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The research history of norcodeine as a narcotic blocking drug is presented. Because of the limitations found for norcodeine usage, naloxone, cyclazocine, and naltrexone have recently received attention, and the results of research with them are detailed.

ICI 66082, a cardioselective beta-adrenoceptor blocking agent, was found to produce hypoglycaemia in fasted rats. In fed rats a hyperglycaemic response was observed. The drug produced hypoglycaemia in fed adrenalectomised animals. The hypoglycaemic response to ICI 66082 was accompanied by elevations in plasma immunoreactive insulin (IRI) concentrations. The drug also reduced plasma glucose and increased IRI in moderately alloxan-diabetic rats. In severely diabetic animals The drug did not increase IRI concentrations and did not unequivocally lower plasma glucose concentrations. In vitro experiments showed ICI 66082 to increase glucose uptake by rat diaphragm muscle and epididymal adipose tissue. the hypoglycaemic response may be mediated by increases in plasms IRI concentrations with a possible contribution from direct effects of the drug on peripheral glucose utilization. As these responses differ from those published in relation to other beta-adrenoceptor blocking drugs it is unlikely that the effects are due to beta-adrenoceptor blockade. However, like other beta-adrenoceptor blocking drugs ICI 66082 reduced isoprenaline-mediated increase in plasma IRI.

1 Indoramin and methyldopa were compared in a randomized controlled double blind trial of 89 patients who continued to be hypertensive after 3 weeks' baseline treatment with a diuretic. 2 The antihypertensive effect of indoramin was significant and similar to that of methyldopa. Although an α-receptor blocking drug, indoramin did not lead to cumulation, postural hypotension or reflex tachycardia. Side-effects were few and comparable with methyldopa.

The treatment of hypertension must be based on pathophysiologic grounds. The drugs that have been used in the classic stepped-care approach are still useful, but the rationale for their usage should not be based on the presumption that all hypertension is mediated by salt and water. Thus, the adolescent obtains greater benefits from a beta-adrenergic blocking drug or a centrally acting antihypertensive. The individual with heart failure may benefit more from a converting enzyme inhibitor than a vasodilator. In cerebrovascular disease with hypertension, dosage must be reduced owing to the enhanced sensitivity of response. New drugs are discussed, and their place in the armamentarium is evaluated.

A single stimulation with isoproterenol (IPR) resulted in a 1.5-fold increase in the total protein in saliva from rat submandibular glands at 1 day after the injection. Large mobile (LM) protein began to be secreted from the glands early after IPR injection, reaching a maximum at 2 days after injection, when the total protein in saliva had returned to the normal level. The secretion of this protein continued for 22 days after injection, indicating that the life of LM protein template is long or that the effect of IPR remains during this period. The increase of LM protein after IPR stimulation was markedly suppressed by β-adrenergic receptor blocking drugs. When both an α-adrenergic receptor blocking drug and adrenaline were injected together into rats, a small amount of the LM protein appeared and an increase in the wet weight of submandibular glands was seen. Repeated injection of these drugs resulted in a remarkable increase of LM protein. These results suggest that the appearance of LM protein was not a consequence of direct action of IPR but was due to a stimulatory effect of IPR on β-adrenergic receptors and that chronic blocking of α-adrenergic receptors has a significant stimulative effect on the production of LM protein through β-adrenergic receptors.

Practolol, a recent and more selective beta-adrenergic receptor blocking drug, was given orally as a single dose of 200 mg to seven healthy volunteers and to six patients suffering from severe renal impairment and submitted to the long-term hemodialysis program. The plasma drug decay was markedly slowed and the plasma half-life was prolonged sixfold in the uremic patients in comparison to healthy volunteers. Hemodialysis (8 hours) starting 48 hours after drug intake lowered plasma practolol significantly but transiently. The shorter half-life during hemodialysis and the detection of equally high values of practolol in the ultrafiltrates as in the plasma demonstrate that this drug is readily removable from the plasma. However, the ascending slope of the plasma drug concentration curve which appeared following hemodialysis is suggestive of an incomplete drug removal from the body.

