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Inhibition of nitric oxide synthesis in vascular smooth muscle by retinoids
Author(s) -
Hirokawa K.,
O'Shaughnessy K.M.,
Ramrakha P.,
Wilkins M.R.
Publication year - 1994
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.1476-5381.1994.tb17159.x
Subject(s) - nitric oxide , nitrite , vascular smooth muscle , nitric oxide synthase , retinoic acid , phenylephrine , endocrinology , medicine , chemistry , retinoid , biology , smooth muscle , biochemistry , blood pressure , organic chemistry , gene , nitrate
1 These studies examine the effect of retinoids on interleukin 1β (IL‐1β)‐induced nitric oxide synthase (NOS) activity in cultured rat aortic vascular smooth muscle (VSM) cells and isolated rat aortic rings. 2 All‐ trans ‐retinoic acid (all‐ transM ‐RA, 0.1–10 μ m ) and its active analogues produced concentration‐dependent inhibition of IL‐1β (0.1–10 ng ml −1 )‐induced nitrite production in cultured VSM cells. In contrast, the inactive retinoid, Ro 14–6113 (0.1–10 μ m ), had no effect on IL‐1β‐induced nitrite production. 3 Since some of the actions of retinoids are mediated by induction of transforming growth factor beta (TGF‐β), its effect on inducible NOS activity in VSM cells was examined. TGF‐β produced concentration‐dependent (0.1–10 ng ml −1 ) inhibition of IL‐1β‐induced nitrite production and the maximum effect (approximately 90% inhibition) was significantly greater than that seen with all‐ trans ‐RA (approximately 70% with 10 μ m ). However, an anti‐TGF‐β antibody (50 μg ml −1 ) which blocked the effect of exogenous TGF‐β (5 ng ml −1 ) did not significantly reverse the inhibitory action of all‐ trans ‐RA (10 μ m ). 4 In addition to inhibiting IL‐1β‐induced nitrite production, all‐ trans ‐RA (10 μ m ) reduced substantially inducible NOS mRNA and protein levels in IL‐1β‐induced VSM cells (P < 0.01). 5 Incubation of isolated rat aortic rings with IL‐1 β (10 ng ml −1 ) caused a progressive resistance of the rings to the vasoconstrictor action of phenylephrine (10 n m to 10 μ m ). This effect was abolished by the addition of the nitric oxide synthase inhibitor L‐ N G ‐monomethyl‐L‐arginine (L‐NMMA, 1 μ m ). All‐ trans ‐RA (IO μ m ) also markedly and significantly reversed this IL‐1β‐induced vascular hyporeactivity (P < 0.01). 6 These data show that all‐ trans ‐RA and other active retinoids are able to block cytokine‐stimulated expression of inducible NOS in cultured VSM cells and isolated aortic rings.