Beta-adrenoceptor Blocking Drug Research Articles

Treating Heart Failure with Preserved Ejection Fraction: A Challenge for Clinicians.

Despite a decline in many forms of cardiovascular disease, heart failure (HF) continues to increase. Heart failure with preserved ejection fraction (HFpEF) is common, especially among persons with multiple comorbidities. HFpEF presents many challenges for clinicians due to the incomplete understanding of the underlying mechanisms and lack of consensus on the most effective strategies for treatment. Angiotensin and beta receptor-blocking drugs, which form the cornerstone for the treatment of systolic HF, have failed to show similar benefits in patients with impaired diastolic function. This article provides an overview of drug therapy for HFpEF, including newer agents now under investigation.

Gastroesophageal varices (bleeding) and splenomegaly: the initial manifestations of some pancreatic body and tail carcinoma.

Gastroesophageal varices (bleeding) and splenomegaly: the initial manifestations of some pancreatic body and tail carcinoma.

Carvedilol suppresses fatty acid oxidation and stimulates glycolysis in C2C12 cells

Beta adrenergic receptor blocking drugs (β-blockers) are used chronically in many cardiovascular diseases such as hypertension, ischemic heart disease, arrhythmia, and heart failure. Beneficial effects are associated with the inhibition of symphathetic nervous system hyperactivity, reduction of heart rate, and remodeling by blocking the mitogenic activity of catecholamines. A possible effect of β-blockers on substrate metabolism has also been suggested. The direct effects of β-blockers on mouse C2C12 cells were investigated in this study. C2C12 cells were grown in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and differentiated into myotubes in the same medium that contained 1% FBS. Palmitic acid oxidation and glycolysis were measured by using [9,10-(3)H]palmitate and [5-(3)H]glucose, respectively. The amount of (3)H(2)O was measured as an indicator of substrate usage. Carvedilol (100 µmol/L) inhibited palmitate oxidation and increased glycolysis by nearly 50%. Prazosin altered substrate metabolism in a similar fashion as carvedilol, whereas propranolol or bisoprolol were devoid of metabolic effects. When added to mimic sympathetic activation, epinephrine stimulated glycolysis but did not alter fatty acid oxidation. Based on these results, carvedilol appears to have direct effects on substrate metabolism that are related to the blockade of α1 adrenergic receptors.

Inhibition of basal and insulin-stimulated gastric acid secretion by phenoxybenzamine or phentolamine.

The present study in the rat was undertaken to investigate the possible involvement of alpha- and beta-adrenoceptors in mediating gastric acid secretion in response to insulin-hypoglycaemia. Phenoxybenzamine, 15 mg kg-1, depressed the basal acid secretion to a level similar to that associated with vagotomy; phentolamine, 15 mg kg-1, had a similar effect. Insulin (1 unit kg-1) significantly stimulated gastric acid secretion. Vagotomy or phenoxybenzamine or phentolamine, 15 mg kg-1 prevented this action. The beta-adrenoceptor blocking drug, propranolol, 5-15 mg kg-1, had no significant effect on the basal acid secretion or its stimulation by insulin. The similarity in action between vagotomy and large doses of phenoxybenzamine and phentolamine suggests that, in the rat, vagal alpha-adrenoceptor stimulation is involved in the mechanisms of basal and insulin-stimulated gastric acid secretion.

Desipramine and nortriptyline antagonize apomorphine and reserpine hypothermia by a different mechanism

The reversal of hypothermia, induced by reserpine or by a high (16 mg) dose of apomorphine, in male Swiss mice, does not seem to utilize a common mechanism. Desipramine (20 mg kg-1 i.p., 60 min) or nortriptyline (8 mg kg-1 i.p., 60 min) increased temperature in both reserpine (2.5 mg kg-1 s.c., 18-19 h) and apomorphine (16 mg kg-1 s.c., 30 min) treated mice. In apomorphine-treated animals the effect of both drugs was reversed by the mixed dopaminergic D1- D2-antagonist haloperidol (1 mg kg-1 i.p., 90 min), the D1-receptor blocking drug SCH 23390 (0.05 mg kg-1 s.c., 30 min), the alpha 1-adrenoceptor blocking drugs prazosin (3 mg kg-1 s.c., 90 min) and phenoxybenzamine (20 mg kg-1 i.p., 65 min), the beta-adrenoceptor blocking drug (+/-)-propranolol (10 mg kg-1 i.p., 120 min), and the opioid antagonist naloxone (2 mg kg-1 i.p., 15 min). In contrast the selective D2-antagonist (+/-)-sulpiride (100 mg kg-1 i.p., 90 min), and the alpha 2-antagonist yohimbine (2 mg kg-1 i.p., 75 min), failed to effect the reversal of apomorphine hypothermia brought about by desipramine or nortriptyline. Their temperature effects in reserpinized mice were not modified by any of the antagonists tested.

