Abstract: To assess the role of hepatic autoregulation in defense against hypoglycemia, we compared the effects of complete blockade of glucose counterregulation with those of blockade of only neurohumoral counterregulation during moderate (approximately 50 mg/dl) and severe (approximately 30 mg/dl) hypoglycemia induced by physiologic hyperinsulinemia during subcutaneous infusion of insulin in normal volunteers. Compared with observations in control experiments, neurohumoral counterregulatory blockade (somatostatin, propranolol, phentolamine, and metyrapone), during which identical moderate hypoglycemia was achieved using the glucose clamp technique, resulted in suppressed glucose production (0.62 +/- 0.08 vs. 1.56 +/- 0.07 mg/kg per min at 12 h, P less than 0.01) and augmented glucose utilization (2.17 +/- 0.18 vs. 1.57 +/- 0.07 mg/kg per min at 12 h, P less than 0.01). Complete blockade of counterregulation (neurohumoral blockade plus prevention of hypoglycemia) did not further enhance the suppressive effects of insulin on glucose production. However, when severe hypoglycemia was induced during neurohumoral counterregulatory blockade, glucose production was nearly two times greater (1.05 +/- 0.05 mg/kg per min at 9 h) than that observed during complete counterregulatory blockade (0.58 +/- 0.08 mg/kg per min at 9 h, P less than 0.01) and that observed during mere neurohumoral blockade with moderate hypoglycemia (0.59 +/- 0.06 mg/kg per min at 9 h, P less than 0.01). These results demonstrate that glucose counterregulation involves both neurohumoral and hepatic autoregulatory components: neurohumoral factors, which require only moderate hypoglycemia for their activation, augment glucose production and reduce glucose utilization; hepatic autoregulation requires severe hypoglycemia for its activation and may thus serve as an emergency system to protect the brain when other counterregulatory factors fail to prevent threatening hypoglycemia.

Abstract: This paper addresses the possibility that anxiolytic drugs, septal lesions and hippocampal lesions have common effects which could (a) he described as an interference with exploration and (b) be attributed to a common interference with the control of hippocampal theta rhythm. Sodium amylobarbitone (20 mg/Kg, i.p.) reduced rearing in a low stress open field test and had complex effects on ambulation. Injection of 0.01 μg amylobarbitone into the medial septum reproduced the effects of systemic injection on ambulation but did not affect rearing. Injection of procaine into the medial septum, which blocks theta rhythm, blocked the habituation of ambulation in a manner similar to that reported for large septal lesions but did not block rearing. It was concluded that the effects of amylobarbitone on ambulation depend on different mechanisms from its effects on rearing and that rearing survives medial septal blockade. Thus amylobarbitone, septal lesions and presumably hippocampal lesions affect explorato...

Abstract: The characteristics of the train-of-four response during neuromuscular blockade with two agents, atracurium and vecuronium, have been compared. During onset of blockade, at 75% depression of the initial twitch, atracurium was associated with significantly more fade than was vecuronium, and larger doses of atracurium were associated with less fade than smaller doses of the same agent. In addition, with both agents, the degree of fade at a given amount of initial twitch depression was significantly less during onset than during spontaneous offset of action. The degree of train-of-four fade bears no fixed relationship to depression of the initial twitch.

Abstract: The physiological effects of local anaesthetic (bupivacaine), neurolytic (phenol) blockade and surgical ablation of the lumbar sympathetic chain were assessed in patients with peripheral vascular disease or sympathetic dystrophy. Local anaesthetic blockade in 49 patients resulted in significant decrease in pain, plantar sweating and in the vasoconstrictor ice response of the foot, as well as a significant increase in skin temperature and foot blood flow. Subsequent neurolytic blockade in 31 of these patients achieved an effective denervation as assessed by the same physiological measurements. The magnitude of changes in blood flow and sympathetic activity were similar for local anaesthetic and neurolytic blockade as well as in six patients who underwent surgical sympathectomy.

