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PubMed1980

Propranolol effects on membrane repolarization time in isolated canine Purkinje fibers: threshold tissue content and the influence of exposure time.

This study has examined the relationship between the Purkinje fiber content of propranolol and effects on membrane repolarization time during prolonged exposure to low concentrations of propranolol in vitro. Canine Purkinje fibers were exposed to both dl-propranolol, 3.4 X 10(-7) M (0.1 microgram/ml) and 1.7 X 10(-6) M (0.5 micrograms/ml), and to d-propranolol, 3.4 X 10(-7) M (0.1 micrograms/ml), in Tyrode's solution for 90 to 180 min. Purkinje fibers exhibited continuous decreases in repolarization time throughout the exposure periods and fibers analyzed for propranolol content demonstrated continuous cumulation of the drug with time. A maximum 8% decrease in repolarization time was observed after 3.4 X 10(-7) M and a 30% decrease after 1.7 X 10(-6) M propranolol. A 40-fold cumulation of propranolol by the Purkinje fibers was found after both concentrations at or near equilibrium. A high degree of correlation (r = 0.98; P < .001) existed between changes in electrical activity and tissue content of propranolol. Extrapolation to zero effect showed a threshold tissue content of propranolol of approximately 1.0 microgram/g, which corresponds to a bath concentration of 25 ng/ml (8 X 10(-8) M). Changes in membrane potentials were the result of direct membrane effects of propranolol, based on the fact that d-propranolol produced membrane alterations and tissue cumulation identical to those produced by the racemic drug.

Action Potentials↗
PubMed1993

Contribution of differences in plasma binding of propranolol to ethnic differences in sensitivity. Comparison between Chinese and Caucasians.

Chinese are more sensitive to the beta-blocking and hypotensive effects of propranolol than Caucasians. To determine the contribution of ethnic differences in the plasma binding of propranolol to the differences in sensitivity, 8 Caucasians (22.8 +/- 1.5 yr) and 8 Chinese (31.8 +/- 2.1 yr) were studied following single doses of 0, 10, 20, 40 and 80 mg propranolol orally. The binding of propranolol in plasma was determined by equilibrium dialysis after addition of 300 mg racemic propranolol to the plasma. The concentrations of free and bound (+) and (-)-propranolol were determined by stereospecific high performance liquid chromatography (HPLC). Dosage had no influence on the plasma binding of either enantiomer. The unbound fractions of both (-)-propranolol (16.06 +/- 0.79% vs 12.41 +/- 0.93%, P < 0.05) and (+)-propranolol (17.73 +/- 0.81% vs 14.33 +/- 0.89%, P < 0.01) were greater in Chinese than Caucasians, respectively. In both groups, the ratio of unbound (-) to (+)-propranolol was less than 1 (P < 0.01) and was greater in Chinese (0.91 +/- 0.01 vs 0.88 +/- 0.01) (P < 0.01), implying that in Chinese less isomers of both types were bound and there was a greater unbound proportion of the pharmacologically active (-)-propranolol which may contribute to their increased sensitivity to propranolol. It is demonstrated that ethnic differences in stereoselective protein binding may be an important variable in interindividual determinants of drug response.

Adult↗
PubMedDate not supplied

Impact of CYP2D6 poor metabolizer phenotype on propranolol pharmacokinetics and response.

