Pyrrolidine dithiocarbamate improves the septic shock syndromes in spontaneously hypertensive rats.
1. The aim of the present study was to evaluate the effect of pyrrolidine dithiocarbamate (PDTC), an inhibitor of nuclear factor-kappa B (NF-kappa B), on septic shock induced by Escherichia coli lipopolysaccharide (LPS) in spontaneously hypertensive rats (SHR). 2. After injection of LPS in SHR, a marked decrease in blood pressure was observed at 3 h and vascular hyporeactivity to noradrenaline (NA) was observed after 1 h. A marked increase in plasma levels of tumour necrosis factor-alpha (TNF-alpha) and nitrite (an indicator of nitric oxide) was also observed in SHR. 3. The delayed hypotension and hyporeactivity to NA induced by LPS were significantly reserved by pretreatment of rats with PDTC (10 mg/kg). The increase in plasma levels of TNF-alpha and nitrite in LPS-treated groups was also significantly suppressed by PDTC pretreatment. In addition, the survival time of SHR treated with LPS was significantly prolonged by PDTC pretreatment. 4. The present ex vivo study demonstrates that the NA-induced contraction is attenuated and the L-arginine-induced relaxation is enhanced in aortic rings obtained from LPS-treated SHR. Both the reduction of the NA-induced contraction and the increase of L-arginine-induced relaxation were reversed by pretreatment with PDTC. However, the relaxation elicited by acetylcholine (ACh) was not affected in LPS-treated SHR when compared with sham-operated SHR. In addition, the ACh-induced relaxation in LPS-treated SHR was not affected by PDTC pretreatment. 5. In normotensive Wistar-Kyoto (WKY) rats, LPS had mild effects on blood pressure, vascular hyporeactivity and plasma levels of TNF-alpha and nitrite. At a higher dose, PDTC (10 mg/kg) also prolonged survival time and improved haemodynamics in LPS-treated WKY rats. In the ex vivo study, it was noted that the relaxation elicited by ACh was significantly (P < 0.05) attenuated in LPS-treated WKY rats. This attenuation of the ACh-induced relaxation by LPS in WKY rats was significantly reversed by pretreatment with 10 mg/kg PDTC. 6. In conclusion, PDTC prolongs survival time in rats with endotoxaemia and improves the septic shock syndromes both in vivo and ex vivo. Thus, we propose that PDTC may be of use in septic patients.
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, ROC. mhyen@ndcml.ndmctsgh.edu.tw
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D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001120:Arginine / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004731:Endotoxins / Q000633:toxicity; D006973:Hypertension / Q000150:complications* / Q000235:genetics / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009573:Nitrites / Q000097:blood; D011759:Pyrrolidines / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012772:Shock, Septic / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy*; D016019:Survival Analysis; D013859:Thiocarbamates / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000975:Antioxidants; D004731:Endotoxins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009573:Nitrites; D011759:Pyrrolidines; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; C020972:pyrrolidine dithiocarbamic acid; C044101:endotoxin, Escherichia coli; D001120:Arginine; D000109:Acetylcholine