Enhancement of the haemodynamic effects of N~G-monomethyl-L- arginine by transforming growth factor-β_1 in conscious, normal, but not endotoxaemic, rats

摘要

1 Male, Long Evans rats (350-450 g) were chronically instrumented for the measurement of regional haemodynamics, and the effects of TGF-β_1 (25 μg kg~(-1) i.v. bolus) were assessed during infusion of saline (n = 9) or lipopolysaccharide (LPS, 150 蘥 kg~(-1) h~(-1); n = 12). In the same animals, responses to N~G-monomethyl-L-arginine (L-NMMA 10 mg kg~(-1) bolus; 10 mg kg~(-1) h~(-1) infusion) were determined 18 h after administration of TGF-β_1. In a separate experiment, the effects of the endothelin antagonist, SB 209670 (10 μg kg~(-1) min~(-1)) on responses to TGF-β_1 and to L-NMMA subsequently, were determined. 2 In the absence of LPS, TGF-β_1 had slow-onset bradycardic and pressor effects accompanied by mesenteric and hindquarters, but not renal, vasoconstriction. Eighteen hours after TGF-β_1, these effects had gone, but the bradycardic, pressor, and mesenteric vasoconstrictor responses to L-NMMA were enhanced. The haemodynamic changes following TGF-β_1, and the augmentation of the subsequent responses to L-NMMA, were inhibited by SB 209670. These results are consistent with TGF-β_1 stimulating the synthesis and release of endothelin, and an involvement of the latter in responses to L-NMMA. 3 The pressor effects of TGF-β_1 were similar in LPS-infused and saline-infused animals, but in the former group the mesenteric vasoconstriction was enhanced and the hindquarters vasoconstriction diminished. Since, in the absence of TGF-β_1, LPS-infused animals showed a developing hindquarters vasodilatation and mesenteric vasoconstriction, it is feasible that, in the presence of TGF-β_1 and LPS together, the haemodynamic profile represented an amalgam of the individual effects of the two interventions, rather than a specific effect of TGF-β_1 on the haemodynamic sequelae of endotoxaemia. 4 In the presence of LPS, haemodynamic responses to L-NMMA were suppressed, and TGF-β_1 generally did not affect this suppression. A possible explanation of this observation is that LPS increased circulating endothelin levels, and thus resulted in desensitization to the effects of endothelin released following administration of L-NMMA.