Jorge Vergara-Galicia

Antihypertensive and vasorelaxant effects of tilianin isolated from Agastache mexicana are mediated by NO/cGMP pathway and potassium channel opening

Current investigation was undertaken to elucidate the mode of action of tilianin, isolated from Agastache mexicana, as a vasorelaxant agent on in vitro functional rat thoracic aorta test and to investigate the in vivo antihypertensive effect on spontaneously hypertensive rats (SHR). Tilianin (0.002-933 microM) induced significant relaxation in a concentration- and endothelium-dependent and -independent manners in aortic rings pre-contracted with noradrenaline (NA, 0.1 microM), and serotonin (5-HT, 100 microM). Effect was more significant (p < 0.05) in endothelium-intact (+E) aorta rings than when endothelium was removed(E). Pre-treatment with N-nitro-L-arginine methyl ester (L-NAME; 10 microM) or 1-H-[1,2,4]-oxadiazolo-[4,3a]-quinoxalin-1-one (ODQ, 1 microM) produced a significant change of the relaxant response and activity was markedly inhibited, but not by indomethacin (10 microM) or atropine (1 microM). Furthermore, tilianin (130 microM) provoked a significant displacement to the left in the relaxation curve induced by sodium nitroprusside (SNP; 0.32 nM to 0.1 microM). Moreover, tilianin induced significant in vitro NO overproduction (1.49 +/- 0.86 microM of nitrites/g of tissue) in rat aorta compared with vehicle (p < 0.05). In addition, pre-treatment with tetraethylammonium (TEA, 5 mM) and 2-aminopyridine (2-AP, 0.1 microM) shifted to the right the relaxant curve induced by tilianin (p < 0.05). Finally, a single oral administration of tilianin (50 mg/kg) exhibited a significant decrease in systolic and diastolic blood pressures (p < 0.05) in SHR model. Results indicate that tilianin mediates relaxation mainly by an endothelium-dependent manner,probably due to NO release, and also through an endothelium-independent pathway by opening K+ channels, both causing the antihypertensive effect.

Antihypertensive and vasorelaxant activities of Laelia autumnalis are mainly through calcium channel blockade

The aim of the present study was to evaluate the possible mechanism of the vasorelaxant action of methanol extract from Laelia autumnalis (MELa) in isolated rat aortic rings, and to establish its antihypertensive activity in vivo. MELa (0.15-->50 microg/mL) induced relaxation in aortic rings pre-contracted with KCl (80 mM), showing an IC50 value of 34.61+/-1.41 microg/mL and E max value of 85.0+/-4.38% (in endothelium-intact rings) and an IC50 value of 45.11+/-4.17 microg/mL and E max value of 80.0+/-12.1% (in endothelium-denuded rings). Serotonin (5-HT, 1 x 10(-4) M) provoked sustained contraction, which was markedly inhibited by MELa (0.15-->50 microg/mL) in a concentration-dependent and endothelium-independent manner. Pretreatment with MELa (15, 46, 150, 300 and 1500 microg/mL) also inhibited contractile responses to norepinephrine (NE 1 x 10(-11) M to 1 x 10(-5.5) M). In endothelium-denuded rings, the vasorelaxant effect of MELa was reduced partially by ODQ (1 microM), but not by tetraethylammonium (5 microM), glibenclamide (10 microM), and 2-aminopyridine (100 microM). The extract also reduced NE-induced transient contraction in Ca2+-free solution, and inhibited contraction induced by increasing external calcium in Ca2+-free medium plus high KCl (80 mM). The antihypertensive effect of MELa was determined in spontaneously hypertensive rats (SHR). A single oral administration of the extract (100 mg/kg) exhibited a significant decrease in systolic and diastolic blood pressure and heart rate (p<0.05) in SHR rats. Our results suggest that MELa induces relaxation in rat aortic rings through an endothelium-independent pathway, involving blockade of Ca2+ channels and a possible cGMP enhanced concentrations and also causes an antihypertensive effect.

Synthesis, vasorelaxant activity and antihypertensive effect of benzo[d]imidazole derivatives

A series of 1H-benzo[d]imidazole analogues of Pimobendan, substituted at position 5 with either -CF(3) or -NO(2), were synthesized using a short synthetic route. All the nitro derivatives were potent, and exhibited a concentration- and partial endothelium-dependent vasorelaxant effects, with EC(50)s <5microM. 2-Methoxy-4-[5-nitro-1H-benzo[d]imidazol-2-yl]phenol (compound 13) was the most potent derivative of the series, showing an EC(50) value of 1.81microM and E(max) of 91.7% for ex vivo relaxant response in intact aortic rings, resulting in a 2.5-fold higher activity compared to Pimobendan. The closely related 5-CF(3) analogue (compound 8), was 19 times less potent than 13. The antihypertensive activity of compound 13 was evaluated at doses of 25, 50 and 100mgkg(-1), using spontaneously hypertensive rats (SHR), showing a statistically significant dose-dependent effect.

