Elimination of vascular fibrointimal hyperplasia by somatostatin receptor 1,4-selective agonist.
The somatostatin analogs octreotide and lanreotide, selective to receptor subtypes 2 and 5, failed clinical efficacy for the prevention of restenosis after percutaneous transluminal angioplasty. These findings might have been the result of targeting a wrong subset of receptors. In rat arteries, subtypes 1 and 4 are expressed 3-4 times more prominently than 2 and 5, and subtype 1 is the nearly exclusive subtype in atherosclerotic human vessels. Here, we demonstrate that daily s.c. injections (50-500 microg/kg/d) of CH275 (DesAA1,2,5(D-W8,IAmp9)Somatostatine-14), selective to subtypes 1 and 4, dose-dependently inhibited intimal hyperplasia 14 days after rat carotid denudation injury (for intimal area P=0.0002 across the dose range). CH275 was more effective than somatostatin-14 (equal affinity to all five subtypes, P=0.03), or octreotide (selective to subtypes 2 and 5, P=0.098). When rats were given the peptides for 14 days with end-point at 28 days, CH275 still significantly inhibited intimal area expansion. Both CH275 and octreotide inhibited the outgrowth of cells from postinjury aortic tissue punch-explants and the distance migrated in vitro, but not cell replication, which indicated that the effects of somatostatin analogs were directed on the migration of intimal cell progenitors rather than on their proliferation.
Aavik
Einari
E
Rational Drug Design Program, Biomedicum, and Transplantation Laboratory, University of Helsinki, and Helsinki University Central Hospital, Finland.
Luoto
Nina-Maria
NM
Petrov
Lubomir
L
Aavik
Silja
S
Patel
Yogesh C
YC
Hayry
Pekka
P
D000818:Animals; D001808:Blood Vessels / Q000166:cytology / Q000187:drug effects; D002340:Carotid Artery Diseases / Q000097:blood / Q000473:pathology / Q000517:prevention & control; D002455:Cell Division; D002465:Cell Movement; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005352:Fibromuscular Dysplasia / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D006207:Half-Life; D008297:Male; D008565:Membrane Proteins; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D015282:Octreotide / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D017481:Receptors, Somatostatin / Q000819:agonists*; D013004:Somatostatin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use*; D017539:Tunica Intima / Q000473:pathology; D015430:Weight Gain
C110576:CH 275; D008565:Membrane Proteins; D017481:Receptors, Somatostatin; C121799:somatostatin 14, Tyr(11)-; C098681:somatostatin receptor subtype-4; C101130:somatostatin receptor type 1; D013004:Somatostatin; D015282:Octreotide