Mechanism of myocardial injury in dogs with hypokalaemia

Hypokalaemia was induced by infusing polystyrene sulphonate into the colon of mongrel dogs. Sixty minutes after infusion adrenaline 10 micrograms.kg-1 was injected intravenously, which had no effect on serum creatine kinase activity or myocardial histology in the control dogs. However, in dogs with hypokalaemia creatine kinase activity was increased, and pronounced histological changes were seen 60 min after injection. A clear reciprocal relation was found between serum potassium concentration and creatine kinase activity. Premedication with an alpha 1 blocking agent prevented the changes associated with hypokalaemia. Heart mitochondria were prepared from other dogs with hypokalaemia 5 min after adrenaline injection and their calcium content measured. Heart mitochondrial calcium content was increased in parallel with the decrease in serum potassium concentration. Alpha 1 blockade also prevented the increase in mitochondrial calcium content. These results indicate that the intracellular calcium concentration is considerably increased by alpha 1 receptor stimulus under hypokalaemic conditions and that this increase in calcium concentration plays a crucial role in the genesis of myocardial damage. Since adrenaline increases coronary blood flow small doses of adrenaline in subjects with hypokalaemia may lead to the development of myocardial injury not associated with ischaemia.     

Differences between the effects of adrenaline and noradrenaline on insulin secretion in the dog

The effects of adrenaline and noradrenaline infusions on pancreaticoduodenal venous insulin output were studied in anaesthetized normal dogs. Two experimental protocols were used. In the first, the dogs had a normal blood glucose level at the start of the catecholamine infusion (normoglycaemic dogs). In the second, the animals were made hyperglycaemic by a continuous glucose infusion (hyperglycaemic dogs). In the normoglycaemic dogs, adrenaline (0.5 micrograms X kg-1 X min-1) provoked hyperglycaemia accompanied by an increase in insulin output. Noradrenaline (0.5 micrograms X kg-1 X min-1) also caused an increase in insulin output but without any significant change in blood glucose. In hyperglycaemic dogs, adrenaline (2 micrograms X kg-1 X min-1) reduced the insulin response and enhanced the hyperglycaemia; noradrenaline (2 micrograms X kg-1 X min-1) markedly increased the insulin response (+ 2250%) without any significant change in blood glucose. Propranolol (0.3 mg/kg, IV) prevented the increase of insulin induced by noradrenaline. These findings show that, in the normal dog, adrenaline and noradrenaline infusions can produce opposite effects on insulin response depending on the experimental conditions.     

Influence of beta 2-adrenoceptor stimulation and blockade on cardiac electrophysiologic properties and serum potassium concentration in the anesthetized dog

The influence of selective beta 2-adrenoceptor stimulation and blockade on cardiac electrophysiologic properties was studied in 18 anesthetized dogs. Selective beta 2-adrenoceptor activation by salbutamol failed to alter myocardia excitability but significantly lowered serum potassium concentration. Excitability, refractoriness, and ventricular fibrillation threshold were also not changed after administration of 100 and 200 micrograms/kg of the selective beta 2-antagonist ICI 118,551. However, at a dose of 500 micrograms/kg, refractoriness was prolonged and ventricular fibrillation threshold increased. These changes appear to be due to blockade of beta 1-adrenoceptors rather than to membrane stabilizing effects, since in catecholamine-depleted animals even the highest dose of ICI 118,551 did not alter myocardial electrical properties. It is concluded that beta 2-adrenoceptors do not influence electrophysiologic properties of the canine myocardium.     

