Chronic Administration Of Propranolol Research Articles

Early chronic administration of propranolol reduces the severity of portal hypertension and portal-systemic shunts in conscious portal vein stenosed rats

We investigated the effects of early chronic administration of propranolol on systemic and splanchnic hemodynamic changes, and the development of portal-systemic shunts in conscious, unrestrained, portal vein stenosed rats. Compared to rats receiving placebo, early chronic propranolol (75 mg kg-1 day-1) administration to rats begun 3 days before portal vein stenosis and then continued for 10 consecutive days, resulted in a significant decrease in both portal pressure (11.8 +/- 1.5 mmHg) and portal-systemic shunts (48 +/- 18%) which were measured 2 to 3 h after the final dose of propranolol (15.2 +/- 1.5 mmHg and 84 +/- 5%, respectively). These beneficial effects were also observed 18 to 24 h after the final dose of chronic propranolol. In rats given propranolol continuously for 5 days starting 5 days after portal vein stenosis, portal pressure (11.8 +/- 1.2 mmHg) was significantly lower than in the placebo group but portal-systemic shunts (76 +/- 14%) were not significantly different. In rats receiving a single dose of propranolol (75 mg/kg) 10 days after portal vein stenosis and measured 2 to 3 h after propranolol administration, portal pressure (12.8 +/- 1.0 mmHg) was significantly lower than in the placebo group. Portal-systemic shunts (72 +/- 17%), however, showed no significant difference from the placebo group. Similar values in portal pressure (13.3 +/- 1.2 mmHg) and portal-systemic shunts (83 +/- 21%) were also observed in rats 18 to 24 h after a single dose of propranolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanism of Growth Retardation following Chronic Administration of β-Adrenoceptor Antagonists to Developing Rats

A total of 112 3-week old Wistar rats were separated into eight groups: control groups I-IV (n = 62) and propranolol-treated groups V-VIII (n = 50). Propranolol hydrochloride (100 mg/kg) was present in the rats' drinking water until 26 weeks of age and growth rates of all groups were monitored daily until 53 days of age and thereafter every third day throughout the study. Chronic oral propranolol administration produced growth retardation (P less than 0.05) in both sexes that was reversible when treatment was discontinued. Organ weights were generally smaller in propranolol-treated rats; on the other hand, the ratio of most organ weights per 100 g of body weight was greater in propranolol-treated rats (especially females). The radio-immunological determination of plasma growth hormone showed increased concentrations of growth hormone in propranolol-treated rats (P less than 0.05), whereas hypothalamic somatostatin content was not significantly changed. The results showed that the retarded growth rate following chronic oral propranolol administration to growing rats was independent of changes in plasma growth hormone and hypothalamic somatostatin concentrations, and that retardation was entirely reversible when the beta-adrenoceptor antagonist was discontinued.

Alterations in β adrenergic and muscarinic receptors in aged rat heart. Effects of chronic administration of propranolol, xamoterol, and atropine

Alterations in β adrenergic and muscarinic receptors in aged rat heart. Effects of chronic administration of propranolol, xamoterol, and atropine

The effect of chronic propranolol treatment on salivary composition and caries in the rat

Many drugs are known to affect salivary secretion. The purpose of this study was to explore the chronic effects of a commonly used β-adrenergic blocker, propranolol. Adult rats were desalivated or treated for 28 days with propranolol HCl (10 or 20 mg/kg, daily) or sterile buffer (sham-operated control) using osmotic pumps for delivery. The parotid and submandibular glands of each rat were cannulated and secretion elicited by pilocarpine (10 mg/kg, intravenous). There were no statistical differences in salivary protein content (Lowry) or output among the groups (ANOVA p > 0.05). Analysis of salivary proteins by SDS-PAGE revealed a constant profile for submandibular secretions, but peak A and SP-3 proline-rich proteins were not detectable in parotid saliva of animals treated with propranolol for the entire experiment. Significantly increased smooth-surface ( p = 0.0003) and sulcal ( p = 0.0011) caries scores were found within these propranolol groups (ANOVA). The findings provide further evidence that chronic administration of propranolol alters salivary composition by decreasing proline-rich proteins and concurrently enhances susceptibility to caries.

Effect of long-term treatment with beta-blocker on cardiac hypertrophy in SHR.

