Effect of ICI 66082, a beta-adrenoceptor blocking drug on blood glucose in the rat
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Abstract:
ICI 66082, a cardioselective beta-adrenoceptor blocking agent, was found to produce hypoglycaemia in fasted rats. In fed rats a hyperglycaemic response was observed. The drug produced hypoglycaemia in fed adrenalectomised animals. The hypoglycaemic response to ICI 66082 was accompanied by elevations in plasma immunoreactive insulin (IRI) concentrations. The drug also reduced plasma glucose and increased IRI in moderately alloxan-diabetic rats. In severely diabetic animals The drug did not increase IRI concentrations and did not unequivocally lower plasma glucose concentrations. In vitro experiments showed ICI 66082 to increase glucose uptake by rat diaphragm muscle and epididymal adipose tissue. the hypoglycaemic response may be mediated by increases in plasms IRI concentrations with a possible contribution from direct effects of the drug on peripheral glucose utilization. As these responses differ from those published in relation to other beta-adrenoceptor blocking drugs it is unlikely that the effects are due to beta-adrenoceptor blockade. However, like other beta-adrenoceptor blocking drugs ICI 66082 reduced isoprenaline-mediated increase in plasma IRI.
Insights
ICI 66082, a beta-blocker, causes hypoglycemia in fasted rats by increasing insulin and glucose uptake. This effect may involve direct actions on glucose utilization, distinct from typical beta-adrenoceptor blockade.
Area of Science:
- Pharmacology
- Endocrinology
- Metabolic Research
Background:
- Cardioselective beta-adrenoceptor blocking agents are used clinically.
- The metabolic effects of beta-blockers, particularly on glucose homeostasis, can vary.
- Understanding the specific mechanisms of novel beta-blockers is crucial for their therapeutic application.
Purpose of the Study:
- To investigate the metabolic effects of ICI 66082, a cardioselective beta-adrenoceptor blocking agent, on glucose regulation in rats.
- To elucidate the potential mechanisms underlying the observed effects of ICI 66082 on plasma glucose and insulin levels.
Main Methods:
- Administration of ICI 66082 to fasted and fed rats, including adrenalectomized and alloxan-diabetic models.
- Measurement of plasma glucose and immunoreactive insulin (IRI) concentrations.
- In vitro assessment of glucose uptake in isolated rat tissues (diaphragm muscle and adipose tissue).
Main Results:
- ICI 66082 induced hypoglycemia in fasted rats and fed adrenalectomized rats, but hyperglycemia in fed rats.
- Hypoglycemia was associated with increased plasma IRI concentrations in non-diabetic and moderately diabetic rats.
- The drug enhanced glucose uptake in vitro and reduced isoprenaline-mediated IRI increase, suggesting complex effects beyond beta-adrenoceptor blockade.
Conclusions:
- ICI 66082 exhibits complex effects on glucose homeostasis, potentially mediated by increased insulin secretion and direct enhancement of peripheral glucose utilization.
- The observed metabolic profile of ICI 66082 appears distinct from other beta-adrenoceptor blocking drugs, suggesting its effects are not solely due to beta-adrenoceptor blockade.
- Further research is warranted to fully characterize the therapeutic potential and safety of ICI 66082 regarding glucose metabolism.