A vasoconstrictor role for cyclooxygenase-1-mediated prostacyclin synthesis in mouse renal arteries

Abstract

This study was to determine whether prostacyclin [prostaglandin I 2 (PGI2)] evokes mouse renal vasoconstriction and, if so, the underlying mechanism(s) and how its synthesis via cyclooxygenase-1 (COX-1) influences local vasomotor reaction. Experiments were performed on vessels from C57BL/6 mice and/or those with COX-1 deficiency (COX-1 Ϫ/Ϫ ). Results showed that in renal arteries PGI2 evoked contraction more potently than in carotid arteries, where COX-1 is suggested to mediate prominent endothelium-dependent contraction. A similar result was observed with the thromboxane-prostanoid (TP) receptor agonist U46619. However, in renal arteries TP receptor antagonism, which inhibited the contraction, did not result in any relaxation in response to PGI2. Moreover, we noted that the endothelial muscarinic receptor agonist ACh evoked an increase in the production of the PGI2 metabolite 6-keto-PGF1␣, which was prevented by endothelial denudation or COX-1 Ϫ/Ϫ . Interestingly, COX-1 Ϫ/Ϫ was further found to abolish a force development that was sensitive to TP receptor antagonism and result in enhanced relaxation evoked by ACh following NO synthase inhibition. Also, in renal arteries the COX substrate arachidonic acid evoked a vasoconstrictor response, which was again abolished by COX-1 Ϫ/Ϫ . Meanwhile, nonselective COX inhibition did not show any effect in vessels from COX-1 Ϫ/Ϫ mice. Thus, in mouse renal arteries, high expression of TP receptors together with little functional involvement from the vasodilator PGI 2 receptors results in a potent vasoconstrictor effect evoked by PGI2. Also, our data imply that endogenous COX-1-mediated PGI2 synthesis leads to vasoconstrictor activity and this could be an integral part of endothelium-derived mechanisms in regulating local renal vascular function. arachidonic acid; TP receptors; contraction; IP receptors; vasodilation CYCLOOXYGENASE (COX), which exists in COX-1 and -2 isoforms, metabolizes arachidonic acid (AA) to produce various vasoactive prostanoids. Among them, prostacyclin [prostaglandin I 2 (PGI 2 )] is the major product generated in the endothelium, acting on the PGI 2 (IP) receptors on medial smooth muscle to mediate vasodilatation and protect vessels from the development of disease (4,25,33). Decreased production of endothelial PGI 2 synthesis has been suggested to cause increased incidence of cardiovascular events (8,12,40). On the other hand, studies also indicate that the endothelial COX-mediated metabolism generates vasoconstrictor products that act on thromboxane-prostanoid (TP) receptors to mediate vasoconstriction (9,14,16,28,30,32,43). Interestingly, PGI 2 can also activate smooth muscle TP receptors (11,21,22,36,38). This has been explained by an excessive production of PGI 2 and/or dysfunction of IP receptors found in conditions such as hypertension (11,36,38). Moreover, both TP and IP receptors may concomitantly modulate the vasomotor reaction to PGI 2 ; hence, in vessels with limited functional IP receptors the process of PGI 2 synthesis itself is suggeste...

Vasoconstrictor role of cyclooxygenase-1-mediated prostacyclin synthesis in non-insulin-dependent diabetic mice induced by high-fat diet and streptozotocin

“…For the control response, inhibitors were replaced with vehicles (water for L-NAME and FR-122047 and DMSO for SQ-29548 or indomethacin). In accordance with previous studies on mouse arteries (25,51), the response elicited by an agent under baseline (unprecontracted) conditions was expressed relative to that of 60 mM K ϩ , whereas that during the contraction evoked by PE at the amount indicated was expressed relative to the value immediately before the application of the agent.…”

“…With the assistance of a binocular microscope, aortas and renal arteries were dissected free of adherent tissues. For functional experiments, the nonbranching area of the abdominal aorta (the section below the renal arteries) and main stems of the renal artery were cut into 1-mm rings (3-4 abdominal aortic or 2 renal arterial rings could be obtained from a single mouse) as previously described (24,25). In addition, in some experiments, mesenteric arteries were also isolated for the control response of PGI 2-induced relaxation (21).…”

“…Analyses of vascular function were performed as previously described (25,51). Briefly, the vascular ring was mounted between two tungsten wires in an organ bath filled with PSS aerated with 95%O 2-5% CO2 and maintained at 37°C.…”

“…However, PGI 2 may also act on thromboxane prostanoid (TP) receptors on smooth muscle to mediate vasoconstriction and functions as an endotheliumderived contracting factor (EDCF) (9,19,23,24,34,47,48,50). In fact, the vasomotor reaction to PGI 2 may be modulated by the functionally opposing TP and dilator IP receptors (9,21,47,50), and an EDCF-like action of PGI 2 can result from little or low functional presence of vasodilator IP receptors that leads to a major activation of TP receptors (10,(23)(24)(25)42). Also, COX-2 has been commonly considered a major source of endothelial PGI 2 synthesis (11); however, in some vascular beds, COX-1 functions as the major COX form (16,17), mediating endothelium-dependent contraction (23-25, 39, 41) or relaxation (21,30,38) under normal physiological conditions.…”

“…Therefore, in this study, non-insulin-dependent diabetes was induced to C57BL/6 mice and those with COX-1 deficiency (COX-1 Ϫ/Ϫ mice) to determine the contribution of COX-1 and PGI 2 synthesis to endothelium-derived vasomotor reactions under the pathological condition in the abdominal aorta and renal arteries, where PGI 2 normally mediates vasoconstrictor activity (23,25). Also, experiments were performed to determine how COX-1 deficiency influences the development of diabetic complications, such as hypertension.…”