Recent studies suggest that beta-blocker treatment may attenuate cardiac hypertrophy induced by pressure overload in the spontaneously hypertensive rat (SHR), but the effect of this therapy on the reconstitution of the intracellular constituents in the heart that occurs during the development of cardiac hypertrophy has not been examined. In this study, we investigated the effect of chronic administration of carteolol (4 mg/kg/day p.o.) or propranolol (20 mg/kg/day p.o.), beta-blockers with distinct modes of action, on the composition of cardiac myosin isozymes and histological findings as well as heart weight. Therapeutic periods were 4, 12 or 30 weeks. Though blood pressure was not significantly reduced, the development of cardiac hypertrophy was suppressed as evidenced by left ventricular weight in both groups of carteolol- and propranolol-treated SHR for all therapeutic periods. Again, beta-blocker treatment for 12 weeks alleviated myocardial degeneration and reactive fibrosis which were observed in all cases of age-matched untreated SHR. However the extent of the transition of cardiac myosin isozymes from V1 to V2 or V3 were essentially the same among all groups including untreated SHR. These results indicate that chronic administration of beta-blockers attenuates the development of cardiac hypertrophy and degeneration without affecting the transition of myosin isozymes which is thought to be a kind of biochemical adaptation of the myocardium to overload.

Chronic propranolol attenuates hypoxic pulmonary vasoconstriction in conscious rats

Experiments were performed on conscious, chronically instrumented rats to assess the effect of chronic propranolol treatment on basal pulmonary hemodynamics and on hypoxic pulmonary vasoconstriction. Rats received either propranolol (4 mg/day) or vehicle for 31 days via implanted osmotic minipumps. Animals were then acutely exposed to 8% and 10% O 2. Pulmonary arterial pressure (PAP), mean arterial blood pressure (MABP) and heart rate (HR) were monitored via chronically implanted catheters, and cardiac output (CO) was measured by thermodilution. Chronic administration of propranolol was associated with minimal changes in MABP, PAP and total pulmonary resistance (TPuR). However, HR and CO decreased and total systemic resistance (TSR) increased in propranolol treated rats. The acute hypoxic pulmonary vasoconstrictor response of propranolol treated rats was significantly less than that of untreated control animals. Systemic hemodynamic responses to acute hypoxia did not differ between the groups. These data indicate that chronic propranolol administration reduces the acute hypoxic pulmonary vasoconstrictor response in conscious rats, but does not alter basal pulmonary hemodynamics.

The effects of beta-antagonists and anxiolytics on conflict behavior in the rat

The present studies were designed to evaluate the effects of beta-adrenoceptor antagonists and traditional anxiolytics (phenobarbital and diazepam), alone and in combination, on behavior in the Conditioned Suppressioned of Drinking (CSD) conflict paradigm, an “animal model” for the study of anxiety and antianxiety agentt. In daily 10-minute sessions, water-deprived rats were trained to drink from a tube which was occasionally electrified (0.5 mA), electrification being signalled by the presence of a tone. Within 2–3 weeks, control responding had stabilized (10–15 shocks/session and 10–15 ml water/session); drug tests were then conducted at weekly intervals. As expected, diazepam (0.6–10 mg/kg) and phenobarbital (10–40 mg/kg) administration resulted in a marked and dose-dependent increase in punished responding at doses which did not markedly alter background responding (water intake). Neither propranol (0.5–8 mg/kg) nor the beta-1-selective antagonist atenolol (1–16 mg/kg) significantly affected punished responding in the CSD. Both propranolol and atenolol produced significant beta-1-adrenoceptor blockade, as evidenced by the production of significant bradycardic effects in conscious rats at the doses employed. Pretreatment with 2.0 mg/kg propranolol did not alter the anticonflict effects of diazepam (0.6–10 mg/kg) or phenobarbital (10–40 mg/kg). Further, reduction of the shock intensity to 0.125 mA (i.e., decreased suppression) failed to alter the behavioral response to propranalol (1.5–5 mg/kg) or the interaction of 2.0 mg/kg propranolol with diazepam. Finally, chronic administration of propranolol (2.0 mg/kg, twice daily) did not affect punished responding over the course of 5 weeks of treatment. These data suggest that the CSD paradigm, although an effective “animal model” for the study of benzodiazepine and barbiturate anticonflict effects, cannot serve as an “animal model” for the study of bee situation-specific (i.e., phobic) anxiety for which propranolol and related agents are presently used.

Effect of prolonged propranolol administration and withdrawal on perfusion of the myocardial capillary bed.