Abstract: Ketanserin is a new antihypertensive agent with affinity to serotonin (5-HT)2 receptors and at higher concentrations also to alpha 1-adrenoceptors The present study was designed to evaluate the relative functional importance of the antagonism of alpha 1-adrenoceptors and 5-HT2-receptors in the antihypertensive mechanism of action of ketanserin and analogues after acute administration In the spontaneously hypertensive rat, ketanserin and the two ketanserin analogues, R56413 and R55667 (which have relatively weaker alpha-adrenolytic properties) were studied with regard to their ability to reduce the blood pressure after acute administration in the conscious rat and their ability to shift the dose response curves for 5-HT and phenylephrine in the pithed rat The agents tested reduced the blood pressure only in a dose range where they blocked alpha 1-adrenoceptors and there was a striking correlation between the degree of hypotension and the degree of inhibition of the phenylephrine induced pressor responses 5-HT2-receptor blockade alone did not influence basal blood pressure However, following pretreatment with R55667 in a low dose the blood pressure reduction to prazosin was enhanced It is concluded that following acute administration in the rat the major portion of the antihypertensive response to ketanserin is due to an alpha 1-adrenoceptor blockade but that the 5-HT2-receptor blockade contributes

Abstract: Maximal treadmill testing was carried out in 50 patients with angiographically documented coronary artery disease (CAD) in the presence and absence of β-adrenoceptor blockade. The results were related to the extent of CAD and interpreted relative to the clinical value of exercise testing. Maximal heart rate and systolic blood pressure were significantly lower during treatment with β-blocking drugs. The average exercise duration was 1.3 ± 1.9 minutes greater (± standard deviation), regardless of coronary anatomy. Of the 20 subjects with 3-vessel or left main CAD (severe CAD), 8 patients completed 3 stages (9 minutes) of exercise during treatment; only 4 did so without treatment. Angina was significantly more often the limiting symptom with severe CAD, and this association was abolished by β blockade; 1 of 20 with severe CAD completed 3 stages of exercise and was not limited by angina without β-blocking treatment, whereas 7 had these features during β-blockade therapy. Maximal ST-segment depression was not related to the extent of CAD with or without therapy. Beta blockade suppressed the occurrence of ST depression, or delayed its appearance by an average of 2.0 ± 2.3 minutes and reduced its severity by 0.5 ± 0.9 mm. All tests in which ST depression was completely suppressed were associated with inadequate heart rate response, regarded as diagnostically inconclusive rather than negative. However, during β-blocking treatment, 14 tests (28%) were inconclusive, which, in routine practice, would have necessitated repeat testing. It is concluded that β blockade significantly obscures the diagnostic interpretation of exercise testing and impairs the ability to select subjects likely to have extensive CAD.

Abstract: The influence of chronic beta 1-adrenoceptor blockade on haemodynamic and metabolic responses was examined in eight young hypertensive subjects during a 40 min submaximal bicycle test at 50% of maximal capacity. The patients were randomly allocated to one placebo and one treatment period of 6 weeks. During treatment atenolol (Tenormin, 100 mg) was given twice daily. Arterial pressure, cardiac output, leg blood flow, oxygen uptake and different metabolites in the blood were determined. The heart rate was reduced by beta 1-adrenoceptor blockade by 30% during exercise, and the decrease was related to plasma concentration of the drug. Cardiac output was decreased by approximately 10%, but the negative chronotropic effect was partly compensated for by a higher stroke volume. Blockade leg blood flow was reduced by 10%, but more oxygen was extracted, giving an unchanged oxygen uptake. Blood concentration and leg uptake of glucose were not influenced by the treatment, but plasma free fatty acids were reduced by 30-40%. Leg lactate release was decreased to half the value in the unblocked situation. Plasma renin activity did not increase at the beginning of exercise, but after 40 min an increase was seen, though only to half of the pretreatment value. It is concluded that beta 1-adrenoceptor blockade during submaximal exercise reduces blood flow to the working muscles and that this reduction is the result of a lower cardiac output. Aerobic metabolism is unchanged as a result of increased oxygen extraction, but less fat is used as lipolysis is inhibited. Glucose uptake by the working muscles is unchanged by beta 1-blockade, but there is evidence for an increased carbohydrate metabolism. As for non-selective blockade, atenolol decreases lactate release but this could be the result of non-specific action on the beta 1-receptor and/or increased carbohydrate oxidation. Furthermore, the beta 1-adrenoceptors seem to have a major influence on the renin release during exercise.

