Excessive Catecholamine Release Research Articles

β- and α-adrenergic cross-signaling for L-type Ca current is impaired in transgenic mice with constitutive activation of εPKC

It is well established that β-adrenoceptor stimulation activates PKA and α 1-adrenoceptor stimulation activates PKC. In normal ventricular myocytes, acute activation of α 1-adrenoceptors inhibits β-adrenoceptor stimulated L-type Ca current ( I Ca-L) and direct activation of εPKC leads to I Ca-L inhibition. Because increased PKC activity has been observed chronically in in vivo setting such as failing human heart, we hypothesized that chronic in vivo activation of εPKC alters I Ca-L and its response to adrenergic stimulation. Therefore, we investigated the interaction between β- and α 1-adrenoceptors vis-à-vis I Ca-L in myocytes from transgenic mice (TG) with cardiac specific constitutive activation of εPKC (εPKC agonist). Whole-cell I Ca-L was recorded from εPKC agonist TG mice and age-matched non-TG (NTG) littermates under: (1) basal condition, (2) β-adrenoceptor agonist, isoproterenol (ISO), and (3) ISO plus α 1-adrenoceptor agonist, methoxamine. The present results are the first to demonstrate that chronic in vivo activation of εPKC leads to reduced basal I Ca-L density. β-adrenoceptor activation of I Ca-L is blunted in εPKC agonist TG mice. α-adrenoceptor cross-talk with β-adrenoceptor signaling pathways vis-à-vis L-type Ca channels is impaired in εPKC agonist TG mice. The diminished response to ISO and methoxamine suggests a protective feedback regulatory mechanism in εPKC agonist TG mice and could be vital in the settings of excessive release of catecholamines during heart failure.

Hypertension in patients with pheochromocytoma.

Adrenal-dependent hypertension syndromes are uncommon forms of hypertension. They include primary aldosteronism, pheochromocytoma, Cushing"s syndrome, and congenital adrenal hyperplasia. Pheochromocytomas are the cause of hypertension in 0.1% to 0.2% of hypertensive patients. Excess catecholamine release and other neural and humoral mechanisms contribute to the pathophysiology of hypertension. Patients with pheochromocytomas have a potentially curable cause of endocrine hypertension and, if undetected, pheochromocytomas confer a high risk for morbidity and mortality, especially during surgical procedures and pregnancy. All patients with incidental adrenal tumors, regardless of tumor size, should be biochemically screened for pheochromocytoma (especially before resection or needle biopsy) to avoid precipitation of a lethal hypertensive crisis.

Control of blood pressure, heart rate and haematocrit during high-dose intravenous paraoxon exposure in mini pigs.

A therapeutic regimen was established to keep blood pressure, heart rate and haematocrit within the normal range during high-dose paraoxon (PX) exposure (ca. 150 x LD50) in mini pigs in order to achieve survival. Previous experiments showed that mini pigs exposed to high-dose PX died shortly after PX infusion due to hypertension, tachycardia and increased haematocrit if no antihypertensive and fluid therapy was initiated. Therefore, antihypertensive and fluid therapy with magnesium (MgSO4) and Ringer's solution was established to keep the blood pressure, heart rate and haematocrit within a pre-established normal range. Anaesthesized mini pigs received intravenously PX (54 mg kg(-1) body wt.) dissolved in alcohol. The control group received alcohol in corresponding amounts. When the blood pressure and heart rate increased, MgSO4 was given intravenously until measured values reached the normal range. When the haematocrit increased, fluids were given intravenously until the haematocrit reached the normal range. The measured values in the PX group were compared with the measured values of the control group using the 'rank order test'. As intended, no statistically significant differences between blood pressure, heart rate or haematocrit were found after therapy, but the PX group required statistically significantly more MgSO4 and fluids than the control group to keep the blood pressure, heart rate and haematocrit within the normal range. We assume that the increased need of antihypertensive therapy is due to a phaeochromocytoma-like pattern caused by an excessive release of catecholamines from the adrenal medulla, which is under sympathotonic control and activated by acetylcholine. Paraoxon is known to cause endogenous acetylcholine poisoning. The high fluid requirements in the PX group are most probably caused by extravasation of fluids due to the damage inflicted on biological membranes by organophosphorus compounds. An activation of secretory glands probably also contributes to the increase in haematocrit through consumption of fluids. In conclusion, the survival of mini pigs exposed to high-dose PX can be achieved by tight control of blood pressure, heart rate and haematocrit using MgSO4 and fluids.

