Angiotensin II type 2 receptor-dependent increase in nitric oxide synthase activity in the endothelium of db/db mice is mediated via a MEK pathway

Angiotensin II type 2 receptor (AT2R) stimulation may cause vasodilation. It could thereby contribute to the antihypertensive effects of angiotensin II type 1 receptor (AT1R) antagonists since AT1R blockade reportedly increases endogenous levels of Ang II, and this may then bind to the unblocked AT2R. Because this is potentially an important consideration in diabetes, we examined whether or not AT2R mediates vasorelaxation in db/db diabetic mice. We also examined if AT2R-mediated vasorelaxation is preserved after long-term treatment with the AT1R antagonist losartan. The effects of AT2R stimulation, with either Ang II or the selective agonist CGP-42112A, were studied in aortas from db/db mice (a type 2 diabetic model). CGP-42112A induced a concentration-dependent relaxation in db/db aortas (not in Lean aortas), and this was significantly weakened by the MEK-inhibitor PD98059. CGP-42112A-induced relaxations were increased by Ang II-stimulation (by the organ-culture method) or by AT1R blockade (by long-term losartan treatment) only in Lean aortas. Basal AT2R expression, and Ang II-stimulated MEK and eNOS phosphorylations were all increased in aortas from db/db (vs. Lean) mice. Long-term losartan treatment increased Ang II-stimulated MEK and eNOS phosphorylations in aortas from Lean, but not db/db, mice. Therefore, this study has provided evidence that AT2R-mediated NO production and vasorelaxation through a MEK pathway are enhanced (under basal conditions) in aortas from db/db (vs. Lean) mice. The preservation of such AT2R function during AT1R blockade needs to be considered in the search for a physiological role for AT2R.

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