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PubMed2001

Randomized comparison of long-term losartan versus propranolol in lowering portal pressure in cirrhosis.

BACKGROUND & AIMS: It has been suggested that losartan, an angiotensin II (A-II) type 1 receptor blocker, may have a pronounced portal pressure reducing effect, far greater than that of propranolol. This randomized controlled trial compared the hemodynamic and renal effects of continued 6-week administration of losartan (n = 25) vs. propranolol (n = 15) in portal hypertensive patients with cirrhosis treated endoscopically after a variceal bleeding episode. METHODS: Hepatic venous pressure gradient (HVPG), systemic hemodynamics, renal function, and vasoactive factors were measured before and at 6 weeks of treatment. RESULTS: Losartan did not reduce HVPG (-2% +/- 12%, NS) but significantly decreased mean arterial pressure (MAP, -8% +/- 10%, P = 0.001). On the contrary, propranolol significantly reduced HVPG (-10% +/- 11%, P = 0.003) and cardiac output (-16% +/- 12%, P = 0.001) but did not modify MAP (2.5% +/- 10%, NS). Losartan increased A-II levels, reduced aldosterone, and decreased glomerular filtration rate (GFR) in Child B patients. Propranolol did not modify renal function. Adverse events related to therapy were mild and similar in both groups. CONCLUSIONS: Unlike propranolol, long-term losartan administration does not significantly reduce HVPG in patients with cirrhosis treated after a variceal bleeding episode, and it caused hypotension and reduced GFR in patients with moderate liver failure. Therefore, losartan is not an alternative to propranolol in preventing variceal rebleeding.

Adult↗
PubMed2005

Randomized study comparing banding and propranolol to prevent initial variceal hemorrhage in cirrhotics with high-risk esophageal varices.

BACKGROUND & AIMS: Standard care for prevention of first esophageal variceal hemorrhage is beta-blockade, but this may be ineffective or unsafe. Our purpose was to compare endoscopic banding with propranolol for prevention of first variceal hemorrhage. METHODS: In a multicenter, prospective trial, 62 patients with cirrhosis with high-risk esophageal varices were randomized to propranolol (titrated to reducing resting pulse by > or =25%) or banding (performed monthly until varices were eradicated) and were followed up on the same schedule for a mean duration of 15 months. The primary end point was treatment failure, defined as the development of endoscopically documented variceal hemorrhage or a severe medical complication requiring discontinuation of therapy. Direct costs were estimated from Medicare reimbursements and fixed or variable charges for services up to treatment failure. RESULTS: Background variables of the treatment groups were similar. The trial was stopped early after an interim analysis showed that the failure rate of propranolol was significantly higher than that of banding (6/31 vs. 0/31; difference, 19.4%; P = .0098; 95% confidence interval for true difference, 6.4%-37.2%). Significantly more propranolol than banding patients had esophageal variceal hemorrhage (4/31 vs. 0/31; difference, 12.9%; P = .0443; 95% confidence interval for true difference, 0.8%-29%), and the cumulative mortality rate was significantly higher in the propranolol than in the banding group (4/31 vs. 0/31; difference, 12.9%; P = .0443; 95% confidence interval for true difference, 0.8%-29%). Direct costs of care were not significantly different. CONCLUSIONS: For patients with cirrhosis with high-risk esophageal varices and no history of variceal hemorrhage, propranolol-treated patients had significantly higher failure rates of failure, first esophageal varix hemorrhage, and cumulative mortality than banding patients. Direct costs of medical care were not significantly different.

Adrenergic beta-Antagonists↗
PubMed2002

Randomized comparison of long-term carvedilol and propranolol administration in the treatment of portal hypertension in cirrhosis.