Studies of grip strength in man have indicated that a new steroid compound, ORG.6368, has the features of a myoneural blocking agent. In comparison with the action of pancuronium, the onset is more rapid although the duration is similar. Further investigation is indicated to assess its possible clinical use as a myoneural blocking drug suitable for endotracheal intubation, especially in the emergency induction of anaesthesia.

The calcium channel blocking drug nifedipine was shown to be more effective than placebo as a treatment for Raynaud's phenomenon. Given in a dose of 10 mg four times a day it was well tolerated and reduced both the frequency and the severity of vasospastic attacks. There was, however, a large individual variation in response and while approximately half the patients showed marked improvement others showed no improvement at all. Patients with idiopathic Raynaud's phenomenon responded more favourably than those with systemic sclerosis. Nifedipine was shown to inhibit mitogen-induced lymphocyte proliferation but only in patients who responded to the drug clinically. Calcium channel blocking drugs may therefore have potential as immunoregulatory agents.

1. The early electrophysiological patterns of regional subendocardial ischaemia were studied by using the paced endocardial evoked response and simultaneous endocardial monophasic action potential recordings in 16 experiments in open chested dogs. Ischaemia was produced by transient (1-3 min) coronary artery occlusion. 2. Regional subendocardial isochaemia caused asynchronous activation due to differential conduction delay and shortened repolarization as evaluated by the duration of the paced evoked response from 175±(sd) 18.7 ms to 167 ± 16 ms (P 3. In simultaneous endocardial monophasic action potentials there was a decrease in plateau amplitude and the duration of repolarization shortened from 180±(sd) 21.2 ms to 167 ±20.4 ms (P 4. The delay in endocardial activation after 2 min ischaemia was 5.5 ms, which is considerably shorter than the conduction delay previously reported in the subepicardial layers. 5. The calcium-channel blocking drug verapamil (infused at 0.4 mg/kg) altered the rate at which shortening of repolarization and asynchronous activation occurred during ischaemia in six experiments. 6. These experiments suggest that intracavitary electrodes could provide earlier and more sensitive detection of regional subendocardial ischaemia and may permit the assessment of therapy on the early electrical changes in the intact heart.

Most alpha-receptor blocking drugs require divided daily administration because of a short plasma half-life. This multicenter study examined the effectiveness and safety of once-daily administration with doxazosin, a quinazoline analog alpha 1-receptor blocking drug with a plasma half-life of 19 hours. Patients with diastolic blood pressure (BP) of 90 to 115 mm Hg entered 4 weeks of single-blind placebo therapy and then were randomized to double-blind treatment with doxazosin (63 patients) or placebo (67 patients). After 10 weeks of titration, standing arterial BP was lowered by 14/11 mm Hg with doxazosin and by 0.5/0.9 mm Hg with placebo (p less than 0.001). Measured hourly for 12 hours after the dose, all standing and supine arterial BP values were significantly lower in the doxazosin group at each hour. Pulse rate increased slightly in both groups int he double-blind phase, but the increase with doxazosin never significantly exceeded that of placebo. Dizziness was the most common complaint with doxazosin, but syncope did not occur. Side effects were mild and transient and did not necessitate withdrawing any participants from the study. Body weight increased by 1.5 kg in the doxazosin group and decreased by 0.2 kg in the placebo group (p less than 0.01). Safe and effective in once-daily administration, doxazosin is suitable for initial therapy in mild and moderate hypertension.

Despite numerous suggestions in the literature that thromboxane A2 is involved in a variety of occlusive vascular diseases, no definitive evidence is available. Arguments have been presented to support the view that such evidence can only come from clinical studies with a highly specific thromboxane receptor-blocking drug. We have now identified such a drug, AH23848, in our laboratories. Preliminary experiments with AH23848, ([1 alpha (Z), 2 beta,5 alpha]-(+/-)-7-[5-[[(1,1'-biphenyl)-4-yl]methoxy]-2-(4-morpholin yl)-3-oxocyclopentyl]-4-heptenoic acid), show that it is a potent, specific thromboxane receptor-blocking drug that is orally active and has a long duration of action. It should be a valuable tool in elucidating any physiologic or pathologic role of thromboxane A2.

