Vasorelaxation by extracts of Casimiroa spp. in rat resistance vessels and pharmacological study of cellular mechanisms |
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Authors: | Froldi Guglielmina Bertin Riccardo Secchi Enrico Zagotto Giuseppe Martínez-Vázquez Mariano García-Argaéz Aída |
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Institution: | a Department of Pharmacology and Anaesthesiology, University of Padova, Largo E. Meneghetti 2, 35131 Padova, Italy b Department of Pharmaceutical Sciences, University of Padova, Via Marzolo, 5, 35131 Padova, Italy c Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, Coyoacán 04510, México D.F., Mexico |
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Abstract: | Aim of the studyCasimiroa spp. are Mexican plants traditionally used for treatment of hypertension. To study their antihypertensive action, we determined the arterial dilatation induced by extracts from leaves and seeds of Casimiroa calderoniae F. Chiang & Medrano, Casimiroa edulis Llave et Lex, and Casimiroa pubescens Ramirez.Materials and methodsThe vascular effects of Casimiroa spp. extracts were investigated on rat caudal and aortic arteries. In addition, the extracts were characterized by HPLC using heraclenol, isopimpinellin, heraclenin and phellopterin as external standards. The methanolic extract of Casimiroa pubescens seeds (Cp12) was also studied by H-NMR and LC-MS (ESI-TOF) for the determination of casimiroin and zapotin.ResultsThe hexanic and methanolic extracts of Casimiroa spp. (20 μg/ml) showed vasorelaxation in arterial tissues precontracted by phenylephrine (0.5 μM); the extracts from seeds always caused a greater relaxation in comparison to those from leaves. The most active were the methanolic seed extracts of Casimiroa edulis (Ce8) and Casimiroa pubescens (Cp12). To study the pharmacological mechanisms of vasodilatation we used various inhibitors selective to different receptor subtypes or intracellular enzymes. The vasorelaxant effect of Ce8 (20 μg/ml) remained unaffected by the pretreatment with pyrilamine (10 μM), an antagonist of histamine H1 receptors, but was inhibited by atropine (0.1 μM), a muscarinic receptor antagonist. Therefore, to determine muscarinic receptor subtypes, we used pirenzepine (1 μM), a selective inhibitor of M1 receptor, and 4-diphenylacetoxyl-N-methylpiperidine methiodide (DAMP, 0.01 μM), a selective inhibitor of M3 receptor. Only the latter reduced the vasodilatation by Ce8 and Cp12. To investigate the role of the nitric oxide synthase (NOS), we used NG-nitro-l-arginine methyl ester (l-NAME, 10 μM), a selective NOS inhibitor, which decreased the dilatation induced by Ce8 and Cp12. Finally, we studied the action of (1H-1,2,4]oxadiazolo4,3-a]quinoxalin-1-one) (ODQ, 3 μM), a selective guanylyl cyclase inhibitor, which inhibited the dilatation by Casimiroa extracts.ConclusionThe data show that methanolic seed extracts of Casimiroa edulis (Ce8) and Casimiroa pubescens (Cp12) induce vasorelaxation by M3 receptor through the activation of cGMP-dependent NO signaling. These results support the traditional use of Casimiroa decoctions for antihypertensive treatments in the Mexican ethnomedicine. |
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Keywords: | Casimiroa spp Rutaceae Vasorelaxation Muscarinic receptor subtypes Nitric oxide pathway |
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