Chronic Propranolol Research Articles

Development of insulin sensitivity in rat aorta after chronic propranolol treatment

Spontaneously hypertensive rats and normotensive Kyoto Wistar controls were divided into 3 groups of 10 animals each and treated with phenoxybenzamine (5 mg/kg once daily), propranolol (25 mg/kg twice daily) or saline (once daily). After 5 weeks the in vitro incorporation of D-[U- 14C]-glucose into aortic lipids and glycogen was measured in the presence and absence of insulin (1 mU/ml). In both normotensive and hypertensive rats treated with propranolol 14C-incorporation into triglycerides was reduced. Furthermore, insulin significantly stimulated 14C-incorporation into triglycerides, phospholipids and glycogen in propranolol-treated hypertensive rats. This effect was not statistically significant (0.05 < p < 0.1) in propranolol-treated normotensives. Phenoxybenzamine treatment did not significantly modify aortic lipogenesis of glycogen synthesis from glucose. Chronic propranolol treatment of spontaneously hypertensive rats resulted in aortic tissue becoming sensitized to insulin. Possible mechanisms and explanations for this are discussed.

Elevated beta-adrenergic receptor number after chronic propranolol treatment

Treatment of rats with the beta-adrenergic antagonist propranolol for two weeks leads to a 100% increase in the number of beta-adrenergic receptors ((−) [ 3H]dihydroalprenolol binding sites) in cardiac particulate fractions. No change in receptor affinity was observed. These findings may l) represent the converse of agonist-induced desensitization which is associated with decreases in beta-receptor number, 2) provide a potential explanation for the clinically observed “propranolol withdrawal syndrome”.

PLASMA AND ATRIAL PROPRANOLOL AFTER PREOPERATIVE WITHDRAWAL

Of 34 patients scheduled for aortocoronary bypass operations who were withdrawn from chronic propranolol therapy between 18 and 48 hours before anesthesia and operation, propranolol was detected in the plasma of nine and in atrial tissue of five patients. Higher plasma levels were associated with higher propranolol intake and with shorter time of withdrawal. In 15 patients withdrawn preoperatively from propranolol the heart rate and blood pressure response to 3 mug isoproterenol was not significantly different from the response of similar patients who had received no propranolol. In contrast to the response of healthy subjects, most patients with coronary artery disease responded to isoproterenol with a decrease in systolic blood pressure. Plasma propranolol levels after a 0.5 mg bolus given intravenously during operation produced a peak level of 40 ng/ml in one minute and disappeared in five minutes. These studies suggest that no beta blockade persists 18 hours after acute preoperative withdrawal of propranolol in patients taking up to 300 mg per day for control of angina. In view of the reported hazards of abrupt withdrawal of propranolol before operation and the reported usefulness of propranolol in treating tachyarrhythmias during operation, we suggest that early preoperative withdrawal of propranolol may be more hazardous than its continuation before coronary bypass operations.

Chronic propranolol administration and acute myocardial infarction

Chronic propranolol administration and acute myocardial infarction

Residual effects when chronic propranolol therapy is discontinued within 48 hours of cardiopulmonary bypass

Recommendations regarding the safe waiting period between discontinuing chronic oral propranolol therapy and beginning cardiopulmonary bypass have varied from a few hours to 2 weeks. In the present study, utilizing adult dogs, propranolol was discontinued 8 or 48 hours prior to surgery. A reduction in cardiac output and elevations of left ventricular end-diastolic pressure, peak systolic pressure, and systemic resistance were noted when cardiac function was evaluated following the induction of anesthesia and prior to undertaking cardiopulmonary bypass. The magnitude of these differences was directly related to the degree of volume loading and inversely related to the interval between the last dose of propranol and the determination of cardiac function. Reduction of heart rate was the most evanescent of propranolol's hemodynamic effects as the marked bradycardia which persisted throughout the course of propranolol therapy was no longer evident 8 hours after the last oral dose of the drug. Following total cardiopulmonary bypass of 1 hour's duration, undertaken 8 hours after the last oral dose of propranolol, cardiac output and left ventricular end-diastolic pressure had returned to normal but peak systolic pressure and systemic resistance remained significantly elevated, When 48 hours had elapsed between discontinuing propranolol and beginning cardiopulmonary bypass, postbypass cardiac function was essentially normal with only slight persistent elevations of peak systolic pressure and systemic resistance detected. When the combined effects of ischemic heart disease and propranolol therapy, the altered metabolic and hemodynamic effects of different routes of drug administration, and the varying durations of cardiopulmonary bypass are taken into consideration, some of the discrepancies between previously reported clinical and experimental findings regarding the duration of persistent propranolol effects can be understood. The clinical course is usually benign in patients who have received propranolol to within a few hours of surgery without specific indication. However, it is often complicated when the drug is continued until just prior to surgery in patients dependant on propranolol for pain or arrhythmia control. In patients demonstrating propranolol dependence, control of symptoms with intra-aortic balloon counterpulsation is recommended followed by the gradual withdrawal of propranolol and elective aortocoronary bypass surgery.