Brain Damage and Myocardial Dysfunction: Protective Effects of Magnesium in the Newborn Pig

Background. Brain damage is associated with myocardial dysfunction resulting from excessive release of endogenous catecholamines and Ca 2+ overload. Magnesium ion, a natural Ca 2+ blocker, has recently been recognized as a myoprotective agent. Methods. Myocardial function was assessed in 3- to 7-day-old piglets from pressure–volume data (obtained by the conductance catheter/micromanometer technique) before and for 4 hours after ligation of the aortic arch vessels and was correlated with ultrastructural changes. Group a (n = 6) received MgSO 4 immediately after induction of brain damage for 4 hours, whereas group b (n = 6) did not receive MgSO 4 and served as control. Results. In both groups after induction of brain damage, there was a significant ( p < 0.05) increase in end-systolic elastance and preload-recruitable stroke work that persisted for 1 hour. However, after 2 and 4 hours, there was a significant ( p < 0.05) reduction in both variables in group b (end-systolic elastance, 74% ± 5% and 59% ± 6%, respectively, and preload-recruitable stroke work, 77% ± 4% and 64% ± 3%, respectively, compared with baseline), and in group a, the values returned to baseline. The chamber stiffness index rose significantly ( p < 0.05) in group b 15 minutes after induction of brain damage and remained significantly ( p < 0.05) higher for 4 hours versus no significant change in group a. Plasma levels of epinephrine and norepinephrine were similar in the groups before and after brain damage. Electron microscopic study showed severe ultrastructural changes in group b and significantly milder changes in group a. Conclusions. We conclude that MgSO 4 may protect the neonatal myocardium when administered immediately after brain damage.

Autonomic neurotoxicity of jellyfish and marine animal venoms.

Venoms and poisons of jellyfish and other marine animals can induce damage to the human nervous and circulatory systems. Clues to the pathogenesis and clinical manifestations of these lesions can be obtained from data of human envenomations and animal experimentation. Because many investigators are unaware that marine animal venoms have autonomic actions, this paper aims to elucidate the broad antagonistic or toxic effects these compounds have on the autonomic nervous system. Marine venoms can affect ion transport of particularly sodium and calcium, induce channels or pores in neural and muscular cellular membranes, alter intracellular membranes of organelles and release mediators of inflammation. The box jellyfish, particularly Chironex fleckeri, in the Indo-Pacific region, is the world's most venomous marine animal and is responsible for autonomic disorders in patients. The symptoms induced by these venoms are vasospasm, cardiac irregularities, peripheral neuropathy, aphonia, ophthalmic abnormalities and parasympathetic dysautonomia. Cases of Irukandji syndrome, caused by the jellyfish Carukia barnesi, have symptoms that mimic excessive catecholamine release. Coelenterate venoms can also target the myocardium, Purkinje fiber, A-V node or aortic ring. Actions on nerves, as well as skeletal, smooth or cardiac muscle occur. Recent studies indicate that the hepatic P-450 enzyme family may be injured by these compounds. The multiplicity of these venom activities means that a thorough understanding of the sting pathogenesis will be essential in devising effective therapies.

Mechanisms of alterations in cardiac membrane Ca2+ transport due to excess catecholamines.