Bepridil, a fast and slow channel blocking drug, was administered intravenously over 5 minutes in a dose of 3 mg/kg body weight to 19 patients. Ten patients received intravenous bepridil during electrophysiologic study, performed for the investigation of known or suspected cardiac arrhythmias. Sinus cycle length increase from 764 +/- 56 to 886 +/- 62 ms (p less than 0.002). AH interval increased from 101 +/- 6.9 to 137 +/- 11.9 ms (p less than 0.01). HV and QRS durations were not significantly affected. QTc interval increased from 395 +/- 13 to 423 +/- 13 ms (p less than 0.001). Atrial effective refractory period increased from 211 +/- 8 to 242 +/- 8.7 ms (p less than 0.005), and atrioventricular nodal effective refractory period increased from 299 +/- 26 to 366 +/- 30 ms (p less than 0.02). Right ventricular effective refractory period increased from 233 +/- 9.3 to 259 +/- 8.1 ms (p less than 0.001). In an additional 9 patients with coronary artery disease, a hemodynamic and metabolic study was performed. A transient mean decrease dP/dt max from 1,646 +/- 164 to 1,506 +/- 238 mm Hg/s (p less than 0.05) and a mean increase of 2.6 mm Hg (p less than 0.05) in left ventricular end-diastolic pressure were observed. Both values had returned to control levels 15 minutes after drug infusion. Blood pressure, cardiac output, coronary sinus blood flow and myocardial lactate extraction ratio did not change significantly. This profile of powerful electrophysiologic and minor hemodynamic changes indicates a potentially useful role for bepridil in the acute management of supraventricular arrhythmias and, possibly, ventricular arrhythmias.

An experimental method for blocking maternal lactation is reviewed and the possible application of this technique for experimentally manipulating weaning is considered. Maternal milk production can be inhibited using the prolactin-suppressing drug bromocriptine. The suitability of bromocriptine for use in behavioural experiments is considered. The pharmacology of bromocriptine (CB 154) is briefly outlined and a compilation of the reported lactation-inhibiting doses for various species is presented. The possible endocrine and behavioral side-effects and the toxicity of the drug are discussed. It is concluded that, in most species studied so far, the drug is relatively free from significant side-effects at the low doses needed to suppress lactation. Guidelines for the practical use of bromocriptine are suggested. Finally, some ideas about the possible application of the drug to the study of behavioral development and parent-offspring relationships are discussed.

In two groups of patients with well-defined obstructive lung disease – a group of bronchitics according to WHO criteria and a group of patients with extrinsic allergic asthma – the effect of carazolol, a so-called non-cardioselective β -blocking drug, was investigated. Pindolol was used to compare the results with a second blocking drug. Carazolol increased bronchial resistance in the bronchitic group but not in the asthmatic group; with the exception of 1 patient in whom carazolol induced a status asthmaticus. The effect of the drug on bronchial resistance depends only in part upon the drug itself, but was influenced much more by the characteristics of the patients. We therefore conclude that the quality of β1-receptorspecificity was, at least in part, a result of the qualities of the patients. The designation of a drug as β1-specific should therefore be used very cautiously. Serious side-effects on the bronchial system in particular persons are also possible from drugs shown to be safe in some groups of patients

Postural finger tremor was measured in sixteen normal subjects at hourly intervals between 10.00 and 17.00 h. Order effects were allowed for by starting recording at different times of day. Self-ratings of tremor, anxiety and tension were completed after each recording. The amount of tremor between 2 and 32 c/sec was computed by occured in the amount of tremor within the physiological range (6–14 c/sec) but not at other frequencies. Most tremor was recorded at 11.00 h and the least at 14.00 h. Self-ratings showed a similar trend but this was not significant. To test whether the variation in tremor was due to changes in circulating adrenaline ten of the subjects were retested at hourly intervals between 10.00 and 14.00 h after pre-treatment with the adrenergic beta-receptor blocking drug, propranolol. The variation was much reduced but not entirely eliminated. It is concluded that the diurnal variation demonstrated is primarily due to changes in circulating catecholamines.

