Relaxation of vascular smooth muscle by cicletanine in aged wistar aorta under stress conditions: importance of nitric oxide.

ABSTRACT

The vascular mechanism of action of cicletanine, an antihypertensive agent, was studied on isolated Wistar rat aortas (24-months-old) in presence and in absence of endothelium in two different stress conditions, normoxic and hypoxic, in presence of norepinephrine (NE). Under normoxic conditions, in presence of endothelium, cicletanine (10(-9)-10(-5)M) induced a concentration-dependent relaxation, whereas in absence of endothelium, cicletanine (10(-9)-10(-5)M) was ineffective although it relaxed the smooth muscle at higher concentrations (10(-4)M). At pharmacologic concentrations (below or equal 10(-5)M), relaxation induced by cicletanine, in presence of endothelium, was prevented by N(omega)-nitro-L-arginine (L-NNA) (P <.005) and relaxation induced by the highest concentration (10(-4)M) was reversed by BaCl2 (P <.005). Under hypoxic conditions, in presence of NE and endothelium, the aorta displayed an increased developed tension that was significantly (P <.05) attenuated by cicletanine (10(-5)M) and insensitive to indomethacine (10(-7)M). When the two compounds were added together, the relaxation induced by cicletanine was significantly improved (P <.005). These results indicated that cicletanine, under stress conditions, relaxes vascular smooth muscle through an endothelium-dependent action mediated by the nitric oxide (NO) synthase pathway. We proposed that the observed vascular effects could be associated with the counter-regulation mechanisms linked to the antihypertensive action of cicletanine.