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.

Nitric oxide (NO)-cyclic GMP (cGMP) signaling is a vasoprotective pathway therapeutically targeted for example in pulmonary hypertension. Its dysregulation in disease is incompletely understood. Here we show in pulmonary artery endothelial cells that feedback inhibition by NO of the NO receptor, the cGMP forming soluble guanylate cyclase (sGC), may contribute to this. Both endogenous NO from endothelial NO synthase or exogenous NO from NO donor compounds decreased sGC protein and activity. This was not mediated by cGMP as the NO-independent sGC stimulator or direct activation of cGMP-dependent protein kinase did not mimic it. Thiol-sensitive mechanisms were also not involved as the thiol-reducing agent, N-acetyl-L-cysteine did not prevent this feedback. Instead, both in-vitro and in-vivo and in health and acute respiratory lung disease, chronically elevated NO led to the inactivation and degradation of sGC whilst leaving the heme-free isoform, apo-sGC, intact or even increasing its levels. Thus, NO regulates sGC in a bimodal manner, acutely stimulating and chronically inhibiting, as part of self-limiting direct feedback that is cGMP-independent. In high NO disease conditions, this is aggravated but can be functionally recovered in a mechanism-based manner by apo-sGC activators that re-establish cGMP formation.