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Angiotensin II stimulation alters vasomotor response to adenosine agonist in mesenteric artery: ole for A1 and A2B receptors (1140.4)

Angiotensin II (Ang II) is one of the major mediators that lead to the development of hypertension. However the signaling pathway that leads to hypertension are not well understood. Ang II activates several intermediate molecules which may alter localized signaling events to further regulate vascular tone that may contribute to the development of hypertension. Adenosine is the important metabolite which controls local blood flow through activation of four subtypes of adenosine receptors (ARs). Previously, we have reported that A1AR is the major determinant of contractions while A2B produces relaxation in mouse mesenteric arteries (MAs). In this study, we sought to investigate whether acute exposure to Ang II alters vasomotor responses to non‐selective AR agonist, NECA, in MAs. We used DMT myograph system for muscle tension measurement in isolated resistant MAs. We have found that acute exposure (15 min) to Ang II (10 nM) altered dose‐dependent vasodilatation to NECA producing significantly higher contractions (~37%) in MAs. Notably, these higher contractions were absent in MAs from A1 KO mice. Interestingly, we have also found that NECA induced relaxation in MAs from A1 KO mice were inhibited (~10%) after exposure to Ang II. Importantly, in MAs from WT mice, we have found that pre‐treatment with HET0016 (10 µM, 20HETE inhibitor) significantly inhibited Ang II and NECA‐induced contractions. In addition, in MAs from A2B KO mice, NECA produced contractions which were significantly higher after Ang II stimulation. These contractions were considerably inhibited by HET0016 and completely blocked by DPCPX (1 µM, A1 antagonist). Moreover, Ang II contractions were higher in MAs from A2B KO mice (p<0.05). Taken together, our data indicate that acute Ang II stimulation enhances A1 and reduces A2B‐dependent signaling in MAs. Thus, these altered A1 and A2B dependent signaling pathway may contribute to the development of hypertension.