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 micro M) 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 micro M) 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.