Pharmacologycal activity of peperina (Minthostachys verticillata) on gastrointestinal tract.

ETHNOPHARMACOLOGICAL RELEVANCE: Minthostachys verticillata (Griseb.) Epling (Lamiaceae), known as Peperina is a medicinal native plant, with a traditional use as a digestive, antispasmodic and antidiarrheic. AIM OF THE STUDY: Despite its folkloric use, no scientific evaluation of this plant related to the gastrointestinal inflammatory process has been carried out to date. The present study aims to assess the effects of M. verticillata on gastrointestinal system in experimental models. MATERIALS AND METHODS: M. verticillata (250 and 500 mg/kg) was orally tested in a colitis model induced by acetic acid. Colon weight/length ratio, oxidative stress (oxidized and reduced glutathione), histological changes using Alcian blue and hematoxylin & eosin staining and expression of IL1ß, TNFα, iNOS, COX-2 were evaluated. The effect of the extract in three additional in vivo models were studied: intestinal motility and diarrhea induced by ricin oil, and visceral pain induced by intracolonic administration of capsaicin. Finally, the activity on concentration response curves of acetylcholine, calcium chloride, potassium and serotonin were achieved in isolated rat jejunum. RESULTS: In the colitis model, M. verticillata induced a significant reduction in the colon weight/length ratio, oxidative stress and expression levels of IL-1ß, iNOS and COX-2. Also, the extract diminished the severity of microscopic tissue damage and showed protective effect on goblet cells. Intestinal motility, diarrhea, visceral pain-related behaviors and referred hyperalgesia were significantly reduced when the animals were treated with the extract. Furthermore, in isolated jejunum, M. verticillata significantly reduced the contraction induced by serotonin and acetylcholine. Likewise, the extract non-competitively inhibited the response-concentration induced by CaCl2 and inhibited both low and high K+-induced contractions. CONCLUSIONS: This is the first study to validate traditional use of M. verticillata for digestive disorders and demonstrated that its aqueous extract could represent a promising strategy in targeting the multifactorial pathophysiology of inflammatory bowel disease.

Tempol-nebivolol therapy potentiates hypotensive effect increasing NO bioavailability and signaling pathway.

Nebivolol is a third generation beta blocker with endothelial nitric oxide synthase (eNOS) agonist properties. Considering the role of reactive oxygen species (ROS) in the uncoupling of eNOS, we hypothesized that the preadministration of an antioxidant as tempol, could improve the hypotensive response of nebivolol in normotensive animals increasing the nitric oxide (NO) bioavailability by a reduction of superoxide (O2(•-)) basal level production in the vascular tissue. Male Sprague Dawley rats were given tap water to drink (control group) or tempol (an antioxidant scavenger of superoxide) for 1 week. After 1 week, Nebivolol, at a dose of 3 mg/kg, was injected intravenously to the control group or to the tempol-treated group. Mean arterial pressure, heart rate, and blood pressure variability were evaluated in the control, tempol, nebivolol, and tempol nebivolol groups, as well as, the effect of different inhibitor as Nß-nitro-l-arginine methyl ester (L-NAME, a Nitric oxide synthase blocker) or glybenclamide, a KATP channel inhibitor. Also, the expression of α,ß soluble guanylate cyclase (sGC), phospho-eNOS, and phospho-vasodilator-stimulated phosphoprotein (P-VASP) were evaluated by Western Blot and cyclic guanosine monophosphate (cGMP) levels by an enzyme-linked immunosorbent assay (ELISA) commercial kit assay. We showed that pretreatment with tempol in normotensive rats produces a hypotensive response after nebivolol administration through an increase in the NO bioavailability and sGC, improving the NO/cGMP/protein kinase G (PKG) pathway compared to that of the nebivolol group. We demonstrated that tempol preadministration beneficiates the response of a third-generation beta blocker with eNOS stimulation properties, decreasing the basal uncoupling of eNOS, and improving NO bioavailability. Our results clearly open a possible new strategy therapeutic for treating hypertension.

Pharmacokinetic and pharmacodynamic alterations of methyldopa in rats with aortic coarctation. A study using microdialysis.

