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Ligustrazine‐induced endothelium‐dependent relaxation in pulmonary arteries via an NO‐mediated and exogenous L‐arginine‐dependent mechanism
Author(s) -
Peng W.,
Hucks D.,
Priest R.M.,
Kan Y.M.,
Ward J.P.T.
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15778.x
Subject(s) - myograph , tetramethylpyrazine , vasodilation , mesenteric arteries , endothelium , phenylephrine , chemistry , nitric oxide , vasoconstriction , pulmonary artery , prostaglandin h2 , prostaglandin , in vivo , pharmacology , anesthesia , medicine , biochemistry , artery , biology , pathology , cyclooxygenase , blood pressure , enzyme , alternative medicine , microbiology and biotechnology
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 endothelium‐independent, 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. 2 The study was performed on isolated pulmonary (1 − 2 mm i.d.), intrapulmonary (200 − 850 μ m ) and mesenteric (200 − 400 μ m ) arteries of the rat using a Mulvaney‐Halpen small vessel myograph, following preconstriction with phenylephrine (PE, 10 μ m ), prostaglandin F 2α (PGF 2α , 100 μ m ), or 75 mM K + (KPSS, equimolar substitution for Na + ). Values are shown as mean ± s.e.mean, or for EC 50 s as mean [± 95% confidence limits]. 3 TMP caused a concentration‐dependent relaxation against all three agonists in both large (1.56 ± 0.04 mm) and small (399 ± 20 μ m ) pulmonary arteries; it was more potent in small compared to large arteries constricted with PE or PGF 2α ( P < 0.05), but not those constricted with KPSS. The NO synthase (NOS) inhibitor, N G ‐monomethyl‐L‐arginine (L‐NMMA, 100 μ m ) caused a significant shift to the right of these relationships, such that the EC 50 for TMP in large pulmonary arteries constricted with PE increased from 522 [+130, −104] μ m ( n = 12) to 1828 [+395, −325] μ m ( n = 6, P < 0.01). Both removal of the endothelium and methylene blue (10 μ m ) had similar effects. 4 L‐Arginine substantially reduced the EC 50 for TMP in pulmonary arteries; in the presence of 400 μ m L‐arginine the EC 50 for TMP in large arteries constricted with PE was 14.7 [+21.0, −8.6] μ m , ( n = 6, P < 0.001), and with 10μ m L‐arginine 96.7 [+45.1, −30.7] μ m , ( n = 6, P < 0.001). 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 μ m ) had no significant effect on TMP‐induced relaxation in mesenteric arteries ( n = 5). 5 L‐Arginine itself caused a concentration‐dependent relaxation in intrapulmonary arteries (639 ± 34 μ m ) constricted with PE, reaching a maximum relaxation around 100 − 400 μ m (42.4 ± 3.0%, n = 16), but this was independent of the endothelium. TMP (10 and 100 μ m ) significantly enhanced the relaxation to L‐arginine, with a maximum relaxation in the presence of 100 μ m 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 PGF 2α ‐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 μ m 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.