St Thomas' Campus, London SEl 7EH 1 Ligustrazine (tetramethylpyrazine, TMP) is a vasodilator that has been reported to have pulmonary selective properties in vivo, but not in vitro. Although TMP is generally described as being endotheliumindependent, we provide evidence here that TMP may have an endothelium-dependent and nitric oxide (NO)-mediated mechanism in pulmonary arteries that could predominate at concentrations used therapeutically in China. Similar effects were seen in small arteries. L-Arginine had no effect in the absence of an endothelium. D-Arginine was ineffective, and inhibition of L-arginine uptake with L-lysine blocked the action of L-arginine. L-Arginine (400 gM) had no significant effect on TMP-induced relaxation in mesenteric arteries (n = 5).
L-Arginine itself caused a concentration-dependent relaxation in intrapulmonary arteries(639 + 34 gM) constricted with PE, reaching a maximum relaxation around 100 -400 gM (42.4 + 3.0%, n = 16), but this was independent of the endothelium. TMP (10 and 100 pM) significantly enhanced the relaxation to L-arginine, with a maximum relaxation in the presence of 100 gM TMP of 81.7 + 6.2%(n = 5, P<0.01), but the effect of TMP was entirely dependent on the endothelium. A similar effect was observed in PGF2,-constricted pulmonary arteries.6 These results show that TMP stimulates NO production at low concentrations in pulmonary arteries, via an apparently novel endothelium-resident mechanism that is dependent on exogenous L-arginine.Normal plasma L-arginine levels of around 150 gM would allow this mechanism to be maximally activated. As mesenteric arteries do not seem to express the mechanism to any significant extent, at low concentrations TMP would be effectively selective to the pulmonary vasculature, and may thus have potential as a therapeutic agent in pulmonary vascular disease.