Article date: October 2002
By: David J Behm, Christopher L Herold, Eliot H Ohlstein, Steven D Knight, Dashyant Dhanak, Stephen A Douglas in Volume 137, Issue 4, pages 449-458
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.
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.
SB‐710411 (10 μM) inhibited hU‐II‐induced contraction in rat isolated aorta causing a significant, parallel shift in the agonist concentration‐response curve (pKb 6.28±0.11; n=8) with no suppression of the Emax. 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 (pEC50 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.
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.
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.
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.
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.
SB‐710411 (10 μM) inhibited hU‐II‐induced contraction in rat isolated aorta causing a significant, parallel shift in the agonist concentration‐response curve (pKb 6.28±0.11; n=8) with no suppression of the Emax. 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 (pEC50 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.
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.
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.
British Journal of Pharmacology (2002) 137, 449–458. doi:10.1038/sj.bjp.0704887
DOI: 10.1038/sj.bjp.0704887
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