Abstract: The effects of pharmacological stimulation or blockade of adrenergic receptors on plasma testosterone levels were studied in healthy men subjected to bicycle ergometer exercise. Plasma testosterone in

Abstract: Much as we enjoyed these authors' novel approach to the presentation of data. we feel impelled to offer their potential followers a more depressing analysis. On the basis of the results from Sutton-in-Ashfield, the denial of medical care to babies under 1500 g at birth is likely to result in death for more than half, with half of the survivors handicapped, one in seven severely so. Perhaps this paper should have carried a Government health warning?

Abstract: Although cotton smuggling through the North's blockade of the South during the American Civil War has often been viewed as a highly profitable activity, only a small percentage of blockade-running ships made more than one run. New figures for capture rates reconcile these observations by showing that the risks of blockade running were substantial. Estimates are also provided for the amount of cotton smuggled through the blockade and of its disposition between the North and Europe.

Abstract: Increases in metabolic rate, heart rate and ventilation occur following carbohydrate feeding or during beta sympathetic stimulation. Furthermore, insulin secretion and hypokalemia are features common to both which raises the question as to whether these effects of carbohydrate depend upon an intact sympathetic nervous system. Accordingly, in the present study, we measured the effects of carbohydrate feeding (250 gram meal) before and after chronic beta sympathetic blockade in sex normal men. Before blockade metabolic rate (02 consumption) rose (P < 0.05) from a fasting mean of 248 ± 19.7 (SEM) ML 02/min to 292 ± 15.2 at 1 hr, 269 ± 13.7 at 2, and 262 ± 18.0 at 3 hr following the meal. During blockade (oral propranolol 80 mg p.o. Q 6 h for 3 days) the post-prandial increase in 02 consumption was also significant (P < 0.05) and almost identical to that found before blockade. A similar pattern was found for ventilation, heart rate, insulin secretion and hypokalemia, where the significant postprandial changes were not altered by blockade. A transient increase in serum triiodothyronine from a mean of 92 ± 8.4 μg/ML to 109 ± 9.4 occurred at 1 hr (P < 0.05) only during blockade. No other changes in thyroid hormonal concentrations occurred as a result of the meal. We conclude that although similarities exist between beta sympathetic stimulation and carbohydrate feeding, the post-prandial effects studied do not depend on intact beta sympathetic receptors.

Abstract: The effects of cholinergic and adrenergic blocking agents on the period and amplitude of sustained oscillations in plasma levels of insulin and glucose were studied in 16 overnight-fasted conscious rhesus monkeys. Blood samples were withdrawn at 2-min intervals before and during or following administration of drugs that affect neurotransmission. Cholinergic blockade with atropine had no effect on the oscillations. alpha-Adrenergic blockade with phentolamine caused a rise in plasma insulin that lasted less than 10 min and was followed by a slight, although not consistent, decrease in mean insulin and a consistent small decrease in glucose. There was a sustained increase in heart rate, but no effect on the oscillations of insulin or glucose. beta-Adrenergic blockade induced by propranolol led to persistent decreases in mean plasma insulin 60% below the base line, small but variable decreases in glucose, and a sustained decrease in heart rate, but no change in period or relative amplitude of the oscillations in plasma levels of either insulin or glucose. General anesthesia with pentobarbital did not eliminate these oscillations. Our observations on the failure of the blockade of certain putative efferent pathways or depression of higher cortical centers to alter the period of the oscillations of insulin reduce the likelihood that the oscillations are transmitted from a pacemaker in the central nervous system.

