PT - JOURNAL ARTICLE AU - Erica A. Wehrwein AU - Carrie A. Northcott AU - Robert D. Loberg AU - Stephanie W. Watts TI - Rho/Rho Kinase and Phosphoinositide 3-Kinase Are Parallel Pathways in the Development of Spontaneous Arterial Tone in Deoxycorticosterone Acetate-Salt Hypertension AID - 10.1124/jpet.103.062265 DP - 2004 Jun 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 1011--1019 VI - 309 IP - 3 4099 - http://jpet.aspetjournals.org/content/309/3/1011.short 4100 - http://jpet.aspetjournals.org/content/309/3/1011.full SO - J Pharmacol Exp Ther2004 Jun 01; 309 AB - Hypertension is characterized by abnormal vascular contractility and function. Arteries from deoxycorticosterone acetate (DOCA)-salt hypertensive rats develop spontaneous tone that is not observed in arteries from normotensive rats. Inhibition of phosphoinositide 3-kinase (PI3-kinase) by 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) reduces spontaneous tone development. The Rho/Rho-kinase pathway has been suggested to play a role in hypertension and may be dependent on PI3-kinase activity. We hypothesized that Rhokinase is involved in spontaneous tone development and that Rho/Rho-kinase is a downstream effector of PI3-kinase. Using endothelium-denuded aortic strips in isolated tissue bath, we demonstrated that (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) (Y27632) (1 μM), a Rho-kinase inhibitor, significantly reduced spontaneous tone in the DOCA aorta but that it did not affect sham aorta basal tone (DOCA 63.5 ± 15.9 versus sham 1.2 ± 0.4 total change in percentage of phenylephrine contraction). We examined the interaction between the PI3-kinase and Rho pathways by observing the effects of LY294002 on a Rhokinase effector, myosin phosphatase (MYPT), and Y27632 on a PI3-kinase effector, Akt, using Western blot analysis. Inhibition of PI3-kinase reduced spontaneous tone, but it had no effect on the phosphorylation status of MYPT, indicating that PI3-kinase is not a downstream effector of Rho/Rho-kinase. These data indicate that there is little interaction between the Rho/Rhokinase and PI3-kinase pathways in the DOCA-salt aorta, and the two pathways seem to operate in parallel in supporting spontaneous arterial tone. These data reflect spontaneous tone only and do not rule out the possibility of interaction between these pathways in agonist-stimulated tone. The American Society for Pharmacology and Experimental Therapeutics