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Enhancement of the haemodynamic effects of N G ‐monomethyl‐ l ‐arginine by transforming growth factor‐β 1 in conscious, normal, but not endotoxaemic, rats
Author(s) -
Gardiner S.M.,
Kemp P.A.,
March J.E.,
Bennett T.
Publication year - 1995
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1995.tb15961.x
Subject(s) - transforming growth factor , chemistry , arginine , hemodynamics , biochemistry , biophysics , endocrinology , medicine , biology , amino acid
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 μg 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.