Abstract: The role of histamine H1 and H2 receptors in the lung is not clear. H1 receptor blockade results in bronchodilatation and inhibition of histamine induced bronchoconstriction. H2 receptor blockade in vitro prevents the normal negative feedback of histamine on further mediator release in antigen challenge. Bronchospasm in guinea pigs given antigen challenge is enhanced by previous administration of metiamide or burimamide but not of cimetidine. These findings suggest the possible deleterious effect of H2 receptor antagonists in asthmatic subjects. The effects of H2 receptor blockade with cimetidine on bronchial hyperreactivity to histamine were studied in 10 asthmatic volunteers by whole body plethysmography. Cimetidine 800 mg and placebo were administered orally on two separate days, eight hours and two hours before study. No significant difference in baseline levels of airways obstruction was seen with the two agents. Inhalational challenge with increasing concentrations of histamine revealed no significant difference in bronchial hyperreactivity to histamine between cimetidine and placebo treatment days. H2 receptor blockade with cimetidine does not appear to affect ventilatory function or bronchial hyperreactivity to histamine in asthmatic subjects. It has been suggested that cimetidine may have H1 as well as H2 receptor blocking properties which prevent this effect.

Abstract: To study the influence of acute and chronic angiotensin-converting enzyme blockade on the pressor response to exogenous angiotensin II, vasopressin and norepinephrine, we gave normal female Wistar rats 100 mg of captopril or 1 ml of 5% glucose twice daily by gavage for 2 weeks. On the 15th day, rats were anesthetized with pentobarbital, and dose-response curves to angiotensin II, lysine-vasopressin, and norepinephrine were obtained before and after intraperitoneal injection of 100 mg/kg of captopril or 1 ml of 5% glucose. Acute as well as chronic converting enzyme blockade enhanced the pressor response to exogenous angiotensin II. Similarly, sensitivity to exogenous vasopressin was increased by both acute and chronic converting enzyme inhibition. In contrast, chronic converting enzyme blockade significantly blunted the response to exogenous norepinephrine, whereas acute blockade tended to accentuate its pressor effect. These results suggest that chronic angiotensin-converting enzyme blockade may partly inhibit sympathetic activity which, in turn, might contribute to the antihypertensive efficacy of this therapeutic approach. These results also point to an important physiological interaction between the two pressor hormones, angiotensin II and vasopressin.

Abstract: 1. The effects on glucose and lipid metabolism and on plasma catecholamines at rest and during exercise, of 4 weeks treatment with non-selective beta-blockade (pindolol, 15 mg daily) and with cardio-selective blockade (metoprolol, 200 mg, and acebutolol, 500 mg, respectively) were compared in different groups of hypertensive men (mean age 37 years) by single blind cross-over technique. All patients continued the treatment with either metoprolol or acebutolol for another 12--14 months. 2. All antagonists reduced blood pressures and exercise heart rates in a virtually identical manner. Whereas lipolysis was similarly inhibited by both selective beta 1-antagonists and non-selective beta 1-beta 2-blockers, glycogenolysis in the muscle was inhibited only by non-selective beta-receptor blockade. 3. The inhibition of glycogen breakdown resulted in exercise hypoglycaemia and in increases of plasma adrenaline and ACTH, which probably reflect counter-regulatory mechanisms. No major metabolic changes occurred after 12--14 months compared with 4 weeks of treatment.

Abstract: Bronchial and cardiac beta-adrenoceptor blockade have been compared in six normal subjects after three beta-adrenoceptor antagonists. Single and double doses of atenolol (50 and 100 mg), acebutolol (100 and 200 mg) and labetalolol (150 and 300 mg) were studied on separate occasions. 2 Salbutamol airway dose-response curves were obtained by measuring the airway response as the change in specific airway conductance (sGaw) after increasing doses of inhaled salbutamol. Bronchial beta-adrenoceptor blockade was assessed after each drug as the dose of salbutamol needed to cause a 50% increase in sGaw (sGaw D50). 3 Cardiac beta-adrenoceptor blockade was assessed after the same doses of each beta-adrenoceptor antagonist, by measuring the percentage reduction in exercise heart rate from control, after exercise for 5 min at 70% of the subject's maximum work rate. 4 Atenolol 50 and 100 mg caused least bronchial beta-adrenoceptor blockade and the greatest reduction in exercise heart rate. 5 Acebutolol 100 and 200 mg and labetalol 150 and 300 mg produced more bronchial beta-adrenoceptor blockade than atenolol. 6 With this approach new beta-adrenoceptor antagonists can be assessed without putting asthmatic patients at risk.

