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.

Synergistic suppression of rat neointimal hyperplasia by rapamycin and imatinib mesylate: implications for the prevention of accelerated arteriosclerosis.

BACKGROUND: Accelerated arteriosclerosis remains a major limitation to therapeutic interventions such as angioplasty, stent deployment, and solid organ transplantation. Rapamycin, a powerful new immunosuppressant set to replace calcineurin inhibitors in the transplant setting, and imatinib mesylate, a receptor tyrosine kinase inhibitor, are both angioprotective. Here, we explored the pharmacological and therapeutic interactions of these two agents in a rat model of neointimal hyperplasia. METHODS: Wistar rats, subjected to balloon catheter-induced aortic injury, received daily drug treatment until postoperative day 14 and were subsequently sacrificed or followed up to day 40 without further treatment. Development of neointimal lesions was assessed histologically and immunohistochemically. Steady-state rapamycin levels in whole blood were determined by HPLC-UV. RESULTS: Rapamycin and imatinib, administered individually or in combination, produced no signs of overt toxicity. Continuous postoperative therapy with either rapamycin (0.5-1.5 mg/kg/day) or imatinib (2- 50 mg/kg/day) dose-dependently suppressed neointimal hyperplasia on day 14. Combined treatment (0.5 or 1 + 10 mg/kg/day, respectively) showed a trend towards synergistic action on day 14. Withdrawal of medication on day 14 nullified the early therapeutic effect of either agent by day 40. In contrast, early combination therapy (1 + 10 mg/kg/day) achieved long-term suppression of neointimal hyperplasia by approximately 81%. Notably, coadministration of imatinib appeared to reduce exposure to rapamycin, although this finding did not reach statistical significance. CONCLUSIONS: Short-term combination therapy with rapamycin and imatinib is well tolerated and produces synergistic, sustained suppression of neointimal hyperplasia in rats. Subject to clinical evaluation, this new drug regimen may afford definitive prophylaxis against accelerated arteriosclerosis.

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.