Short-term exposure to homocysteine depresses rat aortic contractility by an endothelium-dependent mechanism

The effect of short-term exposure to homocysteine (Hcy) on the contractile characteristics of rat aortic tissue was assessed both in vitro and in vivo . The contractile response of Hcy-treated aortic rings in culture for 1 or 4 days was unchanged from control responses. By comparison, aortic rings fr om animals injected with Hcy showed marked attenuation of response compared with controls injected with saline, cysteine or methionine. The contractil e response to K+ was decreased within 24 hours of Hcy injection, whereas th e response to both K+ (-27%) and noradrenaline (-56%) was significantly dec reased by 4 days. In contrast, the contractile response to phorbol-12,13-di butyrate was not different between Hcy and control groups. Intimal rubbing completely restored the responsiveness of Hcy-treated tissue to K+ and nora drenaline. By comparison, L-NAME only partially restored contractile respon siveness, while the cyclooxygenase inhibitor indomethacin had no effect on contractile attenuation induced by Hcy. Western blot analysis showed a 2-fo ld increase of endothelial nitric oxide synthase (eNOS) and a 3-fold increa se in inducible nitric oxide synthase (iNOS) protein expression in the aort ic endothelial cells from Hcy-injected rats. The results indicate an early detectable effect of Hcy on the in vivo contractile properties of vascular smooth muscle. The effect is endothelium-mediated and may vary depending on the agonist studied. The mechanism is uncertain but appears to involve inc reased nitric oxide (NO) production. Finally, the data suggest that attenua tion of contraction may not be due to a direct effect of Hcy but that the c ompound is modified or acts indirectly in vivo.