Abstract
This study tested the hypothesis that in hypertensive arteries cyclooxygenase-1 (COX-1) remains as a major form, mediating prostacyclin (prostaglandin I2; PGI2) synthesis that may evoke a vasoconstrictor response in the presence of functional vasodilator PGI2 (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 PGI2 metabolite 6-keto-PGF1α and an endothelium-dependent vasoconstrictor response; both of them were abolished by COX-1 inhibition. At the same time, PGI2, 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 PGI2 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.
Highlights
Cyclooxygenase (COX), which exists mainly as COX-1 and -2 isoforms, metabolizes arachidonic acid (AA) to produce vasoactive prostanoids
We demonstrated that the muscarinic receptor agonist ACh stimulated a production of the PGI2 metabolite 6-keto-PGF1α and an endothelium-dependent contraction in 2K1C hypertensive carotid arteries; both of them were sensitive to COX-1 inhibition
We noted that in COX-1-/- 2K1C hypertensive mice, was the contraction to ACh or arachidonic acid (AA) abolished, and the increase of systolic blood pressure (SBP) and/or heart mass did not reach an extent seen in WT counterparts
Summary
Cyclooxygenase (COX), which exists mainly as COX-1 and -2 isoforms, metabolizes arachidonic acid (AA) to produce vasoactive prostanoids. Prostacyclin (prostaglandin I2; PGI2) is a major product produced by the vascular endothelium, acting on smooth muscle PGI2 (IP) receptors to mediate vasodilatation and protect vessels from the development of diseases [1,2,3,4]. Studies indicate that PGI2 may activate smooth muscle thromboxane prostanoid (TP) receptors to mediate vasoconstriction and function as an endotheliumderived constrictor factor (EDCF) [5,6,7,8,9,10,11,12]. The role and pathways of COX-1 in regulating diseased vessels still remain controversial
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