Selective bronchodilatory effect of Rooibos tea (Aspalathus linearis) and its flavonoid, chrysoeriol

BACKGROUND: Rooibos tea (Aspalathus linearis) is commonly used for hyperactive gastrointestinal, respiratory and cardiovascular disorders. AIM OF STUDY: The aqueous extract of Rooibos tea (RT) was studied for the possible bronchodilator, antispasmodic and blood pressure lowering activities in an attempt to rationalize some of its medicinal uses. METHODS: Isolated tissue preparations, such as rabbit jejunum, aorta and guinea-pig trachea and atria were set up in appropriate physiological salt solutions and aerated with carbogen. For in vivo studies rats were anesthetized with pentothal sodium and blood pressure was measured through carotid artery cannulation. RESULTS: In jejunum, RT caused a concentration-dependent relaxation of low K(+) (25 mM)-induced contractions, with mild effect on the contractions induced by high K(+) (80 mM). In presence of glibenclamide, the relaxation of low K(+)-induced contractions was prevented. Similarly, cromakalim caused glibenclamide-sensitive inhibition of low K(+), but not of high K(+), while verapamil did not differentiate in its inhibitory effect on contractions produced by the two concentrations of K(+). Like in jejunum, RT caused glibenclamide-sensitive relaxation of low K(+)-induced contractions in trachea and aorta, but with a 20 times higher potency in trachea. In atria, RT was least potent with weak inhibitory effect on atrial force and rate of contractions. RT caused a dose-dependent fall in arterial blood pressure in rats under anesthesia. Among the tested pure compounds of Rooibos, chrysoeriol showed selective bronchodilator effect. Chrysoeriol (luteolin 3'-methyl ether) is a bioactive flavonoid known for antioxidant, antiinflammatory, antitumor, antimicrobial, antiviral, and free radical scavenging activities. CONCLUSION: These results indicate that the bronchodilator, antispasmodic and blood pressure lowering effects of Rooibos tea are mediated predominantly through K(ATP) channel activation with the selective bronchodilatory effect. This study provides a sound mechanistic basis for the wide medicinal use of Rooibos tea, with the therapeutic potential to be developed for congestive respiratory ailments.     

K_(ATP)开放剂克罗卡林对新生鼠缺氧缺血性脑损伤细胞凋亡的影响

目的:探讨ATP敏感性钾通道(KATP)开放剂克罗卡林(cromakalim)对新生大鼠缺氧缺血性脑损伤(hy-poxic-ischemic brain damage,HIBD)细胞凋亡的影响,为临床治疗新生儿缺氧缺血性脑病提供依据。方法:建立新生大鼠HIBD模型,应用HE染色、DNA原位末端标记法(TUNEL)、免疫组化染色方法观察正常对照组、假手术组、HIBD组,克罗卡林用药组(用药1组),克罗卡林+格列苯脲用药组(用药2组)病理变化、细胞凋亡及Bcl-2,Bax蛋白表达情况。结果:①HIBD组大脑皮质区病理变化明显,用药1组病理变化减轻,用药2组病理变化加重;②对照组及假手术组见少量凋亡细胞;HIBD组凋亡细胞明显增多,与对照组及假手术组比较差异有显著性(P<0·01);用药1组凋亡细胞明显减少,与HIBD组比较差异有显著性(P<0·01);用药2组凋亡细胞与HIBD组比较差异无显著性(P>0·05);③正常对照组及假手术组大脑皮质区Bcl-2有一定量的表达,Bax几乎无表达,HI后该区Bcl-2表达减弱,Bax表达增强,用药1组Bcl-2表达较HIBD组明显增强(P<0·01),Bax表达明显减弱(P<0·01),而用药2组Bcl-2表达及Bax表达与HIBD组比较差异无显著性(P>0·05)。结论:HIBD后Bcl-2蛋白表达减弱,Bax蛋白表达增强,细胞凋亡增加;克罗卡林可上调Bcl-2表达,下调Bax表达,使凋亡细胞减少,而KATP阻断剂格列苯脲可拮抗克罗卡林以上作用,这可能是克罗卡林治疗新生儿缺氧缺血性脑损伤的机制之一。     