Effect of isoproterenol and propranolol on halothane MAD in dogs.

To evaluate the effect of propranolol on anesthetic requirement, changes in minimum alveolar concentration (MAC) of halothane accompanying acute (2 and 10 mg/kg IV) and chronic (200 mg/day orally for 10 days) propranolol administration were determined in dogs. MAC did not change significantly in either case. Beta-adrenergic blockade was achieved with the 2 mg/kg propranolol dose, as indicated by abolition of the pulse rate increase in response to isoproterenol infusion. Isoproterenol itself did not alter MAC. Mean arterial pressure (MAP) and heart rate (HR) at any given level of alveolar halothane were the same before and after chronic propranolol administration. Acute IV administration of propranolol, especially at the 10 mg/kg dose, reduced MAP and increased HR only transiently.

Pharmacokinetics of beta-receptor-blocking agents in relation to their anti-hypertensive effect.

1. Beta-Recptor-blocking drugs are rapidly and completely absorbed after oral administration. Systemic availability is nevertheless incomplete for propranolol, alprenolol and oxprenolol, owing to "first-pass' extraction by the liver. 2. Plasma half-life is between 2 and 4 h, except for sotalol (10-12 h). Plasma elimination of propranolol is reduced with decreased liver blood flow observed in congestive heart failure or during chronic propranolol therapy itself. 3. beta-Receptor blockade is usually achieved in these concentration ranges: propranolol and alprenolol, 50-100 ng/ml; oxprenolol, 500-1000 ng/ml; pindolol, 10-30 ng/ml; sotalol, 2-6 microng/ml. Higher concentrations are often found with high doses administered to hypertensive patients.

Plasma and atrial propranolol after preoperative withdrawal.

Of 34 patients scheduled for aortocoronary bypass operations who were withdrawn from chronic propranolol therapy between 18 and 48 hours before anesthesia and operation, propranolol was detected in the plasma of nine and in atrial tissue of five patients. Higher plasma levels were associated with higher propranolol intake and with shorter time of withdrawal. In 15 patients withdrawn preoperatively from propranolol the heart rate and blood pressure response to 3 mug isoproterenol was not significantly different from the response of similar patients who had received no propranolol. In contrast to the response of healthy subjects, most patients with coronary artery disease responded to isoproterenol with a decrease in systolic blood pressure. Plasma propranolol levels after a 0.5 mg bolus given intravenously during operation produced a peak level of 40 ng/ml in one minute and disappeared in five minutes. These studies suggest that no beta blockade persists 18 hours after acute preoperative withdrawal of propranolol in patients taking up to 300 mg per day for control of angina. In view of the reported hazards of abrupt withdrawal of propranolol before operation and the reported usefulness of propranolol in treating tachyarrhythmias during operation, we suggest that early preoperative withdrawal of propranolol may be more hazardous than its continuation before coronary bypass operations.

Beta-adrenergic mechanisms in action tremor.

To study the mechanisms by which propranolol suppresses essential tremor, accelerometric recordings were made from four normal subjects and eight patients with that tremor, and small amounts of isoproterenol and propranolol were infused intravenously or into one brachial artery. Intra-arterial isoproterenol increased tremor amplitude selectively in that arm in normal subjects and in patients with essential tremor (range, 1.85 to 3.50 with mean 2.74 times the base-line level). Intra-arterial or intravenous propranolol quickly blocked the enhanced action tremor in both groups. It did not simultaneously affect the underlying essential tremor, whereas long-term oral propranolol therapy did diminish the amplitude of the essential tremor in each patient. Peripheral beta-adrenergic tremorogenic receptors function normally even in patients with essential tremor; their function is not necessary for the production of essential tremor, and the efficacy of chronic propranolol therapy in the suppression of essential tremor is not mediated via its peripheral beta-adrenergic blocking action.

