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-mu-g/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 < 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 N(G)-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.