Influence of aminoguanidine and the endothelin antagonist, SB 209670, on the regional haemodynamic effects of endotoxaemia in conscious rats.
1. We compared the regional haemodynamic responses to lipopolysaccharide (LPS; 150 micrograms kg-1 h-1, i.v.) in the presence of saline, aminoguanidine (AG; 45 mg kg-1 bolus, 45 mg kg-1 h-1 infusion), or AG and the non-selective endothelin receptor antagonist, SB 209670 (600 micrograms kg-1 h-1), in conscious, chronically instrumented, Long Evans rats (350-450 g; n = 8 in all groups). We used AG because there is evidence that it is a selective inhibitor of inducible nitric oxide synthase (iNOS), although recently it has been claimed AG also inhibits constitutive NOS. 2. Infusion of LPS in the presence of saline caused an early, transient hypotension (1-2 h) and a renal vasodilatation, with a secondary, delayed fall in mean arterial blood pressure (MAP), progressive tachycardia, and renal and hindquarters vasodilatation. 3. AG alone caused a rapid (within 30 s) transient rise in MAP (delta 27 +/- 3 mmHg), accompanied by tachycardia and regional vasoconstrictions, but no reduction in regional flows, indicating the pressor effect of AG was, probably, largely due to an increase in cardiac output. These effects are not consistent with AG inhibiting constitutive NOS. In the presence of AG, LPS still caused an early, transient fall in MAP accompanied by a renal vasodilatation, but thereafter there was a significant rise in MAP (17 +/- 3 mmHg, 3 h after onset of LPS infusion) accompanied by bradycardia and marked mesenteric and hindquarters vasoconstrictions. However, 23 h after the onset of co-infusion of AG and LPS all variables were not different from baseline, except heart rate and renal vascular conductance, which were increased. 4. In the presence of AG and SB 209670, LPS caused progressive hypotension and increases in renal, mesenteric and hindquarters vascular conductances. Hence, SB 209670 prevented the rise in MAP and the regional vasoconstrictions seen with AG and LPS, indicating an involvement of endothelin in these events. 5. In the presence of AG and SB 209670, 23 h after the onset of LPS infusion, the AT 1-receptor antagonist, losartan (10 mg kg-1), and the V 1-receptor antagonist, d(CH2)5-0-Me-Tyr-AVP (10 micrograms kg-1, 10 micrograms kg-1 h-1) caused additional incremental falls in MAP and increases in renal, mesenteric and hindquarters vascular conductances. Under these circumstances, MAP was lower and regional vascular conductances higher than in the other experiments following administration of losartan and d(CH2)5-0-Me-Tyr-AVP. Thus, although the findings are consistent with AG inhibiting iNOS, thereby revealing the pressor and vasoconstrictor actions of endothelin released by LPS, it is clear that LPS activates a very powerful hypotensive/vasodilator mechanism(s) which is resistant to AG, and whose full influence is only unmasked when the actions of endothelin, angiotensin II and vasopressin are inhibited.
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; D065092:Antidiuretic Hormone Receptor Antagonists; D001127:Arginine Vasopressin / Q000031:analogs & derivatives / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D002302:Cardiac Output / Q000187:drug effects; D003894:Deamino Arginine Vasopressin; D016232:Endothelins / Q000037:antagonists & inhibitors*; D019446:Endotoxemia / Q000503:physiopathology*; D004731:Endotoxins / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology; D007189:Indans / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D019808:Losartan; D008297:Male; D051381:Rats; D012039:Regional Blood Flow / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology
D065092:Antidiuretic Hormone Receptor Antagonists; D001713:Biphenyl Compounds; D016232:Endothelins; D004731:Endotoxins; D004791:Enzyme Inhibitors; D006146:Guanidines; D007093:Imidazoles; D007189:Indans; D008070:Lipopolysaccharides; D013777:Tetrazoles; 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)-; D001127:Arginine Vasopressin; C044101:endotoxin, Escherichia coli; C025044:argipressin, beta-mercapto-beta,beta cyclopentamethylenepropionic acid(1)-; D003894:Deamino Arginine Vasopressin; D019808:Losartan; C004479:pimagedine