Mechanisms of vasorelaxant effect of dehydroevodiamine: a bioactive isoquinazolinocarboline alkaloid of plant origin.
We examined the mechanisms underlying the vasorelaxant effect of dehydroevodiamine (DeHE), one of the bioactive components of the Chinese herbal drug Evodia rutaecarpa that has been shown to produce vasorelaxant and hypotension. DeHE (10(-7)-10(-4) M) concentration-dependently relaxed isolated rat mesenteric arteries precontracted with phenylephrine (PE). This vasorelaxant potency was diminished by 15% by endothelial removal, L-NG-nitro arginine, or methylene blue (MB), but not indomethacin treatment, indicating that the vasorelaxant effect of DeHE was partially endothelium dependent and mediated by nitric oxide (NO) and the cyclic GMP pathway. In endothelium-denuded preparations, DeHE caused a rightward shift of the contractile concentration-response curve (CRC) to PE in a dose-dependent manner with a pA2 value of 6.15. Maximal response was unaffected. Receptor binding assay indicated that DeHE competed with alpha 1-adrenoceptor ligand prazosin with a Ki value of 3.57 microM. Potassium channel activity-attenuating conditions such as increased level of extracellular K+ (20 mM) and treatment with the antagonist tetraethylammonium (TEA) significantly inhibited DeHE's effect, suggesting a mode of action similar to that of a potassium channel activator. In addition, high concentrations of DeHE (3 x 10(-5) and 10(-4) M) relaxed high K+ (80 mM)-evoked contraction, indicating that DeHE might possess K+ channel blocking properties. Multiple-action mechanisms, including endothelium dependence, alpha 1-adrenoceptor blockade, K+ channel activation, and Ca2+ channel blockade were probably involved in the vasorelaxant effects of DeHE.
Chiou
W F
WF
National Research Institute of Chinese Medicine, Taipei Hsien, Taiwan. R.O.C.
Liao
J F
JF
Shum
A Y
AY
Chen
C F
CF
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D008914:Minoxidil / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology*
D000470:Alkaloids; D014665:Vasodilator Agents; D019335:Nitroarginine; D008914:Minoxidil; C028633:dehydroevodiamine; D019001:Nitric Oxide Synthase