The effect of chronic propranolol administration (2 mg.kg-1.d-1 for 14d) and withdrawal on microvascular perfusion was studied in rabbit myocardium. Fluorescein isothiocyanate-dextran was injected into four groups of anaesthetised open chest rabbits. Fluorescent microscopy was used to identify the perfused vessels and alkaline phosphatase stain was employed to locate the total microvasculature. Beta adrenoceptor density (Bmax), measured using 125I-iodopindolol, increased from 20.3(SD 6.3) fmol.mg-1 protein in control to 52.4(8.9) in chronically treated rabbits. The proportion of the capillary bed which was perfused, 61.4(4.3)% was significantly decreased by acute injection of propranolol to 51.1(5.1)%, but not affected by chronic administration, remaining at 57.0(4.0)%. The percentage of the capillary bed perfused increased significantly after cessation of chronic propranolol treatment to 69.1(6.5)%. Similar results were seen for myocardial arterioles. Thus, while diffusion distances are increased by acute adrenoceptor blockade, this effect is not seen in the chronic condition. Diffusion distance decreased significantly after withdrawal of chronic propranolol treatment. We conclude that the percentage of perfused capillaries is strongly influenced by the number of beta adrenoceptors or their effect.

Neurogenically mediated plasma extravasation in dura mater: effect of ergot alkaloids. A possible mechanism of action in vascular headache.

C-fiber-dependent neurogenic plasma extravasation developed in the dura mater but not the brain after electric stimulation of the rat trigeminal ganglion or after chemical stimulation of perivascular axons with intravenous capsaicin, a drug that depolarizes sensory nerve fibers. C-fiber-independent extravasation also developed in this tissue after intravenous injections of substance P or neurokinin A (two constituents of unmyelinated C fibers) and after serotonin, bradykinin, or allergic challenge in presensitized animals. Intravenous dihydroergotamine or ergotamine tartrate, in doses similar to those used to treat migraine and cluster headache, prevented the stimulation-induced leakage of plasma proteins within the dura mater. Not unexpectedly, the acute administration of methysergide, a drug effective in the prophylactic treatment of headache, was inactive in this acute model. Neither acute nor chronic administration of propranolol affected stimulation-induced leakage of plasma protein. These results demonstrate that neurogenic inflammation develops within the dura mater in the rat and that ergot alkaloids prevent the process by a C-fiber-dependent mechanism.

Systemic haemodynamics, renal and platelet function during chronic propranolol administration in patients with compensated cirrhosis.

Chronic propranolol administration is followed by some haemodynamic alterations, which may impair renal function. It has also been suggested that it may reduce platelet production of proaggregatory thromboxane (TX) A2. We therefore evaluated cardiac index (CI), systemic vascular resistance (SVR), creatinine clearance, daily sodium excretion under controlled sodium intake, platelet aggregation and platelet TXA2 production during whole blood clotting in eight patients with cirrhosis, portal hypertension and no ascites, before and after 3 months of propranolol administration. Liver function was also assessed by evaluating the galactose elimination capacity (GEC) and galactose clearance (Cgal). The expected, significant reduction of CI and increase of SVR was observed. Creatinine clearance and sodium balance were unchanged throughout the study. Furthermore, the renal prostaglandin system, as reflected by urinary prostaglandin E2 and TXB2 excretion, was also unaffected by the drug. No modification of platelet aggregation, platelet TXA2 production during whole blood clotting, GEC and Cgal was observed. We conclude that chronic propranolol administration is followed by alterations of CI and SVR, but it does not impair renal function and platelet aggregation in patients with cirrhosis, portal hypertension and no ascites. The maintenance of renal function during beta-adrenergic blockade is not due to an increased renal production of vasodilating prostaglandins.

Effects of Chronic Administration of Enalapril and Propranolol on the Large Arteries in Essential Hypertension

The forearm arterial effects of enalapril and propranolol were compared by means of pulsed Doppler velocimetry in 28 patients with hypertension after treatment for 3-6 months. Enalapril decreased blood pressure, increased both brachial artery diameter and blood flow, decreased vascular resistance, and increased the arterial compliance of the forearm. Propranolol also decreased blood pressure but did not produce any other changes. It may be concluded that the treatment of hypertension with enalapril, but not propranolol, is associated with dilatation effects on the arterial circulation of the forearm.

Single and combined therapy for systemic hypertension with propranolol, hydralazine and hydrochlorothiazide: Hemodynamic and neuroendocrine mechanisms of action

