This work was aimed to determine whether isometric contraction in Wistar rat aorta is related to the phosphatidylinositol 3-kinase (PI3K)/Akt-dependent activation of endothelial nitric oxide synthase (eNOS). Basically, we hypothesized that additional increases in active tone occur after the pharmacological inhibition of a transduction pathway involved in NO synthesis or action. In intact aortic rings contracted with phenylephrine or high K+, the cumulative administration of the PI3K inhibitor, LY294002, elicited significant decreases - but not supplementary increases - in tone. In endothelium-intact tissues, on the other hand, the Akt1/2 kinase inhibitor did not alter phenylephrine- and K+-induced isometric contractions. The PI3K inhibitor wortmannin (1×10-7m) produced a significant supplementary contraction only in endothelium-intact aortic rings precontracted with phenylephrine. Higher concentrations of this inhibitor produced relaxations of phenylephrine and high K+-constricted endothelium-intact and endothelium-denuded aortic rings. LY294002 and wortmannin did not cause any potentiating effect on phenylephrine- and angiotensin II-induced concentration-dependent contractile responses in endothelium-intact tissues. In intact aortic rings contracted with phenylephrine or high K+, the addition of the NOS inhibitor, L-NAME, or the guanylyl cyclase inhibitor, ODQ, further augmented tone in a concentration-dependent manner, and these supplementary contractions were significantly reduced by endothelium removal. Taken together, our data suggest that the PI3K/Akt pathway is not counteracting aortic isometric contractions by activation of the eNOS. It appears, on the other hand, that the smooth muscle PI3K can stimulate contraction without activation of the protein kinase Akt in response to GPCR agonists and high K+. © 2010 The Authors Fundamental and Clinical Pharmacology © 2010 Société Française de Pharmacologie et de Thérapeutique.
López, R. M., Pérez, T., Castillo, C., & Castillo, E. F. (2011). Effects induced by inhibitors of the phosphatidylinositol 3-kinase/Akt and nitric oxide synthase/guanylyl cyclase pathways on the isometric contraction in rat aorta: A comparative study. Fundamental and Clinical Pharmacology, 313-322. https://doi.org/10.1111/j.1472-8206.2010.00833.x