Absorption of exaprolol from the in-situ gastrointestinal tract of rats and dogs

The absorption rate of the beta-adrenoceptor blocking drug, exaprolol, from the gastrointestinal tract was studied using in-situ methods in the rat and dog. Exaprolol was rapidly absorbed from the small and large intestine of rats and from the ileum of dogs. The cardiac output and regional blood flow decreased in rats to approximately one half of the original values within 30 min of the in-situ experiment. The logarithm of the amount vs time plots from dogs were linear, whereas with rats a curvilinearity appeared apparently because of the blood flow-limited absorption kinetics of this highly lipophilic drug. The data obtained suggest that exaprolol is suitable for administration in sustained release form.

Coma With Absent Brainstem Reflexes Resulting From Zolpidem Overdose

The development and subsequent clinical application of the beta-adrenergic receptor blocking drugs over the past 50 years represent one of the major advances in human pharmacotherapy. No other class of synthetic drugs has demonstrated such widespread therapeutic utility for the treatment of so many cardiovascular and noncardiovascular diseases. In addition, these drugs have proven to be molecular probes that have contributed to our understanding of disease, and on the molecular level, both the structure and the function of the 7 transmembrane G protein receptors, which mediate the actions of many different hormones, neurotransmitters, and drugs. The evolution of beta-blocker drug development has led to refinements in their pharmacodynamic actions that include agents with relative beta1-selectivity, partial agonist activity, concomitant alpha-adrenergic blockers activity, and direct vasodilator activity. In addition, long-acting and ultra-short-acting formulations of beta-blockers have also demonstrated a remarkable record of clinical safety in patients of all ages. Indeed, the beta-adrenergic blockers have provided us with a great clinical legacy for now and in years to come.

From the Editor

In 1988 The Nobel Assembly at the Karolinska Institute decided to award the Nobel Prize in Physiology or Medicine to Sir James Black, jointly with Gertrude Elion and George Hitchings. In their press release they wrote: ‘Sir James W. Black realized the great pharmacotherapeutic potential of receptor blocking drugs and developed in 1964 the first clinically useful beta-receptor blocking drug, propranolol. This type of drug is now being used in the treatment of coronary heart disease (angina pectoris, myocardial infarction) and hypertension. In 1972 Black characterized a new group of histamine receptors, H2-receptors, and subsequently developed the first clinically useful H2-receptorantagonist, cimetidine. A new principle in the treatment of peptic ulcer was thereby introduced.’ The new drugs he invented not only enabled mechanistic discoveries that changed our understanding of physiology and pathophysiology but also changed medical practice to the great benefit of mankind. In the present issue we co-publish with our sister journal BJP, in tribute, an inspirational paper by James Black titled ‘A life in new drug research’, together with an obituary by Alan McGregor.

Atrial fibrillation and cardiac surgery

To discuss the pathophysiology, risk factors, and treatments for atrial fibrillation occurring after cardiac surgery. Atrial fibrillation occurs frequently after cardiac surgery and it may lead to patient morbidity. Many variables have been suggested to be associated with this arrhythmia, but only advanced patient age can consistently identify risk for this complication. Immediate electrical cardioversion is indicated when the arrhythmia leads to hemodynamic instability or myocardial ischemia. Otherwise treatment is aimed at heart rate control, elective cardioversion with drugs or electrical means, and anticoagulation when the arrhythmia persists. Multiple investigations have evaluated methods for preventing postoperative atrial fibrillation, but only beta-adrenergic receptor blocking drugs have been consistently shown to be effective, and then not in all patients. Surgical treatments are increasingly being considered as a therapeutic means for ameliorating chronic atrial fibrillation. The use of these procedures has been simplified with the development of devices that can generate linear scars in the atrium and around the pulmonary vein orifices. These simplifications will allow for broader application of these techniques to patients undergoing other cardiac surgery (e.g. mitral valvular surgery). Atrial fibrillation is one of the most common complications of cardiac surgery. There are three major aims for treating atrial fibrillation: conversion to sinus rhythm, heart rate control, and anticoagulation. Only beta-blockers can be recommended for prophylaxis against postoperative atrial fibrillation. Further refinements in surgical treatments for atrial fibrillation may allow for wider applications of this therapy with lower rates of complications.