We conducted an open-label study to determine the impact of cytochrome P-4502D6 (CYP2D6) on propranolol pharmacokinetics and response in 12 healthy men with CYP2D6 extensive metabolizer (EM) phenotype and 3 healthy men with CYP2D6 poor metabolizer (PM) phenotype. Subjects received R,S-propranolol hydrochloride 80 mg every 8 hours for 16 doses. After the sixteenth dose, blood and urine samples were collected for 24 hours, and serum propranolol and urine metabolite concentrations were determined by chiral high-performance liquid chromatography. Heart rate response to treadmill exercise was measured serially over 24 hours. Apparent oral clearance of propranolol and partial metabolic clearance values of propranolol to 4-hydroxypropranolol (HOP), propranolol glucuronide, and naphloxylactic acid (NLA) were estimated. Apparent oral clearance and elimination half-life of propranolol were not different between EMs and PMs. Partial metabolic clearance of propranolol to HOP was significantly higher and to NLA was significantly lower in EMs than in PMs. No differences in percentage reductions in exercise heart rate were observed between EMs and PMs. The CYP2D6 PM phenotype has no effect on propranolol blood concentrations and does not alter response to propranolol. Our data also suggest that CYP2D6 mediates approximately 65% and 70% of S- and R-propranolol's 4-hydroxylation, respectively.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Increased diastolic time: a possible important factor in the benefical effect of propranolol in patients with coronary artery disease.

Diastolic time (DT) calculated as the cycle length minus electromechanical systole (QS2) has a nonlinear relationship to heart rate (HR), increasing rapidly as rates fall below 75. The effect of propranolol on DT was studied in 150 patients with coronary artery disease. Patients were divided into three groups. Group I included patients with stable angina pectoris: propranolol (2.5 mg, i.v.) significantly increased DT from 411 +/- 18 to 527 +/- 22 msec (p less than 0.001) in 23 patients of group I; therapy with propranolol (mean daily dose 200 +/- 15 mg) increased DT from 446 +/- 29 to 766 +/- 26 msec (p less than 0.001) in 15 patients with stable angina. Group II was made up of patients with acute myocardial infarction: Propranolol (2.5 mg, i.v.) increased DT from 379 +/- 16 to 458 +/- 24 (p less than 0.001) in 18 of these patients. Group III included patients with recent coronary bypass surgery: propranolol (2.5 mg, i.v.) increased DT from 323 +/- 9 to 468 +/- 24 msec (p less than 0.001) in 14 patients 7 days after surgery. In addition, DT at 15 hr and 2 weeks after surgery was compared in 30 patients maintained on propranolol (mean daily dose, 155 +/- 11 mg preoperative and 68 +/- 9 mg postoperative) and 50 other patients who underwent coronary bypass surgery not on propranolol. DT was greater in propranolol patients (546 +/- 21 vs. 388 +/- 16 msec, p less than 0.001), preoperative and 396 +/- 15 vs. 320 +/- 12 msec, p less than 0.001, postoperative). Changes in DT after propranolol are mainly attributed to decreased HR. Changes in QS2 were much less profound and always less (p less than 0.01) than changes in DT. Thus propranolol significantly increased DT per beat in patients with coronary artery disease, which allowed more time for coronary perfusion; this effect of propranolol could well be as important as the reduction of myocardial oxygen consumption.

Adult↗
PubMed1998

Steady-state pharmacokinetics of propranolol enantiomers in healthy male volunteers.

OBJECTIVE: To describe the steady-state pharmacokinetics of (R)-, (S)- and racemic (rac) propranolol in 15 normotensive, male volunteers in a double-blind, randomized, 3-way, crossover study. METHODS: (R)-propranolol 80 mg, (S)-propranolol 80 mg, or rac-propranolol 160 mg was administered twice daily for 3 days. Multiple blood samples were collected for up to 12 hours on the fourth day to characterize the steady-state pharmacokinetic profile of each enantiomer. RESULTS: (R)-propranolol bound to plasma proteins to a lesser extent than (S)-propranolol when it was administered both as a racemic mixture (15.8% versus 13.0%) and as a pure enantiomer (15.8% versus 12.9%), respectively (p < 0.05). No stereoselective pharmacokinetic differences were observed between total (bound and unbound) and unbound (R)- and (S)-propranolol. The AUC(0-720) of (R)-propranolol was significantly higher when administered as a racemic mixture than when given as a pure enantiomer (p < 0.01), suggesting the disposition of (R)-propranolol may be influenced by (S)-propranolol. CONCLUSION: Stereoselective steady-state pharmacokinetic differences in AUC(0-720) were observed between (R)- and (S)-propranolol.

