol before and after coronary ligation in dogs.

Coronary occlusion in the dog results in irreversible myocardial cell injury which develops first in subendocardial areas of severe ischemica and subsequently spreads into mid and subepicardial areas of moderate ischemia. The effect of propranolol on this progression of ischemic injury was evaluated. Three groups of dogs were studied: 1) untreated, 2) treated with propranolol before and throughout coronary ligation, and 3) treated with propranolol beginning three hours after ligation. Dogs were sacrificed 24 hours after coronary ligation and necrosis was quantitated from histologic sections of transmural slices through the posterior papillary muscle. Propranolol reduced infarct size by preventing necrosis in peripheral (subepicardial) areas of moderately ischemic myocardium. Pretreatment with propranolol reduced necrosis from 85 +/- 3% (untreated) to 52 +/- 4% (P less than 0.05). Delayed propranolol therapy was about half as effective as pre-treatment and reduced necrosis to 71 +/- 3% (P less than 0.05). Propranolol also limited microvascular injury so that perfusion defects, detected with the dye thioflavin S, were smaller in treated dogs.

Animals↗
PubMed1978

Impairment of antipyrine clearance in humans by propranolol.

The effect of propranolol on antipyrine clearance in humans was evaluated in six healthy volunteers who received single 1.4 to 1.5 g doses of intravenous antipyrine on two occasions. The first (control) antipyrine trial was without concurrent drug administration; the second trial was done during treatment with therapeutic doses of propranolol (40 mg every 4 to 6 hours). Antipyrine elimination half-life (t1/2), volume of distribution (Vd), and total clearance were determined after each trial. In all subjects isoproterenol sensitivity decreased markedly during propranolol treatment, indicating a high degree of beta blockade produced by the drug. Mean antipyrine t1/2 during the propranolol treatment period was significantly prolonged, and total clearance significantly reduced, over the control values. Twenty-four-hour urinary excretion of 4-hydroxyantipyrine, the major metabolite of antipyrine, likewise was reduced from 23.6% of the dose on the control trial to 14.8% of the dose during propranolol coadministration (0.1 less than P less than 0.2). Vd however, was nearly identical during both trials (0.62 L/kg). Thus propranolol prolongs the half-life and reduces the clearance or biotransformation rate of antipyrine, a drug whose clearance is independent of hepatic blood flow. Propranolol may influence the activity of hepatic microsomal enzymes responsible for drug hydroxylation.

Adult↗
PubMed1982

A double-blind randomized trial of propranolol and verapamil in the treatment of effort angina.

In 18 patients with stable effort angina, verapamil, 80 mg four times daily, was compared with propranolol, 80 mg four times daily, in a double-blind, placebo-controlled trial to assess the effects on anginal threshold, exercise capacity and left ventricular function measured by gated equilibrium blood pool scanning. Both propranolol and verapamil improved exercise capacity (placebo 424 +/- 135 W-min; propranolol 513 +/- 168 W-min, p less than 0.01; verapamil 545 +/- 215 W-min, p less than 0.005) and prolonged the time to 1 mm of ST depression (placebo 4.5 +/- 1.3 minutes; propranolol 7.4 +/- 1.4 minutes, p less than 0.005; verapamil 6.6 +/- 1.9 minutes, p less than 0.005). At rest, the mean left ventricular ejection fraction did not change significantly during drug therapy (placebo 57 +/- 13%, propranolol 55 +/- 12%, verapamil 55 +/- 13%). While taking placebo, all 18 patients had a decrease in exercise ejection fraction. In contrast, 12 patients taking propranolol and 14 patients taking verapamil had a 5% or greater increase in ejection fraction during exercise. Verapamil is an effective primary therapy and a satisfactory alternative to propranolol in patients with stable effort angina.

Adult↗
PubMed1985

Effects of propranolol and diltiazem alone and in combination on the recovery of left ventricular segmental function after temporary coronary occlusion and long-term reperfusion in conscious dogs.