Drugs Handbook 2003

G. Volans & H. Wiseman Palgrave Macmillan 2003 196 pages, price £18.99, ISBN 1403908079 This is a small reference book so we need to know what it contains and who might wish to refer to it. The introduction states that the ‘book is intended for the many health professionals other than clinicians who need information about the mechanisms of action, therapeutic indications and unwanted effects of medicines’. There is a short introduction, which briefly discusses some topics of current interest in relation to drug use, such as cost-effectiveness and drug names. Unfortunately, there is only a paragraph on each of eight topics. Next there is a short section on definitions of drug group names and medical terms. These would be helpful to the layperson who wants to know what is meant by bioavailability, biophosphonates, bradycardia and insecticide. Most of the book is divided into two parts, thoughtfully called Part I and Part II. Part I provides information on most drugs available in the UK presented in alphabetical order using the drug's approved name. Many of the explanatory notes are too short and superficial to be useful to a clinician but perhaps not quite intelligible to the layperson. Thus, for example: (i) Co-beneldopa contains benserazide and levodopa in a fixed ratio; (ii) Enalapril – antihypertensive with actions, uses and adverse effects similar to captopril; (iii) Atenolol – beta adrenoceptor blocking drug with limited cardioselectivity, uses and side-effects as for propranolol. Part II presents drugs in alphabetical order by trade name. This is a useful section for the patient and the health worker who wants to know what they are taking. The book concludes with a short appendix giving slang names for misused (?recreational) drugs – a useful little section. My problem is to decide who are the many health professionals other than clinicians who will refer to this book. The doctor, the nurse and the pharmacist would do better to consult the BNF. However, with a bit of effort this book could be modified to meet the needs of the interested layperson. The vocabulary would have to be simplified and some explanations expanded. Then it may become very popular as ‘What you always wanted to know about the drugs the doctor prescribes and the pharmacist dispenses but you were too afraid to ask’. It could become much appreciated reading material available in the GP's waiting room, the chemist's shop and the outpatient clinic.

Differential effects of short and prolonged exposure to carvedilol on voltage-dependent Na(+) channels in cultured bovine adrenal medullary cells.

We examined the effects of short and prolonged exposure to carvedilol, an antihypertensive and beta-adrenoceptor blocking drug, on voltage-dependent Na(+) channels in cultured bovine adrenal medullary cells. Carvedilol (1-100 microM) reduced (22)Na(+) influx induced by veratridine, an activator of voltage-dependent Na(+) channels. Carvedilol also suppressed veratridine-induced (45)Ca(2+) influx and catecholamine secretion in a concentration-dependent manner similar to that of (22)Na(+) influx. Prolonged exposure of the cells to 10 microM carvedilol increased [(3)H]saxitoxin ([(3)H]STX) binding, which reached a plateau at 12 h and was still observed at 48 to 72 h. Scatchard analysis of [(3)H]STX binding revealed that carvedilol increased the B(max) value (control, 14.9 +/- 0.9 fmol/10(6) cells; carvedilol, 23.8 +/- 1.2 fmol/10(6) cells) (n = 3, P < 0.05) without altering the K(d) value, suggesting a rise in the number of cell surface Na(+) channels. The increase in [(3)H]STX binding by carvedilol was prevented by cycloheximide, an inhibitor of protein synthesis, whereas carvedilol changed neither alpha- nor beta(1)-subunit mRNA levels of Na(+) channels. The carvedilol-induced increase of [(3)H]STX binding was abolished by brefeldin A and H-89, inhibitors of intracellular vesicular trafficking of proteins from the trans-Golgi network and of cyclic AMP-dependent protein kinase (protein kinase A), respectively. The present findings suggest that short-term treatment with carvedilol reduces the activity of Na(+) channels, whereas prolonged exposure to carvedilol up-regulates cell surface Na(+) channels. This may add new pharmacological effects of carvedilol to our understanding in the treatment of heart failure and hypertension.

