Differential sensitivity of the insulin receptor to proteolysis after beta-adrenergic stimulation.

The cellular mechanism by which the specific binding of [125I]insulin to intact rat adipocytes is inhibited by isoproterenol has been studied. By exposing control and isoproterenol-treated cells to trypsin (0-150 micrograms/ml for 20 min at 4 degrees C) and measuring the intact insulin receptor pool following detergent solubilization, a differential sensitivity to proteolysis of the cell membrane receptor was observed. At low trypsin concentration (less than 30 micrograms/ml), approximately 40% of the specific insulin binding in isoproterenol-treated cells was insensitive to proteolysis as compared to control cells. At higher levels of trypsin (50-150 micrograms/ml) both groups displayed similar levels of trypsin-insensitive receptors which, at the highest trypsin concentration, accounted for 10% of the total receptors in intact cells. Detergent-solubilized receptors from isoproterenol-treated cells, on the other hand, exhibited the same sensitivity to trypsin proteolysis as solubilized receptors from control cells. The time course of the onset and reversal of the isoproterenol-induced binding alteration in intact adipocytes has been analyzed by mild trypsinization (20 micrograms/ml). Results indicated that insulin receptors resistant to trypsin under these conditions mediated the decreased surface binding and were re-expressed on the cell surface upon removal of isoproterenol. Experiments in which adipocytes were fractionated into plasma membrane and Golgi-enriched fractions indicated that the loss of surface insulin binding was not accompanied by a decrease in the proportion of receptors in the adipocyte plasma membrane.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of footshock stress on the sensitivity of the isolated rat pacemaker to catecholamines.

The effect of repeated footshock on the sensitivity of the isolated rat pacemaker to the chronotropic effect of catecholamines was studied. Footshock stress caused subsensitivity to noradrenaline and supersensitivity to isoprenaline. The subsensitivity to the neurotransmitter was abolished by cocaine, whereas supersensitivity to isoprenaline was unchanged after blockade of the extraneuronal uptake. The pA2 value of metoprolol was increased by repeated footshock. Butoxamine reversed the supersensitivity to isoprenaline and the alteration of the pA2 value. Repeated footshock stress appears to cause prejunctional subsensitivity to noradrenaline and to increase the function of postjunctional beta 2-adrenoceptors.

Blood lactate. Implications for training and sports performance.

The blood lactate response to exercise has interested physiologists for over fifty years, but has more recently become as routine a variable to measure in many exercise laboratories as is heart rate. This rising popularity is probably due to: the ease of sampling and improved accuracy afforded by recently developed micro-assay methods and/or automated lactate analysers; and the predictive and evaluative power associated with the lactate response to exercise. Several studies suggest that the strong relationship between exercise performance and lactate-related variables can be attributed to a reflection by lactate during exercise of not only the functional capacity of the central circulatory apparati to transport oxygen to exercising muscles, but also the peripheral capacity of the musculature to utilise this oxygen. For example, several studies contrast the relationship between VO2max and endurance running performance with that between a lactate variable and the same running performance. In every study, the lactate variable is more highly correlated with performance. Similarly, prescribing training intensity as a function of the lactate concentration elicited by the training may prove to be a means of obtaining a more homogeneous adaptation to training in a group of athletes or subjects than is obtained by setting intensity as a function of maximal heart rate or % VO2max. A review of the recent literature shows that the lactate response to supramaximal exercise is a sensitive indicator of adaptation to 'sprint training' and is correlated with supramaximal exercise performance. This review also describes the possible applications of lactate measurements to enhance the rate of recovery from high intensity exercise. Although the lactate response to exercise is reproducible under standardised conditions it can be influenced by the site of blood sampling, ambient temperature, changes in the body's acid-base balance prior to exercise, prior exercise, dietary manipulations, or pharmacological interpretation.

Hypokalemia from beta 2-receptor stimulation by circulating epinephrine.

Beta 2-receptor stimulation is required for catecholamine-induced hypokalemia to occur. This hypokalemia is not mediated by insulin, renin or aldosterone. Catecholamine-induced hypokalemia can be prevented by selective beta 2 blockade, which does not abolish the inotropic effect of epinephrine.

Effect of adrenergic receptor blockers on the cardio-respiratory response to cow's urine concoction in rats.

The influence of alpha and beta adrenoceptor blockers on the cardio-respiratory effects of cow's urine concoction (CUC) in rats was studied. The study showed that phenoxybenzamine abolished the pressor response observed in the untreated animal while propranolol had no effect on blood pressure response. The alpha-blocked animals also developed significant post-injection hypotension. Electrocardiographic abnormalities seen in the control group were ameliorated by beta-blockers but alpha-blockers had no such effect. CUC caused an initial depression of respiration with short apnoeic phases and an increase in pulmonary ventilation. The latter was significantly decreased by alpha and beta adrenoceptor blockers. It was concluded that adrenoceptors play an important role in the cardio-respiratory effects of CUC.

Insect sting anaphylaxis and beta-adrenergic blockade: a relative contraindication.

