Interaction between cicletanine and the eicosanoid system in human subcutaneous resistance arteries.
In human subcutaneous resistance arteries in-vitro, the relaxation produced by the novel furopyridine compound cicletanine (30 microMs) was inhibited by 51% (P less than 0.0001) in the presence of 20 microMs of the cyclo-oxygenase inhibitor indomethacin. Maximal cicletanine-induced relaxation was reduced by both the cyclo-oxygenase inhibitor mefenamic acid and the relatively specific blocker of prostacyclin synthetase, tranylcypromine by 55% (P less than 0.0005) and 43% (P less than 0.01), respectively. The potassium channel blocker, glibenclamide (100 microMs), did not affect the relaxation produced by cicletanine but did inhibit the relaxation produced by the potassium channel blocker cromakalim (P less than 0.0001). Cromakalim-induced relaxation was inhibited in the presence of indomethacin; relaxation induced by cromakalim (30 microMs) was reduced by 22% (P less than 0.02). The relaxation produced by the hypotensive agonists sodium nitroprusside, hydrochlorothiazide, bumetanide and nicardipine was unaffected by incubation with indomethacin. The results suggest that the vascular eicosanoid system, specifically prostacyclin, may be involved in the mechanism of the acute vasodilator action of cicletanine. Although at high doses, cicletanine is a diuretic, in this model it did not act like either a thiazide or a loop diuretic. The acute vasodilator action of the thiazide diuretic, hydrochlorothiazide was a novel finding of this study. Cromakalim showed a reduced response in the presence of indomethacin suggesting an involvement of the eicosanoid system in its mechanism of action.
Department of Clinical Pharmacology, St Mary's Hospital, London, UK.
J A
JA
Calder
M
M
Schachter
P S
PS
Sever
D000959:Antihypertensive Agents / Q000494:pharmacology; D001158:Arteries / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004232:Diuretics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015777:Eicosanoids / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D011725:Pyridines; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
D000959:Antihypertensive Agents; D016861:Cyclooxygenase Inhibitors; D004232:Diuretics; D015777:Eicosanoids; D011725:Pyridines; D014665:Vasodilator Agents; C038068:cicletanine; D007213:Indomethacin