The occurrence of excessive catecholamine release is often associated with stress due to the lifestyle of Western societies. Contrary to the general thinking that excess catecholamines produce cardiotoxicity mainly via binding to adrenoceptors, there is increasing evidence that catecholamine-induced deleterious actions may also occur through oxidative mechanisms. In this overview it is shown that a high dose of isoproterenol induces a biphasic change in cardiac Ca2+ transport in the sarcolemma and in sarcoplasmic reticulum. Both sarcolemmal and sarcoplasmic reticular Ca2+-transport activities are initially increased to maintain Ca2+ homeostasis and then are impaired, which may be associated with the occurrence of intracellular Ca2+ overload. On the other hand, mitochondrial Ca2+-transport activities exhibited a delayed increase. Pretreatment with vitamin E partially prevented the deleterious changes in cardiac membranes as well as the depressed energetic status of the heart muscle cell. It is concluded that excess catecholamines affect Ca2+-transport mechanisms primarily via oxidation reactions involving free radical-mediated damage. Thus drug approaches that reduce circulating catecholamines and/or prevent their oxidation should prove beneficial. A combination therapy involving inhibitors of catecholamine release, blockers of adrenoceptors, and antioxidants may be indicated for stress-induced heart disease.

Hypertension and tachycardia during adrenal manipulation

The purpose of this report is to draw attention to haemodynamic changes during intraoperative adrenal gland manipulation. Severe hypertension, ventricular tachycardia and subendocardial ischaemia occurred during the manipulation of adrenal gland in a patient who underwent live related donor nephrectomy. The patient responded well to intravenous lidocaine. Plasma norepinephrine concentration was elevated at the time of event. Further investigations after surgery excluded the possibility of phaeochromocytoma. In two years follow-up patient remains well. Suspicion for the cause of the event remains the excessive release of catecholamines with manipulation of a normal adrenal gland. The presence of halothane might have contributed to the arrythmia.

Excessive hypokalemia and hyperkalemia following head injury

A sudden decrease of serum potassium below 2.5 mmol/l carries the risk of dangerous arrhythmias and requires immediate replacement therapy [6]. We refer to a patient with a brain stem compression after head injury, who developed a profound hypokalemia (K+ = 1.2 mmol/l) with life-threatening arrhythmias, probably due to a catecholamine induced intracellular potassium shift (beta-2-stimulation). Only by aggressive potassium replacement up to 80 mmol/h (610 mmol/16 h) could potassium levels be increased and cardiac arrhythmias terminated. Although replacement therapy was stopped when the serum K(+)-level increased to 2.4 mmol/l, 3.5 h later the patient became hyperkalemic (8.1 mmol/l). This was probably due to a secondary shift of potassium from intra- to extracellular space. In patients with severe head trauma and the potential risk of excessive catecholamine release special attention must be paid to changes in potassium balance.

Adaptation of the poikilothermic heart to chronic catecholamine-induced overload

Excessive release or administration of beta-mimetic catecholamines may induce cardiomegaly, necrotic lesions, and accumulation of connective tissue in the heart of adult homeotherms. The aim of our studies was to analyze whether similar changes can also be observed in the heterogenous heart of poikilothemic animals. Their ventricular myocardium is formed by two different layers: the inner spongious musculature supplied by diffusion from ventricular lumen is covered by an outer compact layer with coronary supply. Sensitivity of the poikilothermic hearts (carp, frog, turtle) to necrogenic doses of isoproterenol (IPRO, 2 × 40 mg/kg/48 h) was significandy lower than in homeotherms. Necrotic lesions, if present, were localized in the inner spongious musculature, which exhibits higher activities of enzymes connected with aerobic oxidation. Repeated administration of lower doses of IPRO (5mg/kg/day, for 10 days) did not influence the total weight of the fish heart (Cyprinus carpio) but significandy increased the absolute weight of the outer compact layer and thus also its proportion (from 33% to 43%) in the whole ventricle. In both layers, the changes were accompanied by a higher water content, an increase of isomyosin with a lower ATPase activity, and an increase of collagenous proteins (types I and III). It may be concluded that the response of the poikilothermic heart to catecholamine-induced overload differs significandy from that in the mammalian myocardium: it results in the remodeling of the cardiac structure without development of cardiac hypertrophy. Whether the described increase of the compact/spongious ratio is the first step or the only mechanism of the adaptation of the poikilothermic heart to overload remains a matter of speculation.

