Enhancement of the haemodynamic effects of N^G‐monomethyl‐l‐arginine by transforming growth factor‐β₁ in conscious, normal, but not endotoxaemic, rats

Abstract

1 Male, Long Evans rats (350-450 g) were chronically instrumented for the measurement of regional haemodynamics, and the effects of TGF-/, (25 jg kg-' i.v. bolus) were assessed during infusion of saline (n=9) or lipopolysaccharide (LPS, 150 jg kg-l h'-; n= 12). In the same animals, responses to NG-monomethyl-L-arginine (L-NMMA 10 mg kg-' bolus; 10 mg kg-' h-' infusion) were determined 18 h after administration of TGF-fA. In a separate experiment, the effects of the endothelin antagonist, SB 209670 (10 pg kg-' min') on responses to TGF-f, and to L-NMMA subsequently, were determined.2 In the absence of LPS, TGF-f, had slow-onset bradycardic and pressor effects accompanied by mesenteric and hindquarters, but not renal, vasoconstriction. Eighteen hours after TGF-pl, these effects had gone, but the bradycardic, pressor, and mesenteric vasoconstrictor responses to L-NMMA were enhanced. The haemodynamic changes following TGF-f0l, and the augmentation of the subsequent responses to L-NMMA, were inhibited by SB 209670. These results are consistent with TGF-fl, stimulating the synthesis and release of endothelin, and an involvement of the latter in responses to L-NMMA. 3 The pressor effects of TGF-f, 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-fl,, LPS-infused animals showed a developing hindquarters vasodilatation and mesenteric vasoconstriction, it is feasible that, in the presence of TGF-fl, and LPS together, the haemodynamic proffle represented an amalgam of the individual effects of the two interventions, rather than a specific effect of TGF-l, on the haemodynamic sequelae of endotoxaemia.4 In the presence of LPS, haemodynamic responses to L-NMMA were suppressed, and TGF-P, 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.

Role of TGF-β in Vascular Development and Vascular Reactivity

“…Unfortunately, expression of ET in the vasculature was not characterized in this study. The discrepancy in results between the studies by Gardiner et al [40] and the studies by Lefer et al [38,39] is not clear, excluding the obvious differences in species, surgical preparations, and dose of TGF-ß1.…”

“…Furthermore, the hemodynamic changes noted after the administration of TGF-ß1 were inhibited by the ET antagonist SB 209670 (10 Ìg/kg/min). These results imply that ET may have contributed to the hemodynamic changes induced by TGF-ß1 [40]. Unfortunately, expression of ET in the vasculature was not characterized in this study.…”

“…Gardiner et al [40] assessed the regional hemodynamic effects of TGF-ß1 in rats. These studies showed that TGF-ß1 (25 Ìg/kg intravenous bolus) induced a significant increase in mean arterial pressure and a decrease in pulse rate after 2 h. Reductions were also noted in mesenteric and hindquarter, but not renal, vascular flows and conductances.…”