Adult↗
PubMed1985

Effects of propranolol on hepatic haemodynamics in the cirrhotic and non-cirrhotic rat.

The effects of systemic and intraportal administration of propranolol on hepatic haemodynamics were studied in cirrhotic and non-cirrhotic rats. In the non-cirrhotic rat systemic infusion of 4 micrograms (kg body wt)-1 min-1 propranolol significantly decreased portal pressure, wedged hepatic venous pressure, portal venous flow and liver blood flow without affecting heart rate. Similar changes were observed in the cirrhotic rat following an infusion of 2 micrograms (kg body wt)-1 min-1 propranolol. Higher rates of propranolol infusion produced greater reductions in portal pressure, wedged hepatic venous pressure, portal venous flow and liver blood flow in cirrhotic and non-cirrhotic rats but these changes were accompanied by a bradycardia. The reduction in portal pressure effected by propranolol was accompanied by an increased splanchnic vascular resistance. Intraportal injection of propranolol resulted in a rapid but transient fall in portal pressure. The decrease in portal pressure was sustained if propranolol was infused intraportally. The results indicate that propranolol effects a reduction in portal pressure via a combination of increased splanchnic vascular resistance, increased hepatic arterial resistance and reduced cardiac output. The observation that propranolol can significantly reduce portal pressure without affecting heart rate may be clinically important in the long-term management of portal hypertension. Furthermore, the rapid reduction in portal pressure following intravenous administration suggests that propranolol may be of value in the acute control of variceal haemorrhage.

Animals↗
PubMed1989

Propranolol decreases portal pressure without changing portocollateral resistance in cirrhotic rats.

Propranolol decreases portal pressure by reducing portal blood inflow. Studies in rats with prehepatic portal hypertension due to portal vein stenosis (a model with extensive portosystemic shunting) have shown that propranolol increases the portocollateral resistance, which hinders the fall in portal pressure. The present study examined the effects of propranolol on splanchnic and systemic hemodynamics in rats with portal hypertension due to cirrhosis of the liver, a model which is characterized by mild portosystemic shunting. Two groups of rats with CCl4-induced cirrhosis were studied: the propranolol group (n = 8), which received a propranolol infusion of 2 mg per 15 min, and controls (n = 9), which received a placebo (saline) infusion. Hemodynamic measurements were done using radiolabeled microspheres. Propranolol-treated rats had significantly lower cardiac output (-31%) and heart rate (-26%) than controls (p less than 0.001). Hepatic artery flow was not modified by propranolol. Propranolol caused splanchnic vasoconstriction, manifested by increased splanchnic resistance (+57%) and by a significant fall in portal blood inflow (4.8 +/- 0.4 vs. 6.3 +/- 0.5 ml per min.100 gm in controls, p less than 0.05). In contrast with rats with prehepatic portal hypertension, propranolol did not increase portal resistance in cirrhotic rats [2.0 +/- 0.2 vs. 2.0 +/- 0.1 mmHg per ml per min.100 gm body weight (not significant)]. Hence, the fall in portal pressure (-19%) was expected from the decrease in portal inflow (-24%). These results suggest that increased portal resistance in rats with prehepatic portal hypertension may represent an intrinsic effect of propranolol on the portocollateral vessels, since beta-blockade does not modify portal vascular resistance in cirrhosis.

Animals↗
PubMed1987

Nonlinear pharmacokinetics of unbound propranolol after oral administration.

