Enhancement of the haemodynamic effects of NG-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 micrograms kg-1 i.v. bolus) were assessed during infusion of saline (n = 9) or lipopolysaccharide (LPS, 150 micrograms kg-1 h-1; n = 12). In the same animals, responses to NG-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-beta 1. In a separate experiment, the effects of the endothelin antagonist, SB 209670 (10 micrograms kg-1 min-1) on responses 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 pressor effects accompanied by mesenteric and hindquarters, but not renal, vasoconstriction. Eighteen hours after TGF-beta 1, these effects had gone, but the bradycardic, pressor, and mesenteric vasoconstrictor responses to L-NMMA were enhanced. The haemodynamic changes following TGF-beta 1, and the augmentation of the subsequent responses to L-NMMA, were inhibited by SB 209670. These results are consistent with TGF-beta 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-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 vasodilatation and mesenteric vasoconstriction, it is feasible that, in the presence of TGF-beta 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-beta 1 on the haemodynamic sequelae of endotoxaemia. 4. In the presence of LPS, haemodynamic responses to L-NMMA were suppressed, and TGF-beta 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.
Gardiner
S M
SM
Department of Physiology & Pharmacology, University of Nottingham Medical School, Queen's Medical Centre.
Kemp
P A
PA
March
J E
JE
Bennett
T
T
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects*; D007189:Indans / Q000494:pharmacology; D007262:Infusions, Intravenous; D008070:Lipopolysaccharides / Q000097:blood / Q000494:pharmacology*; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D051381:Rats; D012016:Reference Values; D012965:Sodium Chloride / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D019323:omega-N-Methylarginine
D004791:Enzyme Inhibitors; D007189:Indans; D008070:Lipopolysaccharides; D016212:Transforming Growth Factor beta; C087551:1H-Indene-2-carboxylic acid, 1-(1,3-benzodioxol-5-yl)-3-(2- (carboxymethoxy)-4-methoxyphenyl)-2,3-dihydro-5-propoxy-, (1S,2R,3S)-; D019323:omega-N-Methylarginine; D012965:Sodium Chloride; D001120:Arginine; D019001:Nitric Oxide Synthase