Mechanisms of copper accumulation in isolated mantle cells of the marine clam Mesodesma mactroides

In vivo copper accumulation was determined in tissues (mantle, gills, digestive gland, and hemolymph) following exposure to Cu (5 μM) for up to 96 h. Mantle was the tissue that accumulated the most Cu, followed by gill, digestive gland, and hemolymph. Therefore, in vitro Cu accumulation was evaluated in isolated mantle cells exposed to 0.5, 1.0, 2.5, and 5.0 μM Cu for 1 and 3 h. After both exposure times, no change in cell viability was observed. However, a significant Cu accumulation was observed in cells exposed to 2.5 and 5.0 μM Cu. Cell exposure to 2.5 μM Cu for 1 h did not affect the ionic (Na(+), K(+), Ca(2+), and Cl(-)) content of isolated mantle cells, characterizing an "ideal" noneffect concentration for the study of the involvement of different ion-transporting proteins (Na(+), K(+), and Cl(-) channels; Na(+)/K(+) 2Cl(-) and Na(+)/Cl(-) cotransporters; Na(+)/Ca(2+), Cl(-)/HCO3-, and Na(+)/H(+) exchangers; Na(+)/K(+) -ATPase; V-ATPase; and carbonic anhydrase) in Cu accumulation. Isolated cells were pre-exposed (30 min) to specific blockers or inhibitors of the ion-transporting proteins and then exposed (1 h) to Cu (2.5 μM) in the presence of the drug. A significant increase of 29.1 and 24.3% in Cu accumulation was observed after cell incubation with acetozalamide (carbonic anhydrase inhibitor) and NPPB (Cl(-) channels blocker), respectively. On the other hand, a significant decrease (48.2%) in Cu accumulation was observed after incubation with furosemide (Na(+) /K(+)/2Cl(-) blocker). Taken together, these findings indicate the mantle as an important route of Cu entry in M. mactroides, pointing to the cotransporter Na(+)/K(+)/2Cl(-) as a major mechanism of Cu accumulation in mantle cells of the clam.     

Effects of postnatal steroids on Na+/K+-ATPase activity and alpha1- and beta1-subunit protein expression in the cerebral cortex and renal cortex of newborn lambs

Na(+)/K(+)-ATPase is a membrane-bound enzyme responsible for Na(+)/K(+) translocation across cell membranes. It is essential for the generation of electrochemical gradients, which control the ionic environment necessary for electrical activity and water and electrolyte balance. Newborn infants who are at risk of developing bronchopulmonary dysplasia (BPD) are frequently treated with corticosteroids. Although these infants are at risk for neurological, water and electrolyte abnormalities, there is little information regarding the effects of clinically relevant doses of corticosteroids on Na(+)/K(+)-ATPase activity and protein isoform expression in the brain and kidney of newborns. In the present study, we examined the effects of dexamethasone on cerebral cortical and renal cortical Na(+)/K(+)-ATPase activity and alpha1- and beta1-protein isoform expression in newborn lambs. Lambs were given four injections of a placebo (n = 11) or one of three different doses of dexamethasone (0.01 mg kg(-1), n = 9; 0.25 mg kg(-1), n = 11; or 0.50 mg kg(-1), n = 9) 12 h apart on Postnatal Days 3 and 4 up to 18 h before harvest of the cerebral cortex and renal cortex. We selected doses in a range to approximate those used to treat infants with BPD. Na(+)/K(+)-ATPase activity was measured in membrane preparations as ouabain-sensitive inorganic phosphate liberation from ATP and alpha1- and beta1-subunit abundance by Western immunoblot. Postnatal treatment of lambs with dexamethasone resulted in a 21.4% increase in Na(+)/K(+)-ATPase activity and a 30.4% increase in catalytic alpha1-protein expression in the cerebral cortex at a dose of 0.50 mg kg(-1) dexamethasone, but not at the lower doses. Dexamethasone treatment was not associated with changes in beta1-isoform expression in the cerebral cortex. In the kidney, dexamethasone treatment was not associated with significant changes in Na(+)/K(+)-ATPase activity or alpha1- or beta1-isoform expression for the doses we examined. Therefore, clinically relevant corticosteroid treatment exerts dose-related, differential organ-specific effects on Na(+)/K(+)-ATPase activity and protein isoform expression in newborn lambs.     