After multiple oral doses, propranolol has been reported to accumulate to a greater degree than expected based on its terminal elimination rate constant and dosage interval. To determine whether the decrease in presystemic elimination can be attributed solely to a decrease in unbound intrinsic clearance or possibly a decrease in unbound fraction, we studied the pharmacokinetics of unbound propranolol in nine healthy subjects who were given 160 mg of regular or sustained-release propranolol orally as single doses, and once daily for 7 d. Unbound propranolol concentrations were calculated by HPLC and equilibrium dialysis on each serum sample. With regular propranolol, the mean unbound oral clearance (CLoral) decreased 29%, from 503 +/- 281 after a single dose to 359 +/- 143 mL/min/kg at steady state (p less than 0.05). Similarly, CLoral decreased 33% with sustained-release propranolol from 1077 +/- 514 to 721 +/- 385 mL/min/kg (NS). The corresponding accumulation ratios for regular and sustained-release propranolol were 1.39 +/- 0.49 and 1.61 +/- 0.81, respectively (NS). Therefore, the mean bioavailability of sustained-release relative to that of regular propranolol was 0.52 +/- 0.23 and 0.54 +/- 0.17 for single doses and at steady-state, respectively. The percent unbound of propranolol ranged from 6.8 to 14.0 with an average of 10.1. Neither the percent unbound nor alpha 1-acid glycoprotein (AAG) serum concentrations were statistically different between single and multiple doses. The binding ratio was significantly correlated to AAG concentration (r = 0.776, p less than 0.05). The data support a decrease in unbound intrinsic clearance of propranolol with no change in unbound fraction, leading to an increase in bioavailability at steady state.

Administration, Oral↗
PubMed1992

Propranolol disposition in the rat: variation in hepatic extraction with unbound drug fraction.

The plasma protein binding of propranolol has been described as nonrestrictive for its hepatic extraction to explain the observation that propranolol is efficiently removed by the liver, in spite of extensive protein binding. The present study was designed to examine the relationship between propranolol protein binding, metabolism by isolated hepatocytes, and extraction by the isolated perfused rat liver. In isolated hepatocytes, the intrinsic clearance of free drug increased three- to fourfold as albumin and alpha 1-acid glycoprotein (AAG) concentrations increased, suggesting that albumin and AAG facilitate the elimination of propranolol by hepatocytes. In the isolated perfused liver, propranolol extraction was almost complete (E = 0.996) in the absence of albumin and AAG. With 40 g/L of albumin and 2 g/L of AAG in the perfusate, the free fraction of propranolol decreased to 0.031, but extraction remained high (E = 0.960). With 40 g/L of albumin and 10 g/L of AAG in the perfusate, the free fraction further decreased to 0.014 and extraction dropped sharply (E = 0.820). The observed relationship between propranolol extraction and the free fraction of propranolol was in good agreement with that predicted using estimates of intrinsic clearance measured in isolated hepatocytes suspensions. These data indicate that propranolol extraction is sensitive to changes in binding at very low free fraction values and suggest a facilitation of propranolol clearance by albumin and AAG.

Animals↗
PubMed1999

The role of sensory nerves in propranolol-induced bronchial hyperresponsiveness in the guinea-pig.

The racemic mixture propranolol (RS-(+/-)-, and the S-(-)- and R-(+)-) isomers of propranolol have been shown to induce bronchial hyperresponsiveness in the guinea-pig unrelated to beta-adrenoreceptor occupancy, that is attenuated by vagal section and mediated via the generation of 5-lipoxygenase metabolites of arachidonic acid. We have investigated the role of sensory nerves in propranolol-induced bronchial hyperresponsiveness in guinea-pigs. Airways responsiveness to acetylcholine, bradykinin and bombesin was determined before and 10 min after intravenous infusion with RS-(+/-)-, S-(-)- and R-(+)-propranolol (1 mg/kg) in vehicle and capsaicin-treated guinea-pigs. Propranolol (1 mg/kg, iv) significantly augmented the bronchoconstrictor response to acetylcholine, bradykinin and bombesin (P<0.001), an effect that was observed for RS-(+/-)-, S-(-)- and R-(+)-propranolol. In capsaicin-treated animals, the increased airways responsiveness to acetylcholine following intravenous infusion of S-(-)-propranolol was significantly inhibited. Capsaicin treatment tended to reduce the increase in airways responsiveness to bradykinin following infusion with R-(+)-propranolol, but was only significant for the highest dose used. Similarly, capsaicin treatment had no effect on the ability of RS-(+/-)-, S-(-)- and R-(+)-propranolol to enhance the bronchoconstrictor response to bombesin. Our results suggest that propranolol-induced bronchial hyperresponsiveness to certain spasmogens is in part mediated by the action of capsaicin-sensitive nerves.