Peritoneal disease, apart from the post-operative variety, is rare, but three female patients, who presented with abdominal symptoms and in whom an unusual peritoneal lesion was found at operation, had one factor common to their medical histories—namely, previous treatment with the β-adrenergic-blocking drug practolol. The main finding at laparotomy was a pattern of massive peritoneal adhesions, but one patient had no history of abdominal surgery, and the findings at laparotomy were unusual. Other possible causes of this sclerosing peritonitis can be excluded, and the possible involvement of practolol in these cases is supported by the identification, via the Committee on Safety of Medicines, of four similar cases.

To assess changes in left ventricular function during antihypertensive treatment using pindolol, a beta-adrenocepter blocking drug with potent intrinsic sympathomimetic activity, serial echocardiographic measurements were obtained in 70 hypertensive patients before and during 15 weeks of treatment with pindolol. For analysis, the patients were separated into three groups on the basis of their baseline left ventricular fractional shortening (Group I, 35 patients with normal fractional shortening of 28 percent or more; Group II, 16 patients with abnormal fractional shortening of 21 to 27 percent; and Group III, 19 patients with markedly abnormal fractional shortening of 20 percent or less). More than half of the patients in Group I and Group II had decreases in mean blood pressure of 10 percent or more in response to pindolol, but only one fourth of Group III patients had similar responses (p less than 0.05). Patients with normal pretreatment fractional shortening had a mild decrease in fractional shortening during pindolol treatment, whereas patients with either abnormal or markedly abnormal fractional shortening had an increase in fractional shortening. This increase in fractional shortening suggests the possibility that the partial agonist or intrinsic sympathomimetic activity of pindolol may play a role in preserving left ventricular function in patients with borderline or impaired function.

Alpha blockade at a dose which produces minimal cardiovascular effects causes a significant fall in the urethral pressure profile in man. No change in profile height has been seen following the administration of a beta blocking drug in a dose producing cardiovascular changes of a similar order of magnitude.

The secretory effect of sympathetic stimulation on the cat's submaxillary gland was augmented greatly when studied against a background of slow secretion evoked by parasympathetic stimulation at a low frequency and imitating the slow resting secretion normally present in the waking state. The sympathetic secretory threshold was markedly lowered, and even at low frequencies sympathetic stimulation caused a large, well-maintained response. After an alpha-adrenoceptor blocking drug sympathetic stimulation alone lost its secretory effect, but during resting secretion part of the accelerating effect was found to remain; this effect was elicited via beta-adrenoceptors. A marked secretory effect of sympathetic stimulation was also obtained during resting secretion in the parotid gland, where the sympathetic secretory effect is normally very small.

SUMMARY Intra-muscular ecchymotic haemorrhages were produced in rats by the repeated application of a 110 volt 50 Hz alternating current immediately prior to dislocation of the neck. Histological examination of these haemorrhages indicated that they were similar to those seen in meat animals slaughtered at abattoirs. The injection of a β-adrenergic blocking drug, propranolol, caused a reduction in the extent of the haemorrhages while the injection of an α-adrenergic blocking drug, phentolamine, increased their extent. It is postulated that an increase in mean capillary blood pressure, as a result of arteriolar dilatation, is one of the factors involved in the production of ecchymoses.

Histamine induced bronchoconstriction was significantly reduced in 6 patients with extrinsic bronchial asthma by thymoxamine, a specific α-adrenergic 3 . Mean pulse rate and blood pressure in 6 asthmatic patients after intravenous thymoxamine (0 · 2 μg/kg) Mean Mean pulse rate blood pressure Basal 77 124 79 Immediate 81 118 76 5 min 80 119 77 10 min 80 120 81 15 min 80 117 79 30 min 80 117 78 60 min 77 119 81 receptor blocking drug. This study suggests that there are α-adrenergic receptors in the bronchial muscle of asthmatics, and that histamine sensitivity in asthma is due to hypersensitivity of these receptors.

