Endotoxin-induced vascular hyporesponsiveness in rat aorta: in vitro effect of aminoguanidine

• Published in: Pharmacological research 2001-07, Vol.44 (1), p.22-27
• Main Authors: Ülker, Sibel, Çinar, Mehtap G., Can, Cenk, Evinç, Akgün, Koşay, Sezen
• Format: Article
• Language: English
• Subjects: Animals; Aorta, Thoracic - drug effects; Aorta, Thoracic - enzymology; Aorta, Thoracic - physiology; Calcium - metabolism; Cyclic GMP - metabolism; Drug Interactions; endotoxaemia, calcium, nitric oxide, aminoguanidine; Endotoxins; Enzyme Inhibitors - pharmacology; Guanidines - pharmacology; In Vitro Techniques; Lipopolysaccharides - pharmacology; Male; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type II; Rats; Rats, Wistar; Vascular Resistance - drug effects
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1006/phrs.2001.0814

The current study was designed to evaluate the endotoxin-induced alterations of the mechanisms involved in Ca2+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 μ M). Phenylephrine contractility in Ca2+-containing buffer or in Ca2+-free buffer, contractions induced by K+depolarization and CaCl2in 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 Ca2+-free buffer to Ca2+-containing buffer. We conclude that endotoxin induces a generalized contractile defect in vascular smooth muscle including impairment in the influx of extracellular Ca2+and release of Ca2+from intracellular stores. An increase in iNOS activation leading to excessive nitric oxide synthesis, possibly non-endothelial in origin, may account for this defect.