Role of COX-2-derived metabolites in regulation of the renal hemodynamic response to norepinephrine

Llinás, María T.; López, Ruth M.; Rodríguez, Francisca; Roig, Francisco J.; Salazar, Francisco

doi:10.1152/ajprenal.2001.281.5.f975

Cited by 29 publications

(31 citation statements)

References 30 publications

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“…Similarly, in the anesthetized dog, nimesulide enhanced the action of norepinephrine to reduce GFR without affecting the increases in renal vascular resistance. 32 Blockade of PGH 2 /TxA 2 receptors by nimesulide cannot explain the inhibition of the vasoconstrictor response to AA in the diabetic rat kidney, as the response to AA in the control rat was not reduced. In retrospect, U46619 rather than phenylephrine would have been the better choice of agonist to address effects on vasoconstrictor responsiveness, as it should mimic the effects of the endoperoxides.…”

Section: Discussionmentioning

confidence: 93%

Role of COX-2 in the Enhanced Vasoconstrictor Effect of Arachidonic Acid in the Diabetic Rat Kidney

Chen

2003

Hypertension

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Abstract-In the rat isolated perfused kidney, arachidonic acid elicits cyclooxygenase-dependent vasoconstriction through activation of PGH 2 /TxA 2 receptors; responses are enhanced in kidneys from diabetic rats. This study examined the roles of cyclooxygenase-1/cyclooxygenase-2 in the enhanced renal vasoconstrictor effect of arachidonic acid in streptozotocin-diabetic rats. Release of 20-HETE was also determined, as this eicosanoid has been reported to elicit cyclooxygenase-dependent vasoconstriction. We confirmed that vasoconstrictor responses to arachidonic acid were enhanced in the diabetic rat kidney associated with a 2-fold-greater increase in the release of 6-ketoPGF 1␣ , which was used as an index of cyclooxygenase activity. One and three micrograms of arachidonic acid increased perfusion pressure by 85Ϯ37 and 186Ϯ6 mm Hg, respectively, in diabetic rat kidneys compared with 3Ϯ1 and 17Ϯ8 mm Hg, respectively, in control rat kidneys. Inhibition of both cyclooxygenase isoforms with indomethacin (10 mol/L) abolished the vasoconstrictor response to arachidonic acid in both diabetic and control rat kidneys, whereas inhibition of cyclooxygenase-2 with nimesulide (5mol/L) reduced perfusion pressure responses to 1 and 3 g arachidonic acid only in the diabetic rat kidney to 15Ϯ8 and 108Ϯ26 mm Hg, respectively, consistent with a 3-fold increase in the renal cortical expression of cyclooxygenase-2. 20-HETE release from the diabetic rat kidney was reduced almost 6-fold and was not increased in response to arachidonic acid. These results demonstrate that the renal vasoconstrictor effect of arachidonic acid is solely dependent on cyclooxygenase activity, with no evidence for a contribution from 20-HETE; in the diabetic rat, cyclooxygenase-2 activity contributes to the renal vasoconstrictor effect of arachidonic acid. iabetes results in changes in vascular responsiveness that have been implicated in the renal hemodynamic adaptations and the development of vascular disease. Vasodilator responses to endothelium-dependent agents are reduced, 1,2 whereas responses to vasoconstrictor agents are decreased, increased, or unchanged. [3][4][5][6][7][8] In studies conducted more than a decade ago, we observed that vasoconstrictor responses to angiotensin II and vasopressin in the isolated perfused kidney obtained from diabetic rats were impaired compared with those in kidneys from age-matched nondiabetic rats, whereas no differences in responses to phenylephrine were noted. 5 In contrast, we found that the vasoconstrictor responses to arachidonic acid (AA) in the perfused kidney of diabetic rats were markedly enhanced. 9 We also showed that the renal vasoconstrictor response to AA was inhibited by indomethacin and a PGH 2 /TxA 2 receptor antagonist but not by a thromboxane synthase inhibitor, indicating that the response was mediated by an endoperoxide. 10 The enhanced responsiveness to AA in the diabetic rat kidney was associated with increased conversion of AA to prostaglandins by cyclooxygenase (COX), and we concluded that in t...

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Section: Discussionmentioning

confidence: 93%

Role of COX-2 in the Enhanced Vasoconstrictor Effect of Arachidonic Acid in the Diabetic Rat Kidney

Chen

2003

Hypertension

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“…It has long been recognized that prostanoids (made by COX-1 and -2) play a critical role in modulating renal blood flow and glomerular hemodynamics (84,85). Besides regulating the vascular tone of the glomerular afferent arterioles, prostanoids with vasodilatory properties, such as prostaglandin E 2 and prostacyclin (PGI 2 ), can oppose the effects of vasoconstrictors (catecholamines, angiotensin, and vasopressin) in hypovolemic conditions or conditions of decreased cardiac output (86)(87)(88)(89)(90). Thus, these mediators can influence medullary blood flow by controlling the vascular tone of the descending vasa recta, which likely requires the activation of the prostanoid receptors EP 2 , EP 4 , or IP (91).…”

