Activated macrophages depress the contractility of rabbit carotids via an L-arginine/nitric oxide-dependent effector mechanism. Connection with amplified cytokine release.
Inflammatory mediators released by macrophages (M phi) are believed to be involved in septic vasoplegia. To investigate the effect of M phi on vascular reactivity, excised rabbit carotids were exposed intraluminally either to peritoneal rabbit M phi, activated by 18 h of incubation with 1 microgram/ml lipopolysaccharide, or to the supernatants (SPN) derived from them. The contractile responses to phenylephrine (PE, 10(-6) M) were determined by measuring changes in diameter using an ultrasonic microdimensiometer 1, 2, and 3 h after the first control contraction. In control arteries (n = 12), PE-induced contractions were, respectively, 102.9 +/- 3.3%, 95.2 +/- 4.1%, and 89.7 +/- 3.8% of the first contraction, after 1, 2, and 3 h. Activated M phi significantly reduced PE-stimulated contractions after as little as 1 h of carotid exposure (percentage of controls at 1, 2, or 3 h: 74.1 +/- 5.6, 57.2 +/- 5.2, and 34.2 +/- 5.6, n = 10, P less than 0.001). The activated macrophage-derived SPN took longer to diminish carotid contractility than the M phi themselves, and became significant only after 2 h. The greater effect of M phi might be due to cooperation between M phi and vascular cells, as suggested by the amplified interleukin-1 release observed after M phi infusion. The presence of the endothelium partially protected carotid contractility from depression by activated M phi. Extraluminal addition of NG-monomethyl-L-arginine, an inhibitor of nitric oxide synthesis prevented this depression in arteries with or without endothelium. No products of the oxidative pathway of L-arginine were detected in rabbit activated M phi. These results suggest that activation of this pathway in smooth muscle cells seems to be involved in vascular hypocontractility.
Bernard
C
C
Institut National de la Santé et de la Recherche Médicale, Unité 141, Hôpital, Lariboisière, Paris, France.
Szekely
B
B
Philip
I
I
Wollman
E
E
Payen
D
D
Tedgui
A
A
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D002339:Carotid Arteries / Q000502:physiology; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D016207:Cytokines / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000502:physiology; D007375:Interleukin-1 / Q000096:biosynthesis; D008070:Lipopolysaccharides; D008262:Macrophage Activation; D008264:Macrophages / Q000502:physiology*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D011817:Rabbits; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014661:Vasoconstriction; D019323:omega-N-Methylarginine
D000975:Antioxidants; D016207:Cytokines; D007375:Interleukin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine