Effect of bosentan (ETA/ETB receptor antagonist) on metabolic changes during stress and diabetes.

Elevated plasma ET-1 levels have been reported in several conditions such as stress and diabetes. ET-1 is found to cause insulin resistance and to stimulate liver glycogenolysis. The question arises whether ET-1 has a role in the metabolic changes occurring in such conditions. To test this, we studied the possible effect of the endothelin receptor antagonist, bosentan (50 and 100 mg kg(-1)) on serum glucose and insulin levels as well as on liver glycogen contents in normoglycemic stressed animals. In addition, the effect of bosentan on serum glucose and insulin levels in both mild and severely diabetic rats and its effect on insulin-induced hypoglycemia were also determined. Restraining water immersion stress was used as a model for severe stress reported to elevate plasma ET-1 level. Mild diabetes was induced in rats by intraperitoneal injection of a low dose of streptozotocin (38 mg kg(-1)) while severe diabetes was induced by intraperitoneal injection of a higher dose of streptozotocin (45 mg kg(-1)). Bosentan partially prevented stress-induced both hyperglycemia and decrease in glycogen content while it completely blocked the stress-induced decrease in insulin level in normoglycemic stressed rats. Bosentan also decreased serum glucose level without any effect on insulin secretion in mild diabetic rats and potentiated the hypoglycemic action of insulin.