Summary The results of a pilot trial of the effects of the β-mimetic drug Du21220 on uterine activity in 6 patients is reported. Du21220 was found to be an effective uterine relaxant. The only cardiovascular side-effect was a rise in maternal heart-rate. Practolol did not reverse the uterine inhibitory effect of Du21220, and in the one patient where tachycardia was marked, it produced a significant lowering of the heart-rate, which suggests that practolol may be a useful adjunct to Du21220 to counteract the tachycardia which may occur. Neither drug caused hypotension.

An additional case of the Romano-Ward syndrome is reported. In three members of a family, the Q-T intervals on the ECGs were found to be prolonged. One of the members was resuscitated on several occasions from Adams-Stokes attacks which occurred the first day postpartum and in subsequent premenstrual periods; these attacks were caused by ventricular fibrillation. The beta-adrenergic blocking drug propranolol proved to be an effective agent in preventing attacks. Given in a relatively small maintenance dose, the patient remained free from complaints, despite the unchanged prolongation of the Q-T interval.

The evaluation of beta-adrenergic blockade in cardiac arrhythmias is difficult because of the complex nature of the arrhythmias and the varied modes of action of blocking drugs. Studies have confirmed the therapeutic value of the beta adrenergic blocking drug pronethalol (Alderlin) (Vaughan Williams, 1963 ; Stock and Dale, 1963 ; Payne and Senfield, 1964 ; Wolf son et al., 1966) and its more potent successor, propranolol (Inderal) in the management of many different atrial and ventricular arrhythmias (Harrison et al., 1965 ; Sloman et al., 1965 ; Stock, 1966 ; Harris, 1966 ; Szekely et al., 1966 ; Cherchi et ed., 1966 ; Rochet and Vastesaeger, 1966 ; Gettes and Surawicz, 1966 ; Luria et al., 1966 ; Epstein and Braunwald, 1966). This study reports our experience in the management of patients with paroxysmal arrhythmias, acute life-threatening arrhythmias, and recurrent arrhythmias associated with pro longed cardiac arrest. An attempt has also been made to assess the prophylactic value of propranolol in reducing the high incidence of arrhythmias associated with acute myocardial infarction.

The relation between cell motility and adenylcyclase activity was studied using culture of L 929 mouse fibroblasts. Treatment with catecholamines resulted in a rapid decrease of cell motility accompanied by an increase of adenylcyclase activity. These effects were prevented by the simultaneous addition of β blocking drug. It is suggested that cell motility may be controlled by intracellular cyclic AMP level.

Experiments have been carried out in 4 healthy human volunteers to find the degree of protection against histamine induced bronchial narrowing given by three different doses of thymoxamine taken by mouth. This drug is believed to be the most specific α-adrenergic blocking drug at present available. If so, our results support the belief that α-adrenergic receptors are present in the human bronchial tree.

1. Thyroid activity in SHR remained elevated even after the difference in adrenocortical activities between SHR and control rats was eliminated by adrenalectomy with supplements of NaCl and small doses of hydrocortisone. 2. Thyroid activity in SHR remained elevated even after the administration of hexamethonium, a ganglionic blocking drug. 3. Acute cold exposure (6-8°C, 6 hours) stimulated thyroid activity in SHR but not in control rats. This phenomenon was not prevented by adrenalectomy (with NaCl and hydrocortisone supplement) or by hexamethonium administration. 4. Chronic cold exposure (2-10°C, 6-12 weeks) stimulated thyroid activity more in SHR than in control rats. 5. Emotional stress (restraint for one hour a day for two days) depressed thyroid activity in control rats but not in SHR. The response was not affected by adrenalectomy (with NaCl and hydrocortisone supplement). 6. These results (1, 2) indicate that the elevated thyroid activity in SHR is mediated by neither the adrenal cortex nor the autonomic nervous system. 7. The significance of the different effects of cold exposure and restraint on the thyroid activi-ty in SHR (3, 4, 5) is discussed.