We evaluated the ability of propranolol and diltiazem alone and in combination to enhance the recovery of left ventricular (LV) segmental function during 1 month of reperfusion after two temporary occlusions of the left anterior descending coronary artery (LAD) in conscious dogs instrumented with ultrasonic crystals for the measurement of regional net systolic wall thickening (NET). LV segments were classified according to their contractile function after 1 hr of LAD occlusion: class 1, greater than 67% of preocclusion (control) NET; class 2, 0% to 66.9%; class 3, less than 0% (paradoxical systolic wall thinning). Propranolol (1 mg/kg iv) or diltiazem (20 micrograms/kg/min) was given 65 min after LAD occlusion in dogs that had 2 (group I) or 4 hr (group II) of LAD occlusion. Diltiazem plus propranolol (same doses) were given to another group of dogs that underwent 4 hr (but not 2) of LAD occlusion. Untreated control dogs received 25 ml of saline and underwent 2 or 4 hr of LAD occlusion. The NET of class 2 and 3 segments in group I control dogs increased significantly during 1 month of reperfusion, from 32 +/- 5% and -43 +/- 6% to 66 +/- 9% and 26 +/- 9%, respectively (p less than .05). Neither diltiazem nor propranolol enhanced the long-term recovery of these segments in group I dogs. However, diltiazem prevented further deterioration of contractile dysfunction observed in control dogs immediately after reperfusion in both segment classes. The NET of class 2 segments in group II control dogs after 4 weeks of reperfusion remained at levels observed during LAD occlusion: 30 +/- 4% to 37 +/- 12%. Class 3 NET increased from -33 +/- 5% to 12 +/- 12% with 1 month of reperfusion, but these segments were essentially akinetic. Propranolol or diltiazem alone did not produce significant overall increases in NET, but diltiazem again prevented further declines in NET of class 2 and 3 segments during early reperfusion. However, the combination of diltiazem and propranolol significantly enhanced overall recovery of class 2 NET in group II dogs (44 +/- 3% to 88 +/- 7%) and prevented the worsening of NET associated with early reperfusion. Compared with untreated dogs, propranolol plus diltiazem also significantly decreased the extent of histologic necrosis in class 2 and 3 segments as well as the macrohistochemically determined infarct size in group II dogs.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Propranolol increases prostacyclin synthesis in patients with essential hypertension.

We tested the hypothesis that vascular prostacyclin synthesis is increased by propranolol and could account for some of the drug's antihypertensive effect. We studied 10 white patients with mild essential hypertension in a randomized, double-blind design to assess the effects of indomethacin with or without the addition of propranolol on blood pressure and vascular prostacyclin biosynthesis, as assessed by the urinary excretion of the major enzymatically produced metabolite of prostacyclin, 2,3-dinor-6-keto-prostaglandin F1 alpha (PGF1 alpha), F1 alpha (PGF1 alpha), measured by gas chromatography-mass spectrometry. Seven patients responded to propranolol with a lowering of mean arterial blood pressure in both supine and upright postures. The fall in mean arterial blood pressure (-14.1 +/- 2.1 mm Hg sitting; -17.4 +/- 1.7 mm Hg supine) with propranolol alone was significantly greater than that produced when propranolol was given to patients receiving indomethacin (-7.8 +/- 1.9 mm Hg sitting; -7.7 +/- 3.0 mm Hg supine). Our drug-responsive patients demonstrated a significantly lower excretion rate of 2,3-dinor-6-keto-PGF1 alpha than was found in an age and sex-matched group of normal volunteers. With propranolol treatment, drug-responsive patients showed a significant increase in the excretion of 2,3-dinor-6-keto-PGF1 alpha, such that the mean excretion was not significantly different from that in normal volunteers. Indomethacin caused a significant rise in mean arterial blood pressure and a significant fall in 2,3-dinor-6-keto-PGF1 alpha excretion, and it blocked the rise in urinary 2,3-dinor-6-keto-PGF1 alpha associated with propranolol therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1975

Effect of salt depletion and propranolol on blood pressure and plasma renin activity in various forms of hypertension.