Developmental Toxicity in the Pregnant Rabbit by theClass III Antiarrhythmic Drug Sotalol

The purpose of this study was to investigate the potential of sotalol to cause developmental toxicity in the pregnant rabbit. Sotalol is a beta-adrenoceptor blocking drug which also has class III antiarrhythmic properties via Ikr channel blockade. EXPERIMENT 1: Nine pregnant New Zealand White rabbits were given doses of either 300, 225, or 150 mg/kg of sotalol during gestational days, called Days, 13-16 which resulted in total litter loss. EXPERIMENT 2: A single dose of sotalol, 100 or 150 mg/kg was administered during Days 8-17 to 15 rabbits. Dosing on Day 8, 9, or 10 resulted in a slightly higher incidence of embryonic death compared to historical controls. There was marked increased embryonic death of 55-90% (four does with total litter loss), decreased number of live foetuses per litter, and elevated mean foetal weight after dosing during Days 12-16. EXPERIMENT 3: 16 pregnant rabbits were administered single doses of sotalol of either 100, 85, 75, 60 or 50 mg/kg on Day 14. The main finding was increased embryonic death, which ranged from total litter loss to approximately 30% at 50 mg/kg. At 50 mg/kg, the maternal Cmax, AUC(1-24 hr), and t1/2 were approximately 45 microM, 340 micromol x hr/l, and 6 hr, respectively. In conclusion, sotalol treatment resulted in embryonic death in the rabbit in early pregnancy in the same way as has been seen for other drugs with Ikr blocking properties (class III antiarrhythmics) in rodents. The observed developmental toxicity in the rabbit is most likely secondary to embryonic arrhythmia as has been shown in rodent studies. The results may indicate that Ikr blocking agents are developmental toxicants across species including man.

Nursing care and education in heart failure.

The number of patients with heart failure has steadily increased during recent decades and the cost of frequent hospitalizations has had a strong economic impact on health care services. The compliance and education in heart failure patients are poor, and only a small proportion of the patients are on optimal therapy. Therefore, it is justified to build up specific heart failure units. Eight years ago we started the first physician-nurse based outpatient heart failure clinic in Sweden, where the nurses after passing an examination in heart failure have special authority to handle this type of patient. The nurses may introduce and uptitrate the dose of ACE inhibitors and beta-receptor blocking drugs, perform and early follow-up of all patients discharged from hospital because of heart failure, perform close follow-ups in patients with severe heart failure, and inform and educate the patients and their family members in self-care. We have also created a computer-based information program to enhance the compliance in our patients. The number of patients hospitalized in our hospital has decreased during the last 5 years and patients discharged from the hospital because of heart failure are mostly on treatment with ACE inhibitors (93%), and whether this is due to the work by the people in the heart failure unit or not is under evaluation in an ongoing randomized study. We believe that this model with a physician-nurse based organization in the management of heart failure creates increased safety and self-confidence in our patients and increase their motivation to follow prescribed medication and improve quality of life and prevent the need for further hospitalization.

Enantioselectivity of bunitrolol 4-hydroxylation is reversed by the change of an amino acid residue from valine to methionine at position 374 of cytochrome P450-2D6.

The enantioselectivity of 4-hydroxylation of bunitrolol (BTL), a beta-adrenoceptor blocking drug, was studied in microsomes from human liver, human hepatoma (Hep G2) cells expressing CYP2D6, and lymphoblastoid cells expressing CYP2D6. Kinetics in human liver microsomes showed that the Vmax value for (+)-BTL was 2.1-fold that of (-)-BTL, and that the Km value for (+)-BTL was lower than that for the (-)-antipode, resulting in the intrinsic clearance (Vmax/Km) of (+)-BTL being 2.1-fold over its (-)-antipode. CYP2D6 (CYP2D6-met) expressed in Hep G2 cells had a methionine residue at position 373 of the amino acid sequence and a rat-type N-terminal peptide (MELLNGTGLWSM) instead of the human-type (MGLEALVPLAVIV), and showed enantioselectivity of [(+)-BTL < (-)-BTL] for the rate of BTL 4-hydroxylation. In contrast, enantioselectivity [(+)-BTL > (-)-BTL] for Hep G2-CYP2D6 (CYP2D6-val) with a human-type N-terminal peptide that had a valine residue at 374, which corresponds to the methionine of the CYP2D6-met variant, was the same as that for human liver microsomes. We further confirmed that CYP2D6-met and CYP2D6-val expressed in human lymphoblastoid cells, both of which have methionine and valine, respectively, at position 374 and a human-type N-terminal peptide, exhibited the same enantioselectivities as those obtained from CYP2D6-met and CYP2D6-val expressed in the Hep G2 cell system. These results indicate that the amino acid at 374 of CYP2D6 is one of the key factors influencing the enantioselectivity of BTL 4-hydroxylation.

