Vasculoprotective effects of somatostatin receptor subtypes.
We have shown that somatostatin agonist peptide CH275, selective to somatostatin receptor (sst) subtypes 1,4, was more effective in preventing intimal hyperplasia than the sst2,3,5-selective octreotide, raising the question what are the separate roles of the sst1- and 4-subtypes. Here, we dissect this observation further with highly subtype-selective peptidomimetics and demonstrate that, after rat carotid denudation, both the sst1- and 4-selective analogs (300 microg/kg/day, s.c.) increased lumen size, while only the sst4-selective analog significantly reduced intimal nuclei number, intimal area, and intima/media ratio. The 2,3,5-selective compounds had no effect on these parameters. The observed in vivo effects were further investigated ex vivo with explant outgrowth from pieces of vascular wall. The sst4-selective analog was more effective than the sst1-selective one in inhibiting the percent of outgrowth and the migration of cells from the explants while neither compound affected proliferation. Thus, selective targeting to sst4 should be considered when developing orally active vasculoprotective therapies.
Tigerstedt
Nina-Maria
NM
Rational Drug Design Programme, Biomedicum Helsinki and Transplantation Laboratory, University of Helsinki, Helsinki, Finland. nina-maria.tigerstedt@helsinki.fi
Aavik
Einari
E
Aavik
Silja
S
Savolainen-Peltonen
Hanna
H
Hayry
Pekka
P
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects; D009924:Organ Culture Techniques; D010455:Peptides / Q000235:genetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017481:Receptors, Somatostatin / Q000145:classification* / Q000187:drug effects; D013004:Somatostatin / Q000819:agonists / Q000235:genetics / Q000494:pharmacology*; D017539:Tunica Intima / Q000187:drug effects* / Q000293:injuries / Q000473:pathology
D008565:Membrane Proteins; D010455:Peptides; D017481:Receptors, Somatostatin; C098681:somatostatin receptor subtype-4; C101130:somatostatin receptor type 1; D013004:Somatostatin