Relaxant effects of danshen aqueous extract and its constituent danshensu on rat coronary artery are mediated by inhibition of calcium channels

Lam, F.; Yeung, John H.K.; Chan, Kam Ming; Or, Penelope M.Y.

doi:10.1016/j.vph.2006.10.011

Cited by 115 publications

(75 citation statements)

References 18 publications

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“…TSL has been shown to dilate coronary arteries (Dong and Jiang, 1982), inhibit platelet aggregation (Li et al, 1983), improve microcirculation (Cheng et al, 1987), and protect the myocardium from reperfusion injury of ischemic heart (Han et al, 2008). These cardiovascular actions may be produced primarily by TSL inhibition of extracellular Ca 2ϩ entry into both cardiac cells (Cao et al, 2003) and vascular smooth muscle cells (Lam et al, 2007). Other effects of TSL may also include scavenging oxygen-free radicals (Zhao et al, 2008) and protecting the endothelial cells against homocysteinemia (Chan et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Plasma and Urinary Tanshinol from Salvia miltiorrhiza (Danshen) Can Be Used as Pharmacokinetic Markers for Cardiotonic Pills, a Cardiovascular Herbal Medicine

Tong¹,

Yang²,

Gao³

et al. 2008

Drug Metabolism and Disposition

117

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ABSTRACT:Cardiotonic pills are a type of cardiovascular herbal medicine. To identify suitable pharmacokinetic (PK) marker(s) for indicating systemic exposure to cardiotonic pills, we examined the in vivo PK properties of putatively active phenolic acids from the component herb Danshen (Radix Salviae miltiorrhizae). We also performed in vitro and in silico assessments of permeability and solubility. Several phenolic acids were investigated, including tanshinol (TSL); protocatechuic aldehyde (PCA); salvianolic acids A, B, and D; rosmarinic acid; and lithospermic acid. Plasma TSL exhibited the appropriate PK properties in dogs, including dose-dependent systemic exposure in area under concentration-time curve (AUC) and a 0.5-h elimination half-life. In rats, more than 60% of i.v. TSL was excreted intact into the urine. In humans, we found a significant correlation between the urinary recovery of TSL and its plasma AUC. The absorption rate and bioavailability of TSL were not significantly different whether cardiotonic pills were given p.o. or sublingually. The gender specificity in plasma AUC disappeared after body-weight normalization, but the renal excretion of TSL was significantly greater in women than in men. PCA was predicted to be highly permeable according to in vitro and in silico studies; however, extensive presystemic hepatic elimination and degradation in the erythrocytes led to extremely low plasma levels and poor dose proportionality. Integrated in vivo, in vitro, and in silico studies on the other phenolic acids showed poor gut permeability and nearly undetectable levels in plasma and urine. In conclusion, plasma and urinary TSL are promising PK markers for cardiotonic pills at the tested dose levels.The use of herbal therapies is escalating worldwide. However, the basis for the therapeutic effects is often poorly interpreted, and the safety, dose, and potential herb-drug interactions require better estimation (Fugh-Berman, 2000;De Smet, 2002;Lazar, 2004). Unlike most synthetic drugs, herbal medicinal products usually contain numerous chemical constituents, especially traditional Chinese medicines that often use a combination of multiple herbs.Determining which constituents of an herbal product have favorable drug-like properties will extend our knowledge of the basis for pharmacological efficacy and safety. An herbal constituent can be defined as drug-like when it possesses the desired potency, a wide safety margin, and appropriate pharmacokinetic (PK) properties and exists in adequate abundance in the herbal product. A deficit in these properties limits the usefulness of the herbal constituent for the herbal product. For a drug, the pharmacologic effect is attained when the drug or its active metabolite reaches and sustains an adequate concentration at an appropriate site of action; this hypothesis should also be applied to the herbal product. Both the dose levels and fates of active constituents in the body govern their target-site concentrations after administration of an herbal product. The releva...

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Section: Discussionmentioning

confidence: 99%

Plasma and Urinary Tanshinol from Salvia miltiorrhiza (Danshen) Can Be Used as Pharmacokinetic Markers for Cardiotonic Pills, a Cardiovascular Herbal Medicine

Tong¹,

Yang²,

Gao³

et al. 2008

Drug Metabolism and Disposition

117

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“…Danshensu is a watersoluble phenolic acids component in Danshen. In vitro and in vivo studies revealed that danshensu possessed diverse pharmacological effects, including relaxation of coronary artery, anticoagulation, protection of myocardial ischemiareperfusion injury, and antiarrhythmia activities [2][3][4][5][6] . However, the effects of sodium danshensu on vessel function in isolated rat aorta are not well demonstrated.…”