SUMMARY 1. The responses of the systemic and pulmonary vascular net pressures to the Valsalva maneuver in patients with emphysema have been studied. 2. In a majority of patients a systemic arterial overshoot after the maneuver was accompanied by an overshoot in right atrial, pulmonary arterial, and pulmonary artery wedge net pressures. 3. In six patients the pulmonary vascular overshoots were reduced or abolished by the ganglionic blocking drug, tetraethyl-ammonium chloride (TEAC). 4. The results support the view that following a Valsalva maneuver a rise in post-arteriolar resistance may contribute to the pressure overshoot in the pulmonary circulation.

The α-adrenergic blocking drug phentolamine was injected into male rats 1 h before resection of 70% of the liver and again 24 h after the operation. Phentolamine inhibited mitotic activity of the regenerating liver. Two injections of propranolol, a β-adrenergic blocking drug, at the same times caused an increase in mitotic activity. It was concluded that adrenalin, which excites β-adrenergic receptors, may inhibit regeneration. By its action through α-adrenergic receptors, however, adrenalin stimulates this process.

The clinical efficacy of bopindolol, a new, long-acting beta-adrenoceptor blocking drug, in a dosage of 1-2 mg daily was compared with that of atenolol (50-100 mg daily) in 33 patients with mild or moderate arterial hypertension who were treated for a total period of 12 months. Both drugs lowered systolic and diastolic blood pressure to about the same extent, but atenolol caused a somewhat greater lowering of heart rate. Over 70% of patients receiving atenolol required a diuretic in addition, whereas only 55% of the bopindolol patients required a diuretic. Both drugs maintained 24-h blood pressure reduction with once-daily therapy, although circadian rhythm (recorded using a Remler device) tended to be lost during treatment with atenolol but not with bopindolol.

SUMMARY 1. Ketanserin, a 5HT2-receptor blocking drug was given to 17 patients with essential hypertension. 2. Satisfactory control was achieved in 13 patients. 3. Control was not as satisfactory when given once daily. 4. There was no rebound effect when the drug was ceased. 5. Side-effects were few. 6. Ketanserin was a satisfactory drug to reduce blood pressure in patients with moderate hypertension.

Summary— Thirty-one patients with urodynamically proven bladder outflow obstruction were treated with Alfuzosin in a 3-month, double-blind, placebo-controlled study. The irritative symptoms of bladder outflow obstruction were improved significantly in the treatment group, according to both objective and subjective evaluation. There was no objective evidence of a reduction in outflow resistance or obstruction in either group.

An unusual case of essential thrombocythemia in a young man presenting with progressive angina pectoris is presented. Angiography revealed proximal left anterior descending artery stenosis. Successful percutaneous transluminal angioplasty along with antiplatelet therapy and a calcium channel blocking drug have rendered this patient asymptomatic.

Summary LB 46 (prinodolol) a β-adrenergic receptor blocking drug which is more potent than propranolol in euthyroid subjects, is less effective in inhibiting hyperthyroid tachycardia. This is probably due to its intrinsic sympathomimetic activity.

Intravenous administration of the beta-adrenergic blocking drug, alprenolol, to a group of patients with severe obstructive disease of the airways caused no deterioration of symptoms and a clinically insignificant fall in FEV1 in the majority. A minor reduction in PaO2 occurred which suggests that alprenolol may cause local hypoventilation and/or pulmonary arteriovenous shunting. The presence of obstructive disease of the airways does not seem to pose an absolute contraindication to the use of alprenolol, although caution must be exercised in its use in such patients.

Social phobia is the least well studied phobic disorder of those included in DSM-III. Reports from the British literature indicate that the condition is a distinct one that usually begins in adolescence and affects males more often than females. Patients characteristically complain of somatic symptoms and a fear of humiliation when confronted with specific social stimuli. Ten social phobic patients were openly treated with the cardioselective, peripherally active beta-adrenergic blocking drug atenolol. Five patients had complete response and four had moderate response. Side effects were minimal. Atenolol appears to work in social phobic patients by reducing autonomic nervous system response to phobic stimuli.