Abstract: The hemodynamic pattern in hypertension varies according to the age of the subject and the stage of the hypertensive disorder. In the early stage, both cardiac output and systemic vascular resistance tend to be elevated. Already at that stage, mild degrees of left ventricular function disturbance can be detected. Advanced stages are characterized by a hypokinetic type of circulation with subnormal cardiac output and considerably increased systemic vascular resistance. Both cardioselective and nonselective beta-receptor antagonists lower cardiac output and tend to raise systemic vascular resistance. Even left ventricular filling pressures tend to be higher. While these effects are most distinct in the acute experiment, cardiac output remains always depressed and systemic vascular resistance stabilizes often at a higher level, compared with pretreatment values, even during long-term therapy. The antihypertensive action of beta-receptor blockers appears to be mainly due to the reduction of cardiac output. Combined alpha--beta-adrenergic blockade lowers blood pressure predominantly by alpha-adrenoceptor-mediated reduction of systemic vascular resistance both when induced acutely and during long-term administration. Owing to its beta-adrenoceptor blocking component, the increase of cardiac output is abolished: cardiac output is maintained at pretreatment levels, as is left ventricular filling pressure. Since a well-balanced blockade of both alpha- and beta-adrenergic receptors counteracts the hemodynamic changes occurring in the course of hypertension and tends to restore cardiovascular dynamics towards normal, combined alpha--beta-adrenoceptor blockade appears to be one of the most logical and rational therapeutical approaches to hypertension.

Abstract: The action of procaine on the terminal erythroid differentiation of murine erythroleukemia (MEL) cells has been investigated at the level of individual cells. At concentrations (7 X 10-4 M) which had no inhibitory effect on cell growth, pretreatment of these cells with procaine for 12-24 hr caused a pronounced inhibition ( greater than 90%) of commitment of terminal erythroid differentiation of dimethyl sulfoxide (DMSO)-treated cells. Simultaneous treatment of MEL cells with DMSO and procaine, however, resulted to only slight inhibition (less than 20%) of commitment. Blockade of commitment by procaine pretreatment appears to be general since it was observed in cells treated with other inducers (6-thioguanine, dimethylformamide). Procaine pretreatment did not abolish the ability of MEL cells to complete the "latent period" and commit upon the removal of the block. Reversal of procaine inhibition of commitment was obtained by the addition of either CaCl2 (1.0 mM), calcium ionophore A23817 (1 microgram/ml), but not of MgCl2 (1.0 mM). From these data we conclude that procaine inhibits the terminal erythroid differentiation of MEL cells by blocking an event or process required for commitment which occurs prior to commitment itself. Our results suggest that this process involves calcium metabolism.

Abstract: The role of the autonomic nervous system (ANS) in the pathogenesis of hypertension induced by methylprednisolone (20 mg/kg/week subcutaneously) was studied in rats before and during chronic renin angiotensin system (RAS) blockade with captopril (20 mg/kg/every 8 hrs by mouth). Sympathetic nervous system (SNS) blockade was accomplished by the intravenous (i.v.) administration of propranolol (0.20 mg/100g) plus phentolamine (1.25 mg/100g/i.v.) and ganglionic (G) blockade by the use of pentolinium tartarate (0.5 mg/100g/i.v.). After 4 weeks, methylprednisolone-treated animals showed significant decreases in mean arterial pressure (MAP) with both SNS (-34 +/- 2 mm Hg) and G (-56 +/- 3 mm Hg) blockades; during chronic RAS blockade, even greater falls in MAP were observed (SNS = -43 +/- 2 mm Hg and G = -75 +/- 3 mm Hg). Nevertheless, for both groups the levels of MAP obtained during SNS and G blockades were higher than those observed in their control groups. At the end of second week, however, in captopril-treated hypertensive rats the values of MAP obtained during ANS blockade were lower than those observed in the control group. An increased responsiveness to exogenous administration of norepinephrine (NE) was observed in animals receiving methylprednisolone and captopril. It is concluded that methylprednisolone hypertension in the rat may be initially explained by activation of RAS and ANS. At later phases, a third mechanism has to be postulated to explain the hypertensive state.