Short-term carvedilol administration is more powerful than propranolol in decreasing hepatic venous pressure gradient (HVPG) in cirrhotic patients, but induces arterial hypotension that may prevent its long-term use in portal hypertensive patients. This study compared the HVPG reduction and safety of long-term carvedilol and propranolol. Fifty-one cirrhotic patients were randomly assigned to receive carvedilol (n = 26) and propranolol (n = 25). Hemodynamic measurements and renal function were assessed at baseline and after 11.1 +/- 4.1 weeks. Carvedilol caused a greater decrease in HVPG than popranolol (-19 +/- 2% vs. -12 +/- 2%; P <.001). The proportion of patients achieving an HVPG reduction >/=20% or </=12 mm Hg was greater after carvedilol (54% vs. 23%; P <.05). Carvedilol, but not propranolol caused a significant decrease in mean arterial pressure (MAP) (-11 +/- 1% vs. -5 +/- 3%; P =.05) and a significant increase in plasma volume (PV) and body weight (11 +/- 5% and 2 +/- 1%, respectively; P <.05). Glomerular filtration rate (GFR) was unchanged with either drug, but the dose of diuretics was increased more frequently after carvedilol (27% vs. 8%; P =.07). Adverse events requiring discontinuation of treatment occurred in 2 patients receiving carvedilol and in 3 receiving propranolol. In conclusion, carvedilol has a greater portal hypotensive effect than propranolol in patients with cirrhosis. However, its clinical applicability may be limited by its systemic hypotensive effects. Further trials are needed to confirm the therapeutic potential of carvedilol.

Antihypertensive Agents↗
PubMed1981

Reduction of liver blood flow and propranolol metabolism by cimetidine.

We studied the influence of cimetidine on liver blood flow in eight normal subjects. Cimetidine acutely reduced liver blood flow during fasting by almost 25 per cent, as measured by indocyanine green clearance. Chronic cimetidine therapy (300 mg four times daily for seven days) reduced the flow by 33 per cent, as measured over eight hours by calculating the relative disposition of oral and intravenous propranolol. In addition to reducing the clearance of intravenous propranolol by decreasing live blood flow, cimetidine also inhibited the metabolism of oral propranolol and thereby further reduced elimination. The reduction in clearance of oral propranolol correlated positively (r = 0.87, P less than 0.05) with the average steady-state concentration of plasma cimetidine, suggesting that the inhibition of drug metabolism by cimetidine is dose related. Pulse rates at rest were markedly lower after propranolol plus cimetidine than after propranolol alone. The reduction in liver blood flow produced by cimetidine has important therapeutic implications for patients with alterations in liver and gastrointestinal blood flow and when drugs are used whose hepatic elimination depends on liver blood flow.

Administration, Oral↗
PubMed1984

Effect of propranolol on myocardial-infarct size in a randomized blinded multicenter trial.

A multicenter randomized single-blind study was performed to evaluate the effects of propranolol administered during the evolution of myocardial infarction. Five centers enrolled a total of 269 patients, with 134 receiving propranolol and 135 placebo. Propranolol or placebo was given intravenously upon randomization (0.1 mg per kilogram of body weight) and then orally for nine days to keep the heart rate between 45 and 60 beats per minute. Less than 2 per cent of patients were treated within 4 hours after the onset of symptoms, but 50 per cent received therapy within 8 hours of onset of chest pain, and the remainder between 8 and 18 hours. The heart rates in the propranolol-treated group were significantly lower than those in the placebo group (P less than 0.001). Base-line characteristics, including the mean heart rate (79.6 vs. 81.3) and the left ventricular ejection fraction (49.0 vs. 49.5), were similar in the two groups. The primary end point evaluated--infarct size as estimated from plasma MB creatine kinase activity--was virtually identical in the two groups, averaging 13.3 and 13.6 gram-equivalents of MB creatine kinase per square meter of body-surface area. Peak plasma levels of the enzyme were also similar in the two groups. No significant difference was observed between the propranolol and placebo groups in the change in left ventricular ejection fraction, extent of area involved in pyrophosphate uptake, R-wave loss on electrocardiograms, or mortality (after three years). These results do not support the use of propranolol administered four or more hours after the onset of symptoms to limit infarct size.

