Cyp‐epoxygenases mediate adenosine A2A receptor induced vascular relaxation via KATP channels

Abstract

A2A adenosine receptor (AR) causes aortic relaxation through generation of epoxyeicosatrienoic acids (EETs) formed via Cyp‐epoxygenases (Nayeem et al, AJP 2008). We hypothesize that A2AAR‐mediated aortic relaxation occurs via EETs through opening of KATP channels in smooth muscle cells. Organ bath experiments were done with isolated aortas from A2AKO and wild type (WT) mice. Pinacidil (KATP opener; 10−6M) caused higher relaxation in WT aorta compared to A2AKO (48.09±5.23% vs. 25.41±2.37%; p<0.05). Cyp‐epoxygenase inhibitor MSPPOH (10−5M) caused significant decrease (p<0.05) in pinacidil response in WT (48.09±5.23% vs. 24.93±5.34%) and A2AKO (25.41±2.37% vs. 14.66±3.88%) aorta. Adenosine analog NECA (10−5M) caused significant relaxation in WT aorta (19.65±3.25%) compared to contraction (13.94±6.57%) in A2AKO, that was lowered by KATP blocker glibenclamide in WT (0.17±6.43%) while higher contraction was observed in KO (28.47±5.1%). Relaxation to A2A agonist CGS 21680 (10−6M) in WT (19.02±2.75%) changed to contraction (23.66±6.31%; p<0.05) with glibenclamide. Mitochondrial KATP opener diazoxide had no effect on precontracted tissues, while 5‐HD (mitochondrial KATP blocker, 100uM) had no effect on CGS 21680 response in WT and A2AKO aorta. These data suggest adenosine mediated aortic relaxation occurs via generation of EETs through sarcolemmal KATP channels. (HL027339, HL09444, HL07180)