Keith N. Frayn

The role of catecholamines in the production of ischaemia-induced ventricular arrhythmias in the rat in vivo and in vitro.

1 The role of catecholamines in the production of ischaemia‐induced ventricular arrhythmias in vivo and in vitro was studied using coronary artery ligation in the rat. 2 Increases in plasma catecholamine concentrations during coronary artery ligation in pentobarbitone‐anaesthetized animals were prevented by either acute adrenalectomy or chronic adrenal demedullation, but these procedures did not protect against the occurrence of ventricular arrhythmias. Thus plasma catecholamines were not obligatory mediators of arrhythmogenesis. 3 Three protocols were used in vitro to evaluate the possible influence of intramyocardial release of noradrenaline, produced by the local conditions of ischaemia, on the production of ventricular arrhythmias. During coronary artery ligation in isolated perfused hearts, no enhanced output of 3H could be detected from [3H]‐noradrenaline loaded hearts, even in the presence of inhibitors of catecholamine uptake processes, although washout of lactate from ischaemic regions was readily demonstrable. 4 Both optical isomers of propranolol were equally effective in reducing the incidence of arrhythmias, implying a non‐specific effect, since the (+)‐isomer possesses considerably less β‐adrenoceptor blocking activity. The equipotency of optical isomers of propranolol combined with a lack of effect of atenolol suggested that arrhythmia production was not a consequence of β‐adrenoceptor stimulation. 5 The α‐adrenoceptor blockers phentolamine and prazosin, both exerted antiarrhythmic actions of similar potency, but phenoxybenzamine and trimazosin had no significant effects. An evaluation of the pharmacological properties of the α‐adrenoceptor blockers showed that those drugs which had demonstrable local anaesthetic properties also exerted significant antiarrhythmic effects. No relationship was found between potency of α‐adrenoceptor blockade and antiarrhythmic efficacy. 6 The overall conclusion from these multifaceted approaches was that catecholamines were not necessary mediators of the early phase of ventricular arrhythmias in the rat.

Hormonal and Metabolic Responses to Glucose Infusion in Sepsis Studied by the Hyperglycemic Glucose Clamp Technique

Although nutritional support is vital to treatment of severe sepsis, the septic patient does not respond normally to glucose infusion. We have used the hyperglycemic glucose clamp technique to investigate the initial hormonal and metabolic responses of the septic patient to glucose under controlled conditions. The plasma glucose concentration was raised to and maintained at 12 mmol/liter for 2 hr in 12 septic patients and 11 normal controls. Glucose utilization, assessed from the amount infused, was significantly depressed in the patients, despite similar plasma insulin concentrations in the two groups. Forearm glucose uptake was similarly impaired. Despite very similar plasma free fatty acid concentrations in the two groups, which were suppressed equally by the glucose infusion, whole-body fat oxidation was elevated in the patients compared with the controls, and suppressed to a lesser extent in response to glucose. Glycerol and ketone body concentrations were elevated in the patients in keeping with a picture of accelerated release, clearance, and oxidation of fatty acids. Plasma cortisol, epinephrine, and norepinephrine concentrations were elevated in the septic patients in a severity-related manner, but not to high levels compared with experimental work. Norepinephrine showed no response to the glucose infusion in either group. Plasma glucagon concentrations were not significantly elevated in the septic patients. We conclude that the hyperglycemic glucose clamp provides a useful model for studying glucose intolerance in sepsis. Impaired glucose utilization in septic patients is associated with increased fat oxidation, although the hormonal basis for these changes is still unclear.

The post-scald metabolic response in the growing rat: Evidence for a transient phase of muscle protein breakdown

Abstract Growing male rats were studied for 16 days following a full-thickness 30 per cent body surface area dorsal scald. Weight gain post scald was reduced despite normal food intake. Evaporative weight loss increased after the injury and remained elevated. Oxygen consumption also increased and was significantly correlated with evaporative loss in injured rats although not in controls. Plasma branched-chain amino acid concentrations and urinary Nr-methylhistidine excretion were increased over the first 72 h after injury, and were associated with net loss of muscle protein. Plasma branched-chain amino acids fell below control levels 5–7 days after scalding as muscle protein content increased. It was concluded that a 30 per cent scald in the growing rat leads to a transient ‘flow’ phase with net muscle protein breakdown, followed by a more prolonged period of hypermetabolism which is due largely to increased evaporative heat loss.