Severe anaphylaxis is reported in a bee venom-sensitive 31-year-old male while receiving propranolol. His anaphylactic reaction was mainly respiratory and was refractory to emergency treatment. We believe that his use of beta-blockers contributed to the severity of his anaphylaxis and refractoriness to treatment. We suggest that beta-blockers should be contraindicated or alternate medications used in hymenoptera allergic patients.

Symposium on the management of ventricular dysrhythmias. Antifibrillatory versus antiectopic therapy.

The concept of antifibrillatory action distinct from antiarrhythmic effect has recently been recognized. An antiarrhythmic (antiectopic) action leads to a decrease in the frequency of ventricular ectopic beats. In contrast, an antifibrillatory drug action increases myocardial electric stability, decreasing the propensity for ventricular fibrillation. Agents with predominant antiarrhythmic action (designated class I) include lidocaine, quinidine, procainamide and disopyramide. Bretylium is an agent with predominant antifibrillatory action (class III). Amiodarone and sotalol are experimental class III drugs. The beta-blockers (class II) also possess antifibrillatory action, particularly in ischemic heart disease. The rationale for the use of agents with antiarrhythmic (antiectopic) effects is the reduction of triggering events for more complex ventricular tachyarrhythmias. These agents act by slowing conduction, decreasing abnormal automaticity and affecting phase IV depolarization. In contrast, agents with antifibrillatory action may exert little effect on cardiac conduction and automaticity. However, they raise the energy threshold required for premature electrical discharge to initiate ventricular fibrillation (ventricular fibrillation threshold). The inhomogeneity of electrophysiologic properties and adrenergic tone in different portions of the heart may be reduced or eliminated. Direct electrophysiologic effects of agents such as bretylium include a general lengthening of the refractory period and the action potential duration in the heart and a diminution in the disparity of their durations between normal and abnormal myocardium. Clinical studies are incomplete, but they support the concept of antifibrillatory therapy. In postmyocardial infarction patients at intermediate risk of sudden death, the broad use of oral antiarrhythmic agents has not decreased the incidence of sudden death, whereas high-dose beta-blocker therapy, which exerts experimental antifibrillatory effects, may reduce sudden death by 30 to 70%.(ABSTRACT TRUNCATED AT 250 WORDS)

Isometric exercise before and after beta-receptor blockade with propranolol and mepindolol sulfate.

The effect of isometric exercise on hemodynamic parameters before and after beta blockade were investigated in two groups of six male volunteers, ages 25-28 years. On the basis of a randomized scheme, the subjects received either 15 mg propranolol i.v. or 0.5 mg mepindolol sulfate i.v. Cardiac output (CO) was determined by means of the Swan-Ganz thermodilution technique, and blood pressure was measured invasively in the radial artery. Analysis of the results pointed to the following conclusions. Isometric contraction brings about a reflex constriction of arterial and venous vessels, and thus an increase in blood pressure, pulmonary artery wedge pressures (PAWP) and CO, as well as a reduction in stroke volume (SV). The circulatory reflex mechanism operative during isometric exercise cannot be significantly influenced by beta blockade with propranolol or mepindolol sulfate. The increase in heart rate during isometric exercise is therefore unlikely to be the result of sympathetic activation, but rather of other (vagal?) reflex mechanisms.

Evidence that presynaptic beta-receptors account for the low affinity site in Schild plots for beta-adrenergic antagonists in the field stimulated rat vas deferens.

The low affinity site in the Schild plot of (-)-propranolol as an antagonist of isoproterenol in the field stimulated rat vas deferens was absent after reserpinization or treatment with rauwolscine. The apparent dependence of intact catecholamine stores and functional alpha 2-adrenoreceptors for demonstration of the low affinity site for propranolol in this preparation suggests that the low affinity site reflects the ability of beta-adrenergic blockers to antagonize an action of isoproterenol upon presynaptic beta-receptors.

Catecholamine-mediated arrhythmias in acute myocardial infarction. Experimental evidence and role of beta-adrenoceptor blockade.

Ventricular fibrillation is a major mechanism of sudden death. The cellular link between catecholamine activity and the development of serious ventricular arrhythmias may be in the formation of cyclic adenosine monophosphate (cAMP). Cyclic AMP and agents promoting cAMP accumulation allow development of slow responses which, especially in the presence of regional ischaemia, could develop into ventricular fibrillation. The role of beta-antagonist agents in the therapy of acute myocardial infarction is analysed in relation to the hypothesis linking cAMP and ventricular fibrillation. Reasons for the limited effectiveness of anti-arrhythmic therapy with beta-antagonist agents are given.

Clinical usefulness of the beta-adrenergic antagonists.

The pharmacology of the beta-adrenergic antagonists, particularly their role as competitive antagonists at the receptor site, is discussed. The clinical use of these agents is listed and a detailed outline of their use in angina pectoris, hypertension and conditions associated with increased sympathetic activity is provided. The relative contraindications to the use of beta-adrenergic antagonists are summarized and the pharmacology of those drug interactions involving these agents is discussed. A thorough understanding of the pharmacology and therapeutics of these agents, which interfere with physiological function, is mandatory prior to their clinical use.