Effects of melatonin on rat pial arteriolar diameter in vivo.
1. Based on our finding that melatonin decreased the lower limit of cerebral blood flow autoregulation in rat, we previously suggested that melatonin constricts cerebral arterioles. The goal of this study was to demonstrate this vasoconstrictor action and investigate the mechanisms involved. 2. The effects of cumulative doses of melatonin (10-10 to 10-6 M) were examined in cerebral arterioles (30 - 50 microM) of male Wistar rats using an open skull preparation. Cerebral arterioles were exposed to two doses of melatonin (3x10-9 and 3x10-8 M) in the absence and presence of the mt1 and/or MT2 receptor antagonist, luzindole (2x10-6 M) and the Ca2+-activated K+ (BKCa) channel blocker, tetraethylammonium (TEA+, 10(-4) M). The effect of L-nitro arginine methyl ester (L-NAME, 10-8 M) was examined on arterioles after TEA+ superfusion. Cerebral arterioles were also exposed to the BKCa activator, NS1619 (10(-5) M), and to sodium nitroprusside (SNP, 10-8 M) in the absence and presence of melatonin (3x10-8 M). 3. Melatonin induced a dose-dependent constriction with an EC50 of 3.0+/-0.1 nM and a maximal constriction of -15+/(-1%). Luzindole abolished melatonin-induced vasoconstriction. TEA+ induced significant vasoconstriction (-10+/(-2%). No additional vasoconstriction was observed when melatonin was added to the aCSF in presence of TEA+, whereas L-NAME still induced vasoconstriction (-10+/(-1%). NS1619 induced vasodilatation (+11+/(-1%) which was 50% less in presence of melatonin. Vasodilatation induced by SNP (+12+/(-2%) was not diminished by melatonin. 4. Melatonin directly constricts small diameter cerebral arterioles in rats. This vasoconstrictor effect is mediated by inhibition of BKCa channels following activation of mt1 and/or MT2 receptors.
Régrigny
O
O
Laboratoire de Pharmacologie Cardio-vasculaire, Faculté de Pharmacie de l'Université Henri Poincaré-Nancy I, 5 rue Albert Lebrun, 54000 Nancy, France.
Delagrange
P
P
Scalbert
E
E
Lartaud-Idjouadiene
I
I
Atkinson
J
J
Chillon
J M
JM
D000465:Algorithms; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001160:Arterioles / Q000033:anatomy & histology / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D010841:Pia Mater / Q000098:blood supply* / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects; D026423:S-Nitroso-N-Acetylpenicillamine; D019789:Tetraethylammonium / Q000494:pharmacology; D014363:Tryptamines / Q000494:pharmacology
D000975:Antioxidants; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D015221:Potassium Channels; D014363:Tryptamines; C057154:luzindole; C086491:NS 1619; D019789:Tetraethylammonium; D026423:S-Nitroso-N-Acetylpenicillamine; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D010396:Penicillamine; D008550:Melatonin; D019331:NG-Nitroarginine Methyl Ester