The effect of propranolol therapy on the mean arterial pressure (MAP) and plasma renin activity (PRA) was studied in three groups of hypertensive patients who were also treated with saliuretics. Group A: In 14 patients with essential hypertension on chlorthalidone treatment, an additional daily dose of 640 mg propranolol for two months led to a significant reduction of the MAP (from 124 to 105 mm Hg) and PRA (from 5.3 to 2.0 ng AI/ml/hr standing). There was no correlation between MAP reduction and either the original levels or change in PRA. Group B: In 14 patients with essential hypertension and 5 with renal artery stenosis studied on a fixed salt intake, the plasma and extracellular volumes, PRA, and blood pressures were recorded before and after three days of diuretic induced salt depletion and, with maintenance of the depleted state, after three days of propranolol. Salt depletion resulted in a decrease in MAP from 132 to 128 mm Hg (NS), and PRA increased from 3.4 to 22.3 ng AI/ml/hr (P less than 0.01). There was no correlation between change in MAP and PRA control values, PRA change, or any of the volume parameters. Addition of propranolol was followed by a rapid MAP decrease to 111 mm Hg (P less than 0.01), and the PRA dropped to a mean of 8.5 (P less than 0.01). No correlation was found between change in MAP and change in PRA. The patients with renal artery stenosis did not differ in their reactions from those with essential hypertension. Group C: In five patients with moderate renal failure and normal to expanded 82-Br distribution volume, propranolol lowered MAP by 10% and lowered the PRA in all five. Salt depletion by furosemide to 82-Br volumes below normal resulted in a 10% decrease of MAP and a marked rise in PRA. In this state propranolol was followed by a further MAP reduction of 18% and a decrease in PRA. There was no quantitative relationship between MAP and PRA change during either of the treatment regimes. It is concluded that in various forms of hypertension, the blood pressure can be effectively lowered by combining diuretics and propranolol regardless of the pretreatment PRA level.

Adult↗
PubMed1976

Electrophysiological and antiarrhythmic effects of propranolol in canine acute myocardial ischemia.

To correlate the antiarrhythmic and electrophysiological effects of propranolol in acute myocardial ischemia, we examined the effects of temporary (15-minute) ligations of the left anterior descending coronary artery in studies on 15 dogs. We recorded bipolar electrograms and monophasic action potentials from the ischemic and normal zones and measured the intervals from the onset of QRS in a standard electrocardiogram lead to the major deflection of electrograms recorded from the ischemic and normal zones. We also determined monophasic action potential duration (APD) and effective refractory period (ERP). Data for control ligations were compared to those during which propranolol, 40 mug/kg, was administered intravenously immediately after ligation. Propranolol reduced the mean number of ventricular beats per minute (from 15 to 6) (P less than 0.01). Propranolol slowed conduction in the ischemic zone (by 10 msec at peak effect, P less than 0.01) and had no or only a very slight effect (by 1-msec at 15 minutes, P less than 0.05) on conduction in the normal zone. Propranolol also prolonged APD in the ischemic (32-msec) and normal (14-msec) zones (P less than 0.01), prolonged ERP in the ischemic (41-msec) and normal (20-msec) zones (P less than 0.01), and reduced the APD/ERP ratio in the ischemic (1.62 to 1.47) (P less than 0.01) and normal (1.62 to 1.55) (P less than 0.05) zones. During the control ligation, APD in the ischemic zone was 25 msec shorter than in the normal zone (P less than 0.01), but with propranolol the difference was not significant. The effects of propranolol in slowing conduction in the ischemic zone, in prolonging refractoriness, in reducing APD/ERP, and in reducing the disparity in APD between ischemic and normal zones may explain its demonstrated antiarrhythmic effects in acute myocardial ischemia.

Action Potentials↗
PubMed1987

Propranolol treatment externalizes beta-adrenergic receptors in guinea pig myocardium and prevents further externalization by ischemia.

