Adenosine kinase inhibition enhances microvascular dilator function and improves left ventricle diastolic dysfunction

• DOI: 10.1111/micc.12624
• Publication Date: 2020-04-30T19:08:26Z
• Authors: Alec Davila; Yanna Tian; Istvan Czikora; Amanda S. Weissman; Nicholas Weinand; Guangkuo Dong; Jiean Xu; Jie Li; Huabo Su; Gaston Kapuku; Yuqing Huo; Zsolt Bagi
• Keywords: Male; Mice, Knockout; 0301 basic medicine; 2. Zero hunger; Morpholines; Rats; Rats, Zucker; 3. Good health; Vasodilation; Mice; Ventricular Dysfunction, Left; 03 medical and health sciences; Pyrimidines; Diastole; Microvessels; Animals; Adenosine Kinase

AbstractObjectiveInhibition of adenosine kinase (ADK), via augmenting endogenous adenosine levels exerts cardiovascular protection. We tested the hypothesis that ADK inhibition improves microvascular dilator and left ventricle (LV) contractile function under metabolic or hemodynamic stress.Methods and ResultsIn Obese diabetic Zucker fatty/spontaneously hypertensive heart failure F1 hybrid rats, treatment with the selective ADK inhibitor, ABT‐702 (1.5 mg/kg, intraperitoneal injections for 8‐week) restored acetylcholine‐, sodium nitroprusside‐, and adenosine‐induced dilations in isolated coronary arterioles, an effect that was accompanied by normalized end‐diastolic pressure (in mm Hg, Lean: 3.4 ± 0.6, Obese: 17.6 ± 4.2, Obese + ABT: 6.6 ± 1.4) and LV relaxation constant, Tau (in ms, Lean: 6.9 ± 1.5, Obese: 13.9 ± 1.7, Obese + ABT: 6.0 ± 1.1). Mice with vascular endothelium selective ADK deletion (ADKVECKO) exhibited an enhanced dilation to acetylcholine in isolated gracilis muscle (lgEC50 WT: −8.2 ± 0.1, ADKVECKO: −8.8 ± 0.1, P < .05) and mesenteric arterioles (lgEC50 WT: −7.4 ± 0.2, ADKVECKO: −8.1 ± 1.2, P < .05) when compared to wild‐type (WT) mice, whereas relaxation of the femoral artery and aorta (lgEC50 WT: −7.03 ± 0.6, ADKVECKO: −7.05 ± 0.8) was similar in the two groups. Wild‐type mice progressively developed LV systolic and diastolic dysfunction when they underwent transverse aortic constriction surgery, whereas ADKVEC‐KO mice displayed a lesser degree in decline of LV function.ConclusionsOur results indicate that ADK inhibition selectively enhances microvascular vasodilator function, whereby it improves LV perfusion and LV contractile function under metabolic and hemodynamic stress.