Synthesis, biological activity and conformational study of 1,4-benzoxazine derivatives as potassium channel modulators

With the aim of discovering new molecules with K⁺-channel activating properties, we have synthesized derivatives of cromakalim (CRK), an important molecule which shows specific affinity towards K⁺ channels, by replacing the benzopyrane ring of this reference compound with a 1,4-benzoxazine moiety. A different number of substituents showing a good discrimination between hydrophobic and electronic properties have been inserted at the 6-position of the 1,4-benzoxazine ring. We describe here the synthesis and discuss the solid state conformation of these new molecules. When tested on rat aorta ring precontracted with phenylephrine, two compounds (2c and 2d) showed a concentration-dependent relaxation similar to that measured for cromakalim but less potent than this reference drug.     

A quantitative structure-activity relationship study on a novel class of calcium-entry blockers: 1-[(4-(aminoalkoxy)phenyl)sulphonyl]indolizines

A quantitative structure-activity relationship (QSAR) study has been made on two different series of 1-[(4-(aminoalkoxy)phenyl)sulphonyl]indolizines acting as calcium entry blockers, using some physicochemical and structural parameters. Two different assays were reported for both the series: (IC(50))(A), referring to the molar concentration of the compound required to reduce [3H] nitrendipine binding by 50%, and (IC(50))(B), referring to that required to block Ca(2+) induced concentration of K(+) depolarised rat aorta by 50%. For series 1, where the 2-position substituents of indolizine ring were varied along with the aminoalkoxy moieties of the phenyl ring, the QSAR analysis shows that the 2-position substituents can equally affect both the activities through their hydrophobic and electronic properties and the aminoalkoxy moiety through some steric effects. For series 2, where the indolizine ring has been replaced by varying heterocyclic rings, along with the changes in aminoalkoxy moiety of the phenyl ring, the QSAR exhibits that these different heterocyclic rings affect both the activities through some steric roles, altering the conformations of the receptors from system A to system B. Among the different heterocyclic rings, the N-substituted indole ring is shown to be more conducive to both the activities than any other ring. However, a 5-membered ring is indicated to be less effective than a 9- or 10-membered ring for activity B. Additionally, the amino moieties having phenyl ring with methoxy groups at 3,4,and 5-positions are shown to favour both A and B activities.     

A possible subcellular mechanism underlying the "French paradox": the opening of mitochondrial K(ATP) channels

A reduction in the risk of coronary heart disease has been associated to moderate red wine consumption. We tested whether a nonalcoholic red wine extract would open mitochondrial K(ATP) channels in guinea pig myocytes. The opening of mitochondrial K(ATP) channels was assessed by endogenous flavoprotein fluorescence. Red wine extract (100 μg·mL(-1)) increased flavoprotein oxidation (10.9% ± 1.2%, n = 20). This effect was prevented by the mitochondrial K(ATP) channel blocker, 5-hydroxydecanoate (500 μmol·L(-1); 0.3% ± 1.1%, n = 13), confirming the hypothesis that red wine extract opens mitochondrial K(ATP) channels.     