Administration, Oral↗
PubMed1989

Racial differences in drug response. Altered sensitivity to and clearance of propranolol in men of Chinese descent as compared with American whites.

To determine whether the pharmacokinetics and pharmacodynamics of beta-blockade differ among racial groups, we gave 10 men of Chinese descent and 10 American white men 10, 20, 40, and 80 mg of propranolol every eight hours; the dosages were given in random order, and each dose was given for one day. The degree of beta-blockade was measured as the reduction in the heart rate and blood pressure in the supine and upright positions and during treadmill exercise testing. The Chinese subjects had at least a twofold greater sensitivity to the beta-blocking effects of propranolol than the white subjects, as indicated by the mean (+/- SEM) plasma concentrations producing a 20 percent reduction in the heart rate in both the supine position (197 +/- 31 vs. 536 +/- 58 nmol per liter; P less than 0.05) and the upright position (131 +/- 27 vs. 343 +/- 39 nmol per liter; P less than 0.05) and after exercise testing (96 +/- 12 vs. 185 +/- 23 nmol per liter; P less than 0.05). In addition, the Chinese subjects had much greater sensitivity to the hypotensive effects of propranolol, as shown by the concentrations that reduced blood pressure by 10 percent in the supine position (73 +/- 5 vs. 748 +/- 7 nmol per liter; P less than 0.01) and in the upright position (89 +/- 5 vs. 401 +/- 6 nmol per liter; P less than 0.01). No difference in beta-receptor density or affinity of lymphocytes was found between the groups. The Chinese group had a 45 percent higher free fraction of propranolol in plasma, which may have contributed to the increased drug effect but cannot explain it entirely. This group metabolized propranolol more rapidly than the white group, which resulted in a 76 percent higher clearance of an oral dose (3740 +/- 737 vs. 2125 +/- 214 ml per minute; P less than 0.05) because of increased metabolism through multiple metabolic pathways. We conclude that Chinese men have greater sensitivity than white men to the effects of propranolol on heart rate and blood pressure. Decreased protein binding may be responsible in part, but most of the effect remains to be explained.

Adult↗
PubMed2002

Propranolol for small abdominal aortic aneurysms: results of a randomized trial.

PURPOSE: Animal and human studies have suggested that beta-blockade may decrease the growth rate of aneurysms. We investigated whether propranolol decreases the growth rate of small abdominal aortic aneurysms (AAAs). METHODS: We randomly assigned patients with an asymptomatic AAA between 3.0 and 5.0 cm to receive either a placebo (n = 272) or propranolol (n = 276) in a double-blind fashion. Patients were observed for a mean of 2.5 years. The primary end point was the mean annual growth rate as determined by means of ultrasound scanning performed every 6 months. Secondary outcomes were death, surgery, withdrawal from study medication, and quality of life measured by means of the Short-form Health Survey (SF-36). The main analyses were performed by means of intention to treat. RESULTS: The two groups were similar at baseline: 84% were men with a mean age of 69 years and a mean AAA size of 3.8 cm. Fewer patients in the placebo group stopped their study medication (26.8% vs 42.4%; P =.0002). The annual growth rate was similar in the two groups (placebo, 0.26 cm/y vs propranolol 0.22 cm/y; P =.11). There was a trend toward more elective surgery in the placebo group (26.5% vs 20.3%; P =.11), but there was no difference in death rate (placebo, 9% vs propranolol, 12%; P =.36). Patients in the propranolol group had significantly poorer quality of life scores in the physical functioning, physical role, and vitality dimensions of the SF-36. CONCLUSION: Patients with AAAs do not tolerate propranolol well, and the drug did not significantly affect the growth rate of small AAAs.

Adrenergic beta-Antagonists↗
PubMed1997

Effect of a beta-adrenergic antagonist, propranolol, on induced HSV-1 ocular recurrence in latently infected rabbits.