Acetylcholine↗
PubMed1993

The pharmacokinetic and pharmacodynamic interactions of ramipril with propranolol.

We have studied the pharmacodynamic effects of ramipril, propranolol, and their combination, as well as the effect of propranolol on the pharmacokinetics of ramipril in 12 healthy men (age 24 (SD 6) y, weight 72 (7) kg). Propranolol and placebo, ramipril and placebo, or propranolol and ramipril were given orally for four days in a crossover, double-blind fashion. The pharmacokinetics of ramipril and ramiprilat were investigated on day 4. Effects on plasma renin activity, ACE activity, and heart rate and blood pressure both before and after a standardized exercise test were measured on days 1 and 4. On day 4 the combination reduced the mean arterial pressure by 2.8 mmHg compared with propranolol alone and by 3.7 mmHg compared with ramipril alone. Ramipril had no effect on the bradycardia induced by propranolol. Propranolol reduced exercise mean arterial pressure by 9 mmHg (day 4) and heart rate by 7 beats.min-1 (day 4) compared with ramipril; this was not affected by co-administration of ramipril. On day 4 the average plasma renin activity was not significantly higher than after the combination. ACE activity was not affected by propranolol. The pharmacokinetics of ramipril and ramiprilat were not influenced by propranolol. The combination of ramipril and propranolol has additive pharmacodynamic effects that may be useful in the treatment of hypertension.

Administration, Oral↗
PubMed1985

The affinity of (-)-propranolol for beta 1- and beta 2-adrenoceptors of human heart. Differential antagonism of the positive inotropic effects and adenylate cyclase stimulation by (-)-noradrenaline and (-)-adrenaline.

An appraisal of the affinity of (-)-propranolol was made for beta-adrenoceptors of isolated heart preparations and myocardial membrane particles from patients undergoing open heart surgery. In order to eliminate possible distorting influences of neuronal and extraneuronal uptakes of catecholamines on the affinity estimates for (-)-propranolol, isolated tissues were pretreated once with 5 or 10 mumol/l phenoxybenzamine for 2 h. Phenoxybenzamine caused potentiation of the positive inotropic effects of (-)-noradrenaline and (-)-adrenaline but not of (-)-isoprenaline; potentiation was more pronounced in atrial than in ventricular preparations. Potentiation was greater for (-)-noradrenaline than for (-)-adrenaline. It is concluded that the concentration of physiological catecholamines at the human heart beta-adrenoceptors is limited by neuronal capture but not by extraneuronal uptake. The antagonism of the positive inotropic effects of (-)-adrenaline and (-)-noradrenaline by (-)-propranolol was simple competitive in left ventricular myocardium of patients with mitral lesion. The effects of (-)-adrenaline and (-)-noradrenaline were antagonized to similar extent by (-)-propranolol. An equilibrium dissociation constant KB (-log mol/l) of 8.6 was estimated for (-)-propranolol. In atrial preparations the inotropic effects of (-)-adrenaline were antagonized significantly more by (-)-propranolol than those of (-)-noradrenaline. KB-Values (-log mol/l) of 8.9 [against (-)-adrenaline] and 8.5 [against (-)-noradrenaline] were estimated for (-)-propranolol. Concentration-effect curves for the stimulation of adenylate cyclase of both atrium and ventricle were biphasic for (-)-noradrenaline and monophasic for (-)-adrenaline. The high-sensitivity and low-sensitivity components of (-)-noradrenaline comprised 1/3 and 2/3, respectively, of maximum cyclase stimulation. As expected from beta 1-adrenoceptors, the high-sensitivity component of the curve for (-)-noradrenaline was selectively antagonized by (-)-bisoprolol; as expected from beta 2-adrenoceptors, the low-sensitivity component was selectively antagonized by ICI 118,551. (-)-Propranolol antagonized the effects of (-)-noradrenaline mediated by beta 2-adrenoceptors 2 to 3 times more potently than the effects mediated by beta 1-adrenoceptors. (-)-Propranolol competed with 3H-(-)-bupranolol for binding to left ventricular beta-adrenoceptors. An equilibrium dissociation constant (-log mol/l) of 8.6 was estimated for (-)-propranolol.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenylyl Cyclases↗
PubMed1993