ADRENALINE CAUSES HYPOKALAEMIA IN MAN BY β2 ADRENOCEPTOR STIMULATON

Increased circulating adrenaline produces systemic hypokalaemia by the stimulation of a membrane bound Na/K ATPase. In man, this enzyme appears to be linked to an adrenoceptor of the beta-subtype. We have further studied the subtype of beta-adrenoceptor involved by infusing adrenaline intravenously in normal volunteers after pretreatment with either a selective beta 2 antagonist (ICI 118551) or placebo. During the adrenaline infusion the serum potassium fell from 4.08 +/- 0.21 to 3.32 +/- 0.25 mmol/l (P less than 0.002). This adrenaline induced hypokalaemia was completely blocked by ICI 118551 (3.82 +/- 0.13 to 4.03 +/- 0.22 mmol/l, NS). Adrenaline also caused electrocardiographic changes of T wave flattening (-1.8 +/- 1.5 mm, P less than 0.05) whereas the T wave height increased after ICI 118551 (+ 1.0 +/- 0.9 mm, P less than 0.05). This suggests that adrenaline acts via beta 2 adrenoceptors in man to cause potassium influx and systemic hypokalaemia.     

Comparison of the effects of the ionophore salinomycin and adrenaline on the haemodynamics and work efficiency of the dog heart

The positive inotropic, chronotropic, pressor, and coronary vasodilative effects of infused adrenaline (1 microgram X kg-1 X min-1) were compared with those of an intravenous injection of the carboxylic ionophore salinomycin (150 micrograms X kg-1) in 10 dogs anaesthetised with pentobarbital. At doses normalised to produce a doubling of left ventricular dP/dtmax both drugs produced pronounced increases in blood pressure, cardiac output, and plasma catecholamine concentration and a small increase in heart rate. After 10 minutes of adrenaline infusion coronary artery blood flow doubled whereas salinomycin produced a sixfold increase, reflecting its specific coronary vasodilative properties. The increases in cardiac output and pressor, chronotropic, and inotropic actions of salinomycin were related to the release of endogenous catecholamines into the plasma by the ionophore, whereas the increase in coronary blood flow indicated a non-adrenergic relaxation of the coronary blood vessels. Calculated values of left ventricular hydraulic work appreciably increased with both drugs, but left ventricular oxygen consumption was much higher during adrenaline infusion than the peak effect obtained with salinomycin. Accordingly, the mechanical efficiency of the left ventricle was slightly decreased by adrenaline and doubled by salinomycin. Because of its favourable haemodynamic profile, salinomycin has potential as a drug for increasing cardiac output, blood pressure, and left ventricular force of contraction and for improving the myocardial blood perfusion and mechanical efficiency of the heart.     

Protection against ventricular and atrial fibrillation by sotalol

Sotalol is not only a beta blocker but a class III antiarrhythmic drug. Its possible antifibrillatory activity was therefore investigated in both the ventricles and atria of dog heart in situ, since vulnerability to fibrillation is not the same in both these parts of the myocardium. Fibrillation threshold was measured concurrently with the duration and amplitude of monophasic action potential, the effective refractory period, the conduction time in the contractile fibres, and after fibrillation had been triggered the fibrillation rate. Variables were measured at 5 and 10 min after sotalol had been given intravenously in closed chest dogs in three doses (1, 1, and 2 mg X kg-1) at 15 min interval. Sotalol produced a rise in fibrillation threshold that occurred simultaneously with a prolongation in monophasic action potential duration and effective refractory period of the contractile fibres and a slowing in fibrillation rate, whereas conduction time was not affected. The changes appeared, however, to be less pronounced in the ventricles than in the atria, in which vulnerability to fibrillation, normally increased by vagal tone, had been previously enhanced by acetylcholine. Sotalol antagonised the changes due to acetylcholine. In both the atria and the ventricles the first dose (1 mg X kg-1), which produced plasma concentrations of approximately 2 micrograms X ml-1 10 min after injection, produced a submaximal effect. Nevertheless, subsequent administrations increased the beneficial effects but not in proportion to the dose and plasma concentrations.     

Metabolic and haemodynamic effects of increased circulating adrenaline in man. Effect of labetalol, an alpha and beta blocker.

