Endothelium-dependent and independent properties of cicletanine in Wistar rat aorta under normoxic and hypoxic conditions

Objective: the vascular mechanism of action of cicletanine, an antihyperten sive agent, was studied on isolated Wistar rat aorta in presence and in abs ence of endothelium both in normoxic and hypoxic conditions. Design and Methods: isolated aorta, from 24 month-old rats, were precontrac ted with noradrenaline (10(-7) M), in presence and in absence of endotheliu m and exposed to cumulative cicletanine concentrations in presence and abse nce of either L-NNA (10(-4) M) or indomethacine (Indo) (10(-7) M). Thereaft er, aorta were precontracted by noradrenaline 10(-7) M, and hypoxia was ind uced by switching gas mixture from 95%O-2/5%CO2 to 95%N-2/5%CO2 during 10 m inutes. Results are expressed as mean +/- sem and statistical analysis were done using one-way analysis of variance. Results: when aorta were precontracted with noradrenaline (10(-7) M), in pr esence of endothelium, cicletanine (10(-9)-10(-4) M), induced a biphasic co ncentration-dependent relaxation (EC(50)similar to 10(-7) M and 3.10(-5) M) . In absence of endothelium, the effect of cicletanine was abolished (10(-9 ) and IO-SM). Whereas, at higher concentration (10(-4) M), the magnitude of the relaxation reached 94+/-2% and 67+/-5% of the initial developed tensio n in presence and in absence of endothelium respectively. The endothelium-d ependent relaxation induced by cicletanine was significantly reduced by Ind o (10(-7) M)(p<0.05) and L-NNA(10(-4) M)(p < 0.005). Addition of 1.0 mM of BaCl2 significantly reversed the relaxation induced by the higher concentra tion of cicletanine used (p < 0.005). Under hypoxic conditions, the aorta, in presence of endothelium, displayed an increased developed tension which was significantly attenuated by cicletanine. Conclusion: these results indicated that cicletanine relaxes Vascular smoot h muscle through both, an endothelium-dependent action which was mediated b y cyclooxygenase and NOsynthase pathways and an endothelium-independent act ion that was mediated through K+ channels opening. Under hypoxic conditions , our findings indicate that the effects of cicletanine, appear related to an endothelium protective action associated to NO release.