Abstract: Neuromuscular blockade with pancuronium and its antagonism was evaluated in 33 critically ill infants. The evoked contraction of the adductor pollicis from indirect stimulation of the ulnar nerve was measured. The neuromuscular blockade recovered spontaneously from pancuronium in seven infants, 23 required one or more doses of atropine 0.02 ng kg−1 and neostigmine 0.06mg kg−1. In three infants the blockade railed to reverse. Immature infants less than 32 weeks did not show any significant difference in their requirement for pancuronium compared with mature infants. Age and birth weight of the infant, dose of pancuronium and duration of its administration did not affect the requirements for reversal. Train-of-four and tetanus:twitch ratios were lower (P

Abstract: We have used multiple isotope infusions to study the integrated response of glucose, fat, and protein metabolism to combined alpha + beta-adrenergic blockade in conscious, unstressed, fasting (15 h) dogs. The response to the blocking agents was evaluated both with and without control of the glucoregulatory hormones. The hormones were controlled at the basal level by infusions of somatostatin and metyrapone to block their secretion, and by the infusion of insulin, glucagon, growth hormone, and cortisol at physiological rates. We found that adrenergic blockade markedly inhibited lipolysis, as reflected by falls in glycerol and plasma FFA appearance. The decrease in fat mobilization after blockade resulted in a proportionate shift from fat as an energy substrate toward carbohydrate. Glucose production and oxidation were both enhanced after blockade. The source of the increased glucose production was presumably hepatic glycogen because urea production was presumably hepatic glycogen because urea production was unaffected and glycerol uptake was decreased. These results are consistent with the interpretation that basal adrenergic activity plays an important role in the mobilization of fat in fasting dogs. A secondary consequence of that action is apparently a diminution of glucose production and oxidation, although the mechanism responsible for the latter response is not clear.

Abstract: The effects of stimulation and blockade of α and β-adrenoceptors on early postinfarction ventricular arrhythmias have been examined in a standardised and reliable animal model (coronary artery ligation in male rats under pentobarbitone anaesthesia). Protection (decreases in number of ventricular ectopic beats, in the incidence and duration of ventricular tachycardia (YT) and of ventricular fibrillation, and increased survival) was observed following acute intravenous administration of β-adrenoceptor blocking drugs (e.g. oxprenolol) 15 min prior to coronary artery ligation and following chronic (6 week) oral treatment (oxprenolol). This protection depended solely on β-adrenoceptor blockade. Marked protection was also observed following acute pretreatment with prazosin (in doses as low as 200 μg/kg) and, to a less marked extent, with yohimbine and phentolamine. Marked suppression of ventricular ectopic activity also resulted from the continuous intravenous administration of either adrenaline or noradrenaline (0.1 μg/kg/ minute). The possible mechanisms of protective effects are discussed.

Abstract: The effects of stress and opiate blockade upon motor activity were parametrically examined in experimentally naive adult male Sprague-Dawley rats. Activity was not affected by either factor in isolation, however, it was reduced by their combined effect. This reduction was evident only after prolonged (60 min) prestress, suggesting that the decrement is not general. Previous reports of opiate blockade upon activity or exploration may have been due in part to implicitly stressful or arousing aspects of testing procedures.