The Pharmacology of Physostigmine

The Pharmacology of Physostigmine

Different Actions Between Pindolol and Propranolol on the Ionic Currents in Spontaneously Beating Rabbit Sino-Atrial Node Cells

Electrophysiological effects of beta-adrenoceptor blocking drugs (pindolol and propranolol) on the action potentials (APs) and the membrane currents in spontaneously beating rabbit sino-atrial (SA) node cells were examined by the two-microelectrode voltage-clamp technique. Cumulative administrations of both blocking drugs (10(-7)-10(-6) M) prolonged the AP duration (APD) and caused a negative chronotropic effect in a concentration-dependent manner. Propranolol exhibited stronger responses than pindolol. At 10(-6) M, propranolol depolarized the maximum diastolic potential (MDP) and pindolol decreased the maximum rate of depolarization significantly, but the drugs had little or no effect on the AP amplitude (APA). In voltage-clamp experiments, both blockers (10(-7)-10(-6) M) inhibited the slow inward and the time-dependent outward currents in a concentration-dependent manner. Holding potential was -40 mV. The hyperpolarization-activated inward current was not affected by pindolol, but it was concentration-dependently inhibited by propranolol. The inactivation curve of Isi was not modified by either pindolol or propranolol. The activation curve of IK was unaffected by pindolol, but was shifted by propranolol 10(-6) M by approximately 11 mV in the depolarizing direction. These results indicate that both beta-adrenoceptor blocking drugs (pindolol and propranolol) inhibit the slow inward and the time-dependent outward currents, but produce different actions on the hyperpolarization-activated inward current and the activation kinetic of IK due to their pharmacological properties, thereby resulting in difference in decrease in the spontaneous activity of rabbit SA node cells.

Low-frequency subthreshold sympathetic stimulation augments maximal reflex parasympathetic salivary secretion in cats

Electrical stimulation of the peripheral cut end of the cervical sympathetic trunk for 3 min at frequencies < 1 Hz with pulses of 2-ms duration at supramaximal intensities did not elicit any salivary secretion, but an increase of stimulus frequency over the range 2-10 Hz produced progressively greater salivary secretion, the maximum volume of salivary secretion being evoked at 10 Hz. Frequency-dependent augmentation of parasympathetic reflex submandibular salivary secretion occurred when the lingual nerve was stimulated during repetitive sympathetic stimulation (at frequencies of 0.1-2 Hz) in our sympathectomized cats. The augmentation was found to be linearly related to sympathetic stimulus frequency (regression line calculated by method of least squares; r = 0.939, P < 0.01). This augmentation was abolished by prior treatment with the beta-adrenoceptor blocking drug propranolol (1 mg/kg, P < 0.01 vs. before propranolol) but not by the alpha-adrenoceptor blocking agent phentolamine (1 mg/kg), indicating that the augmented response was mediated via an activation of beta-adrenoceptors. The reduction of the augmentation caused by propranolol had diminished 1 h after its administration, showing that the effect was reversible.