Influences of the calcium antagonists nicardipine and nifedipine, and the calcium agonist BAY-K-8644, on the pharmacokinetics of propranolol in rats.

To determine the effect of dihydropyridines on the metabolism of propranolol, we studied the effects of a single oral dose of nicardipine, nifedipine, and BAY-K-8644 on the pharmacokinetics of propranolol in male Wistar rats fitted with a catheter in the jugularis vein. Oral propranolol (15 mg/kg and 1.5 mg/kg) and intravenous propranolol (1.5 mg/kg) were administered either alone or together with oral nicardipine (2.5 mg/kg). Oral propranolol (15 mg/kg) was administered with oral nifedipine (1.5 mg/kg) and with oral BAY-K-8644 (1.5 mg/kg). Nicardipine increased significantly the AUC and Cmax of oral propranolol (1.5 mg/kg and 15 mg/kg). However, the plasma concentration time curve of intravenous propranolol (1.5 mg/kg) was unaffected. Nifedipine also significantly increased the AUC and Cmax of oral propranolol (15 mg/kg), whereas with BAY-K-8644 there was only a slight increase in the bioavailability of oral propranolol (15 mg/kg). The results indicate that the dihydropyridine calcium antagonists decrease the metabolism of propranolol as a result of a decrease in first-pass clearance. Although an interaction at the level of cytochrome P450 may also be involved, the results of the present study suggest that the inhibitory effect can be largely attributed to changes in liver blood flow.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1985

Influence of food on the intravenous and oral dose kinetics of propranolol in the dog.

The intravenous and oral dose kinetics of propranolol were studied in the dog both in a fasted state and immediately after a meal consisting of 100 g of cooked beef liver. Fifty microCi of 3H-propranolol was administered intravenously simultaneously with a 40-mg oral dose of unlabeled propranolol. Plasma 3H-propranolol was measured by specific extraction and liquid scintillation spectrometry, and unlabeled plasma propranolol was determined by gas chromatography-mass spectrometry. Feeding significantly reduced (25%) the elimination half-life and increased (52%) the systemic clearance of intravenous propranolol. The increase in the systemic clearance of propranolol after feeding was mostly due to an increase (60%) in apparent hepatic blood flow, which appeared to remain elevated for 5-7 hr. The meal had no influence on the apparent volume of distribution or plasma binding. Feeding did not affect the area under the concentration-time curve of oral propranolol, but significantly delayed the rate of oral propranolol absorption, shifting the time to reach peak plasma levels from 60 to 158 min. The results of this study suggest that feeding alters the disposition of propranolol in the dog by producing a sustained increase in hepatic blood flow.

Administration, Oral↗
PubMedDate not supplied

Propranolol and thyroxine-induced hypertrophic rabbit hearts: effect on heart size and regional O2 supply/consumption variables.