The antihypertensive mechanisms of single and combined therapy with a β-adrenergic antagonist (propranolol) and a vasodilator (hydralazine) were investigated in 9 patients with moderately severe hypertension, who were receiving maintenance diuretic (hydrochlorothiazide) treatment. Hemodynamic and neuroendocrine responses were determined at rest and during lower body negative pressure, and dynamic and static exercise stress after the chronic administration of propranolol and hydralazine, given alone or in combination. All 3 drug regimens, each administered for at least 10 weeks, reduced blood pressure (p <0.05) compared with diuretic-only therapy in patients at rest, in both the supine and standing position, and during lower body negative pressure and dynamic exercise. There was a significant additive antihypertensive effect when propranolol and hydralazine were combined. Only combination therapy effectively lowered pressure during static exercise. The regimens produced divergent effects on the supine cardiac output: a decrease with propranolol (p <0.05), no change with combination therapy and an increase with hydralazine (p <0.05). Both hydralazine and combination therapy significantly reduced supine total peripheral resistance (p <0.05), whereas propranolol produced no change. All 3 drug treatments significantly reduced total peripheral resistance during upright rest and dynamic exercise (p <0.05), without changing cardiac output or maximal exercise capacity. During exercise, cardiac output was maintained in patients treated with propranolol and in those treated with combined therapy by increases in stroke volume (p <0.05). Despite lower blood pressure, plasma norepinephrine concentrations were unchanged, although plasma renin activity decreased with propranolol and combination therapy. These findings indicate that propranolol's predominant antihypertensive mechanism in patients treated with diuretic drugs is a reduction in cardiac output in the supine position and a reduction in total peripheral resistance in the upright position. The propranolol-hydralazine combination effectively lowered blood pressure during static exercise without affecting exercise capacity or orthostatic tolerance.

Propranolol-induced changes in ventricular isomyosin composition in the rat

The ventricular isomyosin composition in the rat is characterized by three isoenzymes, V 1, V 2, and V 3, with high, intermediate, and low Ca ++-activated ATPase activity, speed of muscle shortening, and contractile economy. In this study, we examined the effects of propranolol on ventricular isomyosin composition in the rat. Eight 4-week-old male Wistar rats were treated from 4 to 12 weeks of age with daily 10 mg/kg subcutaneous doses of propranolol; four control rats were given subcutaneous distilled water. At the end of the treatment period, the efficacy of beta blockade was confirmed by isoproterenol test in some rats from each group. After the rats were killed left ventricular myosin from both control and propranolol-treated animals was purified and tested for Ca ++-activated ATPase activity. Ventricular isomyosin composition was studied by gel electrophoresis in non-denaturing conditions. Heart rate was significantly lower in the propranolol group, while no differences in blood pressure, body weight, or ventricular weight were found between the two groups. Lower Ca ++-activated ATPase activity values and a higher expression of myosin isoenzymes V 2 and V 3 were found in propranolol-treated rats. Possible links between the observed shift in ventricular isomyosin composition and the well-known modifications in myocardial contractility and oxygen consumption occurring after chronic propranolol administration remain to be established.

Effects of Acute and Chronic Administration of Propranolol During Submaximal Exercise in Essential Hypertension

Effects of Acute and Chronic Administration of Propranolol During Submaximal Exercise in Essential Hypertension

Chronic propranolol administration impairs glucagon release during insulin-induced hypoglycemia in normal man.

Failure of a plasma glucagon rise in response to insulin-induced hypoglycemia was demonstrated in normal subjects taking therapeutic doses of the nonselective beta-adrenergic blocker, propranolol, for 7 days before testing. This is the first study to examine glucose homeostasis in normal subjects exposed to chronic propranolol therapy and helps to explain the development of spontaneous hypoglycemia in patients, either diabetic or nondiabetic, during beta-adrenergic receptor blockade. Previous studies of the acute parenteral effects of propranolol administration failed to show any significant effect on glucagon secretory dynamics in response to insulin-induced hypoglycemia. In the present study, however, chronic oral administration of propranolol resulted in severe impairment of the expected glucagon rise in response to hypoglycemia and was associated with severe hypoglycemia in one normal subject.

Pharmacologic antagonism of propranolol in dogs: III. Effects of dopamine-isoproterenol and glucagon on hemodynamics and myocardial oxygen consumption in ischemic hearts during chronic propranolol administration

In 31 dogs chronically beta blocked with oral propranolol (12 to 14 mg/kg/day), glucagon (20 micrograms/kg) and combined dopamine (10 micrograms/kg/min) and isoproterenol (0.2 micrograms/kg/min) were given intravenously and tested for hemodynamic efficacy. Dogs were divided into four groups. Basal hemodynamics were obtained In Group I (n = 8) without cardiopulmonary bypass. In Group II (n = 8), hemodynamics were studied after 15 minutes of global ischemia during cardiopulmonary bypass. In Group III (n = 8), hemodynamics were studied after regional ischemia produced by ligation of the proximal left anterior descending coronary artery. In Group IV (n = 7), myocardial oxygen consumption and left ventricular mechanics were studied before and after 1 hour of cardiopulmonary bypass. Our results indicate the following: (1) Dopamine-isoproterenol improves hemodynamics in basal, post-global ischemic, and post-regional ischemic states. Glucagon improves hemodynamics either insignificantly or to a lesser extent than dopamine-isoproterenol. Furthermore, glucagon produces a larger increase in heart rate, which is not desirable. (2) Both dopamine-isoproterenol and glucagon increase myocardial oxygen consumption in comparison with control.