Abstract: Renal (cortex and medulla) and splanchnic (duodenum, liver, pancreas and spleen) blood flows were measured with 25-µ radioactive microspheres in anesthetized, open-chest dogs. The effects of nicotine (36 µg/kg/min i.v.), beta adrenergic blockade (propranolol, 1 mg/kg i.v.) and nicotine (36 mg/kg/min i.v.) after beta blockade were evaluated. Nicotine alone caused marked elevations of systemic arterial (+68%), central venous (+45%) and left atrial (+62%) blood pressures, and it reduced flow to renal cortex (–29%) and pancreas (–54%) while not affecting flow to renal medulla, duodenum, liver or spleen. Vascular conductance was decreased by nicotine in all tissues except spleen. Beta adrenergic blockade decreased heart rate (–9%) but had no other systemic hemodynamic effects. Regionally, beta adrenergic blockade decreased flow to liver (–59%) and to pancreas (–30%) but had no effect on flow to other splanchnic organs or to the renal cortex and medulla. Nicotine after beta adrenergic blockade resulted in systemic hypertension similar to that without beta blockade and in more pronounced elevations of central venous and left atrial pressures. Despite concurrent hypertension, flow decreased in all organs except liver. Vascular conductance in renal cortex and medulla, duodenum, liver and pancreas was decreased to a greater extent when nicotine was preceded by propranolol. In spleen, nicotine caused a pronounced decrease in vascular conductance after beta blockade, although without blockade it had had no effect. Results indicate that nicotine has a heterogeneous influence on regional vascular conductances in renal and splanchnic circulations that is associated with regional differences in activity of beta adrenergic receptors.

Abstract: Adrenal blood flow was measured during hemorrhagic hypotension in pentobarbital-anesthetized dogs using the radioactive-microsphere technique. A decrease in adrenal vascular resistance occurred during hemorrhage that was sufficient to maintain adrenal blood flow at prehemorrhage levels even with a decrease in mean arterial blood pressure (MABP) to as low as 50 mmHG. Blockade of alpha- and beta-adrenergic receptors, H1- and H2-histamine receptors, and prostaglandin synthesis all decreased resting adrenal blood flow. However, blood flow did not decrease further with hemorrhage subsequent to these interventions. Neither cholinergic blockade (muscarinic) alone nor ganglionic blockade subsequent to cholinergic blockade changed adrenal blood flow. However, ganglionic blockade alone increased adrenal blood flow. Hemorrhage subsequent to hypophysectomy also did not change blood flow to the adrenal. These data suggest that the maintenance of adrenal blood flow during hemorrhagic hypotension to 50 mmHg MABP is independent of the autonomic nervous system, prostaglandin synthesis, histamine receptors, or an intact pituitary-adrenal axis, even though all of these systems do influence adrenal blood flow.

Abstract: The possibility of an interaction between diazepam and pancuronium bromide was investigated in six patients undergoing general anaesthesia maintained with fentanyl, droperidol and nitrous oxide. Neuromuscular blockade was controlled using a feedback mechanism which automatically adjusted the rate of injection of pancuronium to maintain between 71.4 and 72.9% blockade. Diazepam 0.14mg kg–1 i.v. produced blood concentrations within the therapeutic range, but did not produce consistent changes in the level of blockade, pancurornum concentration in the blood or pancuroniurn consumnrion measured over 20 nun.

Abstract: Heretofore it has been assumed that the brain's reward system shows a response to opiate receptor blockade that is (a) immediate in nature and (b) close to asymptote after the initial dose. On theoretical grounds a graded and gradual response to blockade might also be predicted. To test this, rats were implanted with subcortical electrodes for self-stimulation and trained to panel-press for contingent intracranial reinforcement. Chronic blockade of the opiate system was produced by repeated injections of naltrexone HCl. A small percentage of self-stimulation sites proved refractory to opiate blockade both acutely and chronically. Also, some sites showed an immediate decrease in response level, as previously reported. As was predicted, a number of sites originally showing no response alteration showed a graded response decrease over a 4-day test period. These findings indicate the existence of a novel class of opiate sensitive reward sites and suggest (a) some apparently insensitive sites may become sensitive to opiate blockade under appropriate testing circumstances and (b) opioid neuropeptides may control certain tonic as well as more immediate aspects of motivation.

Abstract: Summary Adrenergic beta-receptor blockade was induced to attenuate the pressor response to laryngoscopy and tracheal intubation; the patient subsequently suffered cardiovascular collapse culminating in cardiac arrest. The rationale of the technique is discussed.