The purpose of this study was to determine the effect of acute and chronic propranolol on heart size and regional O2 supply/consumption variables in thyroxine (T4)-treated rabbit hearts. New Zealand white rabbits were given 0.5 mg/kg T4 for 3 or 16 days with and without concomitant 2 mg/kg propranolol. Another group was given 16 days of propranolol alone and another 3-day T4 group was given 2 mg/kg propranolol 1 h before the experiment began. Another group served as control. Myocardial blood flows were determined using radioactive microspheres and small arteriolar and venous O2 saturations were determined using microspectrophotometry. Treatment with T4 for 3 or 16 days increased the heart weight/body weight ratio, myocardial blood flow, and regional O2 consumption. 16-day T4 treatment resulted in myocardial flow 195% and O2 consumption 300% above control group values. When propranolol was given chronically along with T4, heart weight/body weight ratios did not increase to the degree seen with 3 or 16 days of T4, alone. Propranolol given acutely in 3-day T4-treated animals, resulted in a reduced O2 consumption and O2 extraction, though not to the extent seen with chronic propranolol treatment of T4-treated animals. Acute propranolol treatment slightly reduced myocardial blood flow in 3-day T4-treated animals, while chronic treatment significantly reduced it. Chronic propranolol treatment in 16-day T4-treated animals resulted in a significant reduction in flow and O2 consumption. Thus, T4 treatment increased O2 consumption, flow, and heart size and these effects could be attenuated using acute and chronic propranolol.

Animals↗
PubMedDate not supplied

Propranolol induces contractions of canine small and large coronary arteries.

Using isolated canine small (right coronary branch, left coronary branch; o. d. 0.4-0.8 mm) and large (left coronary, circumflex; o. d. 1-2 mm) coronary arteries, the beta-adrenergic antagonist dl-propranolol (5 X 10(-7) to 5 X 10(-5) m/l) was found to produce concentration-dependent contractions. Interestingly, most of these contractile events take place with concentrations of propranolol (0.1-1 microgram/ml) found in the blood of patients who are taking this drug for various therapeutic reasons. These propranolol-induced contractions were enhanced in Krebs-Ringer solution containing slightly elevated (weak contractile) concentrations of potassium (15 mmol/l). Experiments with specific pharmacologic antagonists indicated that propranolol-induced contractions on canine coronary arteries can not be mediated by release (or inhibition) of catecholamines, histamine, serotonin or acetylcholine. Propranolol contractions could be released by low concentrations of potassium ions (4 mmol/l), suggesting that the beta receptor antagonist might inactive coronary arterial membrane Na+, K+-ATPase. Other experiments demonstrated that propranolol can enhance coronary arterial membrane permeability to calcium ions; these observations suggest that propranolol might sensitize coronary vascular smooth muscle cells to calcium ions. Removal of calcium ions from the Krebs-Ringer solution or addition of the calcium entry blocker, verapamil, prevented completely the propranolol-induced contractions. Catecholamines (i.e., epinephrine, norepinephrine, isoproterenol), which normally induce relaxation on these isolated coronary arteries, always induced contraction after use of dl-propranolol. Overall, these experiments suggest that the so-called "beta-blocker poisoning" sometimes noted with propranolol in patients might be brought about by four actions of this drug acting in concert: 1. direct coronary arterial vasospasm; 2. an unmasking of normally silent alpha-adrenergic receptors, thus allowing circulating and released catecholamines to induce potent coronary constriction; 3. attenuation of membrane Na+, K+-ATPase activity, and 4. an enhancement of coronary vascular smooth muscle membrane permeability to calcium ions.

Adrenergic Agonists↗
PubMedDate not supplied

The effects of the propranolol enantiomers on the intracardiac electrophysiological activities of Langendorff perfused hearts.

