Tetrandrine and related bis-benzylisoquinoline alkaloids from medicinal herbs: cardiovascular effects and mechanisms of action.
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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.
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