Effect of copper on ion content in isolated mantle cells of the marine clam Mesodesma mactroides

The effect of copper on ion content (Na(+), K(+), Ca(2+), and Cl(-)) was evaluated in isolated mantle gills of the marine clam Mesodesma mactroides. Clams were collected at the Mar Grosso Beach (S?o José do Norte, Rio Grande do Sul [RS], southern Brazil), cryoanesthetized, and had their mantles dissected. Mantle cells were isolated and incubated in a calcium-free phosphate solution without (control) or with Cu (CuCl(2)). Cells were exposed to Cu for 1 h (5 μM) or 3 h (2.5 and 5 μM). In cells incubated with 2.5 μM Cu, a significant decrease in intracellular Cl(-) content was observed. However, in cells incubated with 5.0 μM Cu, significant reductions in Na(+), K(+), and Cl(-) intracellular content were observed. Given the mechanisms involved in ion transport in mantle cells of the marine clam M. mactroides, the findings described here suggest that Cu exposure inhibits carbonic anhydrase and Na(+)/K(+) -ATPase activity. Also, it can be suggested that Cu is competing with Na(+) for the same mechanisms of ion transport in the cell membrane, such as the Na(+) channels and the Na(+)/K(+)/2Cl(-) cotransporter. Results from the present study also clearly indicate that processes involved in cellular anion regulation are more sensitive to Cu exposure than those associated with the cellular cation regulation. Characterization of sites for Cu accumulation and toxicity in aquatic animals is important for derivation of metal binding constants at the biotic ligand. Also, identification of the mechanism of metal toxicity is needed for modeling metal accumulation in the biotic ligand and its consequent toxicity. Therefore, the findings reported here are extremely valuable for the development of a biotic ligand model version for marine and estuarine waters.     

The effect of L-cysteine and glutathione on inhibition of Na+, K+-ATPase activity by aspartame metabolites in human erythrocyte membrane

BACKGROUND: Reports have implicated Aspartame (N-L-a-aspartyl-L-phenylalanine methyl ester, ASP) in neurological problems. AIM: To evaluate Na(+), K(+)-ATPase activities in human erythrocyte membranes after incubation with the ASP metabolites, phenylalanine (Phe), methanol (MeOH) and aspartic acid (Asp). METHODS: Erythrocyte membranes were obtained from 12 healthy individuals and were incubated at 37 degrees C for 1 h with the sum or each of the ASP metabolites separately, which are commonly measured in blood after ASP ingestion. Na(+), K(+)-ATPase and Mg(2+)-ATPase activities were measured spectrophotometrically. RESULTS: Membrane Mg(2+)-ATPase activity was not altered. The sum of ASP metabolite concentrations corresponding to 34, 150 or 200 mg/kg of the sweetener ingestion resulted in an inhibition of the membrane Na(+), K(+)-ATPase by -30, -40, -48%, respectively. MeOH concentrations of 0.14, 0.60 or 0.80 mM decreased the enzyme activity by -25, -38, -43%, respectively. Asp concentrations of 2.80, 7.60 or 10.0 mM inhibited membrane Na(+), K(+)-ATPase by -26, -40, -46%, respectively. Phe concentrations of 0.14, 0.35 or 0.50 mM reduced the enzyme activity by -24, -44, -48%, respectively. Preincubation with L-cysteine or reduced glutathione (GSH) completely or partially restored the inhibited membrane Na(+), K(+)-ATPase activity by high or toxic ASP metabolite concentrations. CONCLUSIONS: Low concentrations of ASP metabolites had no effect on Na(+), K(+)-ATPase activity. High or abuse concentrations of ASP hydrolysis products significantly decreased the membrane enzyme activity, which was completely or partially prevented by L-cysteine or reduced GSH.     

Synthesis of some 2-[(benzazole-2-yl)thioacetylamino]thiazole derivatives and their antimicrobial activity and toxicity

Some 2-[(benzazole-2-yl)thioacetylamino]thiazole derivatives (III) were synthesized by reacting 4-methyl-2-(chloroacetylamino)thiazole derivatives (I) with benzazol-2-thiole (II) in acetone in the presence of K(2)CO(3). The chemical structures of the compounds were elucidated by (1)H NMR and FAB(+)-MS spectral data. The prepared compounds were tested for antimicrobial activity and toxicity.     

Effect of cadmium on transmembrane Na+ and K+ transport systems in human erythrocytes.