Neuroblastoma and anaesthesia

SummaryThe haemodynamic problems associated with anaesthesia and neuroblastoma were reviewed in 52 children who underwent 138 operations at The Hospital for Sick Children, London, UK. At diagnosis 42 patients (81%) had elevated urinary catecholamine metabolites; nine (17%) were hypertensive, of whom eight were treated with adrenergic blockade. The incidence of intra‐operative hypertension due to excess catecholamine release was 9% (13/138), and was confined to the group undergoing tumour excision (29%; 13/45). Hypertension was observed more frequently in patients who had not received chemotherapy. It was effectively controlled by labetalol. Patients symptomatic of catecholamine secretion before surgery should be managed in a similar manner for those with a phaeochromocytoma. Surgical manipulation of the tumour predisposes to paroxysmal hypertension. Careful monitoring is advised.

Catecholamine release and arrhythmias in acute myocardial ischaemia

Increased sympathetic activity is assumed to contribute substantially to the occurrence of malignant arrhythmias in patients with coronary heart disease, since the rate of sudden cardiac death is significantly reduced by beta-adrenoceptor blockade, but not by antiarrhythmic agents such as flecainide or encainide. During acute myocardial ischaemia, adrenergic stimulation of the ischaemic myocardium is independent of plasma catecholamines. Rather, it is caused by the combination of excessively high local noradrenaline concentrations and an enhanced responsiveness of the myocyte to catecholamines. Myocardial ischaemia of 15 min duration results in a 100-fold increase in catecholamine concentrations within the extracellular space of the ischaemic zone, a two-fold increase in functionally coupled alpha-adrenoceptors, and a 30% increase in beta-adrenoceptors. Within the first 10 min of ischaemia, the myocardium is protected from excessive catecholamine release. Ischaemia-associated metabolic alterations, such as extracellular potassium accumulation, acidosis, and especially the accumulation of adenosine reduce the transmitter release caused by central sympathetic activation. Furthermore, the functional neuronal amine reuptake (uptake1) prevents excessive local accumulation of noradrenaline. With progression of ischaemia to more than 10 min, local nonexocytotic catecholamine release becomes predominant. This release is independent of central sympathetic nerve activity, availability of extracellular calcium, activation of both neuronal calcium channels and protein kinase C, and it is not accompanied by the release of sympathetic cotransmitters such as neuropeptide Y. It has been demonstrated to be nonexocytotic and to be caused by a carrier-mediated transport of noradrenaline from the sympathetic nerve ending into the synaptic cleft. This release is not modulated through presynaptic receptors. It is, however, suppressed by blockers of uptake1 and by inhibitors of sodium-proton exchange. Depletion of cardiac catecholamine stores by chronic surgical or chemical sympathectomy effectively suppresses malignant arrhythmias induced by experimental coronary ligature. Accordingly, inhibitors of nonexocytotic noradrenaline release, such as uptake1 blocking agents or sodium-proton exchange inhibitors, effectively reduce the occurrence of ischaemia-associated ventricular fibrillation, emphasizing the relevance of nonexocytotic release mechanisms in myocardial ischaemia.

