Cicletanine stimulates nitric oxide release and scavenges superoxide in endothelial cells.
Cicletanine ((+/-)3-(4-chlorophenyl)-1,3-dihydro-7-hydroxy-6-methylfuro-[3,4-c] pyridine) 3-(4-chlorophenyl)-1,3-dihydro-7-hydroxy-6-methylfuro-[3,4-c] pyridine) is a novel antihypertensive vasodilator with an incompletely understood mechanism of action. In the studies described here, the release of nitric oxide and superoxide (O2-) stimulated by cicletanine was measured simultaneously in the endothelium of isolated rat aortic rings. Highly sensitive electrochemical nitric oxide and O2- microsensors were placed near the surface of endothelial cells and the kinetics of nitric oxide and O2- release were monitored in situ. The response times for nitric oxide and O2- microsensors were 100 micros and 50 micros, respectively, and detection limit was 10(-9) M. Cicletanine stimulated nitric oxide release in aorta endothelium at (micromolar) therapeutic concentrations that were consistent with the concentrations of the compound to induce endothelium-dependent vasorelaxation in isolated rat aorta. The peak concentration of nitric oxide was 160+/-8 nM. This concentration was about 70% and was 60% lower as compared with the nitric oxide peak concentration observed after stimulation with receptor-independent agonist (calcium ionophore A23187) and receptor-dependent agonist (acetylcholine), respectively. However, after administration of cicletanine, only a small concentration of O2- was recorded (peak 3.1+/-0.2 nM) contrary to a large concentration (27+/-1.35 nM) observed after stimulation with A23187). Cicletanine not only stimulated nitric oxide release but also was a potent scavenger of O2- at nanomolar level. Both of these effects may contribute to potent vasorelaxation properties of cicletanine and its long-term therapeutic actions, resulting in cardiovascular tissue protection.
Kalinowski
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Department of Chemistry and Biochemistry, Ohio University, Athens 45701-2979, USA.
Dobrucki
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IT
Malinski
T
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D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001012:Aorta, Abdominal / Q000187:drug effects / Q000378:metabolism; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011921:Rats, Inbred WKY; D013481:Superoxides / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D007476:Ionophores; D011725:Pyridines; D013481:Superoxides; D009569:Nitric Oxide; D000001:Calcimycin; C038068:cicletanine; D010100:Oxygen