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

Abstract

Arterial hypertension is one of the main risk factors in the development of cardiovascular diseases. Therefore, it is important to look for new drugs to treat hypertension. In this study, we carried out the screening of 19 compounds (triterpenes, diterpenes, sesquiterpenes, lignans, and flavonoids) isolated from 10 plants used in Mexican traditional medicine to determine whether they elicited vascular smooth muscle relaxation and, therefore, could represent novel anti-hypertension drug candidates. The vasorelaxant activity of these compounds was evaluated on the isolated rat aorta assay and the results obtained from this evaluation showed that three compounds induced a significant vasodilatory effect: meso-dihydroguaiaretic acid [half maximal effective concentration (EC₅₀), 49.9 ± 11.2 µM; maximum effect (Emax), 99.8 ± 2.7%]; corosolic acid (EC₅₀, 108.9 ± 6.7 µM; Emax, 96.4 ± 4.2%); and 5,8,4′-trihydroxy-3,7-dimethoxyflavone (EC₅₀, 122.3 ± 7.6 µM; Emax, 99.5 ± 5.4%). Subsequently, involvement of the NO/cyclic guanosine monophosphate (cGMP) and H₂S/ATP-sensitive potassium channel (K_ATP) pathways on the vasodilator activity of these compounds was assessed. The results derived from this analysis showed that the activation of both pathways contributes to the vasorelaxant effect of corosolic acid. On the other hand, the vasodilator effect of meso-dihydroguaiaretic acid and 5,8,4′-trihydroxy-3,7-dimethoxyflavone, partly involves stimulation of the NO/cGMP pathway. However, these compounds also showed an important endothelium-independent vasorelaxant effect, whose mechanism of action remains to be clarified. This study indicates that meso-dihydroguaiaretic acid, corosolic acid, and 5,8,4′-trihydroxy-3,7-dimethoxyflavone could be used as lead compounds for the synthesis of new derivatives with a higher potency to be developed as drugs for the prevention and treatment of cardiovascular diseases.

Keywords: 5,8,4′-trihydroxy-3,7-dimethoxyflavone; corosolic acid; meso-dihydroguaiaretic acid hydrogen sulfide; nitric oxide; vasorelaxation.

Figure 1

Chemical structures of studied compounds.

Figure 1

Chemical structures of studied compounds.

Figure 1

Chemical structures of studied compounds.

Figure 2

Concentration-response curves of the vasodilator effect of corosolic acid (3), meso-dihydroguaiaretic acid (15), and 5,8,4′-trihydroxy-3,7-dimethoxyflavone (18). Acetylcholine was used as a positive control.

Figure 3

Concentration-response curves of the vasodilator effect of (a) corosolic acid (3), (b) meso-dihydroguaiaretic acid (15), and (c) 5,8,4′-trihydroxy-3,7-dimethoxyflavone (18) in the presence and absence (E-) of endothelium. A typical trace in which meso-dihydroguaiaretic acid (15) inhibited Phe-induced contraction in endothelium-intact (d), and -denuded aorta (e). Analysis by an unpaired t-test was made to test for differences between EC₅₀s of each compound in the presence and absence of endothelium (3, p < 0.0001; 15, p < 0.0001; 18, p = 0.0093).

Figure 4

Vasodilatory effect of (a) corosolic acid (3), (b) meso-dihydroguaiaretic acid (15), and (c) 5,8,4′-trihydroxy-3,7-dimethoxyflavone (18) in the absence (control) and presence of L-NAME (100 µM). Analysis by one-way analysis of variance (ANOVA) was made between the curves of each compound in the absence and presence of N^G-nitro-l-arginine methyl ester (L-NAME) followed by a post hoc Tukey’s test (3, p < 0.0001; 15, p = 0.006; 18, p = 0.991).

Figure 5

Vasodilatory effect of (a) corosolic acid (3), (b) meso-dihydroguaiaretic acid (15), and (c) 5,8,4′-trihydroxy-3,7-dimethoxyflavone (18) in the absence (control) and presence of propargylglycine (PAG, 1 mM). Analysis by one-way ANOVA was made between the curves of each compound in the absence and presence of PAG followed by a post hoc Tukey’s test (3, p = 0.001; 15, p = 0.803; 18, p = 0.102).

Figure 6

Vasodilatory effect of (a) corosolic acid (3), (b) meso-dihydroguaiaretic acid (15), and (c) 5,8,4′-trihydroxy-3,7-dimethoxyflavone (18) in the absence (control) and presence of tetraethylammonium (TEA, 10 mM). Analysis by one-way ANOVA was made between the curves of each compound in the absence and presence of TEA followed by a post hoc Tukey’s test (3, p < 0.0001; 15, p = 0.868; 18, p = 0.429).