Urocortin relaxes rat tail arteries by a PKA-mediated reduction of the sensitivity of the contractile apparatus for calcium.
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.
Lubomirov
L
L
Institute of Biophysics, Bulgarian Academy of Sciences, Acad. G. Bonchev Str., Bl. 21, 1113 Sofia, Bulgaria.
Gagov
H
H
Petkova-Kirova
P
P
Duridanova
D
D
Kalentchuk
V U
VU
Schubert
R
R
D000818:Animals; D001158:Arteries / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology*; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004004:Dichlororibofuranosylbenzimidazole / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D011921:Rats, Inbred WKY; D013623:Tail / Q000098:blood supply; D013873:Thionucleotides / Q000494:pharmacology; D054832:Urocortins; D014661:Vasoconstriction / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects
D004791:Enzyme Inhibitors; D013873:Thionucleotides; D054832:Urocortins; C071644:5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole-3',5'-monophosphorothioate; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D004004:Dichlororibofuranosylbenzimidazole; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium