Mecamylamine suppresses Basal and nicotine-stimulated choroidal neovascularization.
OBJECTIVE
Nicotinic acetylcholine receptors (nAChR) are best known for their role in neurotransmission, but they have recently been demonstrated on vascular endothelial cells. Acetylcholine is their endogenous ligand, but they are also stimulated by nicotine. By stimulating nAChR, nicotine promotes tumor angiogenesis as well as atherosclerotic plaque neovascularization. In this study, the authors investigated the role of nAChR in the pathogenesis of choroidal neovascularization (CNV).


METHODS
The effect of the nonselective nAChR antagonist mecamylamine was tested on human retinal and choroidal endothelial cells in vitro and in a murine model of CNV.


RESULTS
Several nAChR isoforms were identified in retinal and choroidal microvascular endothelial cells, and the ability of these cells to form tubules when grown in growth factor-reduced basement membrane matrix and supplemented with VEGF was suppressed by the nAChR antagonist mecamylamine. Supplementation of the drinking water of mice with nicotine increased the size of CNV lesions at Bruch membrane rupture sites, an effect that was blocked by subcutaneous administration of mecamylamine (50 mg/kg/d) by an osmotic pump. In the absence of nicotine, CNV formation was suppressed by the infusion of 50 mg/kg/d mecamylamine or by topical application 0.1 or 1% mecamylamine to the cornea.


CONCLUSIONS
These data suggest that endogenous activation of nAChR promotes CNV and that activation of nAChR by nicotine may contribute to the increased incidence of CNV seen in smokers with age-related macular degeneration (AMD). Topically administered mecamylamine could provide an appealing new treatment approach for CNV.
Kiuchi
Katsuji
K
Department of Ophthalmology, The Johns Hopkins University of Medicine, Baltimore, MD 21287-9277, USA.
Matsuoka
Masato
M
Wu
Jenny C
JC
Lima e Silva
Raquel
R
Kengatharan
Muralitharan
M
Verghese
Mary
M
Ueno
Shinji
S
Yokoi
Katsutoshi
K
Khu
Naw Htee
NH
Cooke
John P
JP
Campochiaro
Peter A
PA
D000818:Animals; D002478:Cells, Cultured; D002829:Choroid / Q000098:blood supply; D020256:Choroidal Neovascularization / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D015151:Immunoblotting; D008464:Mecamylamine / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009538:Nicotine / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D020033:Protein Isoforms / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D012171:Retinal Vessels / Q000166:cytology
D018733:Nicotinic Antagonists; D020033:Protein Isoforms; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D008464:Mecamylamine; D009538:Nicotine