To simulate increased sympathoadrenal activity adrenaline was infused in normotensive subjects to achieve plasma adrenaline concentrations similar to those seen after myocardial infarction or hypoglycaemia. Adrenaline was infused after pretreatment for five days with labetalol 200 mg twice daily or placebo given in a random order. The rise in systolic blood pressure and the fall in diastolic blood pressure observed after the infusion of adrenaline (0.06 micrograms/kg/min) were prevented by labetalol and no increase in blood pressure was seen. Adrenaline infusion after pretreatment with placebo caused a profound fall in the serum potassium concentration (4.12-3.20 mmol(mEq)/l). Pretreatment with labetalol completely blocked adrenaline induced hypokalaemia (3.92-3.95 mmol(mEq)/l). Adrenaline induced T wave flattening and QTc prolongation were also prevented by labetalol. Thus labetalol can prevent the electrocardiographic, haemodynamic, and hypokalaemic effects of increased circulating adrenaline in man. The combination of alpha and beta blockade appears to be required to block the haemodynamic effects of adrenaline, and labetalol may, therefore, be useful in controlling both the metabolic and circulatory responses during increased sympathoadrenal activity.     

Hypokalaemia and ventricular fibrillation in acute myocardial infarction

Serum potassium concentrations obtained on admission to hospital were inversely related to the incidence of ventricular fibrillation in 289 women and 785 men with acute myocardial infarction, 92 of whom developed ventricular fibrillation. Hypokalaemia (serum potassium concentration less than or equal to 3.5 mmol/l) was found in 122 patients (11.4%). The incidence of ventricular fibrillation was significantly greater in patients with hypokalaemia compared with those classified as normokalaemic (serum potassium concentration greater than or equal to 3.6 mmol/l) (17.2% v 7.4%). The increased risk of ventricular fibrillation in the hypokalaemic group was about the same for women and men. While they were in hospital patients with hypokalaemia developed ventricular fibrillation significantly earlier than did normokalaemic patients (median 0.3 hours v 7 hours). Hypokalaemia was more common in women (17.3%) than in men (9.2%), and 55% of the hypokalaemic patients had been treated with diuretics before admission compared with 22% of the normokalaemic group. Hypokalaemia on admission to hospital predicts an increased likelihood and early occurrence of ventricular fibrillation in patients with acute myocardial infarction.     

Extra-adrenergic mechanisms responsible for the effects of glucose-insulin-potassium solution on vulnerability to ventricular fibrillation

In 53 chloralose-anesthetized dogs, the actions of glucose (10 mg/kg per min), insulin (0.025 U/kg per min) and potassium (0.025 mEq/kg per min) on the ventricular fibrillation and repetitive extrasystole thresholds were examined. Measurements were initially made in the control state and then repeated at 30, 60 and 120 minutes of infusion of glucose-insulin-potassium solution at a constant rate of 1.23 ml/min. The dogs received on the average 36 g of glucose, 44 U of insulin and 44 mEq of potassium over a 2 hour period. In the nonischemic myocardium, the infusion raised the threshold for ventricular fibrillation and repetitive extrasystole to a peak of 94 and 61 percent, respectively, without significantly changing serum potassium or circulating catecholamine concentration. In the ischemic myocardium, the incidence of spontaneous ventricular fibrillation during 10 minutes of coronary occlusion was reduced from 83 percent in the control state to 17 percent with glucose-insulin-potassium infusion. However, the infusion did not alter the incidence of ventricular fibrillation associated with reperfusion.Because cardio-cardiac sympathetic reflexes are elicited in response to coronary occlusion, the effect of glucose-insulin-potassium infusion on ventricular vulnerability during left stellate ganglion stimulation and norepinephrine infusion was investigated. The infusion completely prevented the reduction in the vulnerable period threshold during stellate stimulation and norepinephrine infusion. Furthermore, the peak protection afforded by the infusion was greater than that achieved with beta adrenergic blockade and was still present in catecholamine-depleted hearts.It is concluded that infusion of glucose-insulin-potassium solution protects against ventricular fibrillation in the normal and ischemic canine heart but not during reperfusion. This protection may be due in part to antagonism of adrenergic activity; however, the primary influence of the solution is mediated by extra-adrenergic mechanism.     

Hypokalaemia and ventricular fibrillation in acute myocardial infarction.