Abstract: The authors determined whether increasing alpha 1-adrenergic blockade resulted in progressively less arrhythmic activity in the canine halothane-epinephrine arrhythmia model. Dogs (n = 7) were anesthetized with halothane (1.5%) in oxygen. Stepwise increases in steady-state plasma levels of either of two alpha 1-adrenoceptor antagonists (droperidol, doxazosin) were produced by applying Wagnerian principles to the known pharmacokinetic parameters of these drugs. At each steady state plasma level of these antagonists, the extent of the alpha 1-adrenergic blockade produced was assessed by defining a phenylephrine (PE) dose pressor response curve. The degree of alpha 1-blockade produced was quantitated as the dose of PE that caused a 25-mmHg increase in mean arterial pressure (ED25) as derived by polynomial regression analysis. By analysis of variance (ANOVA) the ED25 increased significantly for each targeted steady state plasma level of either droperidol (P less than 0.001) or doxazosin (P less than 0.001). For an assessment of the antiarrhythmic activity of these alpha 1-antagonists, the arrhythmogenic dose of epinephrine (ADE) was determined at each of the states of alpha 1-adrenergic blockade previously defined. By ANOVA there was a significant increase in the ADE over the range of alpha blockade produced for either droperidol (P less than 0.001) or doxazosin (P less than 0.001). A close correlation (r2) existed between the ED25 and the ADE for the target steady state levels that were achieved for either droperidol (0.99) or doxazosin (0.74).(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract: Modifications of drug-inducedVmax inhibition by the combined treatment of the cardiac membrane with several class 1 antiarrhythmic agents were studied in guinea pig's ventricular myocardium taking the depression of upstroke velocity in fast action potentials as an indicator for INa blockade. A novel analytical procedure, first beat phasic block determination, provided the opportunity to estimate phasic drug binding initiated by a single action potential. 1. TotalVmax blockade increased in response to the addition of quinidine (1×10−5 mol/l), lidocaine (3×10−5 or 3×10−4 mol/l) or prajmalium (2.5×10−5 mol/l) to a propafenone-containing (5×10−6 mol/l) medium. This intensification originated from an increase of both tonic (rested-state) and phasic (use-dependent)Vmax blockade when kinetically similar drugs such as propafenone and quinidine may interact simultaneously with Na+ channels and, thus, resembles the effects of a rise in drug concentration. Accordingly, the development kinetics of phasicVmax blockade were accelerated but block relaxation kinetics remained unaffected. 2. Intensification of totalVmax blockade induced by combining propafenone with the kinetically different lidocaine resulted exclusively from an increase of tonic blockade at driving rates between 0.2 and 1 Hz. Steady state phasicVmax blockade remained within this frequency range unchanged or decreased depending on whether the lidocaine concentration in the propafenone-containing medium was low or high. Although the strength of first beat phasicVmax block went up in both cases, the propafenone-induced fraction declined in the presence of the higher lidocaine concentration. 3. Development and relaxation kinetics of phasicVmax blockade became modified when Na+ channels were exposed to a mixture of kinetically different drugs, propafenone plus lidocaine or propafenone plus prajmalium. Instead of a single exponential time course, development and removal of phasicVmax blockade consisted of two different components. 4. The biexponential time course of phasic block onset in propafenone plus prajmalium, the biexponential time course of phasic block relaxation in propafenone plus lidocaine and the interference of one drug with the blocking action of another strongly suggest a Na+ channel-associated drug receptor. Propafenone and lidocaine very probably find a common target which might bear a single or two allosterically linked binding sites.

Abstract: In the spontaneously hypertensive rat (SHR), ketanserin and the ketanserin analogues R56413 and ritanserin were studied with regard to their ability to reduce the blood pressure in conscious rats and shift the dose-response curves for phenylephrine and serotonin (5-HT) in pithed rats after acute administration. There was a striking correlation between the degree of hypotension and the degree of inhibition of the phenylephrine-induced pressor responses. 5-HT2-receptor blockade alone by ritanserin did not influence the blood pressure but it potentiated the hypotensive response to alpha 1-adrenoceptor blockade by prazosin. Thus, following acute administration in the SHR, the major portion of the antihypertensive response to ketanserin is due to an alpha 1-adrenoceptor blockade but the 5-HT2-receptor blockade may contribute.