Complications of Head Injury and Their Therapy

Common intracranial complications following head injury are meningitis, usually associated with a basilar skull fracture or open-depressed skull fracture; delayed hematoma; hydrocephalus; and vascular injuries. Prophylactic antibiotics are not recommended for the management of basilar skull fractures. The best means of preventing infection from open-depressed skull fractures is operative debridement and thorough irrigation, though recent evidence suggests that select cases can be safely managed without operation. Serial CT scans should be obtained in severely head-injured patients to identify delayed hematomas. CT and MRI scans obtained several weeks or months after severe head injury frequently reveal enlarged ventricles, though only a small percentage of these patients have clinical hydrocephalus. Those that do, often benefit from a shunt. Vascular injuries frequently are not detected until ischemic symptoms develop hours or days after the injury. Recommended treatment for intimal tears or dissection is full anticoagulation, but in those with cerebral contusions or other intracranial lesions, this may present an unacceptable risk for intracranial hemorrhage. Pulmonary infections frequently occur following head injury, and can be associated with admission to the ICU and intubation. A large percentage of these infections are caused by enteric gram-negative organisms, and aggressive treatment with appropriate antibiotics is necessary. Aspiration of gastric contents is common in head-injured patients and is frequently complicated by bacterial superinfection. The routine use of antacids and H2 blocking agents leads to bacterial colonization of the stomach with anaerobes and gram-negative aerobes. Thus, empiric therapy for aspiration pneumonia should include clindamycin. Sinusitis is a frequent cause of fever and leukocytosis in patients with nasotracheal or nasogastric tubes in place for several days and often subsides spontaneously with removal of the tubes. Pulmonary edema is often caused by excessive fluid administration during resuscitation of these patients, and can be avoided by monitoring central venous pressures. Pulmonary edema may also be caused by ARDS, excessive catecholamine release, or primary cardiac failure. Most of these patients will benefit from early intubation and PEEP. Pulmonary emboli most often originate from deep venous thrombi, and there is increasing evidence that prophylaxis with low-dose heparin and pulsating boots can significantly reduce the incidence of both complications. Erosive gastritis is found in the majority of severely head-injured patients and may be due to ischemia of the gastric mucosa as well as gastric hyperacidity.(ABSTRACT TRUNCATED AT 400 WORDS)

Analysis of Eight Sipple's Syndrome Patients and Review of Eighty-two Cases from the Japanese Literature

Eight Sipple's syndrome patients from four families have been reviewed. One family had the largest number of members with pheochromocytoma and/or medullary thyroid carcinoma. A total of 82 cases (47 females and 35 males) collected from the Japanese literature during the period 1960-1989, are also reviewed. The ages ranged from 22 to 73 (median 41) years, 13%, being over the age of 60 years (elderly patients). Pheochromocytoma occurred bilaterally in 72% of cases. With Sipple's syndrome, a relatively high urinary excretion of the epinephrine fraction and a high content of epinephrine in the tumor tissues were thought to be characteristic. Seventy-three patients underwent adrenalectomy with a successful outcome for 62 (85%). There needs to be careful periodic follow-up after unilateral adrenalectomy. Medullary thyroid carcinoma (MTC) also occurred bilaterally and was multicentric in 66% of cases, and was often found to be metastasized to the cervical lymph nodes at the time of surgery (35%). Parathyroid disease was found in 22% of cases: parathyroid adenoma in nine, hyperplasia in 10. Fourteen patients (17%) died of surgical complications, hypertensive crisis caused by excessive catecholamine release and/or widespread MTC metastases.

Some functional characteristics of adrenal medullary tumors in aged male Wistar rats.

Neither analysis of the urinary catecholamine metabolites vanillymandelic acid and 4-hydroxy-3-methoxyphenylglycol nor blood pressure measurements allowed the detection of adrenal medullary tumors or hyperplasia in 115 aged male Wistar rats (70 rats, 24 months of age and 45 rats, 30 months of age). Histochemical examination of the adrenal glands demonstrated that the 55 hyperplastic and 25 neoplastic lesions of the medulla usually had little or no chromaffinity. Chromaffinity was found comparable to normal medulla in only three tumors examined histochemically. Of these tumors, two were partially and one completely chromaffin-positive, but all three were small and did not result in elevated blood pressure or catecholamine metabolite excretion values. These observations indicate that excessive catecholamine synthesis and release is not a feature of adrenomedullary tumors and hyperplasia occurring spontaneously in aged male Wistar rats.

