Vasorelaxing action of rutaecarpine: effects of rutaecarpine on calcium channel activities in vascular endothelial and smooth muscle cells.
Rutaecarpine (Rut) has been shown to induce hypotension and vasorelaxation. In vitro studies indicated that the vasorelaxant effect of Rut was largely endothelium-dependent. We previously reported that Rut increased intracellular Ca2+ concentrations ([Ca2+]i) in cultured rat endothelial cells (ECs) and decreased [Ca2+]i in cultured rat vascular smooth muscle (VSMCs) cells. The present results showed that the hypotensive effect of Rut (10-100 microgram/kg i.v.) was significantly blocked by the nitric oxide synthase inhibitor Nomega-nitro-L-arginine. In aortic rings, Rut (0. 1-3.0 microM)-induced vasorelaxation was inhibited by Nomega-nitro-L-arginine and hydroquinone but not by antagonists of the various K+ channels, 4-aminopyridine, apamin, charybdotoxin, or glibenclamide. Rut (0.1 and 1.0 microM) inhibited the norepinephrine-induced contraction generated by Ca2+ influx and at 1.0 microM increased cyclic GMP (cGMP) production in endothelium-intact rings and to a lesser extent in endothelium-denuded rings. In whole-cell patch-clamp recording, nonvoltage-dependent Ca2+ channels were recorded in ECs and Rut (0.1, 1.0 microM) elicited an opening of such channels. However, in VSMCs, Rut (10.0 microM) inhibited significantly the L-type voltage-dependent Ca2+ channels. In ECs cells, Rut (1.0, 10.0 microM) increased nitric oxide release in a Ca2+-dependent manner. Taken together, the results suggested that Rut lowered blood pressure by mainly activating the endothelial Ca2+-nitric oxide-cGMP pathway to reduce smooth muscle tone. Although the contribution seemed to be minor in nature, inhibition of contractile response in VSMCs, as evidenced by inhibition of Ca2+ currents, was also involved. Potassium channels, on the other hand, had no apparent roles.
Wang
G J
GJ
National Research Institute of Chinese Medicine, Taipei Taiwan, Republic of China. jenny@cma23.nricm.edu.tw
Wu
X C
XC
Chen
C F
CF
Lin
L C
LC
Huang
Y T
YT
Shan
J
J
Pang
P K
PK
D015761:4-Aminopyridine / Q000494:pharmacology; D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology*; D020746:Calcium Channels, L-Type; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D006873:Hydroquinones / Q000494:pharmacology; D066298:In Vitro Techniques; D026121:Indole Alkaloids; D007537:Isometric Contraction / Q000187:drug effects*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008955:Models, Cardiovascular; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D019335:Nitroarginine / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D011799:Quinazolines; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology*; D052999:Quinazolinones
D015761:4-Aminopyridine; D000470:Alkaloids; D002118:Calcium; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D006152:Cyclic GMP; D006873:Hydroquinones; D026121:Indole Alkaloids; D019335:Nitroarginine; D009638:Norepinephrine; D026902:Potassium Channel Blockers; D011799:Quinazolines; D014665:Vasodilator Agents; C028632:rutecarpine; D052999:Quinazolinones; C031927:hydroquinone