Effect of phosphatidylinositol 3-kinase-γ inhibitor CAY10505 in hypertension, and its associated vascular endothelium dysfunction in rats

This study has been designed to investigate the role of phosphatidyl-inositol 3-kinase-γ (PI3Kγ) in deoxycorticosterone acetate salt (DOCA) hypertension induced vascular endothelium dysfunction. Wistar rats were uninephrectomised and DOCA (40 mg·(kg body mass)⁻¹, subcutaneous injection) was administered twice weekly for 6 weeks to produce hypertension. Rats with mean arterial blood pressure ≥ 140 mm Hg (1 mm Hg = 133.322 Pa) were selected as hypertensive. Vascular endothelium dysfunction was assessed in terms of attenuation of acetylcholine-induced endothelium-dependent relaxation (isolated aortic ring preparation), decrease in serum nitrate and (or) nitrite level, as well as reduced level of glutathione and disruption of integrity of vascular endothelium (histopathology). Five weeks of DOCA administration were followed by 7 days of daily administration of PI3Kγ inhibitor (5-[[5-(4-fluorophenyl)-2-furanyl]methylene]-2,4-thiazolidinedione (CAY10505), 0.6 mg·kg⁻¹, per os (p.o.)), atorvastatin (30 mg·kg⁻¹, p.o.), and losartan (25 mg·kg⁻¹, p.o.) (positive control of hypertension), which significantly improved acetylcholine-induced endothelium dependent relaxation, serum nitrate and (or) nitrite level, glutathione level, and the vascular endothelial lining in hypertensive rats.Therefore, it may be concluded that CAY10505, a specific inhibitor of PI3Kγ, improves hypertension-associated vascular endothelial dysfunction. Thus, inhibition of PI3Kγ might be a useful approach in the therapeutics of vascular endothelium dysfunction.