Effect of CGP 17/582, a selective beta-adrenoceptor antagonist, on the haemodynamic and hypokalaemic response to adrenaline.

1. CGP 17/582B is a new beta-adrenoceptor antagonist which on experimental studies appears to combine selective beta 1-adrenoceptor blockade with partial agonist activity (ISA). Assessing beta-adrenoceptor selectivity and the degree of partial agonist activity in vivo can be difficult. 2. In a double-blind placebo controlled crossover study we have compared the effect of oral pretreatment for 7 days with CGP (100 mg twice daily), with propranolol (non-selective beta-adrenoceptor blocker with no ISA) and metoprolol (selective beta-adrenoceptor blocker with no ISA) on resting heart rate and heart rate response to submaximal exercise on a bicycle ergometer to assess the degree of beta-adrenoceptor blockade and also the changes in blood pressure, heart rate and potassium during the intravenous infusion of (-)-adrenaline to determine the degree of beta 2-adrenoceptor blockade. 3. Subjects underwent submaximal exercise testing on the second and fifth day of each treatment period and on the seventh day received a 2 h infusion of (-)-adrenaline (0.06 microgram kg-1 min-1). Heart rate, blood pressure, plasma potassium and catecholamines were measured throughout the study period. 4. All three active treatments significantly reduced exercise induced tachycardia. The (-)-adrenaline infusion significantly reduced plasma noradrenaline levels following propranolol and metoprolol and to a lesser extent with placebo but were unaltered on CGP. Baseline heart rate was unaltered by CGP but was significantly reduced by metoprolol and propranolol. Adrenaline significantly reduced plasma potassium levels following placebo and CGP pretreatment but plasma potassium was unaltered by adrenaline with metoprolol and propranolol pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Salbutamol induced hypokalaemia: the effect of theophylline alone and in combination with adrenaline.

1. We have previously shown that salbutamol induced hypokalaemia, like adrenaline induced hypokalaemia, is the result of stimulation of a membrane bound beta 2-adrenoreceptor linked to Na+/K+ ATPase. We have also demonstrated that adrenaline induced hypokalaemia is potentiated by therapeutic concentrations of theophylline. 2. In a single-blind study of 14 normal volunteers, we infused salbutamol in doses used in clinical practice and examined the effects of the addition of theophylline alone or combined with (-)-adrenaline on plasma potassium levels, heart rate and blood pressure. The combinations studied were (i) salbutamol + vehicle control adrenaline infusion + placebo theophylline; (ii) salbutamol + vehicle control adrenaline infusion + theophylline; (iii) salbutamol + adrenaline + theophylline. 3. In a randomised, balanced placebo controlled design oral slow release theophylline or placebo was given for 9 days. Subjects were studied twice on the active limb (days 7 and 9) and once on the placebo limb (day 9) and the procedure was identical on each of the 3 study days except for the solutions administered. 4. Theophylline increased salbutamol induced hypokalaemia and in some individuals profound hypokalaemia (less than 2.5 mmol l-1) was observed with these relatively low doses of salbutamol and theophylline. Adrenaline did not further increase the magnitude of the fall in potassium observed. Combining theophylline with salbutamol increased the tachycardia resulting from the salbutamol infusion. Salbutamol infusion caused a fall in diastolic and rise in systolic blood pressure on all 3 study days and this was not altered by either theophylline or adrenaline alone or together.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of diuretic therapy on adrenaline-induced hypokalaemia and hypomagnesaemia.

We have examined the interaction between the administration of bendrofluazide, frusemide, spironolactone, and placebo and increased plasma adrenaline concentrations in a double-blind, placebo-controlled, cross over study. We studied healthy subjects on the fourteenth day of each treatment period and after a two hour infusion of adrenaline (0.06 micrograms.kg-1.min-1 [0.33 nmol.kg-1.min-1]) we measured their heart rates, blood pressures, and plasma potassium and magnesium concentrations. There were no differences in heart rates or blood pressures for all four treatments. Baseline potassium concentrations were not significantly different compared to placebo, and plasma potassium fell during the period of the infusion on all study days. this fall was significantly greater on frusemide (0.5 mmol.l-1) and bendrofluazide (0.4 mmol.l-1) compared with both placebo and spironolactone. Baseline plasma magnesium concentration were not different and similar falls in plasma magnesium were seen on all four treatments during and after the adrenaline infusion. We conclude that chronic diuretic therapy with a thiazide diuretic or frusemide may increase the severity of hypokalaemia during short-term rises in plasma adrenaline. Pretreatment with spironolactone had no effect on adrenaline-induced hypokalaemia. None of the diuretics studied altered adrenaline-induced hypomagnesaemia.