Renal and Limb Vasodilatation during Acute Beta‐Adrenoceptor Blockade with Indenolol

Indenolol is a noncardioselective beta-adrenoceptor blocking drug with partial agonist activity. The mechanism of its acute antihypertensive activity has been evaluated in a double-blind, inpatient, crossover, randomized study versus placebo in 12 patients (eight men, four women, mean age 53 +/- 13 yr) with I and II WHO grade essential hypertension. Patients discontinued all antihypertensive and diuretic drugs at least 4 weeks before entry into the study. The effects of indenolol (120 mg) and placebo (2 weeks apart) were measured, in the same patient, 2 hours after a single oral administration. Variations of cardiac function were assessed by radionuclide angiocardiography, renal blood flow by sequential scintigraphy, and leg blood flow by strain-gauge plethysmography. Compared with placebo, indenolol reduced systolic blood pressure by 27.9 mm Hg and diastolic blood pressure by 17.1 mm Hg. Heart rate was also significantly decreased. The hemodynamic profile of indenolol activity was characterized by a decrease of cardiac index, without significant changes in systemic vascular resistance. Both renal and leg blood flow were increased by indenolol, and vascular resistance in these districts was considerably reduced. The percent reduction of renal vascular resistance was correlated significantly with the percent reduction of mean blood pressure. In conclusion, acute administration of indenolol exerts a considerable antihypertensive activity associated with a marked vasodilation in vascular districts involved in the progression of hypertensive disease such as the renal and muscular vasculature.

Beta-Adrenergic Receptor Blocking Drugs in the Management of Hyperthyroidism

Hyperthyroidism is a common disorder whose manifestations can range from minimal symptoms to life-threatening thyroid storm. Several of the clinical features that accompany thyrotoxicosis, including palpitations, tremor, sweating, tachycardia, and increased pulse pressure, are identical to the manifestations of hyperadrenergic states. This association led to early studies of the ability of catecholamine depletion to modify the signs and symptoms of hyperthyroidism [1, 2]. Although use of medications such as guanethidine and reserpine were found to be efficacious, numerous side effects limited their use. Over the past two decades, beta-adrenergic blocking drugs, of which propranolol is the prototype, have been employed extensively in hyperthyroidism. Their ability to improve many of the manifestations of hyperthyroidism is well documented [3–6]; however, since the precise mechanism underlying the hyperadrenergic state of thyrotoxicosis is not fully understood, the mechanisms of action for this class of drugs in this clinical setting remain unclear. This review examines the systemic effects of excess thyroid hormone, including interaction with the adrenergic nervous system, the possible mechanisms by which beta-adrenergic blocking drugs exert their action, and the clinical use of betaadrenergic blocking agents in the hyperthyroid patient.

Modification of myosin isozymes and SR Ca(2+)-pump ATPase of the diabetic rat heart by lipid-lowering interventions.

To define metabolic influences on cardiac myosin expression and sarcoplasmic reticulum (SR) Ca(2+)-stimulated ATPase streptozotocin-diabetic rats were treated for 9-10 wk with etomoxir, an inhibitor of carnitine palmitoyl transferase I (CPT-1) and fatty acid synthesis, or an antilipolytic drug, acipimox. Etomoxir reduced myosin V3 of diabetic rats but did not normalize it. However, the high serum triglyceride, free-fatty acid and cholesterol concentrations in diabetic animals were greatly reduced. After bypassing the CPT-1 inhibition with a medium-chain fatty acid (miglyol) diet, the V3 contents and serum lipids were still reduced in the etomoxir-treated diabetic rats; V3 was also reduced in diabetic rats fed miglyol or treated with acipimox. Since low serum insulin or triiodothyronine concentrations in diabetic rats were not improved by these interventions but changes in V3 were correlated with those in triglyceride, free-fatty acid and cholesterol concentrations, it is likely that myosin may be influenced by some metabolic factors. To assess the role of adrenergic influences, diabetic rats (7-8 wk) were treated with an antisympathotonic drug, moxonidine, a beta-adrenoceptor blocking drug, propranolol, and a bradycardic drug, tedisamil. Myosin V3 was not reduced significantly in moxonidine-treated or propranolol-treated rats in comparison to untreated diabetic rats. Serum thyroid hormones and insulin were not altered, whereas triglycerides were reduced but not significantly by these antiadrenergic agents. Lowering serum lipids in diabetic rats by treatment with etomoxir, miglyol and acipimox increased the depressed SR Ca(2+)-stimulated ATPase activity. On the other hand, in diabetic rats treated with moxonidine, propranolol or tedisamil, the ATPase activity was not increased significantly. These results suggest that normalization of blood lipids is important for improving subcellular organelle function in diabetic hearts with impaired glucose utilization.