Increased responsiveness of the hepatic guanylate cyclase-guanosine 3',5'-monophosphate system to nitrosoguanidine following partial hepatectomy.
When tested at concentrations producing submaximal responses, the N-nitroso carcinogen, N-methyl-N'-nitro-N-nitrosoguanidine (methylnitro-nitrosoguanidine) elicited a 2-fold greater increase in guanosine 3',5'-monophosphate (cyclic GMP) accumulation in slices and a 5-fold greater stimulation of guanylate cyclase activity in whole homogenates of rat liver examined 24 h after 75% hepatectomy compared to the corresponding methylnitro-nitrosoguanidine responses in sham-operated and unoperated controls. Enhanced methylnitro-nitrosoguanidine sensitivity of guanylate cyclase in whole homogenates of regenerating liver was attributable to altered responsiveness of the enzyme activity of the 100 000 X g soluble fraction, which contained 98% of the methylnitro-nitrosoguanidine responsive activity. Basal cyclic GMP accumulation and guanylate cyclase activities of these systems, and their responses to concentrations of methylnitro-nitrosoguanidine eliciting maximal stimulation were unchanged after partial hepatectomy or sham operation, compared to unoperated controls. The findings of (a) increased heme concentrations in the supernatant and the high molecular weight Sephadex G-25 fraction of sham operated, compared to regenerating liver, (b) suppression of methylnitro-nitrosoguanidine responsive activity after addition of exogenous hemoglobin to supernatants from regenerating liver, and (c) enhancement of the responsiveness of soluble guanylate cyclase from sham operated liver to submaximal methylnitro-nitrosoguanidine after reduction of endogenous heme content by in situ perfusion, all suggested that the difference in methylnitro-nitrosoguanidine action observed in control vs. regenerating liver are related to a lower heme-protein content of the latter. These results emphasize the importance of endogenous heme as a factor modulating the response of the hepatic guanylate cyclase system to methylnitro-nitrosoguanidine.
D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism*; D004789:Enzyme Activation; D006162:Guanylate Cyclase / Q000378:metabolism*; D006418:Heme / Q000378:metabolism; D006498:Hepatectomy; D008099:Liver / Q000378:metabolism*; D008115:Liver Regeneration; D008297:Male; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology*; D051381:Rats; D013347:Subcellular Fractions / Q000201:enzymology
D008769:Methylnitronitrosoguanidine; D006418:Heme; D006162:Guanylate Cyclase; D006152:Cyclic GMP