Vasorelaxant and antihypertensive effects of methanolic extract from roots of Laelia anceps are mediated by calcium-channel antagonism.

RMELanc-induced relaxation in aortic rings precontracted with NE, 5-HT and KCl. It also reduced NE-induced transient contraction in Ca(2+)-free solution and inhibited contraction induced by increasing external calcium. Nevertheless, the vasorelaxant effect of RMELanc was not reduced by ODQ, 1-alprenolol, TEA, glibenclamide, and 2-AP. Oral administration of 100 mg/kg of RMELanc exhibited a significant decrease in systolic and diastolic blood pressures in SHR rats. HPLC analysis allowed us to detect the presence of 2,7-dihydroxy-3,4,9-trimethoxyphenantrene (1), which induced a significant relaxation effect. Therefore, our results suggest that RMELanc induces vasorelaxant and antihypertensive effects by blockade of Ca(2+) channels.

Ex Vivo Study of the Vasorelaxant Activity Induced by Phenanthrene Derivatives Isolated from Maxillaria densa

The phenanthrenes gymnopusin (1), fimbriol A (2), and erianthridin (3) from Maxillaria densa were found to induce significant relaxant effects in a concentration-dependent and endothelium-independent manner on aortic rings precontracted with norepinephrine (NE, 0.1 μM) and KCl (80 mM). Compound 1 was the most active and also inhibited the cumulative concentration-response contraction of NE or CaCl(2). Contractions induced by FPL 64176, an agonist of L-type voltage-dependent calcium channels, were blocked by 1. The potassium channel blockers glibenclamide and TEA (tetraethylammonium) reduced the relaxations induced by 1. Nevertheless, the effect of 1 was not modified by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, a specific soluble guanylate cyclase inhibitor. The functional results obtained suggest that 1 induces relaxation through an endothelium-independent pathway by the control of cationic channels (calcium channel blockade and potassium channel opening) in the myogenic response of rat aortic rings.

Micropropagation and vasorelaxant activity of Laelia autumnalis (Orchidaceae)

A simple and efficient protocol has been developed in order to obtain healthy seedlings by asymbiotic germination of seeds from Laelia autumnalis. Seeds from mature capsules were germinated asymbiotically after being cultured on full- or half-strength Murashige and Skoogs (MS) medium, without plant growth regulators and with 3.0% or 1.5% of sucrose. The percentage of germinated seeds (% GS) was recorded during 6 weeks using three different conditions of incubation: light (80% GS, p < 0.05), darkness (30% GS) and white light photoperiod (100% GS, p < 0.05). The best seed germination percentages were found on the light and white light photoperiod conditions. Moreover, we also investigated the vasorelaxant action of the methanolic extracts from wild L. autumnalis (roots, pseudobulbs and leaves) and plantlets generated in vitro. Results showed that the methanolic extract of roots and pseudobulbs produced a significant vasodilator effect, in a concentration-dependent and endothelium-independent manner on norepinephrine (NE) and potassium chloride (KCl)-induced contractions in rat aortic thoracic rings. Nevertheless, the methanolic extract of leaves and plantlets showed no relevant vasorelaxant activity. Therefore, the results suggest that pseudobulbs and roots were the main tissues of the plant where vasorelaxant compounds are stored.

Review of Theoretical Models to Study Natural Products with Antiprotozoal Activity

In nature, pathogenic parasite species with different susceptibility patterns of antiparasitic drugs abound. In this sense, natural products derived from plants are a potency for drugs with potential antiparasitic activity. Unfortunately, there are many metabolites and studying all of them would be costly in terms of money and resources. To this end, theoretical studies such as QSAR models could be useful. These, for the most part, predict the biological activity of the drugs against a single species of parasite. Consequently, foretell the probability with which a drug is active against many different species with a single QSAR model is an important achievement. This review consists of three parts: the first part is a review of metabolites found in nature that have antiparasitic activity, in particular the antiprotozoal (Leishmania and Trypanosoma); the second part includes a review of theoretical studies looking for a model that predicts the antiprotozoal activity of natural products; the third and final part concerns the study of theoretical models focused on the interaction between drug and receptor, analyzing new metabolites with antiprotozoal activity.