ENHANCEMENT OF THE HEMODYNAMIC-EFFECTS OF N-G-MONOMETHYL-L-ARGININE BY TRANSFORMING GROWTH FACTOR-BETA(1) IN CONSCIOUS, NORMAL, BUT NOT ENDOTOXAEMIC, RATS

1 Male, Long Evans rats (350-450 g) were chronically instrumented for the measurement of regional haemodynamics, and the effects of TGF-beta (1) (25 mu g kg(-1) i.v. bolus) were assessed during infusion of salin e (n=9) or lipopolysaccharide (LPS, 150 mu g kg(-1) h(-1); n=12). In t he same animals, responses to NG-monomethyl-L-arginine (L-NMMA 10 mg k g(-1) bolus; 10 mg kg(-1) h(-1) infusion) were determined 18 h after a dministration of TGF-beta(1). In a separate experiment, the effects of the endothelin antagonist, SB 209670 (10 mu g kg(-1) min(-1)) on resp onses to TGF-beta(1) and to L-NMMA subsequently, were determined. 2 In the absence of LPS, TGF-beta(1) had slow-onset bradycardic and presse r effects accompanied by mesenteric and hindquarters, but not renal, v asoconstriction. Eighteen hours after TGF-beta(1), these effects had g one, but the bradycardic, presser, and mesenteric vasoconstrictor resp onses to L-NMMA were enhanced. The haemodynamic changes following TGF- beta(1), and the augmentation of the subsequent responses to L-NMMA, w ere inhibited by SE 209670. These results are consistent with TGF-beta (1) stimulating the synthesis and release of endothelin, and an involv ement of the latter in responses to L-NMMA. 3 The presser effects of T GF-beta(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-beta(1), LPS-infused animals showed a developing hindquarters vas odilatation and mesenteric vasoconstriction, it is feasible that, in t he presence of TGF-beta(1) and LPS together, the haemodynamic profile represented an amalgam of the individual effects of the two interventi ons, rather than a specific effect of TGF-beta(1) on the haemodynamic sequelae of endotoxaemia. 4 In the presence of LPS, haemodynamic respo nses to L-NMMA were suppressed, and TGF-beta(1), generally did not aff ect this suppression. A possible explanation of this observation is th at LPS increased circulating endothelin levels, and thus resulted in d esensitization to the effects of endothelin released following adminis tration of L-NMMA.