Antihypertensive and vasorelaxant effect of leucodin and achillin isolated from Achillea millefolium through calcium channel blockade and NO production: In vivo, functional ex vivo and in silico studies.
ETHNOPHARMACOLOGICAL RELEVANCE
Achillea millefolium L. (Asteraceae), known as yarrow (milenrama), is a plant used in Mexican traditional medicine for the treatment of hypertension, diabetes, and related diseases.


AIM
To determine the vasorelaxant and antihypertensive effect of A. millefollium and to isolate the main bioactive antihypertensive agents.


MATERIALS AND METHODS
Organic (hexane, dichloromethane and methanol) and hydro-alcohol (Ethanol-H2O: 70:30) extracts obtained from flowers, leaves and stems were evaluated on isolated aorta rat rings with and without endothelium to determine their vasorelaxant effect. Hexane extract from flowers (HEAmF) was studied to evaluate its antihypertensive effect on spontaneously hypertensive rats (SHR). From HEAmF, bioactive compounds were obtained by bio-guided phytochemical separation through chromatography.


RESULTS
Organic extracts showed the best vasorelaxant activity. Hexane extract from flowers was the most potent and efficient ex vivo vasorelaxant agent, showing significant decrease of systolic and diastolic blood pressure in SHR (p < 0.05). Phytochemical separation of HEAmF yielded two epimeric sesquiterpene lactones: leucodin (1) and achillin (2), the major components of the extract. Both 1 and 2 showed similar vasorelaxant action ex vivo (p < 0.05), and their effects where modified by L-NAME (10 μM, nitric oxide synthase inhibitor), by ODQ (1 μM, soluble guanylyl cyclase inhibitor), and also relaxed the contraction induced by KCl (80 mM). Finally, 1 and 2 intragastric administration (50 mg/kg) decreased systolic and diastolic blood pressure in SHR.


CONCLUSIONS
Achillea millefolium showed antihypertensive and vasorelaxant effects, due mainly to leucodin and achillin (epimers). Both compounds showed antihypertensive activity by vasorelaxation putatively by endothelium-dependent NO release and cGMP increase, as well as by calcium channels blockade.
['Arias-Durán|Luis|L|', 'Estrada-Soto|Samuel|S|', 'Hernández-Morales|Monserrat|M|', 'Millán-Pacheco|César|C|', 'Navarrete-Vázquez|Gabriel|G|', 'Villalobos-Molina|Rafael|R|', 'Ibarra-Barajas|Maximiliano|M|', 'Almanza-Pérez|Julio C|JC|']
D031162:Achillea D000818:Animals D000959:Antihypertensive Agents D001011:Aorta D001794:Blood Pressure D002121:Calcium Channel Blockers D015220:Calcium Channels D003198:Computer Simulation D006339:Heart Rate D008297:Male D019331:NG-Nitroarginine Methyl Ester D009569:Nitric Oxide D052250:Nitric Oxide Synthase Type III D010069:Oxadiazoles D010936:Plant Extracts D011810:Quinoxalines D011918:Rats, Inbred SHR D017208:Rats, Wistar D012717:Sesquiterpenes D014665:Vasodilator Agents
Antihypertensive Vasorelaxation Leucodin Achillin Calcium channel blockade Aorta