The optical isomers of the beta blocking agent propranolol exert beta receptor blocking as well as membrane stabilizing effects. The latter is thought to be responsible for the antiarrhythmic effect of the drug. In this study we quantified the electrophysiological effects of both isomers of propranolol on the conduction and pacemaker system of the heart. The experiments were performed on isolated hearts using a special ECG recording and stimulation technique. To abolish isoproterenol's beta adrenergic stimulatory effect on heart rate, 30-times higher concentrations of (+)propranolol were necessary than of (-)propranolol in order to be consistent. Both isomers caused a similar and marked slowing of conduction velocity through the bundle of His and ventricular myocardium. Also, heart rate, as well as atrio-ventricular conduction velocity were significantly slowed by a concentration of 10 microM of either drug, (-)propranolol being slightly more effective. Only in the presence of (-)propranolol did significant changes of atrio-ventricular and His-bundle conduction occur at a concentration of 1 microM. During programmed stimulation sinus node recovery time was more prolonged by (-)propranolol than during perfusion with (+)propranolol. The highest rate of pacing with 1:1 conduction of the sino-atrial conduction, the atrial and ventricular myocardium was significantly depressed to a comparable degree by either isomers of propranolol. These effects appear to be primarily responsible for the antiarrhythmic effects of both isomers. Because of the minor effects of (+)propranolol on sinus- and AV-node activity, as well as on beta adrenergic receptors, this isomer may have potential clinical importance in the treatment of arrhythmias.

Animals↗
PubMed1995

Comparison of a lifestyle modification program with propranolol use in the management of diastolic hypertension.

OBJECTIVE: To compare the management of mild diastolic hypertension (90 to 104 mm Hg) using a nonpharmacologic intervention with that using propranolol or placebo. DESIGN: Randomized, placebo-controlled trial with a 2 x 2 factorial design. SETTING: University-based ambulatory care center. PARTICIPANTS: Two hundred seven men and 105 women, 22 to 59 years of age, 73% white, who had mild diastolic hypertension untreated for at least eight weeks. INTERVENTIONS: 1) a multicomponent lifestyle modification intervention (lifestyle focus group, or LFG) administered in eight weekly meetings + placebo, 2) LFG + propranolol, 3) propranolol alone, and 4) placebo alone, followed for 12 months. MEASUREMENTS: Systolic blood pressure (SBP), diastolic blood pressure (DBP), and self-reported adverse effects at each of nine follow-up visits; fasting total cholesterol, triglycerides, and glucose at baseline and 12 months; 24-hour urine sodium (Na+) and potassium (K+), three-day food records and physical activity questionnaire at three and 12 months; and a quality of life questionnaire at 12 months. MAIN RESULTS: The mean decreases in DBP at 12 months were: 8.5 mm Hg in the LFG + propranolol group; 7.7 mm Hg in the propranolol-only group; 5.9 mm Hg in the placebo-only group; and 5.4 mm Hg in the LFG + placebo group. Repeated-measures analysis of covariance showed that level of baseline DBP (p < 0.0001), time of follow-up (p < 0.0001), and propranolol use (p < 0.0001) were significantly associated with a decrease in DBP at 12 months. Despite reductions in urinary Na+ (-35 mEq; 95% CI = -50, -19), dietary Na+ (-521 mg; 95% CI = -710, -332), total calories ingested (-238; 95% CI = -335, -140), and weight (-1.4 lb; 95% CI = -3.7, +0.8), and significant increases in dietary K+ (+294 mg; 95% CI = +107, +480) and in mets-minutes of exercise (+43; 95% CI = +20, +67) at three months, assignment to the LFG intervention had no effect on DBP at three or 12 months. The subjects assigned to take propranolol more frequently reported fatigue during ordinary activities, sleep disturbance, decrease in sexual activity, and depressed feelings, when compared with the subjects taking placebo, but the numbers of study withdrawals did not differ by drug assignment. No significant difference in total cholesterol and glucose levels was observed by group assignment. Triglycerides increased significantly in the subjects assigned to propranolol (mean difference = +20 mg/dL; 95% CI of difference +1.5, +39). There was no difference in the responses to 21 quality of life items between the subjects assigned to propranolol and those assigned to placebo. CONCLUSIONS: This multicomponent lifestyle modification intervention was unable to promote persistent behavior changes and thus was inferior to propranolol therapy for the treatment for mild diastolic hypertension. Future research should focus on single modifiable factors to lower blood pressure.

Adult↗