Endotoxin-induced impairment of vascular smooth muscle contractions elicited by different mechanisms.
The current study was designed to analyse the mechanisms which are impaired in the vascular hyporeactivity to contractile agents induced by E. coli lipopolysaccharide endotoxin (LPS). Endothelium-denuded aortic rings were prepared from thoracic aorta removed from control and LPS-pretreated rats (20 mg/kg i.p., 4 h before the experiment). In order to determine whether LPS treatment altered the contractile components that depend on intracellular calcium release and extracellular calcium entry to the same extent, rings were contracted under various experimental conditions. The responses elicited by indanidine, phenylephrine (without and with nitrendipine 1 microM), (-) Bay K 8644, (+) S 202-791 and the calcium ionophore calimycin in the presence of 1.25 mM external CaCl2 were all impaired by LPS pretreatment (maximal contractions 19, 63, 44, 28, 22 and 22% of controls, respectively). Concentration-effect curves for CaCl2 made in depolarizing medium (KCl 40 and 100 mM) and in the presence of calimycin (3 microM) were shifted to the right in rings from LPS-pretreated rats. However, the LPS-induced depression of contraction was overcome by the addition of CaCl2 (up to 30 mM). Additionally, in the absence of external CaCl2, the contraction induced by caffeine (50 mM) was not significantly altered by LPS treatment. It is concluded that LPS treatment does not reduce the ability of aortic smooth muscle cells to contract. The results suggest that LPS treatment impairs mechanisms involved in calcium handling within smooth muscle cells after stimulation of calcium entry through different pathways and activation of intracellular calcium release by alpha 1-adrenoceptor agonists.
Biguad
M
M
Laboratoire de Pharmacologie Cellulaire et Moléculaire (CNRS URA 0600), Université Louis Pasteur de Strasbourg, Illkirch, France.
Julou-Schaeffer
G
G
Parratt
J R
JR
Stoclet
J C
JC
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D002110:Caffeine / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D003000:Clonidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology; D004731:Endotoxins / Q000494:pharmacology*; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D009568:Nitrendipine / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
D000316:Adrenergic alpha-Agonists; D004731:Endotoxins; D010656:Phenylephrine; D000001:Calcimycin; D002110:Caffeine; D011189:Potassium Chloride; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D015544:Inositol 1,4,5-Trisphosphate; D009568:Nitrendipine; D003000:Clonidine; C034204:indanidine; D002118:Calcium