Yoshiharu Shimizu

Effects of Quercetin and/or Restraint Stress on Formation of Aberrant Crypt Foci Induced by Azoxymethane in Rat Colons

The present study examines the effect of dietary quercetin and/or restraint stress on the formation of aberrant crypt foci (ACF) induced by azoxymethane (AOM) in the colon. Female F344 rats were divided into four groups. All animals were given intraperitoneal injections of AOM. The animals were fed a basal diet (group A, C), or a 2% quercetin-supplemented diet (group B, D). The animals were put individually to narrow wire cages for 1 h every day throughout the study to expose them to mild restraint stress (group C, D). At week 5, all the rats were killed and analyzed for ACF in the colon. The number of ACF increased significantly in the animals subjected to stress (p < 0.05). On the other hand, dietary quercetin significantly reduced the number of ACF in both the nonstress (p < 0.001) and stress groups (p < 0.05). These findings suggest that quercetin might have a potential as a chemopreventive drug for colon cancer despite stress.

Endothelium-dependent contraction in intrapulmonary arteries: mediation by endothelial NK1 receptors and TXA2.

1 We have examined whether three natural tachykinins, substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) induce an endothelium‐dependent contraction (EDC) in the rabbit isolated intrapulmonary artery. 2 Removal of the endothelium almost abolished the contraction induced by SP (10−8 m) while it did not attenuate the contraction induced by SP (10−7 m), NKA (10−9‐10−7 m) or NKB (10−9‐10−7 m). 3 The EDC induced by SP (10−8 m) was abolished by NK1 antagonists (FK‐888, CP‐96345, CP‐99994 and SR‐140333) but not by an NK2 antagonist (SR‐48968). 4 The EDC induced by SP was attenuated by cyclo‐oxygenase inhibitors (aspirin and indomethacin), thromboxane A2 (TXA2) synthetase inhibitors (OKY‐046, KY‐234 and KY‐063) and a TXA2 antagonist (S‐1452). 5 The rank order of potency causing endothelium‐independent contraction (EIC) was NKA>NKB>SP. The EIC induced by SP (10−7 m) was attenuated by an NK2 antagonist but not by NK1 antagonists, cyclo‐oxygenase inhibitors, TXA2 synthetase inhibitors or a TXA2 antagonist. 6 In conclusion, SP at 10−8 m induces EDC via endothelial NK1 receptors and TXA2 production, and SP at 10−7 m induces EIC via NK2 receptors in the rabbit intrapulmonary artery.

Nicotine-induced contraction in the rat coronary artery: possible involvement of the endothelium, reactive oxygen species and COX-1 metabolites.

Summary: Nicotine caused a contraction of the rat coronary artery in the presence of N&ohgr;‐nitro‐L‐arginine methyl ester (L‐NAME) and arachidonic acid, and did not in the absence of these agents. The present experiments were undertaken to pharmacologically characterize the nicotine‐induced contraction in ring preparations of the rat coronary artery. The contraction was abolished by chemical removal of endothelium saponin. Oxygen radical scavengers, superoxide dismutase and catalase, significantly attenuated the contraction. Cyclooxygenase‐1 (COX‐1) inhibitors (flurbiprofen, ketoprofen and ketrolack) attenuated the nicotine‐induced contraction in a concentration‐dependent manner, and cyclooxygenase‐2 (COX‐2) inhibitors at high concentrations (nimesulide and NS‐389) slightly attenuated the contraction. A TXA2 synthetase inhibitor (OKY‐046) attenuated the contraction to a small extent only at high concentrations. A TXA2 receptor antagonist (S‐1452) attenuated the contraction in a concentration‐dependent manner. A nicotinic receptor antagonist (hexamethonium) attenuated the contraction in part and an &agr;‐adrenoceptor antagonist (prazosin) nearly abolished the contraction. From these results, it was suggested that the contraction induced by nicotine in the rat coronary artery in the presence of L‐NAME and arachidonic acid is endothelium dependent, and involves reactive oxygen species and endothelial COX‐1 metabolites of arachidonic acid. Part of the contraction is probably due to release of norepinephrine.

Pharmacological nature of TP receptor mediated contraction in human intrapulmonary artery

The present experiments were undertaken to elucidate the pharmacological nature of thromboxane A2/prostaglandin H2 receptor (TP)-mediated contraction in human intrapulmonary arteries. 9,11-epithio-11, 12-methano-thromboxane A2 (STA2) and (15S)-hydroxy-9 alpha, 11 alpha-(epoxymethano) prosta-5Z, 13E-dienoic acid (U46619) (TXA2 agonists) caused contractions in a concentration-dependent manner with EC50 values of 1.4 x 10(-9) M and 3.1 x 10(-9) M, respectively. S-1452 and ONO-3708 (TP receptor antagonists) concentration-dependently attenuated the STA2 (10(-8) M)-induced contraction with IC50 values of 5.8 x 10(-9) M and 4.2 x 10(-8) M, respectively. U-73122 (3 x 10(-6) M) and 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate (3 x 10(-5) M) (phospholipase C inhibitors) significantly attenuated the STA2-induced contraction. Ca(+2)-induced contraction in the presence of STA2 (10(-8) M) in Ca(+2)-free medium was attenuated by nifedipine (10(-6) M) by 40%. The remaining nifedipine-resistant Ca(+2)-induced contraction was not attenuated by nitroglycerin (10(-5) M), but forskolin (10(-5) M) (adenylate cyclase stimulant) significantly decreased it by 75%. The results clearly indicate that in human intrapulmonary artery, there are TP receptors coupled with phospholipase C activation and that TP receptor-mediated Ca(+2)-mobilization is in part nifedipine- and nitroglycerin-resistant, but forskolin-sensitive.

Involvement of endothelial cyclo-oxygenase metabolites in noradrenaline-induced contraction of rat coronary artery.

1. Noradrenaline (NA; 0.3 µmol/L) caused a contraction of the rat coronary artery that markedly increased in the presence of the nitric oxide synthase (NOS) inhibitor NG‐nitro‐l‐arginine methyl ester (l‐NAME; 100 µmol/L) and arachidonic acid (1 µmol/L; P < 0.05).

Noradrenaline-induced contraction mediated by endothelial COX-1 metabolites in the rat coronary artery.

Summary: Noradrenaline‐induced contraction of the rat coronary arteries was significantly augmented by the presence of NG‐nitro‐ L‐arginine methyl ester (L‐NAME) and arachidonic acid. The experiments in the study presented here were undertaken to characterize pharmacologically the augmented noradrenaline‐induced contraction in ring preparations of rat coronary arteries. The contraction was stopped by a chemical remover of endothelium (saponin). Oxygen radical scavengers, superoxide dismutase and catalase, significantly attenuated the contraction. Cyclooxygenase‐1 inhibitors (flurbiprofen, 10‐7 M) attenuated the noradrenaline‐induced contraction and cyclooxygenase‐2 (nimesulide, 10‐7 M) slightly attenuated the contraction. A thromboxane A2 (TXA2) synthetase inhibitor (OKY‐046) and a TXA2 receptor antagonist (S‐1452) did not affect the contraction. Based on these results, it was suggested that the contraction induced by noradrenaline in the rat coronary artery in the presence of L‐NAME and arachidonic acid is endotheliumdependent, and that it involves reactive oxygen species and endothelial cyclooxygenase‐1 metabolites of arachidonic acid.