Failure of chronic theophylline therapy to alter circulating catecholamines.

An increase in circulating adrenaline and noradrenaline has been reported following acute dosing with theophyllines. This effect on catecholamines has been proposed as a possible mechanism of action of theophyllines. In a double-blind placebo controlled trial we have studied the effects of 5 days oral theophylline therapy on circulating catecholamines and adrenaline clearance. There were no significant changes in circulating catecholamines or adrenaline clearance following theophylline. We also examined the effects of theophylline on the hypokalaemic and haemodynamic actions of adrenaline. Theophylline increased the hypokalaemia, tachycardia and rise in systolic blood pressure which occurs in response to intravenous infusion of doses of L-adrenaline (0.02-0.06 microgram kg-1 min-1). Our results suggest that chronic theophylline therapy does not significantly increase circulating catecholamines. Increased circulating catecholamine concentrations are thus not an explanation for the chronic actions of theophylline. We have demonstrated significant, potentially hazardous metabolic and haemodynamic interactions between theophylline and adrenaline.

Adrenergic control of plasma magnesium in man.

Regulation of magnesium balance is poorly understood. However, hypomagnesaemia has been reported in patients in clinical situations where circulating catecholamines are raised including myocardial infarction, cardiac surgery and insulin-induced hypoglycaemia stress tests. The effects of L-adrenaline infusions, sufficient to achieve pathophysiological levels of adrenaline, and of therapeutic intravenous infusions of salbutamol, a beta 2-agonist, on plasma magnesium, plasma potassium, plasma glucose and plasma insulin levels were studied in a placebo-controlled design in eight normal subjects. Plasma magnesium levels fell significantly during the adrenaline infusion and also during the salbutamol infusion, though more slowly. In a 1 h period of observation after cessation of the infusions no recovery of plasma magnesium levels was seen. Significant falls in plasma potassium levels were also observed during both infusions with spontaneous recovery within 30 min after the infusions. No significant changes in plasma insulin levels occurred with either salbutamol or L-adrenaline compared with control. Plasma glucose levels rose significantly during the adrenaline infusion. The study suggests that both L-adrenaline and salbutamol cause shifts in plasma magnesium which are not mediated by insulin. We propose that intracellular shifts of magnesium occur as a result of beta-adrenergic stimulation.

The mechanism of salbutamol-induced hypokalaemia.

The following four intravenous treatments were administered in a balanced, randomized Latin square design to eight healthy volunteers: (-)-adrenaline (0.06 microgram kg-1 min-1 for 90 min) + vehicle control (+)-glucose infusion (60 min), salbutamol (120 ng kg-1 min-1 for 30 min) + vehicle control (+)-glucose infusion (90 min), (-)-adrenaline (0.06 microgram kg-1 min-1 for 90 min) + salbutamol (120 ng kg-1 min-1 for 30 min) and two vehicle control infusions of (+)-glucose. All active solutions were preceded by a 1 h control infusion and the control infusion was continued for 1 h following the active solutions. Both the active solutions, (-)-adrenaline and salbutamol were increased stepwise to the above doses. Heart rate and blood pressure were recorded at frequent intervals throughout and venous blood was taken for the estimation of potassium, insulin, glucose, catecholamine and salbutamol levels. Adrenaline levels similar to those seen in acute illness were achieved using this infusion protocol. Salbutamol levels rose throughout the period of the salbutamol infusions and steady-state was not achieved. Potassium levels were unchanged on the control + control study day and fell on all active treatments (0.45 mmol l-1 following (-)-adrenaline + control; 0.48 mmol l-1 following salbutamol + control; 0.93 mmol l-1 following (-)-adrenaline + salbutamol). Insulin levels rose insignificantly after salbutamol alone and fell slightly on all other treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

The effects of cardioselective and non-selective beta-adrenoceptor blockade on the hypokalaemic and cardiovascular responses to adrenomedullary hormones in man.

