TxA2 Receptor Antagonist (SQ29548) attenuates Endothelium-Independent recovery from Thromboxane A2 Contraction of Isolated Rabbit Aorta

Abstract

Background: Thromboxane A₂ (TxA₂) is a potent constrictor of blood vessels and has been implicated in the pathogenesis of some cardiovascular diseases. This study examined an intervention that can be used to displace the tight binding of thromboxane mimetic, U46619 to the thromboxane (TP) receptors thereby bringing about a faster relaxation. We hypothesized that the prolonged contraction of U46619 stimulated VSM could be due, in some part, to a tight binding between U46619 and the TP receptor, leading to continual activation of the receptor.

Methods: Aortic rings were obtained from euthanized rabbit (n ═ 28) and placed in an organ bath system with temperature maintained at 37^OC and contractile responses to the thromboxane mimetic, U46619 (0.5 μM) measured. Following a maximum contraction, SQ29548 was added, and the vessels allowed to relax to baseline. We then investigated whether the displacement of U46619 and faster relaxation brought about by SQ29548 was dependent on the release of NO from the endothelium.

Results: Following treatment with SQ29548 (3.0 μM) the aortic vessels relaxed at a significantly higher rate (0.23 ± 0.04 g/min) compared to the vehicle-treated vessels (0.03 ± 0.01 g/min) (P < 0.0001). Vessels treated with an inhibitor of NO production (L-NAME) or vessels where the endothelium was mechanically removed showed the same response to rate of relaxation as vessels treated with the vehicle or vessels in which the endothelium was not denuded (P = 0.93 and P = 0.38).

Conclusion: Focusing on strategies to speed up relaxation of a contracted vessel adds to the significance of this work. Results from our experiments suggest that administration of SQ29548 may be useful in relaxing a vessel that is already contracted by TxA_2, for example, a vessel in spasm and also in an atherosclerotic vessel in which NO the relaxing factor in vascular smooth muscle has been affected

Keywords: Thromboxane A2, mimetic, receptor antagonist, smooth muscle, endothelium, nitric oxide