Tetrandrine and related bis-benzylisoquinoline alkaloids from medicinal herbs: cardiovascular effects and mechanisms of action.
Tetrandrine (TET), a bis-benzylisoquinoline alkaloid purified and identified an active ingredient in a Chinese medicinal herb, radix stephanae tetrandrae, has been used traditionally for the treatment of congestive circulatory disorder and inflammatory diseases. TET, together with a few of its structural analogues, has long been demonstrated to have antihypertensive action in clinical as well as animal studies. Presumably, the primary anti-hypertensive action of TET is due to its vasodilatory properties. TET prevents or inhibits vascular contraction induced by membrane depolarization with KCl or alpha-adrenoceptor activation with phenylephrine (PE). TET (30 micromol/L) also inhibits the release of endothelium-derived nitric oxide (NO) as well as NO production by inducible NO synthase. TET apparently inhibits multiple Ca2+ entry pathways as demonstrated in cell types lacking the L-type Ca2+ channels. In cardiac muscle cells, TET inhibits both L- and T-type Ca2+ channels. In addition to its actions on cardiovascular tissues, TET may also exert its anti-hypertensive action via a Ca2+-dependent manner on other tissues intimately involved in the modulation of blood pressure control, such as adrenal glands. In adrenal glomerulosa cells, KCl- or angiotensin II-induced aldosterone synthesis is highly dependent on extracellular Ca2+. Steroidogenesis and Ca2+-influx in bovine adrenal glomerulosa cells have been shown to be potently inhibited by TET. In bovine adrenal chromaffin cells, TET inhibits Ca2+ currents via L- and N-type channels as well as other unidentified channels with IC50 of 10 micromol/L. Other than the Ca2+ antagonistic effects, TET also interacts with the alpha-adrenergic receptors and muscarinic receptors based on functional as well as radioligand binding studies. Apart from its functional effects, TET and related compounds also exert effects on tissue structures, such as remodelling of hypertrophied heart and inhibition of angiogenesis, probably by causing apoptotic responses. TET is also known for its anti-inflammatory and anti-fibrogenic actions, which make TET and related compound potentially useful in the treatment of lung silicosis, liver cirrhosis, and rheumatoid arthritis. (+info)
Cardiovascular pharmacological effects of bisbenzylisoquinoline alkaloid derivatives.
Tetrandrine, dauricine, daurisoline and neferine are bisbenzylisoquinoline alkaloid derivatives isolated from Chinese traditional medicine and herbs. The cardiovascular pharmacological effects and the mechanism of actions of these compounds were reviewed. Tetrandrine isolated from Stephania tetrandra S Moore possesses antihypertensive and antiarrhythmic effects. The antihypertensive effects of tetrandrine have been demonstrated in experimental hypertensive animals and in hypertensive patients. Recent studies showed that in addition to its calcium antagonistic effect, tetrandrine interacted with M receptors. Modulation by M receptor is one of the pharmacological mechanisms of cardiovascular effects of tetrandrine. Dauricine and daurisoloine were isolated from Menispermum dauricum DC. The antiarrhythmic effects of dauricine have been verified in different experimental arrhythmic models and in cardiac arrhythmic patients. Dauricine blocked the cardiac transmembrane Na+,K+ and Ca2+ ion currents. Differing from quinidine and sotalol, which exhibited reverse use-dependent effect, dauricine prolonged APD in a normal use-dependent manner in experimental studies. The antiarrhythmic effect of daurisoline and neferine which is an alkaloid isolated from Nelumbo nucifera Gaertn, and their mechanisms of actions have also been studied. The antiarrhythmic effect of daurisoline is more potent than that of dauricine. (+info)
Effect of Stephania hernandifolia leaf extract on testicular activity in rats.
AIM: The testicular inhibitory effect of the aqueous fraction of methanol extract of Stephania hernandifolia leaf was studied in male Wistar rats. METHODS: The supernatent and the precipitate part of aqueous fractions of the methanol extract of the leaf were gavaged separately to rat at a similar dose of 200 mg/mL per 100 g body weight per day for 28 days. After cessation of treatment, various observations were conducted. RESULTS: In both treated groups, there were significant decreases in the relative weights of the sex organs, the testicular key androgenic enzymes activities, the plasma level of testosterone, the number of different germ cells at stage VII of seminiferous epithelial cell cycle and the seminiferous tubular diameter in comparison to the controls. Neither of the parts had somatic, renal and hepatic toxicity. This study suggested that the active molecules present in the aqueous fraction of methanol extract of Stephania hernandifolia leaves might be steroids as indicated by thin layer chromatography using specific staining substance for steroid molecules. CONCLUSION: In rats, the aqueous fraction of methanol extract of the S. hernandifolia leaves possesses certain testis-inhibitory substances, which may be steroid-like agents. (+info)
Effects of (-)stepholidine in animal models for schizophrenia.
AIM: (-)Stepholidine (SPD) is an active ingredient of the Chinese herb Stephania intermedia, which binds to the dopamine D(1) and D(2) like receptors. Biochemical, electrophysiological and behavioural experiments have provided strong evidence that SPD is both a D(1) and a D(2) antagonist, which could make SPD a unique antipsychotic drug. The present study aimed to investigate the antipsychotic properties of SPD in two animal models for schizophrenia. METHODS: The effects of SPD, clozapine and haloperidol in increasing forelimb and hindlimb retraction time in the paw test and in reversing the apomorphine and MK801-induced disruption of prepulse inhibition was investigated. RESULTS: In the paw test, clozapine and SPD increased the hindlimb retraction time, with only a marginal effect on the forelimb retraction time, whereas haloperidol potently increased both. In the prepulse inhibition paradigm, all three drugs reverse the apomorphine-induced disruption in prepulse inhibition, while none of the drugs could reverse the MK801-induced disruption. SPD even slightly, but significantly, potentiated the effects of MK801. CONCLUSION: The data show that SPD showed antipsychotic-like effects in both the prepulse inhibition paradigm and in the paw test. Moreover, the results of the paw test suggest that SPD has an atypical character with a relatively small potency to induce extrapyramidal side effects. (+info)
Reproductive effects of ethnomedicinal formulation of tape-vine leaves in female rats.
Documented ethno-contraceptive use of Tape-vine or Stephania japonica (THUNB.) MIERS., Syn. Stephania hernandifolia (WILLD.) WALP. leaves is evaluated with regards to post-coital pregnancy interceptive activity of its aqueous extract (AE) and an ethnomedicinal formulation (EF) in Wistar rats. EF at 500 and 250 mg/kg doses induced 66.7% and 33.3% post-coital pregnancy interception respectively and the higher dose exhibited significant reduction in number of litters born and also anti-implantation property. In contrast, none of the dose levels of AE interfered in pregnancy but significant anti-implantation property was observed at doses of 2 and 1 g/kg, even as the higher dose produced significant reduction in number of litters born as well. EF at 500 mg/kg also exhibited significant uterotrophic activity and histological changes in uterus. Pair-wise comparison of sex hormone-levels exhibited significant increment in serum estradiol, LH and FSH but decrease in progesterone levels. Assessed blood lipid-carbohydrate profile exhibited substantial decrease in glucose, cholesterol, VLDL and triglyceride contents and significant increase in HDL. It is concluded that EF probably acts as better post-coital pregnancy interceptive agent through restriction of implantation by alteration of gonadal hormone levels and decline in blood-glucose levels that possibly disrupts oxidative energy metabolism in uterus during implantation. High surge in LH and FSH suggests negligible interference in ovulatory mechanism. This preparation also seems to be free of cardiovascular risk factors. HPTLC and HPLC analysis of both EF and AE exhibited marked chemical differences. (+info)
Dopamine D1 receptor agonist and D2 receptor antagonist effects of the natural product (-)-stepholidine: molecular modeling and dynamics simulations.
(-)-Stepholidine (SPD), an active ingredient of the Chinese herb Stephania, is the first compound found to have dual function as a dopamine receptor D1 agonist and D2 antagonist. Insights into dynamical behaviors of D1 and D2 receptors and their interaction modes with SPD are crucial in understanding the structural and functional characteristics of dopamine receptors. In this study a computational approach, integrating protein structure prediction, automated molecular docking, and molecular dynamics simulations were employed to investigate the dual action mechanism of SPD on the D1 and D2 receptors, with the eventual aim to develop new drugs for treating diseases affecting the central nervous system such as schizophrenia. The dynamics simulations revealed the surface features of the electrostatic potentials and the conformational "open-closed" process of the binding entrances of two dopamine receptors. Potential binding conformations of D1 and D2 receptors were obtained, and the D1-SPD and D2-SPD complexes were generated, which are in good agreement with most of experimental data. The D1-SPD structure shows that the K-167_EL-2-E-302_EL-3 (EL-2: extracellular loop 2; EL-3: extracellular loop 3) salt bridge plays an important role for both the conformational change of the extracellular domain and the binding of SPD. Based on our modeling and simulations, we proposed a mechanism of the dual action of SPD and a subsequent signal transduction model. Further mutagenesis and biophysical experiments are needed to test and improve our proposed dual action mechanism of SPD and signal transduction model. (+info)
New feruloyl tyramine glycosides from Stephania hispidula YAMAMOTO.
Three new feruloyl tyramine glycosides, N-cis-feruloyl tyramine-4'''-O-beta-D-glucopyranoside (1), N-trans-ferloyl tyramine-4'''-O-beta-D-glucopyranoside (2), and N-trans-feruloyl tyramine-4'-O-beta-D-glucopyranoside (3), along with six known compounds, N-trans-feruloyl-3'''-methoxydopamine-4'-O-beta-D-glucopyranoside (4), haitinosporine (5), tubocurine (6), fuzitine (7), (+)-lyoniresinol-3alpha-O-beta-D-glucopyranoside (8), and (-)-lyoniresinol-2alpha-O-beta-D-glucopyranoside (9), were isolated from the stem of Stephania hispidula YAMAMOTO. The structures were elucidated by spectroscopic and chemical analysis. (+info)
Oral administration of levo-tetrahydropalmatine attenuates reinstatement of extinguished cocaine seeking by cocaine, stress or drug-associated cues in rats.