Adrenaline was infused intravenously in nine normal volunteers to plasma concentrations similar to those found after myocardial infarction. This study was undertaken on three occasions after 5 days' treatment with placebo or the beta-adrenoceptor antagonists, atenolol or timolol. Adrenaline increased the systolic pressure by 11 mmHg, decreased the diastolic pressure by 14 mmHg, and increased the heart rate by 7 beats/min. These changes were prevented by atenolol. However, after timolol the diastolic pressure rose (+19 mmHg) and heart rate fell (-8 beats/min). Adrenaline caused the corrected QT interval (QTc) to lengthen (0.36 +/- 0.02 s to 0.41 +/- 0.06 s). No significant changes were found in the QTc when subjects were pretreated with atenolol or timolol. The serum potassium fell from 4.06 to 3.22 mmol/l after adrenaline. Serum potassium fell to a lesser extent to 3.67 mmol/l after atenolol and actually increased to 4.25 mmol/l after timolol. Adrenaline-mediated hypokalaemia appears to result from the stimulation of a beta 2-adrenoceptor linked to membrane Na+/K+-ATPase causing potassium influx.

Prior thiazide diuretic treatment increases adrenaline-induced hypokalaemia.

Hypokalaemia is a common finding in acutely ill patients and may be related in part to increased sympathoadrenal activity. In an investigation to determine whether pretreatment with thiazide diuretics causes the serum potassium to fall to an even lower level during increased sympathoadrenal activity, adrenaline was infused into healthy subjects after pretreatment for 7 days with either bendrofluazide (5 mg) or placebo. Thiazide diuretic pretreatment had no effect on the adrenaline-induced changes in blood pressure and heart rate. However, not only was the baseline serum potassium lower after bendrofluazide (3 . 40 mmol/l vs 3 . 83 mmol/l) but the serum potassium also fell to a significantly lower level during adrenaline infusion after bendrofluazide (2 . 73 mmol/l vs 3 . 08 mmol/l). Transient profound hypokalaemia may increase the risk of ventricular arrhythmias in patients on diuretics, and routine monitoring of the resting serum potassium may underestimate this risk.

Effect of intravenous adrenaline on electrocardiogram, blood pressure, and serum potassium.

Increased catecholamines after myocardial infarction may contribute to the development of arrhythmias. We have infused adrenaline intravenously in nine normal volunteers to levels similar to those seen after myocardial infarction. Adrenaline caused an increase in systolic blood pressure, a decrease in diastolic blood pressure, and an increase in heart rate. Adrenaline also produced a decrease in T wave amplitude and an increase in the QTc interval. The serum potassium fell dramatically during the adrenaline infusion from a control value of 4.06 mmol/l to 3.22 mmol/l. Hypokalaemia after myocardial infarction is associated with an increased incidence of ventricular arrhythmias. Thus, circulating adrenaline may increase the frequency of arrhythmias both directly via changes in ventricular repolarisation and indirectly via adrenaline induced hypokalaemia.

Parotid salivary gland function in patients with exocrine pancreatic insufficiency.

Parotid function tests were performed on 12 patients with pancreatic insufficiency due to chronic pancreatitis. The concentrations of sodium and bicarbonate in stimulated parotid juice were reduced compared to controls (p less than 0.001). The secretion of 75Se-selenomethionine by the parotid salivary gland and exocrine pancreas following a Lundh test meal was measured in 12 patients with normal pancreatic function and 16 patients with exocrine pancreatic insufficiency. Eight of these patients had chronic pancreatitis both parotid and pancreatic secretion of the isotope were impaired. In pancreatic carcinoma the pancreatic excretion was impaired with no significant impairment of parotid secretion. The combined pancreatic/parotid radio-selenium test may be useful in differentiating between chronic pancreatitis and pancreatic carcinoma as the cause of pancreatic insufficiency.