PURPOSE: Propranolol, a beta-adrenergic antagonist, has been shown to block hyperthermically-induced ocular recurrence of HSV-1 in mice and reduce spontaneous ocular viral shedding and herpetic corneal lesions in latently infected rabbits. The present study was performed to determine the effect of propranolol on epinephrine iontophoresis-induced ocular recurrence and immunosuppression-induced ocular recurrence in the rabbit eye model. METHODS: New Zealand white rabbits were infected with HSV-1 strain 17Syn+ or McKrae. After latency was established, the animals were injected intramuscularly with saline (placebo), or propranolol (5-200 mg/kg) twice daily, and then induced with epinephrine iontophoresis or cyclophosphamide and dexamethasone administration. Tear film swabs were cultured to determine the frequency of viral shedding. RESULTS: Propranolol administered at a range of doses did not affect the frequency or duration of viral shedding following epinephrine or cyclophosphamide/dexamethasone induction as compared to saline treatment. CONCLUSION: These results demonstrate that propranolol does not significantly reduce ocular HSV-1 shedding following induction by epinephrine iontophoresis or immunosuppression. By inference, these results suggest two possibilities: (1) that viral pathways leading to spontaneous and induced shedding of virus are under separate control mechanisms or (2) in rabbits, these inducers are of such potency that propranolol is ineffectual.

Adrenergic beta-Antagonists↗
PubMed1982

Propranolol medication among coronary patients: relationship to type A behavior and cardiovascular response.

The present correlational study compared behavioral and psychophysiological characteristics of coronary patients who were either medicated or not medicated with the beta-adrenergic blocking drug propranolol. Eighty-eight patients were given a structured Type A interview (SI) and a history quiz while heart rate and blood pressure were monitored. Data were analyzed controlling for age, sex, extent of coronary artery disease, and history of angina. Results indicated that patients taking propranolol (n = 65) were significantly lower in intensity of Type A behavior than patients not taking propranolol (n = 23). No effects were obtained for patients medicated or not medicated with diuretics, nitrates, or other CNS active drugs. Propranolol patients also showed lesser heart rate and rate-pressure product responses to the interview, but did not differ in blood pressure responses. Components of Type A which were lower in propranolol patients included speech stylistics (loud/explosive, rapid/accelerated, potential for hostility). Content of responses to the SI and scores on the Jenkins Activity Survey did not differ between the groups. An explanation for these results is offered in terms of the effects of propranolol on peripheral sympathetic responses, and evidence for a physiological substrate for Type A behavior. A conceptualization of the Type A pattern in terms of cognitive and physiological components is advanced, and implications for clinical intervention are discussed.

Adult↗
PubMed2004

Electron cryo-microscopy reveals mechanism of action of propranolol on artificial membranes.

The pharmacological activity of several amphiphilic drugs is often related to their ability to interact with biological membranes. Propranolol is an efficient multidrug resistance (MDR) modulator; it is a nonselective beta-blocker and is thought to reduce hypertension by decreasing the cardiac frequency and thus blood pressure. It is used in drug delivery studies in order to treat systemic hypertension. We are interested in the interaction of propranolol with artificial membranes, as liposomes of controllable size are used as biocompatible and protective structures to encapsulate labile molecules, such as proteins, nucleic acids or drugs, for pharmaceutical, cosmetic or chemical applications. We present here a study of the interaction of propranolol, a cationic surfactant, with pure egg phosphatidylcholine (EPC) vesicles. The gradual transition from liposome to micelle of EPC vesicles in the presence of propranolol was monitored by time-resolved electron cryo-microscopy (cryo-EM) under different experimental conditions. The liposome-drug interaction was studied with varying drug/lipid (D/L) ratios and different stages were captured by direct thin-film vitrification. The time-series cryo-EM data clearly illustrate the mechanism of action of propranolol on the liposome structure: the drug disrupts the lipid bilayer by perturbing the local organization of the phospholipids. This is followed by the formation of thread-like micelles, also called worm-like micelles (WLM), and ends with the formation of spherical (globular) micelles. The overall reaction is slow, with the process taking almost two hours to be completed. The effect of a monovalent salt was also investigated by repeating the lipid-surfactant interaction experiments in the presence of KCl as an additive to the lipid/drug suspension. When KCl was added in the presence of propranolol the overall reaction was the same but with slower kinetics, suggesting that this monovalent salt affects the general lipid-to-micelle transition by stabilizing the membrane, presumably by binding to the carbonyl chains of the phosphatidylcholine.