Serum potassium concentrations obtained on admission to hospital were inversely related to the incidence of ventricular fibrillation in 289 women and 785 men with acute myocardial infarction, 92 of whom developed ventricular fibrillation. Hypokalaemia (serum potassium concentration less than or equal to 3.5 mmol/l) was found in 122 patients (11.4%). The incidence of ventricular fibrillation was significantly greater in patients with hypokalaemia compared with those classified as normokalaemic (serum potassium concentration greater than or equal to 3.6 mmol/l) (17.2% v 7.4%). The increased risk of ventricular fibrillation in the hypokalaemic group was about the same for women and men. While they were in hospital patients with hypokalaemia developed ventricular fibrillation significantly earlier than did normokalaemic patients (median 0.3 hours v 7 hours). Hypokalaemia was more common in women (17.3%) than in men (9.2%), and 55% of the hypokalaemic patients had been treated with diuretics before admission compared with 22% of the normokalaemic group. Hypokalaemia on admission to hospital predicts an increased likelihood and early occurrence of ventricular fibrillation in patients with acute myocardial infarction.     

Cardiovascular reflexes mediated by capsaicin sensitive cardiac afferent neurones in the dog

Reflex circulatory changes mediated by capsaicin sensitive cardiac afferent neurones were studied in anaesthetised, open chest dogs. Application of capsaicin to the epicardium of the left ventricle, either in single doses (0.01-100 micrograms) or by superfusion (20 micrograms X min-1), consistently resulted in dose related increases in blood pressure and heart rate. These responses were not affected by bilateral vagotomy but were abolished or reversed by bilateral sectioning of the upper thoracic (T1-T4) white rami communicantes and stellectomy. Injection of capsaicin (0.3-1 microgram X kg-1) into the left circumflex coronary artery caused either systemic hypotension and bradycardia (70.3% of experiments), a pressor response associated with tachycardia (13.5%), or a biphasic effect with an initial rise and then fall in blood pressure and heart rate (16.2%). With intravenous injections of capsaicin (3-5 micrograms X kg-1) the response was invariably cardioinhibitory and depressor. The reflex bradycardia and hypotension evoked with either intracoronary or intravenous injections of capsaicin were reversed after bilateral vagotomy to increases in cardiac rate and blood pressure. The post-vagotomy tachycardia occurring with intracoronary capsaicin could be abolished by beta adrenoceptor blockade with propranolol (0.5 mg X kg-1 iv), whereas ganglionic transmission blockade with pentolinium (0.5 mg X kg-1 iv) eliminated both the tachycardia and pressor effects. The results indicate that in the dog's heart capsaicin sensitive afferent neurones capable of affecting the circulatory system have both vagal and spinal sympathetic origin. It is suggested that capsaicin induced excitatory cardiogenic reflex is nociceptive in nature and may involve activation of substance P containing afferent fibres incorporated in cardiac sympathetic nerves.     

Effect of hypokalemia on susceptibility to ventricular fibrillation in the normal and ischemic canine heart

To examine the impact of hypokalemia on cardiac electrical stability, the thresholds for repetitive extrasystole and ventricular fibrillation were determined before and after potassium depletion in 15 chloralose-anesthetized dogs. A reduction in serum potassium concentration from 3.6 to 2.1 mEq/L induced by hemodialysis decreased the repetitive extrasystole threshold by 30% and the ventricular fibrillation threshold by 25% (p less than 0.01). The increase in ventricular vulnerability following acute coronary occlusion was markedly augmented by concomitant potassium depletion. Thus, hypokalemia enhances the propensity for ventricular fibrillation in the normal as well as in the ischemic canine heart. These findings shed light on clinical observations of enhanced susceptibility to life-threatening arrhythmias during acute myocardial ischemia in hypokalemic patients.     

