Urotensin II

Urotensin II (U-II) is a cyclic peptide first identified in the urophysis (a neuroendocrine organ) of the goby fish in 1969 by Karl Lederis. Human urotensin II is an 11-amino acid peptide containing a six-residue cyclic region formed by a disulfide bond, with the cyclic portion showing structural similarity to somatostatin. The peptide gained significant attention after it was identified as the most potent vasoconstrictor known in mammals — approximately 10-100 times more potent than endothelin-1 in certain vascular beds.

U-II acts through the urotensin II receptor (UT receptor, formerly GPR14), a G-protein coupled receptor expressed in the heart, blood vessels, kidneys, brain, and other tissues. The vasoactive response to U-II is highly variable between different vascular beds and species. In some vessels it causes profound vasoconstriction, while in others (particularly endothelium-intact vessels) it can cause vasodilation through nitric oxide release. This vascular bed-specific response adds complexity to understanding U-II's role in cardiovascular physiology.

Elevated plasma U-II levels have been documented in various cardiovascular diseases including heart failure, coronary artery disease, systemic hypertension, pulmonary hypertension, and renal failure. In heart failure, U-II levels correlate with disease severity, hemodynamic parameters, and mortality. U-II promotes cardiomyocyte hypertrophy, vascular smooth muscle cell proliferation, and fibrosis, suggesting a role in pathological cardiac and vascular remodeling.

UT receptor antagonists have been developed as potential therapeutics for cardiovascular disease. Palosuran (ACT-058362) was the first UT receptor antagonist to enter clinical trials, studied for diabetic nephropathy. While initial results were disappointing, the UT receptor system remains an active research target, particularly for pulmonary hypertension and heart failure where U-II appears to have a significant pathophysiological role.