Vasomotor Reaction to Cyclooxygenase-1-Mediated Prostacyclin Synthesis in Carotid Arteries from Two-Kidney-One-Clip Hypertensive Mice

This study tested the hypothesis that in hypertensive arteries cyclooxygenase-1 (COX-1) remains as a major form, mediating prostacyclin (prostaglandin I(2); PGI(2)) synthesis that may evoke a vasoconstrictor response in the presence of functional vasodilator PGI(2) (IP) receptors. Two-kidney-one-clip (2K1C) hypertension was induced in wild-type (WT) mice and/or those with COX-1 deficiency (COX-1(-/-)). Carotid arteries were isolated for analyses 4 weeks after. Results showed that as in normotensive mice, the muscarinic receptor agonist ACh evoked a production of the PGI(2) metabolite 6-keto-PGF(1α) and an endothelium-dependent vasoconstrictor response; both of them were abolished by COX-1 inhibition. At the same time, PGI(2), which evokes contraction of hypertensive vessels, caused relaxation after thromboxane-prostanoid (TP) receptor antagonism that abolished the contraction evoked by ACh. Antagonizing IP receptors enhanced the contraction to the COX substrate arachidonic acid (AA). Also, COX-1(-/-) mice was noted to develop hypertension; however, their increase of blood pressure and/or heart mass was not to a level achieved with WT mice. In addition, we found that either the contraction in response to ACh or that evoked by AA was abolished in COX-1(-/-) hypertensive mice. These results demonstrate that as in normotensive conditions, COX-1 is a major contributor of PGI(2) synthesis in 2K1C hypertensive carotid arteries, which leads to a vasoconstrictor response resulting from opposing dilator and vasoconstrictor activities of IP and TP receptors, respectively. Also, our data suggest that COX-1(-/-) attenuates the development of 2K1C hypertension in mice, reflecting a net adverse role yielded from all COX-1-mediated activities under the pathological condition.