[Mechanism of action of cicletanine on the relationship between endothelium and vascular smooth muscle in the rat thoracic aorta under normoxic and hypoxic conditions].
OBJECTIVE
The vascular mechanism of action of cicletanine, an antihypertensive agent, was studied on isolated Wistar rat aorta in presence and in absence of endothelium both in normoxic and hypoxic conditions.


METHODS
Isolated aorta, from 24 month-old rats, were precontracted with noradrenaline (10(-7) M), in presence and in absence of endothelium and exposed to cumulative cicletanine concentrations in presence and absence of either L-NNA (10(-4) M) or indomethacin (Indo) (10(-7) M). Thereafter, aorta were precontracted by noradrenaline 10(-7) M, and hypoxia was induced by switching gas mixture from 95%O2/5%CO2 to 95%N2/5%CO2 during 10 minutes. 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 presence of endothelium, cicletanine (10(-9)-10(-4) M), induced a biphasic concentration-dependent relaxation (EC50 approximately 10(-7) M and 3 x 10(-5) M). In absence of endothelium, the effect of cicletanine was abolished (10(-9) and 10(-5) M). Whereas, at higher concentration (10(-4) M), the magnitude of the relaxation reached 94 +/- 2% and 67 +/- 5% of the initial developed tension in presence and in absence of endothelium respectively. The endothelium-dependent relaxation induced by cicletanine was significantly reduced by Indo (10(-7) M) (p < 0.05) and L-NNA (10(-4) M) (p < 0.005). Addition of 10 mM of BaCl2 significantly reversed the relaxation induced by the higher concentration 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.


CONCLUSIONS
These results indicated that cicletanine relaxes vascular smooth muscle through both, an endothelium-dependent action which was mediated by cyclooxygenase and NOsynthase pathways and an endothelium-independent action 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.
Chamiot-Clerc
P
P
Département de recherche médicale, hôpital Marie-Lannelongue, Le-Plessis-Robinson.
Choukri
N
N
Legrand
M
M
Safar
M E
ME
Droy-Lefaix
M T
MT
Renaud
J F
JF
D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001013:Aorta, Thoracic / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects*; D007213:Indomethacin / Q000494:pharmacology; D016015:Logistic Models; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D019335:Nitroarginine / Q000494:pharmacology; D010100:Oxygen / Q000494:pharmacology*; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D012307:Risk Factors; D014665:Vasodilator Agents / Q000627:therapeutic use*
D000959:Antihypertensive Agents; D011725:Pyridines; D014665:Vasodilator Agents; D019335:Nitroarginine; C038068:cicletanine; D010100:Oxygen; D007213:Indomethacin