Urotensin-II (U-II) is a vasoactive 'somatostatin-like' cyclic peptide which was originally isolated from fish spinal cords, and which has recently been cloned from man. Here we describe the identification of an orphan human G-protein-coupled receptor homologous to rat GPR14 and expressed predominantly in cardiovascular tissue, which functions as a U-II receptor. Goby and human U-II bind to recombinant human GPR14 with high affinity, and the binding is functionally coupled to calcium mobilization. Human U-II is found within both vascular and cardiac tissue (including coronary atheroma) and effectively constricts isolated arteries from non-human primates. The potency of vasoconstriction of U-II is an order of magnitude greater than that of endothelin-1, making human U-II the most potent mammalian vasoconstrictor identified so far. In vivo, human U-II markedly increases total peripheral resistance in anaesthetized non-human primates, a response associated with profound cardiac contractile dysfunction. Furthermore, as U-II immunoreactivity is also found within central nervous system and endocrine tissues, it may have additional activities.

dehydrogenase by phosphorylation involves no long-range conformational change in the free enzyme.

Liver X receptor (LXR) nuclear receptors regulate the expression of genes involved in whole body cholesterol trafficking, including absorption, excretion, catabolism, and cellular efflux, and possess both anti-inflammatory and antidiabetic actions. Accordingly, LXR is considered an appealing drug target for multiple indications. Synthetic LXR agonists demonstrated inhibition of atherosclerosis progression in murine genetic models; however, these and other studies indicated that their major undesired side effect is an increase of plasma and hepatic triglycerides. A significant impediment to extrapolating results with LXR agonists from mouse to humans is the absence in mice of cholesteryl ester transfer protein, a known LXR target gene, and the upregulation in mice but not humans of cholesterol 7 ␣ -hydroxylase. To better predict the human response to LXR agonism, two synthetic LXR agonists were examined in hamsters and cynomolgus monkeys. In contrast to previously published results in mice, neither LXR agonist increased HDL-cholesterol in hamsters, and similar results were obtained in cynomolgus monkeys. Importantly, in both species, LXR agonists increased LDL-cholesterol, an unfavorable effect not apparent from earlier murine studies.These results reveal additional problems associated with current synthetic LXR agonists and emphasize the importance of profiling compounds in preclinical species with a more human-like LXR response and lipoprotein metabolism. The liver X receptors LXR ␣ and LXR ␤ (1) are ligandactivated transcription factors of the nuclear receptor superfamily that control the expression of genes involved in cholesterol homeostasis and fatty acid metabolism (2, 3). LXR ␣ is highly expressed in liver (hence its name) but is also prevalent in adipose tissue, gut, kidney, and macrophages. LXR ␤ is more widely expressed and found in most tissues. Natural ligands for LXRs are oxidized derivatives of cholesterol, such as 24 S -and 25-epoxycholesterol and 24 S -and 22 R -hydroxycholesterol (4-6). LXRs are intracellular cholesterol sensors that upregulate key enzymes and transporters of cholesterol metabolism and transport, such as ABCA1 and ATP binding cassette protein G1 (ABCG1) (7-9), ABCG5 and ABCG8 (10, 11), apolipoprotein E (apoE) in adipocyte and macrophages (12), and cholesteryl ester transfer protein (CETP) (13). In mice but not in primates, hepatic cholesterol 7 ␣ -hydroxylase (cyp7a) is also upregulated by LXR (5,14,15). LXR also affects triacylglycerol metabolism by stimulating lipogenesis and triglyceride synthesis attributable to the upregulation of sterol-regulatory element binding protein 1c (SREBP1c) and the FAS complex (16,17). In addition, LXRs also have direct anti-inflammatory effects by downregulation of several proinflammatory genes in macrophages (18)(19)(20). Based on these data, LXR has been considered an attractive antiatherosclerosis target. Using the potent synthetic LXR agonist GW3965, our group collaborated in a study Abbreviations: ABCG1, ATP binding cassette protei...

The vascular response to mechanical injury involves inflammatory and fibroproliferative processes that result in the formation of neointima and vascular remodeling. The complex cellular interactions initiated by vascular injury are coordinated and modulated by the elaboration of cytokines and growth factors. The production and transduction of many of these mediators require phosphorylation of p38 mitogen-activated protein kinase (MAPK). In the present investigation, we examined the pattern and localization of p38 MAPK activation following balloon vascular injury. The effects of long-term and selective inhibition of p38 MAPK with SB 239063 (trans-1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl)-5-[2-methoxy)pyrimidin-4-yl]imidazole) were also investigated in a model of vascular injury. Western blotting and immunohistochemical staining demonstrated that phospho-p38 MAPK was increased following balloon injury of the rabbit iliofemoral artery. The p38 MAPK activation was noted as early as 15 min after balloon injury and remained elevated for at least 28 days. Phospho-p38 MAPK immunoreactivity (IR) was localized primarily in regions of dedifferentiated, smooth muscle ␣-actin-positive cells in all lamina of the vessel wall. Phospho-p38 MAPK IR was not correlated with the localization of macrophage or proliferating cells (proliferating cell nuclear antigen; PCNA ϩ). Long-term treatment (4 weeks) with SB 239063 (50 mg/kg/day, p.o.) reduced the vascular response to injury in the hypercholesterolemic rabbit. SB 239063 had no effect on platelet-derived growth factor (PDGF)-stimulated migration or proliferation of rabbit vascular smooth muscle cells (VSMCs) in culture. However, SB 239063 produced a concentration-dependent inhibition of transforming growth factor (TGF)-␤-stimulated fibronectin production in VSMCs. In conclusion, sustained activation of p38 MAPK plays an important role in the vascular response to injury and inhibition of p38 MAPK may represent a novel therapeutic approach to limit this response.

Background and Purpose (±)-SB 209670, a potent nonpeptide endothelin (ET) receptor antagonist, was used to investigate the potential role of ET in cerebral vasospasm associated with subarachnoid hemorrhage.Methods The effects of (±)-SB 209670 were evaluated in isolated segments of canine posterior cerebral arteries in vitro, vascular smooth muscle cells in culture, and in the canine two-hemorrhage model of delayed cerebral vasospasm in vivo.Results In the canine basilar and anterior spinal arteries, (±)-SB 209670 caused a dose-related inhibition of contractile responses mediated by ET (X B =4.6 nmol/L and apparent K B =2.7 nmol/L, respectively). The effects of (±)-SB 209670 were mediated by inhibition of ETA receptors since the ETB selective agonist sarafotoxin 6c did not contract these posterior cerebral vessels. (±)-SB 209670 also produced a concentration-dependent inhibition (IC 5O =1 nmol/L) of the mitogenic response induced by ET-1 in vascular smooth muscle cell culture. In the canine model of delayed cerebral vasospasm,