The effects of cadmium (Cd2+) on Na+,K(+)-ATPase in disrupted human erythrocyte membranes and on various transmembrane Na+ and K+ transport systems in intact erythrocyte suspensions were studied. Cadmium2+ inhibited the erythrocyte Na+,K(+)-ATPase enzyme with a 50% inhibition at a Cd2+ concentration of 6.25 microM. The Cd2+ inhibition in the human erythrocyte was non-competitive with respect to Na+,K+, and ATP. Cadmium2+ exerted no acute effect, however, on the Na+,K(+)-ATPase pump activity as measured by the ouabain sensitive 86Rb uptake or Na+ efflux in intact red blood cells. Cadmium2+ also inhibited the Ca2+ dependent K+ channels in human red blood cells, whereas it had no effect on Na+,K+ cotransport, Na+,Li+ countertransport, anion carrier, and the number of active Na+ pump units. The data indicate that in human erythrocytes under acute conditions Cd2+ exerts an inhibitory effect on Na+,K(+)-ATPase enzyme in disrupted erythrocytes and the Ca2+ stimulated K+ efflux in intact red blood cells without affecting the Na+ pump, Na+,K+ cotransport, and Na+,Li+ countertransport activity.     

Effect of cadmium on transmembrane Na+ and K+ transport systems in human erythrocytes.

The effects of cadmium (Cd2+) on Na+,K(+)-ATPase in disrupted human erythrocyte membranes and on various transmembrane Na+ and K+ transport systems in intact erythrocyte suspensions were studied. Cadmium2+ inhibited the erythrocyte Na+,K(+)-ATPase enzyme with a 50% inhibition at a Cd2+ concentration of 6.25 microM. The Cd2+ inhibition in the human erythrocyte was non-competitive with respect to Na+,K+, and ATP. Cadmium2+ exerted no acute effect, however, on the Na+,K(+)-ATPase pump activity as measured by the ouabain sensitive 86Rb uptake or Na+ efflux in intact red blood cells. Cadmium2+ also inhibited the Ca2+ dependent K+ channels in human red blood cells, whereas it had no effect on Na+,K+ cotransport, Na+,Li+ countertransport, anion carrier, and the number of active Na+ pump units. The data indicate that in human erythrocytes under acute conditions Cd2+ exerts an inhibitory effect on Na+,K(+)-ATPase enzyme in disrupted erythrocytes and the Ca2+ stimulated K+ efflux in intact red blood cells without affecting the Na+ pump, Na+,K+ cotransport, and Na+,Li+ countertransport activity.     

Cardiovascular effects of selective serotonin reuptake inhibitor antidepressants

This paper reviews the cardiovascular effects of fluoxetine and other selective serotonin reuptake inhibitors comparing with those of tricyclic antidepressants. The authors survey the electrophysiological mechanisms and the recent data referring on drug's actions on different ionic currents/channels. The paper primarily focuses on preclinical data, showing various effects of fluoxetine and citalopram on cardiac and smooth muscle preparations and on cardiac ionic currents. At concentrations of 0.5-50 microM, fluoxetine and citalopram exhibit depressant effects on Ca(2+)- and Na(+)-dependent electrophysiological parameters of different cardiac preparations and on cardiac Ca2+ current. At concentrations of 0.1-10 microM, fluoxetine and citalopram elicit relaxation of both vascular and intestinal smooth muscles. These results provide evidence for inhibition of cardiac Na+, Ca2+ and more recently K+ channels by fluoxetine and citalopram at concentrations close to therapeutic level. The inhibition of cardiac Ca2+, Na+ and K+ and vascular Ca2+ channels by fluoxetine and citalopram may explain most cardiovascular side effects observed occasionally with the drugs during the chronic treatment. The inhibitory effects on cardiac Ca2+, Na+ and K+ channels of fluoxetine and citalopram may result in antiarrhythmic/proarrhythmic actions. Thus fluoxetine, citalopram and other selective serotonin reuptake inhibitors similarly to tricyclic antidepressants, may exhibit cardiovascular depressant effects. The paper summarizes drug interactions that may lead risk of arrhythmia and vascular side effects. Taking all these into consideration, in depressed patients having also cardiac or liver disorders, these antidepressants should be also more rigorously applied.     

Synthesis and pharmacological evaluation of 2, 3-dihydro-3-oxo-4H-thieno[3,4-e][1,2,4]thiadiazine 1,1-dioxides as voltage-dependent calcium channel blockers

The synthesis of a novel series of 2,3-dihydro-3-oxo-4H-thieno[3, 4-e][1,2,4]thiadiazine 1,1-dioxides and their pharmacological evaluation as drugs with effects on the rat cardiovascular system are described. The compounds under study were synthesized via Curtius rearrangement of appropriate sulfamoylacylazides which, in turn, were prepared from known starting materials. In isolated rat portal vein, these thienothiadiazines, like verapamil and diazoxide, inhibited the spontaneous motility produced by KCl (20 mM). In addition, the new compounds, like verapamil and unlike diazoxide, also exhibited inhibitory effects in the same preparation when the cell membrane was depolarized by an increased extracellular KCl concentration (80 mM) and, consequently, the membrane potential approached a level close to the K(+) equilibrium potential. Further characterization of this inhibitory activity led to the identification of a selective inhibitory effect of the new compounds on KCl (80 mM)-induced 45Ca(2+) uptake in the same vascular tissue. When tested in vivo (anaesthetized normotensive rats), acute administration of verapamil, diazoxide and some of the most in vitro potent compounds in 45Ca(2+) uptake experiments produced a gradual, dose-dependent and sustained decrease in diastolic arterial blood pressure, devoid of cardiac effects. These results suggest that, like verapamil, the cardiovascular effects produced by the new thienothiadiazines seem to be due, at least in part, to a blockade of transmembrane voltage-dependent calcium channels present in vascular smooth muscle cells and not to an activation of ATP-sensitive K(+) channels. Compounds 5b, 5e and 5i have been selected for further studies as antihypertensive agents.     

Effects of quercetin and rutin on vascular preparations

BACKGROUND: Several studies have indicated that quercetin promotes relaxation of vascular smooth muscle both in vivo and in vitro. However, Saponara et al. [(2002) Br J Pharmacol 135: 1819-1827] have demonstrated that quercetin is an activator of vascular L-type Ca(2+) channels. AIM OF THE STUDY: We investigated the mechanical and electrophysiological properties of quercetin and its rutoside, rutin, in an attempt to clarify how Ca(2+) channel activation might be related to the myorelaxing activity. METHODS: Aorta ring preparations and single tail artery myocytes were employed for functional and patch-clamp experiments, respectively. RESULTS: Rutin was found to relax intact rat aorta rings, which had been precontracted with phenylephrine (pIC(50) = 5.65 +/- 0.31) but in contrast had no effect on depolarised (60 mM K(+)) preparations or on those from which the endothelium had been removed. Furthermore, rutin did not affect L-type Ca(2+) current recorded in rat tail artery myocytes. The quercetin-induced relaxation of intact rings precontracted with phenylephrine exhibited two components characterised by 6.23 +/- 0.38 and 4.66 +/- 0.09 pIC(50), respectively. Removal of the endothelium abolished the first component, leaving the second unaltered. Moreover, quercetin was found to relax 60 mM K(+) depolarised rings with a pIC(50) of 4.59 +/- 0.03. The application of quercetin in isolated smooth muscle cells brought about a marked increase of L-type Ca(2+) current (pEC(50) = 5.09 +/- 0.05). Unlike quercetin, Bay K 8644 contracted aorta rings preincubated with 10, 20 or 30 mM K(+). The myotonic effect of Bay K 8644 was observed both in the absence or presence of 30 microM quercetin. The application of Bay K 8644 (10-100 nM) caused a further significant increase in L-type Ca(2+) current in rat tail artery myocytes stimulated with 30 microM quercetin. CONCLUSIONS: Quercetin is a naturally occurring L-type Ca(2+) channel agonist. This effect, however, is overwhelmed by quercetin-induced vasorelaxation taking place via pathways which are more relevant than L-type Ca(2+) influx in the hierarchy of functional competencies.     