Abstract: (1985). Antihypertensive Mechanisms of Beta-Adrenoceptor Blockade: A Review. Clinical and Experimental Hypertension. Part A: Theory and Practice: Vol. 7, No. 1, pp. 1-72.

Abstract: When the opiate antagonist naloxone is administered to anesthetized dogs subjected to hemorrhagic shock, there is a transient decrease in heart rate and sustained increases in mean arterial pressure, maximum left ventricular dp/dt, and cardiac output. Surgical cardiac denervation and pharmacologic blockade of autonomic receptors were employed to investigate the mechanisms of these two responses. The transient bradycardia was prevented by beta-adrenergic receptor blockade or cardiac denervation. The sustained response was unaffected by cardiac denervation, attenuated by either alpha- or beta-adrenergic receptor blockade, and potentiated by cholinergic receptor blockade. Naloxone had no significant effect on plasma catecholamines. The sustained hemodynamic response to naloxone appears to have two components: there is an increase in parasympathetic stimulation which modestly attenuates the adrenergic component of the response. The adrenergic stimulation of the heart after naloxone administration appears to result from potentiation of existing adrenergic stimulation and not from increased sympathoadrenal discharge. These sustained sympathetic and parasympathetic responses appear to result from the action of naloxone at a myocardial site.

Abstract: A double-blind study was carried out to compare the effect of submucous paracervical blockade using 12 mL 0.25% bupivacaine (55 women) to the effect of intramuscular injection of 75 mg meperidine (62 women) during the first stage of labor. All 117 were normal primiparous pregnancies. Seventy-eight percent of the women in the paracervical blockade group achieved full or acceptable pain relief against 31% in the meperidine group (P less than .01). Transient fetal bradycardia occurred in two cases in the paracervical blockade group and one in the meperidine group; all infants were born in good condition. Fetal distress, defined as an umbilical artery pH of 7.15 or less and/or a one-minute Apgar score of 7 or less was more frequent in the meperidine group (16 infants) than in the paracervical blockade group (six infants) (P less than .05). Submucous paracervical blockade is superior to intramuscular meperidine as pain relief during labor. Furthermore, meperidine results in more infants with asphyxia as compared with paracervical blockade.

Abstract: Increased basal and stimulated insulin secretion is a well known phenomenon in obesity. At present the mechanism of hyperinsulinism in obesity is not well defined. Opioid-like peptides have been found in recent years in the human pancreas. Beta-endorphin and somato statin are co-localized in D-cells of the islets of Langerhans

Abstract: Training bradycardia during autonomic blockade has been studied in rats and humans. The heart rate after autonomic blockade (intrinsic heart rate) is also lowered as a part of the adaptation to training. However, this nonautonomic component of the cardiac adaptation requires a long duration of intense endurance training to appear. This is in contrast to the autonomic component of the training bradycardia. From animal studies we have concluded that even if the training bradycardia is due to an adaptation within the heart itself, the adrenergic nerves are important for the development of a slow intrinsic heart rate. Neither the β-receptor stimulation nor the degree of the heart rate increase during exercise is the main stimulus for the development of a training-induced bradycardia. Well-trained bicyclists had an intrinsic heart rate 20 beats lower than untrained normal control subjects. The heart rate at rest and the maximal heart rate were also on an average 20 beats lower for the bicyclists. There was no significant difference between propranolol and the β 1 selective metoprolol in this study regarding their effects on heart rate and on deterioration of the maximal oxygen consumption after blockade. This deterioration was more marked in the well-trained than in the sedentary group. Based upon studies both in normal subjects and patients a careful rating of symptoms including physical exertion, fatigue or pain in the legs, dyspnea and chest pain using a Borg scale is recommended during exercise testing with β blockade. This should facilitate a more optimal and individual prescription and avoid use of β blockers in subgroups of patients with such symptoms as leg fatigue, pain or breathlessness during exercise and β blockade.

