Vascular serotonin 5-hydroxytryptamine2 receptor blockade by LY215840: lack of effect upon neointima formation in balloon-injured rat carotid arteries.
5-Hydroxytryptamine (5-HT) is mitogenic for vascular smooth muscle cells, an effect that may result from 5-HT2 receptor activation. After arterial balloon injury, platelet-derived products including 5-HT are delivered to the denuded vessel wall via platelet adhesion/aggregation and degranulation. To assess the role of 5-HT2 receptors in neointima formation, the selective 5-HT2 receptor antagonist LY215840 was infused continuously in rats with osmotic minipumps from 2 days before until 2 weeks after balloon injury to the left common carotid artery, at which time effects upon intimal thickening were examined. Chronic i.v. infusion of LY215840 (25 micrograms/kg/hr) produced a significant, rightward shift (approximately 500-fold) in the 5-HT pressor-response curve in pithed rats determined at 1 hr, 4 days or 16 days after initiation of infusion. Under these conditions, LY215840 had no significant effect upon cross-sectional intimal area determined 2 weeks postballoon injury (0.118 +/- 0.010 vs. 0.114 +/- 0.017 mm2 for vehicle- and LY215840-treated groups, respectively). Furthermore, the cellular density of neointima from LY215840-treated rats was unchanged relative to that of the vehicle group. As a positive control, heparin infusion produced dose-dependent reductions in intimal thickening in this model. At the infusion rate of 0.22 mg/kg/hr, heparin reduced intimal area from a control value of 0.114 +/- 0.015 to 0.025 +/- 0.007 mm2 (P < .05). Thus, extensive blockade of vascular 5-HT2 receptors does not inhibit neointima formation in this model of vascular balloon injury.
Kauffman
R F
RF
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
Bean
J S
JS
Bloomquist
W E
WE
Cohen
M L
ML
D000818:Animals; D002340:Carotid Artery Diseases / Q000209:etiology / Q000473:pathology; D017536:Carotid Artery, Common / Q000187:drug effects*; D002404:Catheterization / Q000009:adverse effects*; D002455:Cell Division / Q000187:drug effects; D004195:Disease Models, Animal; D006493:Heparin / Q000494:pharmacology; D008237:Lysergic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000502:physiology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017539:Tunica Intima / Q000166:cytology / Q000187:drug effects*
D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C074025:LY 215840; D006493:Heparin; D008237:Lysergic Acid