Cryoelectron Microscopy↗
PubMed1987

Propranolol increases oxygen utilization during hypoxia.

The effects of propranolol on whole body oxygen consumption and blood oxygen content were measured in the dog during extreme hypoxic conditions. At 9% inspired oxygen four of eight control animals died within 40 min. An identical second group was pretreated with propranolol and none died during the same hypoxic stress. Hypoxia decreased oxygen consumption in both groups, but the decrease was less in the propranolol-pretreated dogs. A second set of 16 dogs was ventilated with 10% oxygen and all animals survived. A similar, although less pronounced, effect on oxygen consumption was noted and propranolol once again lessened the hypoxia-induced decrease in oxygen consumption. With hypoxaemia, metabolic acidosis developed in all animals and the arterio-venous oxygen content difference decreased; however, propranolol lessened the acidosis and the decrease in arterio-venous oxygen content difference. We conclude that, during hypoxia, propranolol increases oxygen utilization by the tissues and this might account for better survival.

Animals↗
PubMed1981

Myocardial and peripheral catecholamine responses to acute coronary artery constriction before and after propranolol treatment in the anaesthetised dog.

The left anterior descending coronary artery was constricted for eight minutes on two occasions in 13 anaesthetised open-chest dogs. One group (n = 8) was studied before and afer 1 mg . kg-1 propranolol intravenously; a second group (n = 5) served as controls. Simultaneous blood samples were drawn from arterial and coronary sinus catheters for measurement of lactate and catecholamine concentrations. In controls, coronary artery constriction resulted in a reproducible fall in fractional myocardial lactate extraction and an increase in left atrial pressure, but caused no significant changes in blood pressure, heart rate or plasma concentrations of noradrenaline, adrenaline, or dopamine. In the treated group, heart rate was reduced but blood pressure was the same after propranolol; both remained unchanged during constriction and after release. The fall in fractional lactate extraction was abolished by propranolol. Arterial noradrenaline increased significantly after propranolol, fell during constriction and rose again after release. A similar trend was observed in coronary sinus noradrenaline. Reversible myocardial ischaemia is not associated with peripheral or myocardial release of catecholamines. Pre-treatment with propranolol appears to exert a protective effect on the myocardium even during reversible ischaemia. Although peripheral noradrenaline levels are increased after propranolol, this increase is not maintained during coronary artery constriction.

Acute Disease↗
PubMed1984

Effect of early propranolol treatment in an animal model of congestive cardiomyopathy. II. beta-adrenergic receptors and left ventricular function.

