Relaxant activity of methanolic extract from seeds of Peganum harmala on isolated rat aorta.

The activity of methanolic extract from the seeds of Peganum harmala L. (MEP) on vascular smooth muscle (rat aorta) was investigated. MEP induced relaxation in aorta precontracted with noradrenaline (10(-6) M) or KCl (80 mM) (IC50 = 14.49 +/- 1.15 and 5.93 +/- 1.26 micrograms/mL, respectively) in a dose-dependent manner and this relaxant effect was not endothelium-dependent. The vasodilatory effects were potentiated by isoprenaline (10(-9) M) (1.08 +/- 0.14 micrograms/mL) and negatively affected by a non-specific inhibitor of phosphodiesterase, IBMX (10(-4) M) (20.81 +/- 1.06 micrograms/mL). Pretreatment with MEP (3, 6, 18 micrograms/ml) shifted the phenylephrine-induced dose-response curves to the right and the maximum response was attenuated, indicating that the antagonist effect of MEP on alpha 1-adrenoceptors was non-competitive. These results suggest that MEP exerts a vasodilatory effect not related to the presence of endothelium and the main mechanism may be related to the inhibition of cyclic AMP phosphodiesterase.

Estatinas en el tratamiento de dislipemias / Statins in the treatment of dyslipemias

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Action of tacrine on muscarinic receptors in rat intestinal smooth muscle.

1. The reversible cholinesterase inhibitor, tacrine (THA) was examined against the contractions of rat duodenum to acetylcholine and carbachol (cholinesterase resistant). 2. Tacrine (10(-6) M) showed a similar behaviour to physostigmine (10(-6) M), changing the characters of the concentration-response curve to Ach. The contractual responses were shifted to the left at low concentrations of ACh to reveal a bell-shaped curve with declaring contradictions at high concentrations of ACh. 3. Antagonism by atropine (10(-8) M) was reduced in the presence of tacrine (10.54, dose-ratio) compared with the shift of the curve in the absence of tacrine (73.9, dose-ratio). The declining phase of the concentration-response curve to ACh was also antagonized by atropine. 4. Further evidence for muscarininc receptor antagonism by tacrine was a small rightward shift of the concentration-response curve for carbachol, an agonist immune to cholinesterase. 5. This study has shown that tacrine acts both as a cholinesterase inhibitor and muscarinic antagonist on rat intestinal smooth muscle.

Effects of dietary oleic-rich oils (virgin olive and high-oleic-acid sunflower) on vascular reactivity in Wistar-Kyoto and spontaneously hypertensive rats.

The effects of two monounsaturated fatty acid (MUFA)-rich diets, containing virgin olive oil (OO) and high-oleic-acid sunflower oil (HOSO), on development of vascular response from isolated thoracic rat aorta and lipid composition and fatty acid composition were studied and compared with samples from rats fed on a control diet. Dietary MUFA oils were fed for 6 weeks to spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats from 4 weeks of age. The maximum contraction of aortic ring preparations in response to phenylephrine (10(-6) m) was significantly decreased in SHR rats fed with OO (0.81 (sem 0.05) v. 1.18 (sem 0.09) g, and treatment with HOSO did not alter the phenylephrine-induced contractions. The relaxant responses to acetylcholine (10(-5) m) were significantly enhanced (30.03 (sem 0.70) v. 18.47 (sem 0.28) %, in the rings from SHR rats treated with OO, and were more pronounced than in WKY rats In the same way, OO attenuated the dose-response curves induced by phenylephrine (10(-8)-10(-5) m) from SHR rats, accompanied with a slower contraction. These results suggest that only the chronic feeding of OO diet was able to attenuate the vascular response of rat aorta. In addition, an increase in phospholipid content (186.7 (sd 3.2) v. 159.1 (sd 11.3) g/kg, and changes in the fatty acid composition of aorta (mainly a decrease in arachidonic acid) could contribute to improving endothelial function. Therefore, the effects can not be attributed exclusively to the content of MUFA (mainly oleic acid). Other components of OO, such as polyphenols, not present in HOSO, may help to explain the vascular protective effect of OO consumption.