A pharmacokinetic-pharmacodynamic study of methyldopa (MD) was made in anesthetized sham operated (SO) and aortic coarctated (ACo) rats by using a vascular shunt probe for arterial microdialysis and simultaneous blood pressure recording. Anesthetized Wistar rats were used 7 days after aortic coarctation or sham operation. A vascular shunt probe was inserted into the carotid artery and a concentric probe was placed into the striatum or posterior hypothalamus. MD and 3,4-dihydroxyphenylacetic acid (DOPAC) were determined in the dialysates by HPLC-EC. MD (50 mg kg(-1)i.p.) induced an increase of heart rate in SO (Delta HR: 108 +/- 22 bpm, n= 6) and in ACo rats (Delta HR: 55 +/- 10 bpm, n= 6, P< 0.05, one way ANOVA). Moreover, MD also reduced the mean arterial pressure (MAP) of SO rats (Delta MAP: -10 +/- 4 mmHg, n= 6) and ACo animals (Delta MAP: -51 +/- 9 mmHg, n= 6, P< 0.05, one way ANOVA). Analysis of the arterial blood dialysates showed a lower half-life of MD in ACo rats (t(1/2): 1.5 +/- 0.3 h, n= 6, P< 0.05, 't' test) than in SO rats (t(1/2): 3.7 +/- 1.0 h, n= 6). A low accumulation and a fast decay of striatal MD levels were seen in ACo rats. However, peak levels of drug were greater in the hypothalamic dialysates of ACo rats than in SO animals samples. On the other hand, MD also induced an increase of DOPAC levels in the hypothalamic dialysates of ACo rats. In conclusion, the aortic coarctation modifies the pharmacokinetic and cardiovascular effect of MD in the rat. The action of this drug on dopaminergic neurotransmission is also altered in the ACo animals.

[Effect of treatment with dexamethasone on cardiovascular responses of adrenergic agents]. / Efecto del tratamiento con dexametasona sobre las respuestas cardiovasculares de agentes adrenérgicos.

Cardiovascular responses to several agents should be modified by glucocorticoid administration in the rat. We investigate the response to adrenergic agonists such as phenylephrine, noradrenaline, clonidine and isoproterenol and ganglionic blocking agent such as hexamethonium in conscious rats treated during 7 days with dexamethasone. Wistar rats were treated with either Dex (150 micrograms daily x 7 days, p.o.) or water. Mean arterial pressure were calculated from the intraarterial recordings of blood pressure. No differences in basal mean arterial pressure were seen between dexamethasone and control groups of rats. Phenylephrine and noradrenaline showed a pressor effect in control rats that was reduced by dexamethasone treatment. Clonidine showed similar pressor effect in both groups of rats but ten minutes after drug administration, a light hypotension was seen in dexamethasone rats. Isoproterenol and hexamethonium showed a similar hypotensive effect on control and dexamethasone rats. In conclusion, dexamethasone treatment should reduce the pressor responses to phenylephrine and noradrenaline. Moreover, the alpha adrenergic agonist clonidine showed a hypotensive effect in dexamethasone treated rats, although the response of isoproterenol and hexamethonium remains unchanged.

Renal function conscious one kidney-one clip hypertensive rats. Effect of indomethacin.

These experiments have analyzed: a) Blood pressure (BP) and renal function in one kidney-one clip rats two weeks after clipping; b) The effect of cycloxygenase (CO) inhibition on BP and renal function regulation during the hypertensive period. Using the unanaesthetized, unrestrained and chronically instrumented animal, three groups of rats were studied: Sham, Clip 0.31 mm lumen and Clip 0.29 mm lumen. The animals were examined before (Control period) and during the infusion of indomethacin (IND, 5 mg/kg via aortic cannula, n = 11 for each group) or the buffer vehicle solution (BUF, n = 7 for each group). Effective inhibition of CO by IND was confirmed using radioimmunoassay of prostaglandin E2 (PGE2) in urine. Control BP (mmHg, mean +/- SE) differed significantly among the groups (p < 0.001): Sham, 114 +/- 3; Clip 0.31, 135 +/- 2; Clip 0.29, 154 +/- 4 and did not change by IND infusion. Along with the BP, Control Glomerular Filtration Rate and Renal Plasma Flow did not change by IND infusion, which suggests that CO eicosanoids, particularly PGG2, contribute little to basal renal hemodynamics in sham and hypertensive rats. Sodium excretion was lower in the Control period of Clip 0.29 rats (p < 0.01). A significant natriuretic effect observed in this Clip 0.29 group by the infusion of IND suggests the contribution of an AA related metabolite in renal handling of sodium in more severe renovascular hypertension.