Comparative effects of the opioids fentanyl and buprenorphine on ventricular vulnerability during acute coronary artery occlusion

Fentanyl, a mu selective opioid agonist in wide clinical use, raises the ventricular fibrillation threshold in the normal canine myocardium. We have previously shown that this effect is amplified by haemorrhagic stress. In order to determine if mu receptor activation is antifibrillatory during acute myocardial ischaemia, we compared the effects of two mu selective agents, fentanyl and buprenorphine, in open chest chloralose anaesthetised dogs. Each drug was administered intravenously in two doses 1 h apart (fentanyl 30 micrograms.kg-1.dose; buprenorphine 0.3 mg.kg-1.dose). Ventricular fibrillation threshold was measured during right ventricular pacing using the single stimulus technique. The threshold was determined before and during a 10 min left anterior descending coronary artery occlusion. Prior to fentanyl administration, ventricular fibrillation threshold decreased from a control value of 19(SEM 2) mA to 12(1) mA during coronary artery occlusion. After the first dose of this drug an attenuation in the ischaemia induced fall in fibrillation threshold from 23(4) mA to 15(2) mA was observed. After the second dose of fentanyl the decline in fibrillation threshold was significantly blunted at 22(4) mA during control and 18(3) mA during occlusion, p less than 0.05 compared to no drug. In an additional series of experiments atropine sulphate abolished the antifibrillatory action of fentanyl, indicating that vagal efferent activation is responsible for the protective effect of the drug during acute myocardial ischaemia. This is in contrast with its mode of action during haemorrhage, when it enhances vagal afferent inhibition of sympathetic tone, and atropine pretreatment is without effect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adrenaline inhibits adenosine diphosphate induced intravascular aggregation of rat platelets through stimulation of alpha 2 adrenoceptors.

STUDY OBJECTIVE--The aim was to determine the receptors involved in the antiaggregatory effects of adrenaline in the rat. DESIGN--The 111indium oxine technique was used to evaluate ADP induced pulmonary accumulation of 111In labelled platelets in adrenalectomised rats (ie, no endogenous adrenaline) in the absence of anticoagulants. Adrenaline was infused (10, 20 and 40 micrograms.kg-1.h-1) and ADP aggregation measured. Adrenoceptor agonists, isoprenaline, methoxamine, and BHT 933, were given to evaluate whether they mimic the adrenaline effects. Adrenoceptor antagonists, yohimbine, propranolol, prazosin, and WY 26392, were given to assess whether they block the adrenaline effects. MEASUREMENTS AND MAIN RESULTS--In all cases, pulmonary accumulation of platelets was measured in response to ADP. Adrenaline dose dependently inhibited platelet aggregation. BHT 933 (1.5 micrograms.kg-1.min-1) mimicked, while phentolamine (1 mg.kg-1), yohimbine (2.5 mg.kg-1), and WY 26392 (0.1, 1.0, 5.0 mg.kg-1) blocked, the adrenaline effects. Methoxamine (3.3 micrograms.kg-1.min-1) produced a relatively weak non-specific inhibition of ADP aggregation. Isoprenaline (33 ng.kg-1.min-1) did not mimic the effects of adrenaline, neither did propranolol (1 mg.kg-1) affect the adrenaline inhibition of the aggregatory responses to ADP. Indomethacin (3 mg.kg-1) blocked the inhibitory effects of adrenaline. CONCLUSIONS--Adrenaline stimulates alpha receptors on platelets but inhibits platelet aggregation. There is no evidence to suggest that beta receptors participated in the effects produced by adrenaline. There is a role for cyclo-oxygenase products in the inhibitory effects of adrenaline on aggregation.     

Relationship between sympathetic neural activity, coronary dynamics, and vulnerability to ventricular fibrillation during myocardial ischemia and reperfusion

The relationship between neural sympathetic discharge and vulnerability to ventricular fibrillation during myocardial ischemia and reperfusion was studied in 26 chloralose-anesthetized dogs. Preganglionic cardiac sympathetic impulse activity and ventricular fibrillation thresholds were separately determined before and during a 10-minute period of left anterior descending coronary artery occlusion and during release-reperfusion. Within 2 minutes of occlusion the ventricular fibrillation threshold was significantly decreased (from 25 +/- 1.3 to 16 +/- 2.3 mA, p less than 0.05) corresponding with the period of maximal activation of cardiac sympathetic preganglionic fibers (from 4.4 +/- 0.2 to 6.3 +/- 0.5 impulses/sec). Coronary sinus blood flow and oxygen tension decreased significantly. All these changes persisted for 5 to 6 minutes, thereafter returning to control levels despite continued obstruction of the coronary artery. A transient but significant reduction in ventricular fibrillation threshold also occurred with release of the occlusion but was unaccompanied by increases in sympathetic neural discharge. Bilateral stellectomy completely prevented the ventricular fibrillation threshold changes observed during coronary artery occlusion. However, there was no change in coronary sinus oxygen tension or blood flow. During reperfusion, stellectomy increased rather than decreased vulnerability to ventricular fibrillation. Stellectomy augmented the reactive hyperemic response to release-reperfusion. These findings indicate that enhanced cardiac sympathetic neural activity contributes to ventricular vulnerability associated with coronary artery obstruction. An opposite action results during release-reperfusion. Cardiac sympathetic neural discharge, by reducing the magnitude of reactive hyperemic response through influence on coronary vascular tone, exerts an antifibrillatory effect.     

