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Interactions of doxazosin with insulin or glucagon in the ob/ob mouse
1Central Research Division, Pfizer Inc., Groton, Connecticut 06340.
Abstract:
Doxazosin, a selective inhibitor of alpha 1-adrenergic receptors, when administered alone or in combination with insulin or glucagon to mature ob/ob mice, consistently lowered levels of triglycerides, cholesterol, glycerol, and lactate and increased levels of beta-hydroxybutyrate and glucose. Doxazosin suppressed the tendency of insulin to elevate triglycerides but had no effect on the hypoglycemic response to insulin. Doxazosin and insulin together (but neither alone) lowered free fatty acids (FFA). Glucagon lowered cholesterol and raised glucose but did not affect triglycerides or beta-hydroxybutyrate. Analysis of variance indicates that a simple additive-effects model cannot explain the interactions between doxazosin and insulin on triglycerides, glucose, and FFA. It is suggested that the alpha 1-adrenergic system may contribute to glycemic control and to ambient hypercholesterolemia, especially in the presence of insulin resistance, as in ob/ob mice, and that the hypolipidemic response to alpha 1-adrenergic inhibition may involve insulin pathways.
Insights
Doxazosin, an alpha 1-adrenergic receptor inhibitor, impacts lipid and glucose metabolism in mice. It lowers triglycerides and cholesterol, suggesting a role in glycemic control and lipid regulation, especially with insulin resistance.
Area of Science:
- Pharmacology
- Endocrinology
- Metabolic Research
Background:
- Obese (ob/ob) mice exhibit insulin resistance and metabolic dysregulation.
- Alpha 1-adrenergic receptors play a role in various physiological processes, including cardiovascular and metabolic functions.
Purpose of the Study:
- To investigate the effects of doxazosin, a selective alpha 1-adrenergic receptor inhibitor, on lipid and glucose metabolism in ob/ob mice.
- To explore the interactions between doxazosin, insulin, and glucagon on metabolic parameters.
Main Methods:
- Administration of doxazosin alone or in combination with insulin or glucagon to mature ob/ob mice.
- Measurement of serum levels of triglycerides, cholesterol, glycerol, lactate, beta-hydroxybutyrate, glucose, and free fatty acids (FFA).
- Statistical analysis using analysis of variance to assess interactions between treatments.
Main Results:
- Doxazosin consistently lowered triglycerides, cholesterol, glycerol, and lactate, while increasing beta-hydroxybutyrate and glucose.
- Doxazosin modulated insulin's effect on triglycerides but not on hypoglycemia.
- Combined administration of doxazosin and insulin, but not alone, reduced FFA.
- Glucagon affected cholesterol and glucose but not triglycerides or beta-hydroxybutyrate.
- Interactions between doxazosin and insulin on triglycerides, glucose, and FFA could not be explained by simple additive effects.
Conclusions:
- The alpha 1-adrenergic system may contribute to glycemic control and hypercholesterolemia, particularly in insulin-resistant states like that seen in ob/ob mice.
- The hypolipidemic effects of alpha 1-adrenergic inhibition might involve insulin-dependent pathways.