Urocortin (rat)

1. Urocortin is an endogenous vasodilator although the mechanism of vasorelaxation is not completely understood. The hypothesis that an alteration of smooth muscle calcium concentration is involved was tested using isometric tension recording and calcium fluorimetry. The relationship between contraction and intracellular calcium was also estimated. 2. Urocortin produced a concentration dependent relaxation (pD(2) 8.59+/-0.06, n=6) of vessels pre-contracted with a physiological salt solution containing 42 mM KCl (42 mM K-PSS). 3. Removal of the endothelium did not alter the effect of urocortin, pD(2) was 8.49+/-0.11, n=5. 4. Corticotropin-releasing factor relaxed 42 mM K-PSS pre-contracted vessels with less potency compared to urocortin (pD(2) 6.99+/-0.28, n=5). 5. Urocortin at 100 nM relaxed vessels pre-contracted with 42 mM K-PSS by 59.6+/-4.6% (n=8) and vessels pre-contracted with 500 nM noradrenaline by 25.2+/-6.8% (n=6). Both effects were not accompanied by a change in the intracellular calcium concentration. 6. Urocortin at 100 nM produced a significant rightward shift of 0.33+/-0.07 units of normalized intracellular calcium (n=5) of the relationship between tension and intracellular calcium. 7. The urocortin-induced relaxation was considerably reduced in the presence of 0.3 mM Rp-8-CPT-cAMPS, a cyclic AMP-dependent protein kinase (PKA) inhibitor. 8. The PKA-activator Sp-5,6-DCl-cBIMPS relaxed 42 mM K-PSS pre-contracted vessels (pD(2) 4.98+/-0.07, n=6). Sp-5,6-DCl-cBIMPS at 0.1 mM relaxed vessels by 85.3+/-2.5% (n=5), but did not change the intracellular calcium concentration. 9. In conclusion, the data show that urocortin is a potent, endothelium-independent dilator of rat tail arteries and suggest that this effect is mediated by PKA causing a reduction of the sensitivity of the contractile apparatus for calcium.

1. The mechanisms underlying the vasodilator response to urocortin are incompletely understood. The present study was designed to examine the role of endothelial nitric oxide and Ba(2+)-sensitive K(+) channels in the endothelium-dependent component of urocortin-induced relaxation in the rat left anterior descending coronary artery. 2. Urocortin induced both endothelium-dependent and -independent relaxation with respective pD(2) of 8.64+/-0.03 and 7.90+/-0.10. Removal of endothelium reduced the relaxing potency of urocortin. In rings pretreated with 10(-4) M N(G)-nitro-L-arginine methyl ester, 10(-5) M methylene blue or 10(-5) M ODQ, the urocortin-induced relaxation was similar to that observed in endothelium-denuded rings. L-Arginine (5x10(-4) M) antagonized the effect of N(G)-nitro-L-arginine methyl ester. 3. The relaxant response to urocortin was reduced in endothelium-intact rings preconstricted by 3.5x10(-2) M K(+) and abolished when extracellular K(+) was raised to 5x10(-2) M. Pretreatment with 10(-4) M BaCl(2) significantly inhibited urocortin-induced relaxation. Combined treatment with 10(-4) M BaCl(2) plus 10(-4) M N(G)-nitro-L-arginine methyl ester did not cause further inhibition. In urocortin (10(-8) M)-relaxed rings, BaCl(2) induced concentration-dependent reversal in vessel tone. Tertiapin-Q (10(-6) M) also attenuated urocortin-induced relaxation. In contrast, BaCl(2) did not alter urocortin-induced relaxation in endothelium-denuded rings. 4. In endothelium-denuded rings, hydroxylamine- and nitroprusside-induced relaxation was inhibited by 10(-4) M BaCl(2), but not by 10(-6) M tertiapin-Q. 5. The endothelium of the coronary artery was moderately stained with the antiserum against urocortin. 6. Taken together, the present results indicate that the urocortin-induced endothelium-dependent relaxation of rat coronary arteries is likely attributable to endothelial nitric oxide and subsequent activation of Ba(2+)- or tertiapin-Q-sensitive K(+) channels. The urocortin-induced endothelium-dependent relaxation appears to be mediated by cyclic GMP-dependent mechanisms.

Objectives:The aim of this study was to investigate the possibility that urocortin is the ligand that displaces corticotropin-releasing hormone from its binding protein in the maternal circulation during pregnancy and, if so, to determine whether urocortin, like corticotropin-releasing hormone, is synthesized in substantial quantities in the placenta.Study design:A radioimmunoassay specific for urocortin was developed and used for measurement of the peptide in chorionic villi and fetal membranes (amnion and chorion) from normal and preeclamptic pregnancies. These tissues were also assayed for corticotropin-releasing hormone. Assays for urocortin were also carried out on normal term pregnant and nonpregnant myometrium and on plasma from nonpregnant individuals, and assays for both peptides were performed on sequential normal pregnancy plasma samples taken from mid gestation until term.Results:Corticotropin-releasing hormone was present in normal term (1904 +/- 489 pg/g) and preeclamptic placentas (5897 +/- 1526 pg/g) and in normal term fetal membranes (645 +/- 155 pg/g, n = 6 in all cases). Urocortin was not detected in any of the tissues studied, nor was it found in the normal human plasma samples. Unlike the situation for corticotropin-releasing hormone, no pregnancy-related pattern was seen for urocortin in the plasma from pregnant women.Conclusions:Urocortin is not translated to any great extent in the pregnancy tissues investigated, nor is it present in the circulation of pregnant women in detectable amounts. Furthermore, it is unlikely that urocortin is responsible for the high maternal plasma levels of free corticotropin-releasing hormone circulating in the latter stages of pregnancy, but this does not preclude the possibility that another, as yet uncharacterized, corticotropin-releasing hormone-like peptide may be.