Effect of simvastatin on vascular smooth muscle responsiveness: involvement of Ca(2+) homeostasis.

This report is focused on the study of simvastatin-induced relaxation of rat aorta through its effects on vascular smooth muscle and Ca(2+) signalling. The presence of endothelium affected only the simvastatin-induced relaxation of aortic rings precontracted with noradrenaline, but not by depolarization with KCl 80 mM. Blockade of Ca(2+) entry through voltage-operated Ca(2+) channels (VOCCs) by diltiazem abolished the endothelium-dependent and direct relaxation, whereas Ca(2+)-ATPase inhibition by cyclopiazonic acid (3 x 10(-5) M) only affected the endothelium-dependent relaxation. In KCl-depolarised arteries concentration-response curves for CaCl(2) were shifted to the right in the presence of simvastatin (3 x 10(-6) and 3 x 10(-5) M) or diltiazem (10(-6) and 10(-7) M). The transient contraction caused by noradrenaline in Ca(2+)-free medium, which is mainly due to intracellular Ca(2+) release, was inhibited by simvastatin (3 x 10(-5) M) or cyclopiazonic acid (3 x 10(-5) M) and the contraction induced by CaCl(2) (2 x 10(-3) M) added after noradrenaline was inhibited by diltiazem and simvastatin. All the reported effects of simvastatin were inhibited by the product of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, mevalonate (10(-3) M). These findings demonstrate that the vascular effects of simvastatin may involve both Ca(2+) release from intracellular stores, which could promote activation of endothelial factors, and blockade of extracellular Ca(2+) entry, which promote relaxations independent of the presence of endothelium. This action on Ca(2+) could be related to the inhibition of isoprenoid synthesis, which subsequently affects the function of G-proteins involved in communication among intracellular Ca(2+) pools and capacitative Ca(2+) entry.

Characterization of endothelial factors involved in the vasodilatory effect of simvastatin in aorta and small mesenteric artery of the rat.

1. Vascular effects of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, simvastatin, were studied in conductance (aorta) and resistance vessels (branch II or III of superior mesenteric artery, SMA) of the rat (12 - 14 weeks old). 2. Simvastatin produced relaxation of both aorta and SMA, with and without functional endothelium. These responses were inhibited by the product of HMG-CoA reductase, mevalonate (1 mmol l(-1)). 3. In vessels with functional endothelium, the NO-synthase inhibitor, L-N(G)-nitroarginine (L-NOARG, 30 micromol l(-1)), inhibited simvastatin-induced relaxation. In the presence of L-NOARG, relaxation to simvastatin was lower in vessels with endothelium than in endothelium-denuded arteries without L-NOARG. 4. The cyclo-oxygenase inhibitor, indomethacin (10 micromol l(-1)), abolished endothelium-dependent component of the response to simvastatin in both arteries. The combination of L-NOARG plus indomethacin did not produce further inhibition. The T(p) receptor antagonist, GR 32191B (3 micromol l(-1)), did not affect relaxation in aorta but it reduced response to low concentrations of simvastatin in SMA. However, the inhibitory effect of L-NOARG was less marked in the presence of GR 32191B in aorta but not in SMA. 5. The endothelium-dependent relaxation to simvastatin was inhibited by the superoxide dismutase (SOD, 100 u ml(-1)) or by the tyrosine kinase inhibitor, genistein (30 micromol l(-1)) in the two arteries. 6. The present study shows that simvastatin produces relaxation of conductance and small arteries through mevalonate-sensitive pathway. The endothelium-dependent relaxation to simvastatin involves both NO and vasodilator eicosanoids by a mechanism sensitive to SOD, and to genistein. Also, the results highlighted participation in the aorta of endothelial vasoconstrictor eicosanoids acting on the T(p) receptor after blockage of NO synthase only.

Endothelium modulates contractile response to simvastatin in rat aorta.

