Interleukin 1 and endotoxin activate soluble guanylate cyclase in vascular smooth muscle.
Our recent studies indicate that interleukin 1 (IL-1) and bacterial lipopolysaccharide inhibit agonist-induced contractions in rat aortic rings by an endothelium-independent mechanism. The present study investigated the role of guanosine 3',5'-cyclic monophosphate (cGMP) in the vasodilatory action of IL-1 and endotoxin. Rat aortic rings were denuded of endothelium and incubated for 3 h in physiological salt solution containing no additions, IL-1 (20 ng/ml), or endotoxin (10 micrograms/ml). Contractions induced by phenylephrine (3 x 10(-7) M) were decreased by 40 and 85% in endotoxin- and IL-1-treated rings, respectively. IL-1 increased cGMP content 2.5-fold in the absence of and 5.5-fold in the presence of 3-isobutyl-1-methylxanthine (IBMX). Endotoxin also increased cGMP content in the absence and presence of IBMX (5.5- and 25-fold, respectively). Both IL-1- and endotoxin-induced increases in cGMP occurred 3-4 h after initial exposure. The guanylate cyclase inhibitors, LY 83583 and methylene blue, each abolished IL-1- and endotoxin-induced inhibition of contraction and IL-1-induced production of cGMP. Furthermore, hemoglobin, which binds nitric oxide, completely blocked IL-1-induced increases in cGMP. We conclude that IL-1 and endotoxin inhibit vascular contraction in vitro by increasing aortic cGMP content. Studies with inhibitors suggest IL-1 and endotoxin may induce endothelium-independent production of nitric oxide or another free radical that activates soluble guanylate cyclase.
Evans Memorial Department of Clinical Research, Boston University Medical Center, Massachusetts 02118.
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Beasley
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000201:enzymology; D006152:Cyclic GMP / Q000378:metabolism; D004730:Endothelium, Vascular / Q000502:physiology; D004731:Endotoxins / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006162:Guanylate Cyclase / Q000378:metabolism*; D007375:Interleukin-1 / Q000494:pharmacology*; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology*; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D013189:SRS-A / Q000037:antagonists & inhibitors; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D000634:Aminoquinolines; D004731:Endotoxins; D007375:Interleukin-1; D013189:SRS-A; C041715:6-anilino-5,8-quinolinedione; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D008751:Methylene Blue; D015056:1-Methyl-3-isobutylxanthine