Effects of a Calcium-Channel Blocker (CV159) on Hepatic Ischemia/Reperfusion Injury in Rats

• Published in: Biological & pharmaceutical bulletin Vol. 33; no. 1; p. 77
• Main Authors: Hataji, Keizo, Watanabe, Taiji, Oowada, Shigeru, Nagaya, Masaki, Kamibayashi, Masato, Murakami, Eiichi, Kawakami, Hiroyoshi, Ishiuchi, Atsuko, Kumai, Toshio, Nakano, Hiroshi, Kobayashi, Shinichi, Otsubo, Takehito
• Format: Journal Article
• Language: English
• Published: Tokyo Japan Science and Technology Agency 01.01.2010
• ISSN: 0918-6158; 1347-5215

Nitric oxide (NO) and the partial pressure of oxygen (pO2) in the liver were simultaneously quantified in rats with partial hepatic ischemia/reperfusion injury (PHIRI). Real-time NO/pO2 monitoring and immunohistochemical analysis for superoxide dismutase and inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) were performed to evaluate the protective effects of a dihydropyridine-type calcium-channel blocker--CV159--on PHIRI. Serum high-mobility-group box-1 (HMGB-1) was measured to assess cellular necrosis. Moreover, we used in vitro/ex vivo electron paramagnetic resonance spin trapping to assess the hydroxyl radical (·OH)-scavenging activity (OHSA) of CV159 and the liver tissue. The NO levels were significantly higher in CV159-treated rats than in control rats throughout the ischemic phase. Immediately after reperfusion, the levels temporarily increased in waves and then gradually decreased in the treated rats but remained constant in the control rats. pO2 was continually higher in the treated rats. In these rats, hepatic eNOS expression increased, whereas iNOS expression decreased. The treated rats exhibited significantly higher cytosolic and mitochondrial concentrations NOx (NO2+NO3). The serum HMGB-1 levels significantly decreased in the treated rats. Moreover, CV159 directly scavenged ·OH and both mitochondrial and cytosolic OHSA were preserved in the treated rats. Thus, CV159-mediated inhibition of intracellular Ca2+ overloading may effectively minimize organ damage and also have ·OH-scavenging activity and the cytoprotective effects of eNOS-derived NO.