Vascular reactivity, 5-HT uptake, and blood pressure in the serotonin transporter knockout rat.
The handling of serotonin [5-hydroxytryptamine (5-HT)] depends on the serotonin transporter (SERT). A SERT knockout (KO) rat is a useful model to test the hypothesis that SERT is the primary mechanism for arterial 5-HT uptake and to investigate the impact of SERT removal on blood pressure. Wild-type (WT) and KO rats were used to measure 5-HT content (plasma, raphe, aorta, carotid, and mesenteric artery), aortic isometric contraction, and blood pressure. HPLC supported the lack of circulating 5-HT in plasma (ng/ml plasma, WT, 310 +/- 96; and KO, 1.0 +/- 0.5; P < 0.05). Immunohistochemistry and Western blot analyses validated the presence of the SERT protein in the WT rats and a lesser expression in the KO rat. The aorta isolated from KO rats had a normal contraction to phenylephrine and norepinephrine and a normal relaxation to the endothelium-dependent agonist acetylcholine compared with the aorta from WT. In contrast, the potency of 5-HT was increased in the aorta from KO rats compared with WT rats [-log EC(50) (M); WT, 5.71 +/- 0.08; and KO, 6.7 +/- 0.18] and maximum contraction was reduced [%phenylephrine (10 muM) contraction, WT, 113 +/- 6%; and KO, 52 +/- 12%]. 5-HT uptake was reduced but not abolished in arteries of the KO compared with the WT rats. Diurnal mean arterial blood pressure, heart rate, and locomotor activity level of the KO rats were similar to the WT rats. These data suggest that there are other mechanisms of 5-HT uptake in the arteries of the rat and that although the absence of circulating 5-HT and/or SERT function sensitizes arteries to 5-HT, SERT dysfunction does not impair normal blood pressure.
Linder
A Elizabeth
AE
Dept. of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824-1317, USA.
Diaz
Jessica
J
Ni
Wei
W
Szasz
Theo
T
Burnett
Robert
R
Watts
Stephanie W
SW
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D001158:Arteries / Q000187:drug effects / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D002940:Circadian Rhythm; D004305:Dose-Response Relationship, Drug; D016666:Fluvoxamine / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D007150:Immunohistochemistry; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000097:blood / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000378:metabolism* / Q000494:pharmacology; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology
D000109:Acetylcholine; D016666:Fluvoxamine; D009638:Norepinephrine; D010656:Phenylephrine; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C493232:Slc6a4 protein, rat