Angiotensin II enhances contractile responses via PI3-kinase p110δ pathway in aortas from diabetic rats with systemic hyperinsulinemia

We investigated the involvement of angiotensin II and phosphatidylinositol 3-kinase in the enhanced aortic contractile responses induced by the hyperinsulinemia present in chronic insulin-treated type 1 diabetic rats. Plasma angiotensin II levels were elevated in untreated diabetic rats (versus controls), and further increased in insulin-treated diabetics. Aortic contractile responses and systolic blood pressure were each significantly enhanced in chronic insulin-treated diabetics (versus the other groups). These insulin-induced enhancements were largely prevented by co-treatment with either losartan (an angiotensin II type1 receptor antagonist) or enalapril [an angiotensin–converting enzyme (ACE) inhibitor]. Incubating the tissue with LY294002 (phosphatidylinositol 3-kinase inhibitor) diminished the enhancements of contractile responses seen in both angiotensin II-incubated aortas and aortas from chronic insulin-treated diabetic rats. The norepinephrine-stimulated levels of p110δ-associated phosphatidylinositol 3-kinase activity and p110δ protein expression were each increased in aortas from insulin-treated diabetics (versus control and untreated diabetics), and chronic administration of losartan blunted these increases. In diabetic aortas incubated with a low concentration (inducing ~10% of the maximum contraction) of angiotensin II, or with either norepinephrine or isotonic K, contractions were significantly larger than in non-incubated diabetic aortas. Norepinephrine-stimulated p110 phosphatidylinositol 3-kinase activity was elevated in diabetic aortas co-incubated with a non-contractile dose of angiotensin II. These results suggest that in insulin-treated type 1 diabetic rats with hyperinsulinemia, chronic angiotensin II type1 receptor blockade blunts the increases in both vascular contractility and blood pressure via a decrease in p110δ subunit-associated phosphatidylinositol 3-kinase activity.