Pharmacologic inhibition of nitric oxide synthases and cyclooxygenases enhances intimal hyperplasia in balloon-injured rat carotid arteries Jens W Fischer,

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Presentation transcript:

Pharmacologic inhibition of nitric oxide synthases and cyclooxygenases enhances intimal hyperplasia in balloon-injured rat carotid arteries Jens W Fischer, PhD, Suzanne Hawkins, Alexander W Clowes, MD Journal of Vascular Surgery Volume 40, Issue 1, Pages 115-122 (July 2004) DOI: 10.1016/j.jvs.2004.03.037

Fig 1 Biosynthesis and function of eicosanoids and nitric oxide (NO) in vessel wall. Arachidonic acid is liberated from plasma membrane phospholipids mainly by cytosolic phospholipase A2 (PLA2). Arachidonic acid is subsequently converted by lipoxygenases into leukotrienes (not shown) or by cyclooxygenase-1 and cyclooxygenase-2 (COX1/2) into prostaglandin G2 (PG G2) and further into prostaglandin H2 (PG H2). PGH2 is the substrate of individual synthases generating various prostaglandins, such as PGI2, PGE2, and thromboxane A2 (TXA2). The synthetic pathways of PGE1, PGD2, PGF2α are not shown for reasons of simplicity. NO is synthesized from l-arginine by inducible (iNOS), endothelial (ec), and neuronal (n) nitric oxide synthases (NOS) via the intermediate NG-hydroxy-l-arginine (NOHA). The effects of eicosanoids and NO on vessel diameter, the synthetic smooth muscle cell (SMC) phenotype, and thrombocyte aggregation are indicated (arrows symbolize enhancement; lines with crossbar indicate inhibition). Synthetic SMC phenotype stands for SMC with high proliferative, migratory, and synthetic activity. TXA-S, Thromboxane synthase; PGI2-S, prostacyclin synthase; PGE-S, prostaglandin E synthase. Journal of Vascular Surgery 2004 40, 115-122DOI: (10.1016/j.jvs.2004.03.037)

Fig 2 Carotid arteries 14 days after balloon injury. A, Cross sections of balloon-injured carotid arteries stained with hematoxylin-eosin 14 days after injury. a, Untreated control; b, N-nitro-l-arginine (L-NA, 10 mg/kg/d); c, indomethacin (1.5 mg/kg/d); d, indomethacin (1.5 mg/kg/d) plus L-NA (10 mg/kg/d). Arrows indicate internal elastic laminas. Original magnification ×40. B, Original measurements of intimal areas per cross section derived from one representative experiment. Control animals (n = 4) received vehicle; additional rats were treated with N-nitro-l-arginine (L-NA, 10 mg/kg/d; n = 5), indomethacin (1.5 mg/kg/d; n = 6), or L-NA plus indomethacin (n = 5). *P < .05. Journal of Vascular Surgery 2004 40, 115-122DOI: (10.1016/j.jvs.2004.03.037)

Fig 3 Pooled data from morphometric analysis of carotid arteries and arterial blood pressure 14 days after balloon injury. Rats were treated with N-nitro-l-arginine (L-NA, 10 mg/kg/d), indomethacin (1.5 mg/kg/d), or L-NA plus indomethacin. A, Data pooled from 3 independent experiments expressed as x-fold increase of intima-media ratio over untreated controls. B, Medial area of injured arteries pooled from 3 independent experiments and expressed as x-fold increase over controls. C, Mean arterial blood pressure. Values represent mean ± SD; controls, n = 19; L-NA, n = 14; indomethacin, n = 6, indomethacin plus L-NA, n = 14. *P < .05. Journal of Vascular Surgery 2004 40, 115-122DOI: (10.1016/j.jvs.2004.03.037)

Fig 4 Intimal hyperplasia at 14 days and mean arterial blood pressure in rats receiving subcutaneous infusion of 13 mg/kg/24 hr of hydralazine in addition to N-nitro-l-arginine (L-NA, 10 mg/kg/d) or L-NA plus indomethacin (1.5 mg/kg/d). A, Fold increase of intima-media ratio over balloon-injured controls. B, Mean arterial blood pressure; controls, n = 8; L-NA, n = 6, indomethacin plus L-NA, n = 6. *P < .05. Journal of Vascular Surgery 2004 40, 115-122DOI: (10.1016/j.jvs.2004.03.037)

Fig 5 A, Fourteen days after injury. Controls, n = 19; N-nitro-l-arginine (L-NA), n = 14; indomethacin, n = 6; indomethacin plus L-NA, n = 14. *P < .05, control vs L-NA plus indomethacin. B, Cross sections of balloon-injured carotid arteries by 14 days, immunostaining of versican core protein. a, Untreated control; b, L-NA (10 mg/kg/d); c, indomethacin (1.5 mg/kg/d); d, indomethacin (1.5 mg/kg/d) plus L-NA (10 mg/kg/d); asterisk is located just above the versican-rich luminal part of the neointima. Arrows indicate internal elastic laminas. Original magnification × 40. Journal of Vascular Surgery 2004 40, 115-122DOI: (10.1016/j.jvs.2004.03.037)