Simvastatin is an inhibitor of HMG-CoA reductase used in the treatment of hypercholesterolemia. In the present study simvastatin-induced contraction was observed in rat aortic thoracic rings, this effect increased when the endothelium was removed and when NO synthase was blocked by L-NOARG (3 x 10(-5) M). The contractile effect of simvastatin on intact aortic rings diminished when cyclo-oxygenase was inhibited with indomethacin (10(-5) M). Also in the presence of endothelium, pretreatment with mevalonate (1 mM), the product of HMG-CoA reductase activity, significantly inhibited the contraction. In other experiments carried out on endothelium-removed preparations and in medium containing the calcium antagonist, diltiazem (10(-5) and 10(-6) M), the contraction dose-response curves were significantly reduced and the same happened in the presence of the inhibitor of sarcoplasmic reticulum Ca-2+-ATPase, cyclopiazonic acid (CPA) (3 x 10(-6) M). The results suggest that simvastatin might increase intracellular calcium concentration. This effect could lead to an activation of NO synthase and cyclooxygenase pathways in endothelial cells and to contraction in vascular smooth muscle cells. This rise in Ca2+ concentration could be due to an inhibition of isoprenoid synthesis prevented by mevalonate.

Effects of chronic treatment with simvastatin on endothelial dysfunction in spontaneously hypertensive rats.

OBJECTIVE: To investigate the effects of chronic treatment with simvastatin (SV) on endothelium-dependent relaxation and ouabain-induced contractions in aortic rings from spontaneously hypertensive rats (SHR), comparing with normotensive Wistar-Kyoto rats (WKY). METHODS: After a 12-week period of administration of 1 or 2 mg/kg SV to SHR and WKY, systolic blood pressure (SBP) and vascular reactivity in endothelium-intact aortic rings were assessed. RESULTS: Relaxation in response to acetylcholine (ACh) in WKY remained unaltered, but in SHR treated with 1 mg/kg SV, enhanced ACh-induced relaxation (P<0.05 versus untreated SHR) reached values observed in untreated WKY. The 2 mg/kg treatment also improved ACh relaxation (P<0.01 and P<0.05 versus untreated SHR and WKY respectively). Inhibiting cyclo-oxygenase (COX) with indomethacin (INDO) improved ACh relaxation in SHR (P<0.05) but not in WKY, independent of treatment with SV. Inhibition of nitric oxide synthase (NOS) with N(G)-nitro-L-arginine (L-NOARG) abolished ACh relaxations in all cases (P<0.001). The result was unaltered when combining INDO plus L-NOARG. SV treatment also decreased ouabain-induced contractions in endothelium-intact aortic rings from SHR, diminishing the percentage effect of contraction from 64.56+/-2.95 (untreated SHR) to 26.98+/-7.06 and 38.10+/-8.21 (1 and 2 mg/kg treated SHR respectively). Response to ouabain in WKY was not significantly affected by SV treatment CONCLUSIONS: Chronic treatment of SHR with SV improves endothelium-dependent ACh relaxation of the aortic rings, probably by an NO-involving mechanism more than by inhibiting contractile COX-derived factors. An improvement in endothelial modulation of ouabain-induced contractions was also observed after treatment with SV in SHR, which might be due to an inhibition of a calcium-sodium exchanger.

Cardiovascular effects of lovastatin in normotensive and spontaneously hypertensive rats.

1. Lovastatin (1, 1.5, and 2 mg/kg) decreased systolic (SBP) and diastolic blood pressure (DBP) in spontaneously hypertensive rats (SHRs) and did not modify the basal values of blood pressure in normotensive rats. 2. Lovastatin decreased heart rate in a dose-dependent manner, and significant effects were observed in SHRs 180 min after lovastatin administration. 3. Lovastatin did not act as a diuretic drug at any of the doses used. 4. Lovastatin (10[-6] M-3 x 10[-4] M) depresses contractions evoked by KCl (80 mM) in isolated thoracic aorta from SHRs and WRs and had almost no relaxant effects on NA-induced (10[-5] M) contractions. 5. It is concluded that the main antihypertensive mechanism of lovastatin is due to the relaxation of rat aorta by inhibiting Ca2+ influx through voltage-sensitive calcium channels.