Section: Sodium Danshensu [Sodium D-(+)-β-mentioning

confidence: 99%

Biphasic effects of sodium danshensu on vessel function in isolated rat aorta

et al. 2010

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Aim: To investigate the effects of sodium danshensu on vessel function in isolated rat aortic ring. Methods: Thoracic aortae from normal rats were isolated and equilibrated in organ bath with Krebs-Henseleit buffer and ring tension was recorded. Effects of sodium danshensu on basal tonus of the vessel and its effects on vessel contraction and relaxation with or without endothelium were observed. Results: In thoracic arteries under basal tonus, sodium danshensu (0.3-3 g/L) produced a dose-dependent transient contraction. In phenylephrine-precontracted thoracic arteries with or without endothelium, low concentration (0.1-0.3 g/L) of sodium danshensu produced a weak contraction, while high concentrations (1-3 g/L) produced a pronounced vasodilator after a transient vasocontraction. Pre-incubation with sodium danshensu could inhibit vessel contraction induced by phenylephrine and potassium chloride in a concentration-dependent way. Sodium danshensu inhibited phenylephrine-and CaCl 2 -induced vasoconstriction in Ca 2+ -free medium. Pre-incubation with tetraethylammonium, a non-selective K + channel blocker, and apamin, a small-conductance calcium-activated K + channel blocker partially antagonized the relaxation response induced by sodium danshensu. However, iberiotoxin (big-conductance calcium-sensitive K + channel blocker), barium chloride (inward rectifier K + channel blocker), and glibencalmide (ATP-sensitive K + channel blocker) had no influence on the vasodialtion effect of sodium danshensu. Conclusion: Sodium danshensu showed a biphasic effects on vessel tension. While low dosage of sodium danshensu produced small contraction possibly through transient enhancement of Ca 2+ influx, high dosage produced significant vasodilation mainly through promoting the opening of non-selective K + channels and small-conductance calcium-sensitive K + channels in the vascular smooth muscle cells.

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“…Studies have shown that tanshinol exhibited vasodilatory properties, elevated serum nitric oxide levels and action of endothelial nitric oxide synthase, protected endothelial cells from homocysteine-induced injury and H 2 O 2 -induced apoptosis, and exerted antioxidant effects (Chan et al, 2004;Lam et al, 2007;Zhao et al, 2008;Yang et al, 2009;. Tanshinol also decreased blood pressure in spontaneously hypertensive rats and attenuated cardiac hypertrophy, venular thrombosis, and methionine-induced hyperhomocysteinemia in rats (Cao et al, 2009;Wang et al, 2009;Yang et al, 2010;Tang et al, 2011a,b).…”

Section: Introductionmentioning

confidence: 98%

Renal Tubular Secretion of Tanshinol: Molecular Mechanisms, Impact on Its Systemic Exposure, and Propensity for Dose-Related Nephrotoxicity and for Renal Herb-Drug Interactions

Jia

et al. 2015

Drug Metabolism and Disposition

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Tanshinol has desirable antianginal and pharmacokinetic properties and is a key compound of Salvia miltiorrhiza roots (Danshen). It is extensively cleared by renal excretion. This study was designed to elucidate the mechanism underlying renal tubular secretion of tanshinol and to compare different ways to manipulate systemic exposure to the compound. Cellular uptake of tanshinol was mediated by human organic anion transporter 1 (OAT1) (K m , 121 mM), OAT2 (859 mM), OAT3 (1888 mM), and OAT4 (1880 mM) and rat Oat1 (117 mM), Oat2 (1207 mM), and Oat3 (1498 mM [BCRP], and rat Oct1, Oct2, Octn1, Octn2, Mate1, Mrp2, Mrp4, and Bcrp) showed either ambiguous ability to transport tanshinol or no transport activity. Rats may be a useful model, to investigate the contribution of the renal transporters on the systemic and renal exposure to tanshinol. Probenecid-induced impairment of tubular secretion resulted in a 3-to 5-fold increase in the rat plasma area under the plasma concentration-time curve from 0 to infinity (AUC 0-' ) of tanshinol. Tanshinol exhibited linear plasma pharmacokinetic properties over a large intravenous dose range (2-200 mg/kg) in rats. The dosage adjustment could result in increases in the plasma AUC 0-' of tanshinol of about 100-fold. Tanshinol exhibited very little doserelated nephrotoxicity. In summary, renal tubular secretion of tanshinol consists of uptake from blood, primarily by OAT1/Oat1, and the subsequent luminal efflux into urine mainly by passive diffusion. Dosage adjustment appears to be an efficient and safe way to manipulate systemic exposure to tanshinol. Tanshinol shows low propensity to cause renal transporter-mediated herb-drug interactions.

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Relaxant effects of danshen aqueous extract and its constituent danshensu on rat coronary artery are mediated by inhibition of calcium channels

Cited by 115 publications

References 18 publications

Plasma and Urinary Tanshinol from Salvia miltiorrhiza (Danshen) Can Be Used as Pharmacokinetic Markers for Cardiotonic Pills, a Cardiovascular Herbal Medicine

Plasma and Urinary Tanshinol from Salvia miltiorrhiza (Danshen) Can Be Used as Pharmacokinetic Markers for Cardiotonic Pills, a Cardiovascular Herbal Medicine

Biphasic effects of sodium danshensu on vessel function in isolated rat aorta

Renal Tubular Secretion of Tanshinol: Molecular Mechanisms, Impact on Its Systemic Exposure, and Propensity for Dose-Related Nephrotoxicity and for Renal Herb-Drug Interactions

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