Cardiovascular Role of Urotensin II: Effect of Chronic Infusion in the Rat

Urotensin II (UII) is a potent vaso-active peptide thought to have multiple roles in the regulation of cardiovascular physiology and pathophysiology. The actions of UII are complex and difficult to interpret given its systemic hemodynamic effects and variable action on different vascular beds and isolated vessels. Direct effects of UII on the myocardium, include myocyte hypertrophy, extracellular matrix deposition and contractility. These observations, together with elevated plasma levels found in disease, are common traits reported in other pathophysiologically implicated neurohormonal systems. In this review, we include original data obtained from chronic infusion of UII in rats.We report a reduction in first derivative of left ventricular pressure (+dP/dt), as well as an increase in the ratio of left ventricular collagen I:III, that may contribute to the reduced myocardial contractility observed in these animals

Pharmacological characterization of SB-710411 (Cpa-c[D-Cys-Pal-D-Trp-Lys-Val-Cys]-Cpa-amide), a novel peptidic urotensin-II receptor antagonist

1. Human urotensin-II (hU-II), a cyclic undecapeptide, is amongst the most potent mammalian vasoconstrictors identified, suggesting that hU-II and its G-protein-coupled receptor (UT) may regulate cardiovascular homeostasis. Such a hypothesis would benefit greatly from the development of selective UT antagonists. 2. Although the somatostatin (SST) antagonist SB-710411 (Cpa-c[D-Cys-Pal-D-Trp-Lys-Val-Cys]-Cpa-amide) is purported to block U-II-induced contractions in rat isolated aorta, little is known about its specific pharmacological properties. 3. SB-710411 (10 μM) inhibited hU-II-induced contraction in rat isolated aorta causing a significant, parallel shift in the agonist concentration-response curve (pK(b) 6.28±0.11; n=8) with no suppression of the E(max). In contrast, SB-710411 did not alter the contractile actions of angiotensin-II, phenylephrine, or KCl. Paradoxically, however, SB-710411 potentiated the contractile response to endothelin-1 (pEC(50) 8.02±0.16 and 8.54±0.11, P<0.01; n=8). Rather than being specific toSB-710411, this phenomenon appears to be related to somatostatin receptor affinity and not intrinsic activity since the SST agonist somatostatin-14 and antagonist cyclo-somatostatin also potentiated endothelin-1-induced contraction. 4. SB-710411 (10 μM) did not inhibit carbachol, sodium nitroprusside, IBMX, isoprenaline, and levcromakalim-induced reversal of tone established with noradrenaline. In contrast, however, SB-710411 significantly inhibited the reversal of tone established with endothelin-1 using the same vasorelaxants. 5. In summary, although SB-710411 inhibits the vasoconstrictor actions of hU-II in a competitive, surmountable manner, it also possesses additional pharmacological actions. Thus, whilst the present study is amongst the first to detail the properties of a functional U-II receptor antagonist, the data suggest caution be used when assessing data generated utilizing this moiety and other SST analogues

Identification and pharmacological characterization of native, functional human urotensin-II receptors in rhabdomyosarcoma cell lines

1. In an effort to identify endogenous, native mammalian urotensin-II (U-II) receptors (UT), a diverse range of human, primate and rodent cell lines (49 in total) were screened for the presence of detectable [(125)I]hU-II binding sites. 2. UT mRNA (Northern blot, PCR) and protein (immunocytochemistry) were evident in human skeletal muscle tissue and cells. 3. [(125)I]hU-II bound to a homogenous population of high-affinity, saturable (K(d) 67.0±11.8 pM, B(max) 9687±843 sites cell(−1)) receptors in the skeletal muscle (rhabdomyosarcoma) cell line SJRH30. Radiolabel was characteristically slow to dissociate (⩽15% dissociation 90 min). A lower density of high-affinity U-II binding sites was also evident in the rhabdomyosarcoma cell line TE671 (1667±165 sites cell(−1), K(d) 74±8 pM). 4. Consistent with the profile recorded in human recombinant UT-HEK293 cells, [(125)I]hU-II binding to SJRH30 cells was selectively displaced by both mammalian and fish U-II isopeptides (K(i)s 0.5±0.1–1.2±0.3 nM) and related analogues (hU-II[4-11]>[Cys(5,10)]Acm hU-II; K(i)s 0.4±0.1 and 864±193 nM, respectively). 5. U-II receptor activation was functionally coupled to phospholipase C-mediated [Ca(2+)](i) mobilization (EC(50) 6.9±2.2 nM) in SJRH30 cells. 6. The present study is the first to identify the presence of ‘endogenous' U-II receptors in SJRH30 and TE671 cells. SJRH30 cells, in particular, might prove to be of utility for (a) investigating the pharmacological properties of hU-II and related small molecule antagonists at native human UT and (b) delineating the role of this neuropeptide in the (patho)physiological regulation of mammalian neuromuscular function