In vitro scavenger and antioxidant properties of hesperidin and neohesperidin dihydrochalcone.

We have assesed the actions as free radical scavengers and inhibitors on peroxidation of hesperidin and neohesperidin dihydrochalcone, two flavonoids, flavanone and dihydrochalcone respectively, as some of the pharmacological properties of flavonoids group have been related with these activities. Hesperidin just at 10(-4) and 5 · 10(-4)M is able to show a low inhibitory activity in the superoxide anion radicals (O(2)(-)) genesis (8.66 ± 1.40 and 11.69 ± 2.36% respectively), and on the non-enzymatic lipid peroxidation at 10(-3)M dose (9.78 ± 0.35%), without affecting the hydroxyl radical (•OH) formation, generated by the ascorbic acid-Fe(3+)-EDTA system. In the other hand, neohesperidin dihydrochalcone is an authentic antioxidant drug as tested at all doses. It showed a great scavenger activity and/or inhibition of formation on O(2)(-) radicals (31.53 - 84.62%) and a significant scavenging effect on OH radicals (6.00 - 23.49%), as well as an important inhibitory action on non-enzymatic lipid peroxidation (15.43-95.33%).

Uterine relaxant effect of zolpidem: a comparison with other smooth muscle relaxants.

Zolpidem is an imidazopyridine sedative-hypnotic which interacts with central benzodiazepine-receptors. To examine its effects on uterine smooth muscle we have compared with those obtained by diltiazem, papaverine and diazepam on different experimental models. The IC50 values obtained indicate similar behaviour of zolpidem and diazepam. They showed more active against the spontaneous contractions and those induced by KCl (60 mM) or by CaCl2 (0.01-10 mM) in Ca(2+)-free depolarizing medium than against acetylcholine (0.1 mM)-induced contractions. Both of them also showed more effectiveness against the tonic component of the acetylcholine-evoked contraction than against the phasic one. All the drugs tested were less powerful against contractions induced by oxytocin than against those induced by other agonists. This observation let us speculate that the mechanism of action of zolpidem may be related to an action on Ca2+ influx through voltage-dependent Ca2+ channels due to an interaction with low affinity receptor located at the plasmalemma as has been suggested for diazepam.

Spasmolytic effects of tetrazepam on rat duodenum and guinea-pig ileum.

This study was designed to examine the inhibitory effects exerted by tetrazepam isolated rat duodenum and guinea pig ileum contractive responses and to further clarity the mechanisms involved. Tetrazepam produced concentration-dependent and complete relaxation of muscle contractions induced by KCl (80 mM) in guinea-pig ileum and this relaxant action was not antagonized by pretreatment with hexamethonium (0.1 mM), antagonist for nicotinic receptors, or atropine (1 microM), antagonist for muscarinic receptors, or PK 11195 (1 microM) antagonist for peripheral-type benzodiazepines receptors. Tetrazepam also modified the concentration-response curves of CaCl2 in calcium-free and high K/ depolarizing medium as soon as concentration-response curves of acetylcholine in Tyrode solution. The results suggested that tetrazepam inhibits the contractile responses to guinea-pig ileum and rat duodenum, probably through a reduction of calcium influx by way of calcium channels and these events are not related to high-affinity peripheral benzodiazepine binding sites.

Vasodilating effects of tetrazepam in isolated vascular smooth muscles: comparison with cromakalim and diltiazem.

