Endotoxin-induced vascular hyporesponsiveness in rat aorta: in vitro effect of aminoguanidine.
The current study was designed to evaluate the endotoxin-induced alterations of the mechanisms involved in Ca(2+)handling within the rat thoracic aorta and further to examine whether in vitro inhibition of inducible nitric oxide synthase (iNOS) by aminoguanidine would account for this effect or not. Endothelium denuded aortic rings from rats injected with lipopolysaccharide (LPS) (5 mg kg(-1), i.p. 18 h prior to functional studies) or saline were mounted in isolated organ baths. Various experimental conditions were studied on paired rings of the same animal which were incubated in the presence or absence of aminoguanidine (100 microM). Phenylephrine contractility in Ca(2+)-containing buffer or in Ca(2+)-free buffer, contractions induced by K(+)depolarization and CaCl(2)in depolarized muscle and by caffeine exposure were significantly decreased in LPS-treated rings and were reversed by aminoguanidine exposure. Aminoguanidine also improved the contractions recorded while switching the Ca(2+)-free buffer to Ca(2+)-containing buffer. We conclude that endotoxin induces a generalized contractile defect in vascular smooth muscle including impairment in the influx of extracellular Ca(2+)and release of Ca(2+)from intracellular stores. An increase in iNOS activation leading to excessive nitric oxide synthesis, possibly non-endothelial in origin, may account for this defect.
Ulker
S
S
Department of Pharmacology, School of Medicine, Ege University, 35100 Bornova-Izmir, Turkey.
Cinar
M G
MG
Can
C
C
Evinç
A
A
Koşay
S
S
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004347:Drug Interactions; D004731:Endotoxins; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017208:Rats, Wistar; D014655:Vascular Resistance / Q000187:drug effects
D004731:Endotoxins; D004791:Enzyme Inhibitors; D006146:Guanidines; D008070:Lipopolysaccharides; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D006152:Cyclic GMP; C004479:pimagedine; D002118:Calcium