Somatostatin receptors and the potential use of Sandostatin Ò to interfere with vascular remodelling Christian Bruns, Victor Shi, Daniel Hoyer, Henk Schuurman and Gisbert Weckbecker Novartis Pharma AG, Preclinical Research, Basel, Switzerland (Correspondence should be addressed to C Bruns, c/o Novartis Pharma AG, WSJ-386.6.46, CH-4002 Basel, Switzerland; Email: christian.bruns@pharma.novartis.com) Abstract Graft vessel disease (GVD) is a major cause of graft loss after the ®rst year following transplantation. GVD is a complex, multifunctional process that involves immunological as well as non-immunological events such as ischaemia/reperfusion injury. An important target cell to interfere with the develop- ment of GVD is the smooth muscle cell (SMC). Somatostatin (SRIF) analogues have been shown previously to inhibit the proliferation of SMC in vitro and in vivo. We provide evidence that Sandostatin Ò , an octapeptide SRIF analogue that is known to have anti-proliferative properties on SMC proliferation, inhibits vascular remodelling in a rat angioplasty model. Furthermore, in two allotransplantation models, Sandostatin Ò effectively interferes with the development of signs of chronic rejection/GVD. The role of the different SRIF receptor subtypes in chronic graft rejection is currently under investigation. European Journal of Endocrinology 143 S3±S7 Somatostatin (SRIF) receptor subtypes: pharmacology and receptor coupling There are several endogenous ligands that bind to SRIF receptors, namely, SRIF-14, SRIF-28 and the cortista- tins (1±4). Five distinct SRIF receptor (SRIF) genes have been described that encode receptor proteins of the seven transmembrane domain class within the super- family of G protein-coupled receptors (5, 6). The ®ve receptors show equally high af®nity for SRIF and cortistatins (7, 8). All ®ve receptors appear to couple to G proteins (6, 9, 10). Structural and functional information indicate that the SRIF receptors can be divided into two groups. The SRIF1 group (which comprises sst 2 , sst 5 and sst 3 receptors) can be differ- entiated from the SRIF2 group (which comprises sst 1 and sst 4 receptors) by their selectivity of binding of short synthetic SRIF analogues, as well as on the basis of amino acid homologies (6, 11). Many cellular effector proteins like adenylate cyclase, phospholipase C, calcium channels, potassium chan- nels, Na + /H + exchanger, protein tyrosine phosphatases, phospholipase A 2 , mitogen-activated protein kinase or p53 were reported to be modulated by SRIF receptor subtypes (12). SRIF receptors are coupled to intracel- lular signal transduction cascades via various pertussis toxin-sensitive (G i /G o ) and -insensitive G proteins (e.g. G q ,G 14 ,G 16 ). Depending on the cell type, the various SRIF receptor subtypes have been shown to couple to a diversity of transduction systems. A number of short synthetic, metabolically stable peptide analogues have been studied for their relative af®nities at the human recombinant receptors in radioligand binding studies (8, 13). The proclaimed selectivity of such ligands may, however, vary depending on the assay conditions and radioligands used (8, 14). In general, it is well accepted that sandostatin Ò and somataline Ò show selectivity for two SRIF receptor subtypes, SRIFT2 and SRIFT5 (11). SRIF analogues used to interfere with vascular remodelling A remaining challenge to achieve long-term survival of transplanted organs is to prevent the development of chronic graft rejection (CR). The mechanisms involved are complex and multifactorial, hence multiple approaches have been explored to interfere with CR (15). A key event in the development of chronic graft failure is vascular changes in the graft, also described as graft vessel disease (GVD). These vascular changes include endothelial cell activation, media necrosis, neointima formation, and ®nally vessel occlusion resulting in late graft dysfunction. This process is very similar to the vascular remodelling observed during restenosis following angioplasty (16, 17). GVD appears to be triggered by a combination of alloantigen- dependent immune insult and alloantigen-independent factors such as donor age and ischaemia/reperfusion European Journal of Endocrinology (2000) 143 S3±S7 ISSN 0804-4643 q 2000 Society of the European Journal of Endocrinology Online version via http://www.eje.org