8-pCPT-conjugated cyclic AMP analogs exert thromboxane receptor antagonistic properties.
Membrane-permeable 8-(4-chlorophenylthio)-2'-O-methyl cyclic AMP (8-pCPT-2'-O-Me-cAMP) has been shown to specifically activate cAMP-regulated Epac proteins, without direct effects on protein kinase A and protein kinase G. During isometric tension measurements in thoracic aortic rings from Wistar rats, we observed that 8-pCPT-2'-O-Me-cAMP selectively induced a rightward shift of the concentration response curve for the thromboxane mimetic U46619, without altering the contractile response to noradrenaline. We hypothesised that 8-pCPT-2'-O-Me-cAMP and similar compounds may function as direct thromboxane receptor antagonists. Indeed, in addition to 8-pCPT-2'-O- Me-cAMP, also 8-pCPT-cAMP, 8-(4-chlorophenylthio)-adenosine-3',5'-cyclic monophosphorothioate, Rp-isomer (Rp-8-CPT-cAMPS) and 8-CPT-adenosine, but not 8-Bromo-2'-O-Me-cAMP, induced rightward shifts of the contractile response to U46619. Likewise, 8-pCPT-2'-O- Me-cAMP and Rp-8-CPT-cAMPS, but not 8-Bromo-2'-O-Me-cAMP, specifically reduced U46619-induced aggregation of human platelets. In addition, 8-pCPT-2'-O-Me-cAMP and Rp-8-CPT-cAMPS completely reversed U46619-induced reduction of intercellular adhesion molecule-1 expression and migration of human coronary artery endothelial cells. Most important, the cAMP analogs that reduced the contractile response to U46619 also concentration-dependently inhibited binding of the thromboxane receptor radioligand [5,6-3H]SQ29548 to human platelets. We conclude that 8-pCPT-conjugated cAMP analogs exert competitive thromboxane receptor antagonistic properties.
Institut für Pharmakologie, Universitätsklinikum Essen, Essen, Germany.
Carsten
C
Sand
Maria
M
Grandoch
Christof
C
Börgermann
Paschal A
PA
Oude Weernink
Yvonne
Y
Mahlke
Benjamin
B
Schwindenhammer
Artur-Aron
AA
Weber
Jens W
JW
Fischer
Karl H
KH
Jakobs
Martina
M
Schmidt
D000818:Animals; D001011:Aorta / Q000502:physiology; D015815:Cell Adhesion Molecules; D002465:Cell Movement / Q000187:drug effects; D003331:Coronary Vessels / Q000166:cytology; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D042783:Endothelial Cells / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D014661:Vasoconstriction / Q000187:drug effects
C473217:8-(4-chloro-phenylthio)-2'-O-methyladenosine-3'-5'-cyclic monophosphate; D015815:Cell Adhesion Molecules; D017482:Receptors, Thromboxane; D018799:Intercellular Adhesion Molecule-1; D000242:Cyclic AMP