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pathway in aortas from diabetic rats with systemic hyperinsulinemia
1 Physiology and Morphology, Hoshi University, Tokyo, 142-8501, Japan
* To whom correspondence should be addressed. E-mail: kamata{at}hoshi.ac.jp.
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 p110
-associated phosphatidylinositol 3-kinase activity and p110
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 p110
subunit-associated phosphatidylinositol 3-kinase activity.
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