Tyrosine hydroxylase activity in rat brain regions after chronic treatment with ±-propranolol

Rats were injected twice daily with +/--propranolol (6 mg kg-1 day-1) for 14 days and killed 16 h after the final injection. Tyrosine hydroxylase activity was measured in both soluble and particle-bound forms in various brain regions. The activity of the soluble enzyme was not significantly altered by propranolol treatment in any of the brain regions studied. The tyrosine hydroxylase activity in the particulate fraction was significantly increased in corpus striatum and unchanged in other brain regions. The propranolol concentrations in the various brain regions in this chronic study were far lower than necessary to produce a significant change in tyrosine hydroxylase activity in acute experiments. It was concluded that chronic propranolol treatment produces a persistent increase in bound tyrosine hydroxylase activity in rat corpus striatum.

Circulatory effects of propranolol and cardiopulmonary bypass

Clinical experience has indicated a high operative risk due to depressed ventricular function in certain patients receiving chronic oral propranolol therapy for control of the symptoms of obstructive coronary artery disease. This has led to the recommendation that propranolol be discontinued 2 wk prior to elective coronary bypass surgery [5]. However, the half-life of propranolol in man is less than 6 hr [3] and other workers have reported no significant difference in mortality rates when comparing coronary artery bypass graft patients who had chronic propranolol therapy discontinued 36-48 hr prior to surgery with graft patients who had never received propranolol[4]. Because of the large number of angina patients receiving propranolol, the increasing performance of emergency coronary artery bypass surgery, and the occasional occurrence of acute myocardial infarction after propranolol withdrawal [l] the residual effects of chronic propranolol therapy on cardiac function after induction of anesthesia and after cardiopulmonary bypass were further investigated.

Chronic propranolol treatment in young spontaneously hypertensive and normotensive rats.

Oral treatment with propranolol, 1 or 5 mg/kg per day, was started in young spontaneously hypertensive rats (S.H.R.) 1 week after weaning and continued for 12 weeks. The same doses were administered to age-matched normotensive rats. Propranolol was admixed to a standard laboratory diet in concentrations calculated on the basis of average food consumption. Blood pressure was measured by an indirect method.As compared to control S.H.R., a significantly lower blood pressure was recorded in S.H.R. treated with propranolol, 1 mg/kg, at week 10 and 12 of the treatment and in those treated with 5 mg/kg at weeks 6–12. The heart rate was not consistently affected.The blood pressure of control and treated normotensive rats did not differ significantly with the exception of an elevated blood pressure in both dosage groups at the first reading.The growth of rats was not impaired by propranolol and no morphological organ changes related to the treatment could be detected at the end of the experiment.

Time required for complete recovery from chronic propranolol therapy.

Abstract Propranolol could not be detected in samples of plasma and left atrium obtained from eight patients during coronary bypass surgery 36 to 48 hours after withdrawal from chronic therapy. The norepinephrine sensitivity of strips of left atria obtained from four similar patients was not different from that in six control patients who had not previously received propranolol. In three ambulant patients, serial estimates of the chronotropic and inotropic responses to isoproterenol were made at daily intervals during withdrawal from propranolol. Isoproterenol sensitivity became stable or returned to control levels within 48 hours. These findings were confirmed by experiments in the rat. A withdrawal time of 48 hours thus appears sufficient for complete recovery from the cardiac effects of propranolol and any possibly active metabolites, and coronary bypass surgery should present no additional hazard. (N Engl J Med 289:607–609, 1973)

Ultrasound in the diagnosis and evaluation of therapy of idiopathic hypertrophic subaortic stenosis.

Twenty patients with idiopathic hypertrophic subaortic stenosis (IHSS) were studied with cardiac echography. Eight of these patients were studied during left heart catheterization. The echographic pattern of mitral valve motion during systole was altered in a characteristic manner when hemodynamically significant left ventricular outflow obstruction was present in the eight patients studied at catheterization. The abnormal systolic pattern was abolished by spontaneous loss of outflow obstruction or loss of obstruction induced by beta-adrenergic blockade. An abnormal systolic mitral valve pattern was seen on the echogram in 17 of the 20 patients with proven IHSS. The abnormal pattern was lost after the institution of chronic propranolol therapy in one patient. The three patients not showing an abnormal systolic pattern were also taking propranolol. The pattern of mitral valve motion during diastole indicated an impaired rate of left ventricular filling. The basic abnormalities and variability in the degree of abnormality seen with echography of the left ventricular outflow tract are consistent with the proposed anatomy and pathophysiology of IHSS.

Supersensitivity of the chronically denervated feline heart.

Supersensitivity of the chronically denervated feline heart.