Aldosterone induces endothelial dysfunction in resistance arteries from normotensive and hypertensive rats by increasing thromboxane A₂ and prostacyclin

Abstract

Background and purpose: The present study was designed to assess whether cyclooxygenase-2 (COX-2) activation is involved in the effects of chronic aldosterone treatment on endothelial function of mesenteric resistance arteries (MRA) from Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Experimental approach: Relaxation to acetylcholine was measured in MRA from both untreated and aldosterone-treated strains. Vasomotor responses to prostacyclin and U46619 were also analysed. Release of 6-oxo-prostaglandin (PG)F 1a and thromboxane B 2 (TxB 2 ) was determined by enzyme immunoassay. COX-2 protein expression was measured by western blot. Key results: Aldosterone reduced acetylcholine relaxation in MRA from both strains. In MRA from both aldosterone-treated strains the COX-1/2 or COX-2 inhibitor (indomethacin and NS-398, respectively), TxA 2 synthesis inhibitor (furegrelate), prostacyclin synthesis inhibitor (tranylcypromine) or TxA 2 / PGH 2 receptor antagonist (SQ 29 548), but not COX-1 inhibitor SC-560, increased acetylcholine relaxation. In untreated rats this response was increased only in SHR. Prostacyclin elicited a biphasic vasomotor response: lower concentrations elicited relaxation, whereas higher concentrations elicited contraction that was reduced by SQ 29 548. Aldosterone increased the acetylcholine-stimulated production of 6-oxo-PGF 1a and TxB 2 in MRA from both strains. COX-2 expression was higher in both strains of rats treated with aldosterone. Conclusions and implications: Chronic treatment with aldosterone impaired endothelial function in MRA under normotensive and hypertensive conditions by increasing COX-2-derived prostacyclin and thromboxane A 2 . As endothelial dysfunction participates in the pathogenesis of many cardiovascular disorders we hypothesize that anti-inflammatory drugs, specifically COX-2 inhibitors, could ameliorate vascular damage in patients with elevated aldosterone production.

Mineralocorticoid Receptor Antagonist for Renal Protection

“…6 Aldosteroneinduced kidney injury is likely to be multifactorial, including its effect on systemic blood pressure, renal vasculature, local inflammation, and fibrosis. Various potential pathways and mediators have been proposed, including plasminogen activator inhibitor-1, 13 transforming growth factor-β1, 14 reactive oxygen species, 15 angiotensin type 1 receptor, 16 vascular endothelial growth factor, 17 as well as changes in vascular smooth muscle 18 and endothelial cells 19 (Table 1). In addition to the traditional nuclear receptor and transcription mediation pathway, aldosterone could alter a number of cellular signaling within minutes by the presumably "non-genomic" actions.…”

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

“…In addition, while mice are commonly used as models to study human diseases, such as hypertension, the exact role of PGI 2 synthesis in their renal arteries still remains to be clearly elucidated. Moreover, there is considerable inconsistency regarding the role of each of the two COX isoforms in regulating vasomotor reactions, including those of renal vasculature (6,8,12,17,27,29,34,35,37,38,40), possibly in part due to the use of isoform-selective COX inhibitors that might have effects independent of their intended targets (2,3,20,26).Therefore, the aim of this study was to determine whether PGI 2 evokes contraction in mouse renal arteries and, if so, how TP and/or IP receptors function in the vessel. In addition, experiments were performed to determine how the genetic deficiency of COX-1 (COX-1 Ϫ/Ϫ ) influences on the in vitro PGI 2 synthesis and/or vasomotor reaction.…”

“…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).…”

“…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 suggested to mediate a vasoconstrictor response even under normal physiological conditions (7,19,21,30).…”

“…Moreover, our recent studies suggest that in porcine interlobular renal arteries COX-1-mediated endothelial PGI 2 synthesis is responsible for endothelium-dependent vasoconstrictor activity evoked by agonists, such as bradykinin (22). On the other hand, the effect of PGI 2 on a given vascular bed may vary considerably between species (19,38). In addition, while mice are commonly used as models to study human diseases, such as hypertension, the exact role of PGI 2 synthesis in their renal arteries still remains to be clearly elucidated.…”