Endoanaesthesia of left ventricular mechanoreceptors by steady state infusion of lignocaine and the influence of dopamine

We recorded the afferent activity of 11 left ventricular mechanoreceptors in filaments of the vagus nerve in 10 chloralose-anaesthetised cats. The fibres showed low irregular spontaneous activity of 2.9 (0.2 to 8.4) spikes X s-1. During temporary occlusion of the left anterior descending or left main coronary artery they were activated to 19.1 (4.8 to 47.0) spikes X s-1. Intravenous infusion of 0.175 and 0.35 mg X kg-1 X min-1 lignocaine lowered heart rate and blood pressure. The spontaneous nerve fibre activity remained unchanged by the local anaesthetic, whereas the maximum activity evoked by coronary artery occlusion was reduced to 14.7 (2.6 to 34.1) and 10.9 (2.4 to 27.6) spikes X s-1. An additional infusion of 5 and 10 micrograms X kg-1 X min-1 dopamine during continued application of 0.35 mg X kg-1 X min lignocaine raised heart rate and blood pressure to control values but had only minimal effects on the response of the fibres to coronary occlusion. It is concluded that lignocaine exerts a specific endoanaesthetic effect on the left ventricular mechanoreceptors, which is not mediated by its negative inotropic side effect.     

Influence of propranolol isomers and atenolol on myocardial cyclic AMP, high energy phosphates and vulnerability to fibrillation after coronary artery ligation in the isolated rat heart

The isolated rat heart with ligation of the left coronary artery was used to assess the role of the beta 1- adrenergic receptor-cyclic AMP mechanism in the genesis of vulnerability to ventricular fibrillation in early myocardial ischaemia. Coronary artery ligation was followed after 3 min by a reduction in ventricular fibrillation threshold which reached a minimum at 15 min. This was accompanied by reduction of ATP and phosphocreatine while cyclic AMP was significantly increased in ischaemic myocardium. The dl-, l- and d-isomers of propranolol attenuated the decrease in ventricular fibrillation threshold and the increase in ischaemic myocardial cyclic AMP, without altering the tissue depletion of ATP. Specific beta 1-adrenergic receptor antagonism with atenolol did not prevent either the increase of tissue cyclic AMP or the reduction in ventricular fibrillation threshold and high energy phosphates. These findings suggest that the mechanism whereby vulnerability to fibrillation is increased in very early myocardial ischaemia is linked to changes in cyclic AMP content of ischaemic myocardium and appears independent of depletion of myocardial high energy phosphates.     

Cardiac arrhythmias following acute myocardial infarction: Associations with the serum potassium level and prior diuretic therapy

The relationship between the initial serum potassium level andthe incidence of cardiac arrhythmias following myocardial infarctionhas been reviewed in a coronary care unit setting. The incidenceof arrhythmias in general, and ventricular fibrillation, ventriculartachycardia and frequent ventricular eclopic beats in particular,were inversely related to the initial serum potassium level.Hyperkalaemia was also significantly associated with ventricularfibrillation and ventricular tachycardia. Hypokalaemia was significantlymore common in patients previously treated with diuretics, thoughmost patients with hypokalaemia had not been so treated. Theoccurrence of an acute hypokalaemic syndrome, independent of,but exacerbated by, diuretic therapy, is further supported bythese results.     

