Mechanisms of the dilator action of cryptotanshinone on rat coronary artery.
In this study, we have investigated the actions of cryptotanshinone, an active, lipophilic component of the medicinal herb danshen (Salvia miltiorrhiza), on rat isolated coronary artery rings precontracted with 1 microM 5-hydroxytryptamine (5-HT) and its action compared to the ethanol-extractable fraction of the herb. Extraction of the ethanol-soluble fraction from danshen provided a yield of 1%. The amount of cryptotanshinone determined in this ethanol extract was 3.682%, and it was 6 times more potent than the extract in relaxing 5-HT-precontracted coronary artery rings; IC(50) values were 2.65+/-0.15 microg/ml and 15.82+/-1.07 microg/ml, respectively. Involvement of endothelium-dependant mechanisms in their dilator effects were investigated by pretreatment of the artery rings with a cyclooxygenase inhibitor flurbiprofen (10 microM), a nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 100 microM), a muscarinic receptor antagonist atropine (100 nM), and by mechanical removal of the endothelium; none of these procedures produced a significant change on their dilator actions. Involvement of endothelium-independent mechanisms was investigated in endothelium-denuded artery rings pretreated with a beta-adrenoceptor antagonist propranolol (100 nM), an adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purine-6-amine (SQ22536, 100 microM), a guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 microM), and a potassium channel inhibitor tetraethylammonium (TEA, 100 mM); these also produced no change on their dilator actions. The possible involvement of Ca(2+) channels was investigated in artery rings incubated with Ca(2+)-free buffer and primed with 1 microM 5-HT for 5 min prior to adding CaCl(2) to elicit contraction. The danshen ethanol extract (100 microg/ml) abolished the CaCl(2)-induced vasoconstriction, whereas, cryptotanshinone (30 microg/ml) produced 59% inhibition. These findings suggest their vasorelaxant effects are independent of pathways mediated by the endothelium, muscarinic receptors, beta-adrenoceptors, adenylyl cyclase, and guanylyl cyclase, whereas, inhibition of Ca(2+) influx in the vascular smooth muscle cells is important for their vasodilator actions. The high vasodilator potency and the quantity of salvianolic acid B contained in danshen ethanolic extract suggest it is an important constituent in this medicinal herb.
Lam
Francis F Y
FF
Department of Pharmacology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong. FrancisLam@cuhk.edu.hk
Yeung
John H K
JH
Chan
Kam M
KM
Or
Penelope M Y
PM
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001572:Benzofurans / Q000032:analysis; D020013:Calcium Signaling / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects; D000431:Ethanol / Q000737:chemistry; D006162:Guanylate Cyclase / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010616:Phenanthrenes / Q000032:analysis / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D011976:Receptors, Muscarinic / Q000187:drug effects; D027561:Salvia miltiorrhiza / Q000737:chemistry; D012701:Serotonin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D012997:Solvents / Q000737:chemistry; D014662:Vasoconstrictor Agents / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000737:chemistry / Q000494:pharmacology*; D053630:Depsides
D000262:Adenylyl Cyclases; D001572:Benzofurans; D004365:Drugs, Chinese Herbal; D000431:Ethanol; D006162:Guanylate Cyclase; D019001:Nitric Oxide Synthase; D010616:Phenanthrenes; D011188:Potassium; D011451:Prostaglandin-Endoperoxide Synthases; D011943:Receptors, Adrenergic, beta; D011976:Receptors, Muscarinic; D012701:Serotonin; D012997:Solvents; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C037886:cryptotanshinone; C076944:salvianolic acid B; D053630:Depsides