Renal function conscious one kidney-one clip hypertensive rats. Effect on indomethacin

Los presentes experimentos han analizado: a) la Presión Arterial (PA) y la función renal en ratas un riñón-un clip (IRIC) dos semanas después de la estenosis arterial; b) efecto de la inhibición de la ciclooxigenasa (CO) sobre la PA y la regluación de la función renal durante el período hipertensivo. Se estudiaron tres grupos de ratas utilizando animales sin anestesia, con libertad de movimiento y crónicamente instrumentados: grupo "Sham" (con operación simulada), Clip 0.31mm de luz, Clip 0.29mm de luz. Los animales fueron examinados antes (período Control) y durante la infusión de indometacina (IND, 5 mg/Kg por la cánula aórtica, n = 11 en cada grupo). La efectiva inhibición de la CO por IND fue confirmada por la determinación de prostaglandín E2 (PGE) en orina. La PA Control (mmH, media ñ ES) difirió significativamente entre los grupos (P < 0.001): Sham, 114 ñ 3; Clip 0.31, l35 ñ 2; Clip 0.29, 154 ñ 4 y los valores no variaron la infusión de IND, sugiriendo que la participación de los eicosanoides derivados de la CO, particularmente la PGE2, en la regulación de la hemodinamia renal de las ratas sham e hipertensas no es significativa. La excreción de sodio fue menor en el período Control de las ratas Clip 0.29 (P<0.01). El significativo efecto natriurético observado en este grupo Clip 0.29 por la infusión de IND sugiere la contribución de um metabolito del AA para el manejo renal del sodio en la hipertensión renovascular más severa

Renal function conscious one kidney-one clip hypertensive rats. Effect of indomethacin.

These experiments have analyzed: a) Blood pressure (BP) and renal function in one kidney-one clip rats two weeks after clipping; b) The effect of cycloxygenase (CO) inhibition on BP and renal function regulation during the hypertensive period. Using the unanaesthetized, unrestrained and chronically instrumented animal, three groups of rats were studied: Sham, Clip 0.31 mm lumen and Clip 0.29 mm lumen. The animals were examined before (Control period) and during the infusion of indomethacin (IND, 5 mg/kg via aortic cannula, n = 11 for each group) or the buffer vehicle solution (BUF, n = 7 for each group). Effective inhibition of CO by IND was confirmed using radioimmunoassay of prostaglandin E2 (PGE2) in urine. Control BP (mmHg, mean +/- SE) differed significantly among the groups (p < 0.001): Sham, 114 +/- 3; Clip 0.31, 135 +/- 2; Clip 0.29, 154 +/- 4 and did not change by IND infusion. Along with the BP, Control Glomerular Filtration Rate and Renal Plasma Flow did not change by IND infusion, which suggests that CO eicosanoids, particularly PGG2, contribute little to basal renal hemodynamics in sham and hypertensive rats. Sodium excretion was lower in the Control period of Clip 0.29 rats (p < 0.01). A significant natriuretic effect observed in this Clip 0.29 group by the infusion of IND suggests the contribution of an AA related metabolite in renal handling of sodium in more severe renovascular hypertension.

Renal function conscious one kidney-one clip hypertensive rats. Effect on indomethacin

Los presentes experimentos han analizado: a) la Presión Arterial (PA) y la función renal en ratas un riñón-un clip (IRIC) dos semanas después de la estenosis arterial; b) efecto de la inhibición de la ciclooxigenasa (CO) sobre la PA y la regluación de la función renal durante el período hipertensivo. Se estudiaron tres grupos de ratas utilizando animales sin anestesia, con libertad de movimiento y crónicamente instrumentados: grupo "Sham" (con operación simulada), Clip 0.31mm de luz, Clip 0.29mm de luz. Los animales fueron examinados antes (período Control) y durante la infusión de indometacina (IND, 5 mg/Kg por la cánula aórtica, n = 11 en cada grupo). La efectiva inhibición de la CO por IND fue confirmada por la determinación de prostaglandín E2 (PGE) en orina. La PA Control (mmH, media ñ ES) difirió significativamente entre los grupos (P < 0.001): Sham, 114 ñ 3; Clip 0.31, l35 ñ 2; Clip 0.29, 154 ñ 4 y los valores no variaron la infusión de IND, sugiriendo que la participación de los eicosanoides derivados de la CO, particularmente la PGE2, en la regulación de la hemodinamia renal de las ratas sham e hipertensas no es significativa. La excreción de sodio fue menor en el período Control de las ratas Clip 0.29 (P<0.01). El significativo efecto natriurético observado en este grupo Clip 0.29 por la infusión de IND sugiere la contribución de um metabolito del AA para el manejo renal del sodio en la hipertensión renovascular más severa (AU)