Role of Nitric Oxide and Hydrogen Sulfide in the Vasodilator Effect of Ursolic Acid and Uvaol from Black Cherry Prunus serotina Fruits

The present research aimed to isolate the non-polar secondary metabolites that produce the vasodilator effects induced by the dichloromethane extract of Prunus serotina (P. serotina) fruits and to determine whether the NO/cGMP and the H(2)S/K(ATP) channel pathways are involved in their mechanism of action. A bioactivity-directed fractionation of the dichloromethane extract of P. serotina fruits led to the isolation of ursolic acid and uvaol as the main non-polar vasodilator compounds. These compounds showed significant relaxant effect on rat aortic rings in an endothelium- and concentration-dependent manner, which was inhibited by NG-nitro-l-arginine methyl ester (l-NAME), dl-propargylglycine (PAG) and glibenclamide (Gli). Additionally, both triterpenes increased NO and H(2)S production in aortic tissue. Molecular docking studies showed that ursolic acid and uvaol are able to bind to endothelial NOS and CSE with high affinity for residues that form the oligomeric interface of both enzymes. These results suggest that the vasodilator effect produced by ursolic acid and uvaol contained in P. serotina fruits, involves activation of the NO/cGMP and H(2)S/K(ATP) channel pathways, possibly through direct activation of NOS and CSE.