Young turkeys inbred for congestive cardiomyopathy (CCM) were treated with propranolol prior to the development of cardiac enlargement. One-day-old inbred CCM and commercial turkeys received 2 mg X kg-1 X day-1 of propranolol for 1 month and were compared with untreated age matched inbred CCM and commercial turkeys. Heart weight, body weight, and binding characteristics of cardiac beta-adrenergic receptors, using (-)3H-dihydroalprenolol as a ligand, were determined at 10 and 28 days. Left ventricular shortening fraction was determined at 28 days and at 32 days, 4 days after propranolol was discontinued, in treated and untreated inbred CCM and commercial turkeys. Propranolol did not prevent the development of cardiac hypertrophy in inbred CCM turkeys at 28 days of age and did not effect body weight or heart weight in either inbred CCM or commercial turkeys at 10 or 28 days of age. In the inbred CCM turkeys, the maximum number of binding sites (Bmax) and the binding affinity (Kd) of beta-adrenergic receptors were not changed by propranolol treatment. In the propranolol-treated commercial turkeys, Bmax the of beta-receptors was increased at 28 days of age compared with untreated age matched controls, 382 vs 194 fmol X mg-1 (p less than 0.05). Untreated inbred CCM turkeys when compared with untreated age matched commercial turkeys show a significant reduction of binding affinity of beta-receptors at both 10 and 28 days of age, Kd = 10.4 vs 6.2 nmol X litre-1 at 10 days and 11.3 vs 5.2 nmol X litre-1 at 28 days (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Effect of D-propranolol on growth and motility of flagellate protozoa.

Propranolol inhibits sperm motility and has been considered as a spermicide contraceptive. In view of the inhibitory effects of D-propranolol on sperm flagellar activity, we have investigated its effect on motility and growth of two human flagellate, protozoan parasites. D-propranolol had a dose-dependant inhibitory effect on motility of Giardia lamblia and Trichomonas vaginalis with ED50s of 0.38 and 0.66 mmol/l respectively, D-propranolol also inhibited growth of both parasites with ED50s of 0.18 and 0.23 mmol/l for Giardia and Trichomonas respectively. D-propranolol, unlike DL-propranolol is devoid of the unwanted effects of beta-blockade, and thus may be a useful antiprotozoal drug particularly after vaginal placement when it is concentrated in vaginal mucus.

Animals↗
PubMed1987

The cardiovascular and adrenergic actions of verapamil or diltiazem in combination with propranolol during halothane anesthesia in the dog.

Continuous infusions of verapamil and diltiazem were established in halothane-anesthetized dogs (1.15-1.35% end tidal concentration) with or without a concomitant propranolol infusion to investigate changes: in cardiovascular function, in reflex activation as reflected in circulating catecholamine levels, and in the chronotropic response to the exogenously administered beta agonist, isoproterenol. Verapamil plasma levels of approximately 100 and 250 ng X ml-1, diltiazem plasma levels of approximately 140 and 325 ng X ml-1, and propranolol levels of approximately 70 ng X ml-1 were tolerated individually in the presence of halothane, although atrioventricular conduction was prolonged in the verapamil and diltiazem groups. Catecholamine levels were increased in the high verapamil group. However, when propranolol was combined with the lower levels of verapamil or diltiazem, the result was decreased heart rate, blood pressure, left ventricular maximum rate of tension development (dP/dt), and cardiac index with increased systemic vascular resistance. When the attempt was made to proceed to the increased plasma levels of verapamil or diltiazem in the presence of propranolol, 6/6 animals in the verapamil-propranolol group and 4/6 animals in the diltiazem-propranolol group were unable to maintain a mean arterial blood pressure of greater than 50 mmHg, and many developed 2 degrees or higher heart block.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia, Inhalation↗
PubMed1987

Acute effects of halothane anesthesia on arterial and venous concentrations of propranolol in the dog.

The present study determined the effect of halothane on arterial and venous propranolol concentrations during a continuous intravenous infusion of propranolol. Arterial and venous concentrations of propranolol remained constant during the experiment in the group of dogs anesthetized only with pentobarbital. However, there was a rapid increase in arterial propranolol concentration from 88 +/- 10 ng/ml (mean +/- SEM) prior to halothane to 116 +/- 12 ng/ml (P less than 0.05) and 130 +/- 7 ng/ml (P less than 0.05) 60 and 120 min, respectively, after starting halothane anesthesia (2.0 MAC 1.74%). The increase in venous propranolol concentration lagged substantially behind that of the arterial concentration, so that, 60 min after starting halothane, the arterial to venous (A/V) concentration ratio increased from 1.13 +/- 0.05 to a maximum of 1.48 +/- 0.08. In contrast to the changes following halothane, no significant change in the A/V ratio occurred following fentanyl. Both halothane and fentanyl administration produced a small but significant increase in the free fraction of propranolol (P less than 0.05). The results from this study emphasize the importance of the choice of sampling sites in pharmacokinetic experiments, as well as excluding subtle pharmacokinetic changes during anesthesia before ascribing changes in drug effect to changes in sensitivity to the drug.

