Concomitant activation of functionally opposing prostacyclin and thromboxane prostanoid receptors by cyclo‐oxygenase‐1‐mediated prostacyclin synthesis in mouse arteries

This study aimed to determine whether cyclo‐oxygenase‐1 (COX‐1) mediates dilatation of mouse arteries via synthesis of prostacyclin (PGI2) and, if so, how PGI2 (IP) receptors contribute and whether thromboxane prostanoid (TP) receptors are implicated in the process. Mesenteric arteries were isolated from wild‐type mice or mice with COX‐1 deficiency (COX‐1−/−). The vasomotor reaction to the COX substrate arachidonic acid (AA) was determined with isometric force measurement, while the in vitro production or the plasma level of the PGI2 metabolite 6‐keto‐PGF1α was analysed with high‐performance liquid chromatography–mass spectroscopy or enzyme immunoassay, respectively. Results showed that AA, which evoked endothelium‐dependent 6‐keto‐PGF1α production, elicited relaxation that was inhibited or enhanced by antagonizing IP or TP receptors, respectively. Also, IP receptor blockade resulted in contraction in response to AA (following NO synthase inhibition), which was prevented by a concomitant TP receptor antagonism. Meanwhile, COX‐1−/− or COX‐1 inhibition abolished the in vitro 6‐keto‐PGF1α production and reduced the relaxation or contraction observed with AA. Real‐time PCR showed that whereas TP receptor mRNAs were detected at similar levels, IP receptor mRNAs were present at higher levels in the branches than in the main stem of the mesenteric artery. In addition, antagonizing the IP receptors enhanced the contraction evoked by PGI2 in the carotid artery. Also, we noted that COX‐1−/− mice had a reduced basal plasma 6‐keto‐PGF1α level. These results demonstrate an explicit vasodilator role for COX‐1‐mediated endothelial PGI2 synthesis and suggest that the functionally opposing IP and TP receptors concomitantly mediate the vasomotor reaction to PGI2, with the dilator activity of IP receptors being compromised by the vasoconstrictor effect of TP receptors and vice versa.