Effects of propranolol on renal blood flow and renal function in patients with cirrhosis

Systemic and splanchnic hemodynamics, renal blood flow, and renal function were studied in 13 patients with cirrhosis both before and 1 h after oral administration of 40 mg of propranolol (acute administration) and 1 mo after continuous administration of this substance at doses reducing the heart rate by 25% (chronic administration). Cardiac output and the gradient between wedged and free hepatic venous pressures significantly decreased after acute and chronic administration of propranolol; mean arterial pressure did not change significantly and systemic vascular resistance signficantly increased. Renal blood flow and renal vascular resistance did not change significantly after acute administration of propranolol and renal function did not change significantly after acute or chronic administration of propranolol. We conclude that propranolol does not alter renal function in patients with cirrhosis who are in good physical condition.

Propranolol withdrawal-induced supersensitivity to the chronotropic effects of isoproterenol in the conscious rabbit

The present study was undertaken to determine if chronic administration and abrupt withdrawal of propranolol would induce supersensitivity to the chronotropic effects of isoproterenol in the conscious rabbit. Eight rabbits were pretreated with propranolol (40 mg/kg/day, i.p.) for one week. Dose-response curves were obtained one week prior to pretreatment and 24, 48, 72 and 168 hours after the last dose of propranolol. Isoproterenol (0.01 to 10 ωg/kg) was injected via the marginal ear vein and heart rate was monitored continuously by recording the ECG. During the withdrawal period no significant rebound increase in basal heart rate was noted. Geometric mean ED 50 values and their corresponding 95% confidence intervals were calculated and used as an index of potency. Twenty-four hours after withdrawal of propranolol pretreatment, the ED 50 value for isoproterenol was significantly greater than control indicating continued surmountable β-adrenoceptor blockade. In contrast, 72 hours after withdrawal, the geometric mean ED 50 value was significantly less than control. The maximum chronotropic response to isoproterenol was not found to be different from control at any time during the withdrawal period indicating that a change in responsiveness was not induced. These data are interpreted as evidence of a true supersensitivity to the chronotropic effects of isoproterenol in the conscious rabbit following propranolol withdrawal.

Effects of indomethacin, renal denervation, and propranolol on plasma renin activity in conscious dogs with chronic thoracic caval constriction.

The role of renal prostaglandins and the adrenergic nervous system in the control of renin release was studied in conscious dogs with thoracic caval constriction. Indomethacin reduced plasma renin activity (PRA) in intact animals with thoracic caval constriction by 43% but failed to change PRA after surgical renal denervation and during chronic propranolol administration; adrenergic blockade reduced the initial control level of PRA before indomethacin from 15 to 4 ng angiotensin I/ml per hr. Renal hemodynamic function was markedly reduced by indomethacin both before and after adrenergic blockade. These observations indicate that prostaglandins are involved in the control of renin release, but they appear to have a more important role in the control of renal arterial resistance. The adrenergic nervous system also plays a role in the hyperreninemia of caval constriction and, possibly, a greater role than the renal prostaglandins. In the first experimental design, surgical renal denervation and daily oral propranolol administration in dogs with caval constriction reduced PRA to normal in two of seven dogs and a natriuresis occurred. In four of the five remaining animals, PRA fell, but not to normal, and renal sodium excretion failed to increase. In a second experimental design, the kidneys were denervated and propranolol was given before the dogs were subjected to caval constriction and propranolol was continued for 5 days; PRA increased markedly, sodium retention occurred, and ascites formed. Under these circumstances, compensatory mechanisms secondary to caval constriction led to increased PRA in spite of adrenergic blockade.

Pharmacologic antagonism of beta adrenergic blockade in dogs. II. Hemodynamic effects of simultaneous intravenous infusion of isoproterenol and dopamine during chronic propranolol administration: Spotnitz HM, et al, J Thorac Cardiovasc Surg79:103–108, (Jan) 1980

Pharmacologic antagonism of beta adrenergic blockade in dogs. II. Hemodynamic effects of simultaneous intravenous infusion of isoproterenol and dopamine during chronic propranolol administration: Spotnitz HM, et al, J Thorac Cardiovasc Surg79:103–108, (Jan) 1980