Biochemical evidence of myocardial injury after severe head trauma

Serum levels of creatine kinase (CK) and its myocardial isoenzyme (CK-MB) were measured and serial ECG recorded in 24 male and 6 female patients with severe head trauma. All patients were comatose, but no patient sustained a spinal or chest injury. Total CK activity was elevated in at least one sample in each patient. Elevated CK-MB activity was found in 28 patients. The serial CK-MB data did not follow the same pattern as that of patients suffering from myocardial infarctions. The mean CK-MB remained elevated for at least 3 days after injury, although individual patterns were variable. ECG abnormalities included prolonged corrected QT interval (QTc) in 90% and a variety of nonspecific ST segment and T wave changes in 53%. These ECG findings are consistent with other clinical studies of severe neurological disorders, particularly cerebrovascular accidents. The elevated CK-MB activity indicates that ongoing myocardial damage occurs in patients with severe head injury. Although the underlying mechanism is not entirely clear, an excessive release of catecholamines is the most likely mechanism accounting for diffuse myocardial damage, prolonged elevated CK-MB values and the observed ECG abnormalities.

Accentuated hypoxemia at high altitude in subjects susceptible to high-altitude pulmonary edema

To investigate the hypotheses that activated coagulation, catecholamine release, or arginine vasopressin release are involved in the pathogenesis of high-altitude pulmonary edema (HAPE), we measured these variables in seven subjects susceptible to HAPE and in nine control subjects at an altitude of 1,600 m, and after 6 and 12 h at a simulated altitude of 4,150 m. Each subject was studied twice, once after 3 days of placebo medication and once after 3 days of premedication with aspirin and dipyridamole. At high altitude, HAPE-susceptible subjects showed significantly exaggerated hypoxemia and a slightly higher end-tidal carbon dioxide partial pressure that did not account fully for the hypoxemia. Fibrinolytic activity was significantly accelerated in both groups at high altitude, whereas other coagulation measurements, catecholamines and arginine vasopressin levels, and pulmonary function tests were not significantly changed. Similar findings were obtained after both placebo and platelet-inhibitor premedication. The results indicate that none of the three hypothesized mechanisms, i.e., activated coagulation, excessive catecholamine release, or antidiuresis, would account for HAPE susceptibility. Instead, HAPE-susceptible subjects exhibited exaggerated hypoxemia associated with relative hypoventilation and a widened alveolar-arterial gas pressure difference.

Acute cardiac toxicity of antineoplastic agents as the first manifestation of pheochromocytoma

A 47-year-old male with histiocytic lymphoma and no previous history of heart disease developed significant fluctuations of blood pressure, electrocardiographic evidence of myocardial ischemia, and life-threatening arrhythmia after the first dose of BACOP (bleomycin, adriamycin, cyclophosphamide, Oncovin, and prednisone) chemotherapy. The presence of pheochromocytoma was suspected, and it was demonstrated by elevated urinary metanephrines, catecholamines, and vanillylmandelic acid, and finally confirmed on autopsy. The possible role of chemotherapeutic agents in stimulating excessive catecholamine release, thus causing transient cardiac injury, is suggested.

Antiarrhythmic drugs: clinical pharmacology and therapeutic uses.