Anesthesia, Inhalation↗
PubMed1982

Propranolol and thyroidectomy in the treatment of thyrotoxicosis.

For decades, the preparation of a hyperthyroid patient for surgery took several weeks or months utilizing thyroid blocking agents and iodine. In 1973, a preliminary report of 20 patients with hyperthyroidism treated with propranolol and thyroidectomy was presented. It was found that a thyrotoxic patient could be prepared for surgery, in an emergency, by intravenous propranolol in less than an hour, or electively by oral propranolol within 24 hours. Since then, 140 additional patients have been similarly treated. It continues to be true at this institution that propranolol, a beta-adrenergic blocking agent, effectively neutralizes the symptoms of autonomic hyperactivity, including sweating, tremor, fever, dilation of blood vessels, and increased pulse rate without significantly affecting thyroid function. An average dose of 160 mg/day was used, with a range of 40 to 320 mg/day. In none of these patients was iodine used; in fact, its use with propranolol is considered unnecessary. A subtotal, near total, or total thyroidectomy was done in all patients, resulting in a 55% incidence of hypothyroidism. There was no postoperative thyroid storm, nerve injury, or permanent hypoparathyroidism. It is believed that the administration of propranolol alone provides a rapid, safe, and effective preparation of the thyrotoxic patient for thyroidal or extrathyroidal surgical procedures during the perioperative period.

Adolescent↗
PubMed1999

Propranolol blocks cocaine-induced cerebral vasodilation in newborn sheep.

OBJECTIVE: The objective of this study was to test the hypothesis that cocaine-induced cerebral vasodilation in newborn sheep is mediated via beta-adrenergic receptor activation. DESIGN: The cerebral effects of a single intravenous injection of cocaine (4 mg/kg) given 30 mins after pretreatment with propranolol (1 mg/kg) were studied and compared with the results from a previous study using an identical cocaine protocol without propranolol pretreatment. SUBJECTS: Seven chronically catheterized, unanesthetized newborn sheep (6 +/- 1 days old). MEASUREMENTS: Cerebral blood flow using radiolabeled microspheres, mean arterial blood pressure (MAP), heart rate, and cerebral arterial and venous oxygen content were measured at baseline, after administration of propranolol, and 0.5, 5, 15, and 60 mins after cocaine injection. Cerebrovascular resistance was calculated as the MAP divided by the cerebral blood flow. MAIN RESULTS: Propranolol injection alone caused no systemic or cerebral physiologic changes other than an 11 +/- 2% (mean +/- SEM) decrease in heart rate, which was sustained after cocaine injection. In contrast to previous studies showing cerebral vasodilation (25% decrease in cerebrovascular resistance) and acute hypertension (57% increase in MAP) 30 secs after cocaine injection, there were no changes in cerebrovascular resistance after cocaine injection and after propranolol pretreatment and there was only a 23 +/- 7% increase in MAP 30 secs after injection, with a return to baseline by 15 mins. Cocaine and norepinephrine levels were similar to those previously reported in the newborn sheep after an injection of 4 mg/kg cocaine. CONCLUSION: Propranolol blocks cocaine-induced cerebral vasodilation and blunts the acute hypertension in newborn sheep, suggesting that cocaine's cerebrovascular effects in the developing brain are mediated, at least in part, by beta-adrenergic receptor activation.

Adrenergic beta-Antagonists↗