Effects of dual-action genistein derivatives on relaxation in rat aorta.
Protein tyrosine kinases and nitric oxide (NO) play important roles in several cardiovascular diseases. In this study, we examined the actions of two compounds, each has structure of genistein (a tyrosine kinase inhibitor) and an NO donor, on endothelium-independent relaxation responses in the isolated rat aorta. By rational drug design, genistein was modified to acquire an NO donor, and we synthesized two such compounds (G-II, G-VI). These compounds and genistein induced dose-dependent relaxation responses in endothelium-denuded aortic strips, the rank order of potencies being G-VI > G-II > genistein. Incubation of endothelium-denuded strips with 1H-[1,2,4] oxadiazolo[4,3-a]-quinoxalin-1-one (ODQ, 10 microM), a guanylyl cyclase inhibitor, inhibited both the G-II- and G-VI-induced relaxations, but not the genistein-induced relaxation. The residual relaxations induced by these two compounds were similar to the genistein-induced relaxation. Incubation of endothelium-denuded strips with lysophosphatidylcholine (LPC, 20 microM)-which is a major atherogenic lysophospholipid component of oxidized low-density lipoprotein and is known to activate tyrosine kinase-caused a significant rightward shift in the dose-response curve for genistein. LPC also shifted the G-II- and G-VI-induced relaxation curves to the right; however, these relaxations in the presence of LPC were greater than that induced by genistein. The sodium nitroprusside-induced relaxation in endothelium-denuded strips was similar between in the absence and presence of LPC. These results suggest that each of our newly developed G-II and G-VI compounds has a dual action, as an NO donor and a tyrosine kinase inhibitor. These compounds may be useful against certain cardiovascular diseases.
Matsumoto
Takayuki
T
Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Tokyo, Japan.
Kobayashi
Tsuneo
T
Kikuchi
Toyohiko
T
Honda
Toshio
T
Kamata
Katsuo
K
D000818:Animals; D001011:Aorta / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019833:Genistein / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D008244:Lysophosphatidylcholines / Q000494:pharmacology; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar
D008244:Lysophosphatidylcholines; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D006162:Guanylate Cyclase