Purified sarcolemmal and light vesicle (intracellular) fractions of beta-adrenergic receptors were used to examine the effects of propranolol on receptor translocation in guinea pig heart. Guinea pigs were given propranolol (0.15 mg/kg/hr) via minipumps for 7 days and either killed or made ischemic for 1 hour via a coronary ligature. Propranolol treatment led to an externalization of beta-receptors from light vesicle to sarcolemmal fractions. This externalization increased the number of surface beta-adrenergic receptors that were functional, as assessed by isoproterenol-stimulated adenylate cyclase activity. After chronic propranolol treatment, ischemia did not further alter receptor distribution. These results suggest that externalization of beta-adrenergic receptors from a light vesicle fraction to the sarcolemma contributes to up-regulation of beta-receptors that occur in response to both propranolol treatment and ischemia. Because propranolol-treated animals show blunting in externalization after myocardial ischemia, propranolol treatment and myocardial ischemia appear to access the same pool of intracellular beta-adrenergic receptors. Depletion of this pool of receptors along with receptor blockade may thus contribute to the mechanism by which the drug is efficacious in preventing some adverse effects of ischemia.

Adenylyl Cyclases↗
PubMed1989

Inhibition of sarcolemmal carbon-centered free radical formation by propranolol.

The mechanism of propranolol-inhibited sarcolemmal membrane lipid peroxidation was investigated by electron spin resonance spin-trapping technique using 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) and 2-methyl-2-nitrosopropane (MNP). Highly purified canine myocytic sarcolemma were peroxidized by a superoxide-driven (from dihydroxyfumarate) and Fe3+-catalyzed free radical-generating system. Hydroxyl radicals (.OH), identified by electron spin resonance signals as DMPO-OH adducts, were generated in the aqueous phase. Propranolol up to 500 microM did not effectively reduce the intensity of the DMPO-OH adducts. When the sarcolemma were incubated with MNP before the addition of free radicals, MNP adducts characteristic of carbon-centered radicals were produced. Pretreatment of the membranes with propranolol (3-100 microM) decreased the intensity of the MNP adducts in a log concentration-dependent manner; the EC50 is about 7 microM. D- and L-propranolol were found equally effective. When protein-depleted sarcolemmal lipids were similarly incubated with MNP and the free radical system, identical MNP adducts were observed; this finding suggests that the adducts were lipid-derived products arising from lipid peroxidation. Furthermore, their formation was also inhibited by propranolol pretreatment. Since propranolol is not an effective scavenger of oxygen radicals in the aqueous phase, the data suggest that the antiperoxidative effect of propranolol is due to its lipophilic interaction with the membrane and thus subsequent interruption of the free radical chain reactions.

Animals↗
PubMed1978

Propranolol antagonizes the anti-inflammatory effect of alcohol and improves survival of infected intoxicated rabbits.

We studied the effects of alcohol and propranolol on the course of peritonitis in rabbits. Induction of sterile peritonitis with normal saline led to a 50% augmentation of granulocyte adherence in normal rabbits, and a mean cumulative granulocyte count of 27,000/mm(3) in peritoneal exudate by 8 h. Rabbits intoxicated with alcohol at the time of peritonitis induction maintained a granulocyte adherence below pretreatment values, and only delivered a cumulative mean of 12,000 granulocytes/mm(3) into the peritoneal fluid. When intoxicated rabbits received propranolol intravenously at the time of intoxication, adherence increased above preperitonitis levels, and stayed significantly above values for animals given alcohol alone. In addition, the defect in granulocyte delivery was prevented by propranolol, resulting in a mean cumulative granulocyte count in peritoneal fluid of 24,000/mm(3).When peritonitis was induced with live pneumococci instead of a sterile inflammatory stimulus, 14/18 normal animals survived the infection and were culture-negative when sacrificed at 2 wk. In contrast, 17/18 intoxicated animals died of the infection, in a mean of 2.8 days. 9 of 18 intoxicated animals who also received propranolol survived, and those who died lived a mean of 7.5 days. The survival rates and the time-to-death among the nonsurvivors given propranolol were both significantly greater than in the animals intoxicated without propranolol. Thus, propranolol prevents the granulocyte adherence and delivery defects induced by alcohol intoxication, and significantly improves survival from infection.