Sotalol-induced torsades de pointe in the conscious dog with atrioventricular block. Role of hypokalemia

Sotalol is a beta-blocking agent endowed with class III electrophysiological properties. It has proved clinically effective in the treatment of arrhythmia, but episodes of torsades de pointe have been observed, particularly (though not exclusively) in the presence of hypokalaemia. The effect of sotalol with or without hypokalaemia was studied on a recently developed model for experimental torsades de pointe. Conscious dogs with complete atrioventricular block (ventricular cycle RR = 1530 +/- 170 ms) and provided with permanent atrial and ventricular epicardial electrodes were given sotalol intravenously either as a 4.5 mg/kg bolus injection or as a 1.5 mg/kg/h infusion. Group I dogs (n = 8) had normal blood potassium levels (4.3 +/- 0.1 mEq/1); following sotalol (plasma concentration 3.7 +/- 0.2 micrograms/ml) the ventricular rhythm was electrically driven to 25/min (RR = 240 ms) and QT was increased by 68 +/- 11 ms; torsades de pointe occurred in 5/8 animals (62 p. 100). Group II dogs (n = 6) had diuretic-induced hypokalaemia (2.6 +/- 0.1 mEq/1); following sotalol (plasma concentrations 3.8 +/- 0.3 micrograms/ml) the ventricular rhythm also depended on an external pacemaker to reach 25/min (in all but 1 dog) and QT increased by 46 +/- 11 ms; torsades de pointes were obtained in 5/6 animals (83 p. 100). These torsades de pointe were prevented in every case by rapid ventricular pacing (100-120/min). Thus, the pro-arrhythmic effects of sotalol were very frequent on this experimental model, but hypokalaemia was not necessary for torsades de pointe to occur.(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin and beta adrenergic effects during endotoxin shock: in vivo myocardial interactions

STUDY OBJECTIVE - Catecholamine concentrations are raised during endotoxin shock and may be responsible for myocardial insulin resistance in such a condition. The purpose of the investigation was to examine the effect of insulin on myocardial contractility and glucose uptake in the presence of beta adrenergic blockade during endotoxin shock. DESIGN - Endotoxin shock was obtained in dogs by giving S Typhimurium endotoxin intravenously (1 mg.kg-1) and the cardiac responses to insulin were determined under hyperinsulinaemic (4 U.min-1) euglycaemic clamp conditions during continuous beta adrenergic blockade (propranolol 150 micrograms.kg-1 + 5 micrograms.kg-1.min-1). SUBJECTS - 19 mongrel dogs of either sex, weight 20-25 kg, were studied under pentobarbitone anaesthesia. Seven dogs received endotoxin plus propranolol, and seven others received propranolol alone (control group). Five dogs received endotoxin but no propranolol or insulin. All other procedures were the same in each group. MEASUREMENTS and RESULTS - The exposed heart was prepared for coronary sinus blood sampling and measurements of circumflex artery blood flow (Q), instantaneous left ventricular pressure, and left ventricular wall thickness. Glucose uptake was calculated from product of Q and aortic-coronary sinus concentration difference. End systolic pressure-dimension relationship was used to assess contractility. Myocardial performance was assessed from left ventricular dP/dtmax. Basal shock measurements were made 60 min post endotoxin. beta Adrenergic blockade did not interfere with insulin stimulated glucose uptake in controls, but was unable to restore the uptake response during endotoxin shock. Contractility was increased during endotoxin shock and this effect was abolished by beta adrenergic blockade. In controls the only variable affected by beta adrenergic blockade was left ventricular dP/dtmax (decreased). Insulin increased contractility during beta adrenergic blockade in controls but not in shock. Myocardial performance was depressed during shock. In controls, insulin increased myocardial performance; in shock this response was attenuated. CONCLUSIONS - The findings confirm that the myocardium becomes less responsive to the glucose uptake stimulating and positive inotropic effects of insulin during endotoxin shock. The data show that beta adrenergic activity is responsible for the increased contractile state of the heart during acute endotoxin shock, but is not the cause of the observed insulin resistant state.