SummaryA double-blind, placebo-controlled study was carried out in 10 hypertensive patients who were subject to frequent attacks of Raynaud's phenonzenon and suffered from cold hands, to assess the peripheral vasoconstrictor effects of penbutolol. After a wash-out period of 2 weeks on placebo, patients received two 14-day treatment periods, in random order, with either 20 mg penbutolol twice daily or placebo separated by a second 2-neek single-blind wash-out period on placebo. The results of digital blood flow measurements showed that penbutolol did not produce any additional vasoconstrictor effect on digital circulation. The significance of these findings is discussed.

Handled female Wistar rats were exposed to one of the following stress stimuli: restraint, electric foot shocks, passive avoidance situation, ether, or nembutal anesthesia followed by ip formalin or laparotomy. Trunk blood was collected 2-4 min after initiation of the stress stimulus for the determination of immunoreactive beta-endorphin (beta-ENDi), ACTH (ACTHi), and alpha-MSH (alpha-MSHi). All stressors evoked a rapid increase of circulating beta-ENDi to 0.75-2.10 ng/ml. All except passive avoidance situation also induced a rapid increase of plasma ACTHi to 0.45-0.70 ng/ml, whereas plasma alpha-MSHi increased after ether and restraint to 0.18-0.40 ng/ml but was not affected by formalin stress. To study the involvement of a beta-adrenoceptor mechanism in stress-induced peptide secretion, rats were treated with D-propranolol or L-propranolol 40 min before stress exposure. Propranolol did not prevent the increase of plasma ACTHi to any of the stressors studied. L-Propranolol but not its inactive D-isomer reduced (restraint, passive avoidance) or abolished (electric foot shocks) the increase in plasma beta-ENDi but did not affect the beta-ENDi response to other stressors (ether, formalin, laparotomy). Similarly, L-propranolol attenuated the alpha-MSHi response to restraint but not to ether stress. To discriminate between corticotroph or melanotroph origin of beta-ENDi released during stress, rats were treated with dexamethasone or were subjected to neurointermediate lobectomy (4 weeks). Neurointermediate lobectomy did not affect basal or stress-induced plasma ACTHi but resulted in undetectable alpha-MSHi levels. It largely prevented the beta-ENDi response to restraint stress (propranolol sensitive) but had little effect on the beta-ENDi response to formalin stress (propranolol insensitive). Conversely, dexamethasone prevented stress-induced ACTHi response without affecting plasma alpha-MSHi. The beta-ENDi response to restraint stress (propranolol sensitive) was not changed but the response to formalin stress (propranolol insensitive) was largely prevented by dexamethasone. These results show that the intermediate lobe is the main source of beta-ENDi secreted during exposure to stressors with a high emotional impact. Since intermediate lobe peptide secretion induced by such stimuli can be prevented by beta-adrenoceptor blockade, we speculate that stress-induced discharge of catecholamines, possibly from the adrenal medulla, is the trigger signal for peptide secretion from the melanotrophs during this type of stress.

Summary In ten patients with extrinsic bronchial asthma, allergen provoked bronchospasm was significantly inhibited by the alpha receptor blocking drug thymoxamine given intravenously. In two of these patients thymoxamine by inhalation also effectively inhibited allergen induced broncboconsiriction. It is suggested that thymoxamine may be acting either by increasing intracellular levels of cyclic AMP and thus inhibiting mediator release following allergen challenge or by modifying the airways response to these mediators by altering the bronchomotor tone. The variable responses recorded after allergen challenge in presence of alpha blockade with thymoxamine suggests that the dominant effect is on the bronchomotor tone rather than the mediator release.

1 The effect of acebutolol, a relatively selective beta-adrenoceptor blocking drug and propranolol, a non-selective one, on the hypoglycaemic action of glibenclamide after an oral glucose load has been investigated in a group of maturity-onset diabetic patients. 2 Glibenclamide significantly reduced the blood glucose levels and both acebutolol and propranolol, at therapeutic doses, were found to modify this action significantly. 3 The effect of acebutolol was slightly less than that of propranolol. The difference was not statistically significant. 4 The modes of action of sulphonylureas are reviewed and it is suggested that beta-adrenoceptor blockers may modify their effect on insulin release. This appears to be a drug interaction rather than an effect of beta-adrenoceptor blockade on glucose tolerance.

