Attenuation of lipopolysaccharide-induced hyperreactivity of human internal mammary arteries by melatonin.
Reactive oxygen species (ROS) are thought to be important mediators in ischaemia/reperfusion injury following coronary vasospasm. The most ubiquitous action of melatonin is that of a free radical scavenger. Therefore, we investigated the action of melatonin by monitoring changes in the tone on ring preparations from human internal mammary arteries (IMA). In quiescent IMA rings melatonin (0.1 nm-10 microm) never elicited any change in baseline tension but 1-100 nm melatonin enhanced significantly maximal responses to noradrenaline (NA) in arteries with endothelial function. In NA (1 microm) precontracted arteries inhibition of nitric oxide (NO(*)) formation by N(G)-monomethyl-L-arginine (l-NMMA, 100 and 400 microm) eliminated 43 +/- 7 and 61 +/- 7% of the acetylcholine (ACH) effect. Melatonin (100 and 400 nm) attenuated maximal endothelium-dependent relaxant responses to ACH slightly by 23 +/- 9 and 17 +/- 9% leaving responses to direct stimulation of soluble guanylate cyclase by sodium nitroprusside unchanged. Incubation of IMA for 20 hr at 37 degrees C with 1 microg/mL lipopolysaccharide (LPS) enhanced maximal NA effects to 147 +/- 18% (n = 22, P < 0.01) whereas 50 microg/mL LPS reduced the NA maxima to 68 +/- 9% (n = 10, P < 0.01) of the control effects. The LPS-induced potentiation was completely attenuated by coincubation with melatonin (400 nm) and significantly reduced by coincubation with the thromboxane synthase inhibitor dazoxiben (10 microm). It is suggested that the LPS-induced hyperreactivity of vascular smooth muscle is mediated through enhanced release of ROS and prostanoids and that melatonin inhibits the vascular hyperreactivity through selective scavenging of ROS.
Department of Thoracic and Cardiovascular Surgery, University Hospital, Basel, Switzerland. dremueller36@bluewin.ch
Else
E
Müller-Schweinitzer
Hans
H
Gilles
Martin
M
Grapow
Thomas
T
Kern
David
D
Reineke
Hans-Reinhard
HR
Zerkowski
D000109:Acetylcholine / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000975:Antioxidants / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008323:Mammary Arteries / Q000187:drug effects* / Q000378:metabolism; D008550:Melatonin / Q000494:pharmacology*; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology; D009924:Organ Culture Techniques; D017382:Reactive Oxygen Species
D000975:Antioxidants; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D008550:Melatonin; D000109:Acetylcholine; D009638:Norepinephrine