The vasodilating effects of tetrazepam (1,4-benzodiazepine derivative) were studied and compared with those of the K-channel activator, cromakalim and the Ca-channel blocker, diltiazem, in rat aorta smooth muscle and on the spontaneous contractile activity of the rat portal vein. In the aorta, tetrazepam (3 x 10(-7)-10(-4) M) and diltiazem (10(-8)-3 x 10(-6) M) concentration-dependently relaxed aortic rings contracted by 30 mM as well as 80 m KCl. Although cromakalim (10(-8)-3 x 10(-6) M) concentration-dependently relaxed aortic rings contracted by 30 mM KCl, it did not relax those contrated by 80 mm KCl. In the presence of the ATP-sensitive K-channel blocker, glibenclamide (10(-6) and 3 x 10(-6) M), 30 mM KCl concentration-response curves for the relaxant effect of tetrazepam and diltiazem were unaffected but cromakalim caused a progressive shift of these curves upwards. In the portal vein, tetrazepam inhibited spontaneous contractions, decreased amplitude and increased frequency. Similar behaviour was shown with diltiazem (10(-8)-10(-5) M) and in both cases, pre-treatment with glibenclamide (10(-6) M) was ineffective. Although cromakalim (10(-5)-10(-6) M) decreased both amplitude and frequency, this effect was blocked by glibenclamide. These results indicate that the vasodilator action of tetrazepam is not mediated to the opening of ATP-sensitive K-channels, unlike cromakalim. This may be mediated, like those of diltiazem, by the blockade of calcium movements across the cell membrane.

Relaxant effect of tetrazepam on rat uterine smooth muscle: role of calcium movement.

Tetrazepam is a benzodiazepine derivative clinically used as a muscle relaxant. The aim of the present work was to examine its effect on uterine smooth muscle of the rat in estrus. Tetrazepam required micromolar concentrations to relax contractile responses induced by KCl and acetylcholine in Ca2+ solution, but not oxytocin-induced contraction. In Ca(2+)-free solution, tetrazepam inhibited Ca(2+)-induced contractions in depolarized uterus and vanadate-induced contractions. We suggest that tetrazepam relaxes contractile responses induced by activation of voltage-sensitive calcium channels and receptor-operated calcium channels with little selectivity or that it antagonizes the effect of calcium at subsequent steps, possibly intracellular stores sensitive to vanadate but not sensitive to oxytocin. The inhibition of contraction of rat uterus is not related to high-affinity peripheral benzodiazepine binding sites.

Smooth muscle relaxant effects of tetrazepam on isolated guinea-pig and rat trachealis.

1. Tetrazepam (TZP) suppressed rat and guinea-pig tracheal tone by 100% and there was no difference in the relaxant effects against tone induced by 120 mM K+, carbachol (0.5 microM) or histamine (100 microM). 2. In trachealis pretreated with propranolol (1 microM), the relaxant response to TZP was unaltered. 3. TZP (10 microM) added to the relaxant effect of isoprenaline in tissues precontracted with carbachol. 4. The relaxant effect of TZP appears to be unrelated to peripheral benzodiazepine receptors (PBRs) because pretreatment with PK 11195 (1 microM) did not modify its effect. 5. Diltiazem (a calcium antagonist) was capable of relaxing the KCl (120 mM) or carbachol (0.5 microM) precontracted trachea, although at a different dose range than that of TZP. 6. The tracheal relaxation by TZP may be due to competition at some point in the chain of events linking carbachol, K+ or histamine to contraction, interacting with one of the transduction pathways, probably Ca2+. This inhibition of contraction is not related to the high-affinity PBRS.

Effects of flavonoids on rat aortic smooth muscle contractility: structure-activity relationships.

1. Flavonoids produced a concentration-dependent relaxation of the contractile responses induced by noradrenaline, KCl, or phorbol 12-myristate-13-acetate in rat aortic rings. Only the flavonoid with three contiguous hydroxyls in B rings (myricetin), at low concentrations, potentiates the contractions evoked by these agonists. 2. The relaxant effects of flavanone on the noradrenaline-induced contractions were potentiated by isoprenaline and those of morin, chrysin, flavanone, and naringenin by sodium nitroprusside. 3. Several mechanisms are implicated in the vasodilatory effects of flavonoids: inhibition of protein kinase C; inhibition of cyclic nucleotide phosphodiesterases; and/or decreased Ca2+ uptake.

Antisecretory and gastroprotective effects of aescine in rats.

1. This study was designed to determine the antisecretory effects of aescine in the perfused stomach of the anaesthetized rat. In addition, the effects of aescine on mucosal lesions produced by intragastric instillation of 1 ml of absolute ethanol, its action on the production of mucus and the possible role of PGs in aescine induced gastroprotection were also studied. 2. Pretreatment of aescine (10 and 50 mg/kg) inhibited the increases in acid secretion induced by histamine (5 mg/kg) and carbachol (10 micrograms/kg). At the highest dose used abolished nearly the increase induced by carbachol (P < 0.001). 3. Aescine (10, 25 and 50 mg/kg) was found to be effective in the prevention of gastric ulceration induced by absolute ethanol in rats. The degree of gastroprotection decreased with time, the optime effects occurring 60-120 min after oral administration. Pretreatment with indomethacin (10 mg/kg) partially inhibited the gastric protection but the PGE2 determination did not show an increase in prostanoid levels. Furthermore, the protective effect was not associated with an increase in the amount of gastric mucus and glycoprotein content. 4. These results indicate that aescine exerts an antisecretory action which could play a possible role in its antiulcerogentic activity. Also it shows a marked protective mucosal activity which could be partly explained through non-prostaglandin dependent mechanisms involving its antiinflammatory and vasoactive properties.

Antiulcer effect of naringin on gastric lesions induced by ethanol in rats.

This study was designed to determine the gastroprotective properties of naringin on and the involvement of endogenous prostaglandins in mucosal injury produced by absolute ethanol. Oral pretreatment with the highest dose of naringin (400 mg/kg), 60 min before absolute ethanol was the most effective antiulcer treatment. Subcutaneous administration of indomethacin (10 mg/kg) to the animals treated with naringin (400 mg/kg) partially inhibited gastric protection, but the prostaglandin E2 determination did not show any increase in prostanoid levels. The contents of gastric mucus and total proteins were not significantly modified. Naringin-treated rats showed a marked increase in hexosamine levels, but this increase was less in animals pretreated with indomethacin. These results show that naringin has a 'cytoprotective' effect against ethanol injury in the rat, but this property appears to be mediated by non-prostaglandin-dependent mechanisms.

Prevention by rutin of gastric lesions induced by ethanol in rats: role of endogenous prostaglandins.

1. This study was designed to demonstrate the cytoprotective effect of Rutin against ethanol-induced gastric injury in rats and to determine whether this cytoprotective effect is mediated by endogenous prostaglandins. 100 and 200 mg/kg of Rutin given orally 1 hr before administration of 1 ml of 100% ethanol significantly (p < 0.01) reduced the area of macroscopic lesions induced by ethanol (84.16 +/- 23.01 and 54.75 +/- 16.05 respectively) when compared to distilled water (305.60 +/- 67.20). However, it did not induce changes in the amount and total proteins and hexosamines content of gastric mucus. 2. Pretreatment with indomethacin, 10 mg/kg s.c. 30 min before Rutin administration, slightly but not significantly reduced the cytoprotective effect. 3. The levels of PGE2 present in the mucous material were not significantly modified with administration of Rutin (100 mg/kg). 4. These results show that Rutin has a cytoprotective effect against ethanol injury in the rat, but this property does not appear to be mediated by endogenous prostaglandins.

Effect of naringin and naringenin on contractions induced by noradrenaline in rat vas deferens--I. Evidence for postsynaptic alpha-2 adrenergic receptor.

1. Naringin at all doses (2 x 10(-6), 5 x 10(-7), and 1 x 10(-7) M) significantly increased contractions induced by noradrenaline in rat vas deferens but the increments of maximal contraction were not concentration-dependent. 2. In a medium containing 1 x 10(-6) M yohimbine (a selective blocker of alpha 2-adrenoceptor) and naringin, the curve constructed with noradrenaline decreased below the control curve. 3. Naringenin (aglycone of naringin) (2 x 10(-6) and 1 x 10(-7) M) increased the contractile effect of noradrenaline and the maximal effect evoked was related to the maximal dose of naringenin. 4. The alpha 2 antagonism produced by yohimbine in the naringenin-noradrenaline association were retained at two doses of naringenin tested and we noticed a similar behaviour when we used clonidine-noradrenaline.