The effective therapy of cardiac arrhythmias requires accurate cardiac diagnosis, identification and treatment of specific initiating factors, and appropriate drug therapy. If antiarrhythmic drug therapy is required, therapeutic goals should be determined in advance and treatment that is based on sound physiological and pharmacokinetic rationale should be initiated. Careful follow-up should be undertaken, including monitored documentation of drug effects, observation for side-effects, and drug plasma concentration-response correlations. Antiarrhythmic drugs differ in specific patterns of absorption, volumes of distribution, plasma protein binding and elimination (metabolism and excretion). Disease states may alter these properties. Only by applying a thorough understanding of each drug’s individual pharmacological characteristics can maximum benefit be obtained. Lignocaine is effective against ventricular arrhythmias of many aetiologies, and in the acute situation is usually the agent of first choice. Recently, prophylactic lignocaine has been advocated for younger patients with acute myocardial infarction. Quinidine has a long history of usefulness in both ventricular and supraventricular arrhythmias. It is effective in maintaining sinus rhythm after cardioversion from atrial fibrillation or flutter, and is perhaps the most widely used oral agent in the management of chronic ventricular arrhythmias. Procainamide is a versatile drug with uses comparable with those of quinidine. In addition, it may be administered parenterally in an acute or subacute setting. The anticonvulsant drug phenytoin remains an agent of somewhat limited utility. However, it is recognised as a primary agent for the treatment of digitalis-induced arrhythmias. β-Adrenoceptor blocking drugs are useful for treating arrhythmias due to excessive catecholamine release, for digitalis excess, for therapy of acute and chronic supraventricular arrhythmias, for ventricular arrhythmias unresponsive to first-line agents, and potentially as prophylaxis against sudden death in ambulatory patients with coronary artery disease. These agents have also been useful in preventing tachyarrhythmias associated with Wolff-Parkinson-White syndrome, and in prophylaxis of delayed repolarisation arrhythmias. Propranolol is better tolerated but less effective than quinidine or procainamide in treating chronic ventricular arrhythmias. Bretylium may be useful in the treatment of ventricular fibrillation that is refractory to conventional therapy. Tocainide and mexiletine are relatively new, orally effective agents with structural similarities to lignocaine. Disopyramide, another new antiarrhythmic agent, has actions and versatility which resemble those of quinidine, but it may be better tolerated. Verapamil, whose mechanism of action involves blockade of slow ionic currents, appears to be a highly effective drug for therapy of acute supraventricular tachycardia. Aprindine, amiodarone, and acebutolol are examples of other new antiarrhythmic agents whose properties are discussed. Benefits of antiarrhythmic therapy must always be weighed against the risk of side-effects. For lignocaine, these are primarily neurological and are related to plasma concentration. An initial loading dose or doses followed by constant infusion represents the correct mode of administration. Diseases which alter hepatic blood flow affect lignocaine metabolism, and thus patients with heart failure should receive both smaller initial boluses and smaller infusion rates than normals. The major problems with quinidine therapy are the high incidence of side-effects, such as diarrhoea, leading to intolerance, and the risk, if small, of sudden death from idiosyncratic quinidine-induced ventricular fibrillation. Intravenous administration of procainamide must be carefully monitored to avoid hypotension. In patients with heart failure, smaller boluses should be given and maintenance doses may need to be reduced. The necessity for frequent (3- to 4-hourly) doses and the high incidence of drug-induced lupus after long-term usage have decreased the utility of procainamide for chronic arrhythmia control. With intravenous administration, phenytoin may cause hypotension if administered rapidly. Toxicity with oral therapy may be manifested by nystagmus, ataxia and lethargy. Propranolol is contraindicated where cardiac function depends upon sympathetic stimulation; congestive heart failure has been precipitated in this setting. Sudden withdrawal of propranolol in non-hospitalised patients with severe anginal symptoms may be associated with serious rebound phenomena. When used intravenously, much smaller dosages than for oral use are used, and slow incremental administration with blood pressure and electrocardiographic monitoring is indicated. Side-effects with mexiletine and aprindine have been problematic and include cardiovascular and neurological toxicity. The most frequent side-effects of oral disopyramide are anticholinergic, including dry mouth, constipation and urinary hesitancy. The myocardial depressant potential of verapamil contraindicates its use in patients with marked underlying cardiac dysfunction.

The effect of dl-propranolol, d-propranolol and practolol on the hyperactivity induced in rats by prolonged isolation.

Exploratory behaviour in an open field situation was found to be greatly increased in rats, isolated for 6–8 weeks, when compared with grouphoused controls. Propanolol, dl- and d- and practolol, 0.2–0.5 mg/kg reduced hypermotility, sniffing and rearing in isolated rats without affecting behaviour of group-housed rats. 20 mg/kg dl-propanolol was needed to reduce exploratory behaviour of group housed rats. Chlorpromazine reduced activity of isolated rats at a dose of 0.1 mg/kg, and group housed rats at 0.5–1 mg/kg. The action of propranolol does not appear to result from central receptor blockade because of the almost equal activity of d- and dl-propranolol. Since practolol was also active in this test, the effect of these drugs also does not appear to result from general C.N.S. depression. It is suggested that these compounds may reduce hyperactivity by diminishing an excessive release of central catecholamines.