Some selective nonpeptide NPY receptor antagonists are available for research. The first nonpeptide Y1 receptor antagonist, BIBP3226, is also the most thoroughly studied. It has a short half-life in vivo. In animal models, it blocks the vasoconstrictor and pressor responses to NPY. Structurally related Y1 antagonists include BIB03304 and H409/22; the latter has been tested in humans. SR120107A and SR120819A are orally active Y1 antagonists and have a long duration of action. BIIE0246 is the first nonpeptide antagonist selective for the Y2 receptor; it does not cross the blood-brain barrier. Useful Y4 antagonists are not available. The Y5 antagonists MK-0557 and S-2367 have been tested in clinical trials for obesity.
These drugs have been useful in analyzing the role of NPY in cardiovascular regulation. It now appears that the peptide is not important in the regulation of hemodynamics under normal resting conditions but may be of increased importance in cardiovascular disorders including hypertension and heart failure. Other studies have implicated NPY in eating disorders, obesity, alcoholism, anxiety, depression, epilepsy, pain, cancer, and bone physiology. Y1 and particularly Y5 receptor antagonists have potential as antiobesity agents.
Urotensin II (UII) was originally identified in fish, but isoforms are now known to be present in the human and other mammalian species. Human UII is an 11-amino-acid peptide. An eightamino-acid peptide, UII-related peptide (URP), which is almost identical to the C-terminal of UII has also been identified. Major sites of UII expression in humans include the central nervous system, cardiovascular system, lungs, liver, and endocrine glands including the pituitary, pancreas, and adrenal. UII is also present in plasma, and potential sources of this circulating peptide include the heart, lungs, liver, and kidneys. The stimulus to UII release has not been identified, but increased blood pressure has been implicated in some studies.
In vitro, UII is a potent constrictor of vascular smooth muscle; its activity depends on the type of blood vessel and the species from which the vessel was obtained. Vasoconstriction occurs primarily in arterial vessels, where UII can be more potent than ET-1, making it the most potent known vasoconstrictor. However, under some conditions, UII may cause vasodilation. In vivo, UII has complex hemodynamic effects, the most prominent being regional vasoconstriction and cardiac depression. In some ways, these effects resemble those produced by ET-1. Nevertheless, the role of the peptide in the normal regulation of vascular tone and blood pressure in humans appears to be minor. In addition to its cardiovascular effects, UII exerts osmoregulatory actions, induces collagen and fibronectin accumulation, modulates the inflammatory response, and inhibits glucose-induced insulin release.
The actions of UII are mediated by a Gq protein-coupled receptor referred to as the UT receptor. UT receptors are widely distributed in the brain, spinal cord, heart, vascular smooth muscle, skeletal muscle, and pancreas. They are located at the cell surface, but specific UII-binding sites have also been observed in heart and brain cell nuclei. Some effects of the peptide including vasoconstriction are mediated by the phospholipase C, inositol trisphosphate, diacylglycerol signal transduction pathway.