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

Abstract

Abstract: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.

Vasodilator Activity of Compounds Isolated from Plants Used in Mexican Traditional Medicine

“…Earlier studies have proved that naturally occurring lupane-, oleanane-, and ursane-type triterpenes elicit vasodilator effects [ 34 , 35 , 36 , 37 , 38 ]. The vasodilation produced by the lupane-type triterpene betulinic acid and the oleanane-type triterpenes moronic, morolic, and 3,4-seco-olean-18-enen-3,28-dioic acids is endothelium-dependent [ 35 ].…”

“…Interestingly, our research group previously demonstrated that ursolic acid and uvaol (the alcohol corresponding to ursolic acid) produce an endothelium dependent vasorelaxation, which involves stimulation of the NO/cGMP and H 2 S/K ATP pathways. Molecular docking studies showed that both triterpenes are able to bind with high affinity to endothelial NOS and CSE in allosteric binding sites located relatively far from the catalytic sites [ 34 ]. We found that corosolic acid ( 3 ) (EC 50 = 108.9 ± 3.2 µM; E max = 96.4 ± 4.2%) is approximately two fold less potent than ursolic acid (EC 50 = 47.1 ± 7.6 µM; E max = 97.7 ± 3.9%) and uvaol (EC 50 = 43.6 ± 5.6 µM; E max = 93.4 ± 5.1%) [ 34 ].…”

“…Molecular docking studies showed that both triterpenes are able to bind with high affinity to endothelial NOS and CSE in allosteric binding sites located relatively far from the catalytic sites [ 34 ]. We found that corosolic acid ( 3 ) (EC 50 = 108.9 ± 3.2 µM; E max = 96.4 ± 4.2%) is approximately two fold less potent than ursolic acid (EC 50 = 47.1 ± 7.6 µM; E max = 97.7 ± 3.9%) and uvaol (EC 50 = 43.6 ± 5.6 µM; E max = 93.4 ± 5.1%) [ 34 ]. However, these three compounds exhibited a similar maximum vasodilator effect.…”

“…According to the molecular docking studies of ursolic acid, 3 β-OH forms hydrogen bonds with Asp 480 in eNOS and His 99 in CSE. Whereas, 28 α-carboxyl forms a hydrogen bond with His373 and an electrostatic interaction with Arg367 in eNOS [ 34 ]. All these interactions are key in stabilizing protein-ligand binding.…”

El capulín (Prunus serotina Ehrh.): árbol multipropósito con potencial forestal en México

“…La evaluación del valor nutracéutico y propiedades antihipertensivas de sus frutos permitió determinar que el extracto podría usarse en la prevención de la hipertensión y como coadyuvante en su tratamiento (Luna-Vázquez et al, 2013). Posteriormente se estableció que el ácido ursólico y el uvaol son los principales compuestos vasodilatadores no-polares en los frutos de capulín (Luna-Vázquez et al, 2016).…”