Food intake abolishes the response of rat jejunal Na(+),K(+)-ATPase to dopamine

The aim of the present study was to evaluate whether the sensitivity of jejunal Na(+),K(+)-ATPase to inhibition by dopamine (DA) in young rats is related to the type of food (breast milk vs. solid) or reflects a developmental adaptation. When 18-d-old rats were separated from their dams and fed solid food (the same used to feed adult rats) for 2 d, intestinal Na(+),K(+)-ATPase activity was significantly greater than that of breast-fed pups of the same age (20 d) (127 +/- 8 vs. 52 +/- 4 nmol Pi. mg protein(-1). min(-1); P < 0.05). Activity in rats fed solid food was insensitive to inhibition by 1 micromol/L DA. Na(+),K(+)-ATPase activity in 60-d-old rats (117. 4 +/- 4.2 nmol Pi. mg protein(-1). min(-1)) was also higher (P < 0. 05) than in breast-fed rats, and DA (1 micromol/L) did not inhibit enzyme activity. The B(max) value for binding of [(3)H]-Sch 23390 in 20-d-old breast-fed rats did not differ from that in age-matched rats fed a solid food for 2 d and or that in 60-d-old rats. Levels of DA, but not L-3,4-dihydroxyphenylalanine and amine metabolites, in the jejunal mucosa of 20-d-old rats that had eaten solid food for 2 d were 60% lower than in age-matched rats, breast-fed rats, and not different from those in the jejunal mucosa of 60-d-old rats fed the solid food. We conclude that in adult rats, in contrast to in young rats, DA does not inhibit jejunal Na(+),K(+)-ATPase activity, and food intake in young rats plays an important role in the development of the insensitivity of Na(+),K(+)-ATPase activity to DA.     

(-)-Gossypol: an active male antifertility agent

The enantiomers of gossypol have been resolved by preparative HPLC of diastereomeric Schiff's base derivatives on a chiral bonded phase. Whereas (+)-gossypol has previously been reported to be inactive, (-)-gossypol is now shown to be active as a male oral antifertility agent in hamsters.     

Inhibition by (+) and (-) isomers of gossypol of testosterone release from mouse Leydig cells in vitro

Racemic (+/-) mixtures of gossypol isomers exert an antifertility effect by inhibiting sperm motility and spermatogenesis. Purified (+) gossypol has been shown to be without these actions. In this study pure preparations of both (+) and (-) gossypol were found to inhibit, in a similar manner, both basal and LH-stimulated release of testosterone by isolated Leydig cells at concentrations down to 21 microM. It is possible that use of low doses of pure (-) gossypol could inhibit fertility with less endocrine side effects.     

The effect of paroxetine on ouabain-induced toxicity in isolated guinea pig atria

It has been reported that selective serotonin reuptake inhibitors (SSRIs) possess some cardiac effects. In the present study we have investigated the effect of paroxetine (PX), a potent SSRI agent, on spontaneously as well as ouabain-induced arrhythmia beating isolated guinea-pig atria. The Guinea-pig heart was rapidly removed; the auricles were dissected out in oxygenated modified Krebs solution. The rate and force of spontaneous contractions were recorded isometrically with a photosensitive transducer. PX (1-16 μg/ml) caused a dose-dependent decrease in the rate of contractions (14-70%) and contractile force (8-16%). Ouabain alone (1.2 μg/ml) produced arrhythmia at 7.2 ± 1.5 min and asystole at 20.1 ± 3.1 min. Pretreatment with PX (4 μg/ml) significantly increased the time of arrhythmia onset to 19.8 min. In addition, PX prolonged the duration of action beating from 20.1 ± 3.1 min to 43.1± 2.6 and delayed the occurrence of asystole. The pattern of contractile force by PX + ouabain treatment was more regular than that observed after administration of ouabain alone. The above findings may the probably be due to the inhibition of cardiac Na(+) and Ca(2+) channels or autonomic nervous system. Results also suggest that PX may reduce the membrane conductance through inhibition of ionic channels to prevent ouabain-induced arrhythmia.