Abstract: The mechanisms responsible for the hypotensive action of ketanserin are controversial. Vascular 5-HT2-receptor blockade, resulting in inhibition of serotonin-induced vasoconstriction and amplification of other vasoconstrictors, has been suggested by some investigators, but others have concluded that vascular alpha-adrenoceptor blockade is responsible. In our experiments using pentobarbitone-anaesthetized dogs, ketanserin (0.1-0.4 mg/kg i.v.) produced immediate and sustained falls in systemic arterial blood pressure and vascular resistance in the common carotid and femoral arterial circulations. Constrictor responses to noradrenaline in these circulations were unaffected by 0.1-0.4 mg/kg i.v. of ketanserin; alpha-adrenoceptor blockade was only produced by higher doses (1-4 mg/kg i.v.). Constrictor responses in the common carotid circulation to preganglionic cervical sympathetic nerve stimulation and to nicotine were not inhibited by 0.1-0.4 mg/kg of ketanserin. The systemic pressor responses to nicotine and common carotid artery occlusion, however, were reduced by these doses of ketanserin. These results suggest that alpha-adrenoceptor blockade is not responsible for the hypotensive action of 0.1-0.4 mg/kg of ketanserin, and that a centrally mediated inhibition of sympathetic nerve activity is involved.

Abstract: A potent irreversible β-adrenergic derivative of pindolol possessing a chemically reactive group (Br-AAM-pindolol) was synthesized. This compound devoid of agonist properties, competed for all (3H)-dihydroalprenolol (3H-DHA) binding sites in C6 glioma cell and rat cerebellum membranes. Pretreatment of C6 glioma cell membranes with Br-AAM-pindolol and subsequent washing resulted in a time- and dose-dependent blockade of β-adrenergic receptors. A 50% blockade was achieved in the presence of 1.6 nM Br-AAM-pindolol.

Abstract: Thirty-eight patients undergoing total hip replacement under subarachnoid blockade were allocated randomly to one of two groups. Following institution of the blockade, patients in group A received ephedrine i.v. to maintain the systolic arterial pressure at, or above 100 mm Hg. Patients in group B were managed in an identical way, but did not receive ephedrine. Significant differences in arterial pressure (P

Abstract: Beta-adrenoceptor blockade produces a well-established constellation of hemodynamic effects at rest and during exercise. The beneficial clinical response in patients with hypertension and angina pectoris relates directly to these hemodynamic effects. A number of molecular modifications have accomplished more selective or additional circulatory effects designed to improve the efficacy and reduce the adverse effects of these drugs. In considering further clinical application of these agents, new data relating to the role of the sympathetic nervous system in the response to exercise, in the control of heart rate and in the progression of the syndrome of heart failure must be considered.

Abstract: To assess the effects of serotonin receptor blockade on 5-hydroxytryptophan (5HTP)-induced aldosterone secretion, we studied six normal men using the serotonin antagonists ketanserin and methysergide. The subjects were studied on three separate occasions, and pretreatment with dexamethasone was given before each study. On two occasions, the pretreatment period also included administration of a serotonin antagonist, either ketanserin (120 mg/day) or methysergide (6 mg/day). On the day of study, the subjects were given a single oral 200-mg dose of 5HTP. Plasma levels of aldosterone increased significantly after 5HTP treatment compared to basal levels during each stage of the study. No significant difference in response in the three studies was found. We conclude that peripheral blockade of serotonin2 receptors does not abolish 5HTP-induced aldosterone stimulation, and that this stimulation is most likely mediated by central pathways.

Abstract: Drugs are not absolute in their specificity; the mechanisms by which many agents reduce blood pressure remain disputed. Ketanserin has been shown to have both 5-HT2-serotonergic and alpha 1-adrenergic antagonist activity. Its pharmacological profile makes its designation as a serotonergic antagonist appropriate; however, the relative contributions of at least these two, and perhaps other, mechanisms to the hypotensive effect of ketanserin during long-term oral treatment remain obscure.