Maximiliano Ibarra-Barajas

Antidiabetic activity of N-(6-substituted-1,3-benzothiazol-2-yl)benzenesulfonamides

N-(6-Substituted-1,3-benzothiazol-2-yl)benzenesulfonamide derivatives 1-8 were synthesized and evaluated for their in vivo antidiabetic activity in a non-insulin-dependent diabetes mellitus rat model. Several compounds synthesized showed significant lowering of plasma glucose level in this model. As a possible mode of action, the compounds were in vitro evaluated as 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitors. The most active compounds (3 and 4) were docked into the crystal structure of 11beta-HSD1. Docking results indicate potential hydrogen bond interactions with catalytic amino acid residues.

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.

Vasorelaxant activity of some structurally related triterpenic acids from Phoradendron reichenbachianum (Viscaceae) mainly by NO production: Ex vivo and in silico studies ☆

The aim of the current study was to investigate the vasorelaxant activity of five structurally-related triterpenic acids namely ursolic (1), moronic (2), morolic (3), betulinic (4) and 3,4-seco-olean-18-ene-3,28-dioic (5) acids. The vasorelaxant effect of compounds 1-5 were determined on endothelium-denuded and endothelium-intact rat aortic rings pre-contracted with noradrenaline (0.1 μM). All compounds showed significant relaxant effect on endothelium-intact vessels in a concentration-dependent manner (p<0.05). Ursolic, moronic and betulinic acids were the most potent vasorelaxant agents with 11.7, 16.11 and 58.46 μM, respectively. Since vasorelaxation was blocked by L-NAME, while indomethacin did not inhibit the effect, endothelium-derived nitric oxide seems to be involved in triterpenic 2 and 3 mode of action. Compounds 1-5 were docked with a crystal structure of eNOS. Triterpenes 1-5 showed calculated affinity with eNOS in the C1 and C2 binding pockets, near the catalytic site; Ser248 and Asp480 are the residues that make hydrogen bonds with the triterpene compounds.

Vasorelaxant effect of flavonoids through calmodulin inhibition: Ex vivo, in vitro, and in silico approaches.

In our search for potential antihypertensive agents, a series of structurally-related flavonoids was screened. Ex vivo and in vitro biological evaluations indicated that compounds 1-7 displayed an important vasorelaxant effect on the endothelium-intact (E(+)) and -denuded (E(-)) aortic rings test. Their in vitro anti-calmodulin (CaM) properties were determined by means of the inhibitory effect on the activation of the calmodulin-sensitive cAMP phosphodiesterase (PDE1) assay. Molecular modeling experiments were also performed in order to explore the probable binding site of 1-7 with CaM, and the results indicated that they could bind to the protein in the same pocket as trifluoperazine (TFP), a well-known CaM inhibitor.

Dose-dependent antihypertensive determination and toxicological studies of tilianin isolated from Agastache mexicana.

ETHNOPHARMACOLOGICAL RELEVANCE Agastache mexicana is used in Mexican traditional medicine for the treatment of hypertension, anxiety and related diseases. AIM OF THE STUDY Current work was developed to establish pharmacological/toxicological parameters of tilianin, a flavone extracted from Agastache mexicana in order to propose it for clinical trials. MATERIALS AND METHODS Acute and sub-acute toxicology studies in Imprinting Control Region (ICR) mice and median effective dose (ED50) determination in conscious spontaneously hypertensive rats (SHR) were done. RESULTS A median lethal dose (LD50) of 6624 mg/kg (6201, 7076) in mice and significant antihypertensive effect (ED50=53.51 mg/kg) in SHR were determined. Moreover, sub-acute oral administration of tilianin did not alter body weight, clinical chemistry parameters (alanine amino-transferase, aspartate amino-transferase, total cholesterol, high density lipoprotein, low density lipoprotein, triglycerides, glucose and insulin), and also did not induce any toxic or adverse effects on kidney, heart, liver, and lung functions. CONCLUSIONS We have shown that tilianin, isolated from Agastache mexicana, was not toxic for rodents. Also, its antihypertensive effect was dose-dependent and ED50 (53.51 mg/kg) calculated was lesser than LD50 determined (6624 mg/kg), which suggest a wide range of pharmacology-toxicology patterns. Results support the hypothesis that tilianin must be investigated and developed for clinical trials as antihypertensive drug.

Cochlospermum vitifolium induces vasorelaxant and antihypertensive effects mainly by activation of NO/cGMP signaling pathway.

AIM OF THE STUDY Cochlospermum vitifolium is a medicinal plant used for the treatment of diabetes, hepatobilary and cardiovascular illnesses. The aim of current study was to determine the in vivo antihypertensive and in vitro functional vasorelaxant mechanism of methanol extract of Cochlospermum vitifolium (MECv) and naringenin (NG). MATERIALS AND METHODS Test material was assayed on rat isolated aorta rings test with- and without-endothelium to determine their vasorelaxant mechanism. Also, the in vivo antihypertensive effect was evaluated on spontaneously hypertensive rat (SHR) model. In addition, presence of NG into the extract was confirmed by reverse phase high performance liquid chromatography (RP-HPLC) analysis. RESULTS MECv (120 mg/kg) and NG (50 and 160 mg/kg) showed acute antihypertensive effects on SHR when systolic and diastolic pressure were decreased at 1 h and 24 h after administration, respectively. Vasorelaxant effect of MECv and NG was shifted to the right when endothelium-intact aortic rings were pre-incubated with L-NAME (10 microM) and ODQ (1 microM). Also, NG relaxant curves were displaced to the right in the presence of tetraethylammonium (TEA, 1 mM) and 2-aminopyridine (2-AP, 100 microM) on endothelium-denuded aortic rings. CONCLUSION Experiments described above showed that MECv play an important role in hypertension regulation through NO synthesis and may be PGI(2) production and potassium channel activation on excessive endothelial dysfunction conditions. Unfortunately, presence of NG into the extract is not significant on bioactivity of the extract; however, this compound could be tested and evaluated as structural scaffold for future drug design for development of antihypertensive agents.

Captopril avoids hypertension, the increase in plasma angiotensin II but increases angiotensin 1–7 and angiotensin II-induced perfusion pressure in isolated kidney in SHR

We investigated captopril effects, an ACE inhibitor, on hypertension development, on Ang II and Ang-(1-7) plasma concentrations, on Ang II-induced contraction in isolated kidneys, and on kidney AT1R from spontaneously hypertensive (SHR) rats. Five weeks-old SHR and Wistar Kyoto (WKY) rats were treated with captopril at 30 mg/kg/day, in drinking water for 2 or 14 weeks. Systolic blood pressure (SBP) was measured, and isolated kidneys were tested for perfusion pressure and AT1R expression; while Ang II and Ang-(1-7) concentrations were determined in plasma. Captopril did not modify SBP in WKY rats and avoided its increase as SHR aged. Plasma Ang-II concentration was ∼4-5 folds higher in SHR rats, and captopril reduced it (P<0.05); while captopril increased Ang-(1-7) by ∼2 fold in all rat groups. Captopril increased Ang II-induced pressor response in kidneys of WKY and SHR rats, phenomenon not observed in kidneys stimulated with phenylephrine, a α₁-adrenoceptor agonist. Captopril did not modify AT1R in kidney cortex and medulla among rat strains and ages. Data indicate that captopril increased Ang II-induced kidney perfusion pressure but not AT₁R density in kidney of WKY and SHR rats, due to blockade of angiotensin II synthesis; however, ACE inhibitors may have other actions like activating signaling processes that could contribute to their diverse effects.