Alcoholic Intoxication↗
PubMed1980

Propranolol decreases sympathetic nervous activity reflected by plasma catecholamines during evolution of myocardial infarction in man.

Plasma 1-norepinephrine and epinephrine contents were strikingly elevated in 70 patients during evolution of myocardial infarction. Propranolol or placebo, 0.1 mg/kg i.v., was administered randomly an average of 10 h after infarction and continued orally for 3 d. Propranolol, but not placebo, acutely decreased 1-norepinephrine contents from 2.24 +/- 1.33 (mean +/- SD) to 1.31 +/- 0.74 microgram/liter, P less than 0.001, and epinephrine contents from 0.97 +/- 0.42 to 0.74 +/- 0.42 microgram/liter, P less than 0.02. Decreases in 1-norepinephrine contents were related to the initial plasma concentrations, r = 0.85, P less than 0.001. A similar, but less strong relationship was observed between the initial epinephrine contents and propranolol-induced changes, r = -0.51, P less than 0.01. Propranolol reduced plasma-free fatty acid contents from 1,121 +/- 315 to 943 +/- 274 mumol/liter, P less than 0.001. Decreases in plasma contents of free fatty acids were related to decreases in epinephrine, r = 0.66, P less than 0.001. Propranolol did not cause significant additional changes in plasma catecholamine contents during the subsequent 3 d. In the placebo group 1-norepinephrine contents had decreased 24 h after infarction from 1.92 +/- 0.99 to 1.37 +/- 0.93 microgram/liter, P less than 0.02. Plasma epinephrine contents did not change. Heart rate remained below the control values during the entire study period in the propranolol, but increased in the placebo group. The data indicate that sympathetic hyperactivity, indirectly reflected by plasma catecholamine contents, is acutely reduced by propranolol during evolution of myocardial infarction.

Adult↗
PubMed1983

Transport of propranolol and lidocaine through the rat blood-brain barrier. Primary role of globulin-bound drug.

Basic lipophilic drugs such as propranolol and lidocaine are strongly bound by alpha(1)-acid glycoprotein, also called orosomucoid. Although the liver is known to rapidly clear plasma protein-bound propranolol or lidocaine, it is generally regarded that peripheral tissues, such as brain or heart, are only exposed to the small fraction of drug that is free or dialyzable in vitro. The "free drug" hypothesis is subjected to direct empiric testing in the present studies using human sera and an in vivo rat brain paradigm. Serum from 27 human subjects (normal individuals, newborns, or patients with either metastatic cancer or rheumatoid arthritis) were found to have up to a sevenfold variation in orosomucoid concentrations. The free propranolol or lidocaine as determined in vitro by equilibrium dialysis at 37 degrees C varied inversely with the orosomucoid concentration. Similarly the rate of transport of propranolol or lidocaine through the blood-brain barrier (BBB) was inversely related to the existing serum concentration of orosomucoid. However, the inhibition of rat brain extraction of drug by orosomucoid in vivo was only about one-fifth of that predicted by free drug measurements in vitro. This large discrepancy suggested orosomucoid-bound drug was readily available for transport into brain in vivo. Studies using purified human orosomucoid in the rat brain extraction assay also showed that orosomucoidbound propranolol or lidocaine is readily transported through the BBB. Conversely, albumin-bound propranolol or lidocaine was not transported through the BBB. The studies using albumin provide evidence that the in vivo rat brain paradigm used in the present investigations is capable of confirming, when possible, predictions made by the "free drug" hypothesis. These data suggest that the amount of circulating propranolol or lidocaine that is available for transport into a peripheral tissue such as brain is not restricted to the free (dialyzable) moiety but includes the much larger globulin-bound fraction. Therefore, existing pharmacokinetic models should be expanded to account for the transport of protein-bound drugs into peripheral tissues similar to what is known to occur in liver.

Adult↗