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L-nitro-Arginine Inhibits Increase in Endothelin Binding Sites Induced by Ischemia and Reperfusion

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Abstract

T. Saito, E. Fushimi, T. Tamura, Y. Fujiwara, H. Miura, H. Watanabe, S. Kibira, H. Hasegawa and M. Miura. L-nitro-Arginine Inhibits Increase Endothelin in Binding Sites Induced by Ischemia and Reperfusion. Journal of Molecular and Cellular Cardiology (2002) 34, 1041–1047. We have demonstrated that ischemia and reperfusion promoted augmented contractile response to endothelin-1 (ET) in coronary arteries in the presence of polymorphonuclear leukocytes (PMN). It has been also reported that ischemia and reperfusion increase ET binding sites in cardiac membrane in isolated rat heart perfused by blood cell-free system. To determine the role of PMN and L-arginine to nitric oxide (NO) pathway in these phenomena, isolated perfused rabbit hearts were subjected to 30 min of global ischemia followed by 30 min of reflow in the absence or presence of PMN and 10−5 M of L-nitro-arginine (LNA). PMN was prepared with Percoll density gradients from peritoneal exudate elicited by glycogen. PMN activated with 10−6 M of phorbol myristate acetate or their supernatant were infused into the coronary perfusion circuit after 5 min of reflow. LNA was added to perfusate also after reflow. The effect of superoxide dismutase (SOD: 50 IU/ml) was also determined. After the end of protocols, membrane fraction was isolated from the hearts for 125I-ET-1 binding assay. ET-1 binding (Bmax) showed a significant increase by ischemia and reperfusion (P<0.01 vs control). That was markedly augmented with addition of activated PMN or their supernatant (both P<0.01), but abolished either by LNA or SOD (P<0.01 and P<0.05, respectively). These results indicate that increase in ET-receptor by ischemia and reperfusion is mediated by free radicals generated via L-arginine to NO pathway.

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    Please address all correspondence to: Takashi Saito, MD, Associate Professor, The 2nd Department of Internal Medicine, Akita University School of Medicine, 1-1-1 Hondo, Akita 010, Japan. Tel: 81-018-884-6106; Fax: 81-188-836-2612; E-mail:[email protected]

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