Three patients with dyspeptic symptoms who were being treated with the H2-receptor blocking drug, cimetidine, were later found to have gastric carcinoma. It was not possible to determine whether the association was fortuitous, whether the drug had masked the neoplastic change, or whether it was involved in some other way. Repeated clinical and endoscopic evaluation is essential in patients on this treatment for any length of time.

1 In an open, randomized cross-over investigation of thirteen patients (nine and four women, aged 37-67 years) with mild or moderate essential hypertension a comparison between atenolol and metoprolol was carried out in order to study the effects of 50, 100 and 200 mg given once daily on blood pressure and heart rate at rest and during exercise. 2 Before one beta-adrenoceptor blocking drug was replaced by the other in a patient an intervening drug-free interval of sufficient length was secured to allow an increase in the blood pressure to pretreatment levels. 3 A maximal fall in blood pressure was achieve with 50 mg atenolol once daily, with no further reduction when the dose was increased to 100 mg or 200 mg. Maximal blood pressure reduction was achieved with 100 mg metoprolol daily, while the hypertensive effect of 50 mg once daily was not consistent. Significant reductions in heart rate in all test situations were observed with 50 mg atenolol, while 200 mg metoprolol 100 was necessary to reduce exercise-induced tachycardia. 4 Atenolol 50 mg and metoprolol 100 mg once daily are efficient in treating mild or moderate hypertension and doses beyond these may not reduce the blood pressure further. On the contrary lower doses than generally recommended may be effective in the individual patient.

The value of giving pigs the beta-adrenergic blocking drug carazolol preslaughter to improve meat quality was tested in a stress-resistant breed (Large White) and a stress-susceptible breed (Pietrain). Pigs averaging about 70kg liveweight were injected intramuscularly (1 mg per 100 kg liveweight) 0·5h before being transported to the slaughterhouse. The journey lasted 4 h and covered about 150 km and the pigs were slaughtered after 1 h in lairage. Treatment with carazolol reduced the incidence of PSE meat and considerably improved meat quality in the stress-susceptible Pietrain breed but had little effect in the stress-resistant Large Whites which produced good meat quality in both control and treated groups.

The action of beta-adrenergic blocking agents on the urethral pressure profile was studied. Sotalol, 20 mg, and inderal, 7 mg, were administered intravenously. Whereas the alpha-adrenergic blocking drug phentolamine, as already known, changed the maximum value of the pressure profile with an average decrease of 33%, the beta-adrenergic blocking drugs did not show any action at all. There was no difference between the results obtained with Sotalol and Inderal.

To examine the role of chronic calcium entry blocking drug administration on perioperative myocardial ischemia and, specifically, the frequency of hemodynamically unrelated ischemia, the authors studied 444 patients undergoing coronary artery bypass operations. Before induction of anesthesia, 119 patients who chronically took calcium entry blocking drugs received nifedipine 20 mg or diltiazem 60 mg orally, 74 received calcium entry and beta adrenergic blocking drugs, 71 received beta blocking drugs only, and 180 received neither. New ischemia occurred in 208 (46.8%) patients; 55 at arrival to the operating room, 86 only after induction, and 67 separately during both periods. Two-thirds of all ischemia was not related to extremes of heart rate or blood pressure; this type was not less frequent in patients receiving calcium entry blocking drugs. Ischemia did occur less frequently in the two patient groups receiving beta adrenergic blocking drugs (34% vs. 53%), a result of less tachycardia both on arrival (3.4% vs. 15.4%) and during anesthesia, when peak heart rate exceeded 109 bpm in only one of 145 beta-blocked patients compared to 29 of 299 not receiving beta blocking drugs. While ischemia appeared during anesthesia in 34.5% of all patients, its incidence was doubled (63%) when heart rate was greater than or equal to 110 bpm. At lower heart rates, the incidence of ischemia did not differ among groups. With respect to all types of ischemia, patients receiving calcium entry blocking drugs only were indistinguishable from those receiving no antianginal therapy.(ABSTRACT TRUNCATED AT 250 WORDS)