Augmented angiotensin II‐induced arteriolar constrictions in mice with type 2 diabetes mellitus ‐ role for cyclooxygenase‐2

Abstract

Inhibitors of the renin angiotensin system have beneficial vascular effects in diabetes mellitus. Thus we hypothesized that angiotensin II (Ang II) elicits augmented arteriolar constriction in mice with type 2 diabetes (db/db mice) is due to factor(s) produced by the increased activity and expression of cyclooxygenase‐2 (COX‐2). We found that isolated, pressurized gracilis arterioles of db/db mice exhibited enhanced constrictions to Ang II (10‐11‐10‐8 M) compared to controls (db/db max: 82±4%, control max: 59±2%, P<0.05). Constrictions to norepinephrine (NE) were similar in the two groups (db/db max: 68±4%, control max: 72±2 %). Inhibition of nitric oxide synthesis with L‐NAME did not affect Ang II‐ and NE‐induced constrictions in arterioles of control and db/db mice. In arterioles of db/db mice the enhanced constrictions to Ang II were reduced by the selective COX‐2 inhibitor, NS‐398 (max: 62±3%) or by the EP1 receptor antagonist, AH‐6809 (max: 57±4%) to the levels observed in control mice. Also, in gracilis muscle arterioles of db/db mice an increased COX‐2 protein expression was detected by immunohistochemistry. Thus, we propose that in type 2 diabetes there is an increased activity and expression of COX‐2, a mechanism by which Ang II stimulates the production of PGE2, which via activating EP1 receptors augments constrictions of arterioles to Ang II. (AHA 0855910D, 0735540T and NIH PO1‐HL‐43023)