Section: Microvascular Dysfunction and The Balance Between Vasoconstrmentioning

confidence: 99%

Renal Hypoxia and Dysoxia After Reperfusion of the Ischemic Kidney

Legrand

Mik

Johannes³

et al. 2008

Mol Med

238

169

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Ischemia is the most common cause of acute renal failure. Ischemic-induced renal tissue hypoxia is thought to be a major component in the development of acute renal failure in promoting the initial tubular damage. Renal oxygenation originates from a balance between oxygen supply and consumption. Recent investigations have provided new insights into alterations in oxygenation pathways in the ischemic kidney. These findings have identified a central role of microvascular dysfunction related to an imbalance between vasoconstrictors and vasodilators, endothelial damage and endothelium-leukocyte interactions, leading to decreased renal oxygen supply. Reduced microcirculatory oxygen supply may be associated with altered cellular oxygen consumption (dysoxia), because of mitochondrial dysfunction and activity of alternative oxygen-consuming pathways. Alterations in oxygen utilization and/or supply might therefore contribute to the occurrence of organ dysfunction. This view places oxygen pathways' alterations as a potential central player in the pathogenesis of acute kidney injury. Both in regulation of oxygen supply and consumption, nitric oxide seems to play a pivotal role. Furthermore, recent studies suggest that, following acute ischemic renal injury, persistent tissue hypoxia contributes to the development of chronic renal dysfunction. Adaptative mechanisms to renal hypoxia may be ineffective in more severe cases and lead to the development of chronic renal failure following ischemia-reperfusion. This paper is aimed at reviewing the current insights into oxygen transport pathways, from oxygen supply to oxygen consumption in the kidney and from the adaptation mechanisms to renal hypoxia. Their role in the development of ischemia-induced renal damage and ischemic acute renal failure are discussed.

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“…13 The greater renal vasoconstriction found in the present study during low sodium intake could be partly secondary to the vasoactive effects elicited by the endogenous norepinephrine levels because it is known that renal sympathetic activity is enhanced during low sodium intake 22 and that COX-2-derived PGs modulate the renal vasoconstriction induced by norepinephrine. 23 COX-2 may also be more important in regulating renal hemodynamic during low sodium intake because it can metabolize 20-hydroxyeicosatetraenoic acid (20-HETE) to PG analogs and therefore can reduce the vasoconstrictor effects of 20-HETE. 24 It was not expected to find that prolonged COX-2 inhibition elicits a similar renal vasoconstriction during normal and high sodium load because it has been reported that COX-2 expression in the renal cortex decreases when sodium intake changes from a normal to a high level.…”

Section: Figurementioning

confidence: 99%

Role of Cyclooxygenase-2 in the Prolonged Regulation of Renal Function

et al. 2002

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Abstract-The role of cyclooxygenase-2 (COX-2) in the prolonged regulation of renal function was evaluated during changes in sodium intake and reduction of NO synthesis. It was evaluated in conscious dogs by administering a selective inhibitor (nimesulide) during 8 consecutive days. Nimesulide administration to dogs with normal or high sodium load did not modify glomerular filtration rate but reduced renal blood flow (16%; PϽ0.05). The vasoconstriction elicited by COX-2 inhibition was greater when NO production was inhibited because glomerular filtration rate decreased by Ͼ25% when nimesulide was administered to dogs with a reduced NO synthesis. During low sodium intake, COX-2 inhibition elicited a decrease (PϽ0.05) of both glomerular filtration rate (34%) and renal blood flow (31%). Sodium excretion only decreased (PϽ0.05) during the first day of COX-2 inhibition in dogs with normal or high sodium load. The increase in plasma potassium levels elicited by COX-2 inhibition was greater in dogs with low sodium intake and was enhanced when NO production was inhibited. This change in potassium was not secondary to a decrease in plasma aldosterone levels. The results of this study suggest that COX-2-derived metabolites (1) play a more important role in the long-term regulation of renal hemodynamic when sodium intake is low, (2) protect the renal vasculature from the vasoconstriction secondary to a reduction in NO, (3) are only acutely involved in regulating urinary sodium excretion, and (4) Key Words: cyclooxygenase Ⅲ nitric oxide Ⅲ renal blood flow Ⅲ hemodynamics Ⅲ sodium Ⅲ prostaglandins Ⅲ renin Ⅲ aldosterone N umerous studies have demonstrated that cyclooxygenase-2 (COX-2) expression in the renal cortex increases in response to low-salt diet, and decreases when sodium intake is elevated. 1-4 These variations in COX-2 expression suggest that COX-2-derived metabolites play a major role in the control of renal hemodynamic when sodium intake is low, and probably a minor role in regulating renal hemodynamic when sodium intake is high. However, the role of COX-2 in the prolonged regulation of renal blood flow (RBF) and glomerular filtration rate (GFR) during changes in sodium intake is not well defined. [5][6][7][8] In the renal medulla, COX-2 expression increases in response to a high sodium intake. 3,4 Considering the role of prostaglandins (PGs) in the control of sodium excretion, 9 it may be proposed that COX-2 is more involved in regulating renal excretory function during high sodium intake than during normal sodium intake, but so far, it has not been evaluated whether this hypothesis is correct. The first objective of the present study was to evaluate the role of COX-2-derived metabolites in the prolonged regulation of renal hemodynamic and excretory function when sodium load is elevated or low.The role of COX-derived PG in the regulation of plasma potassium (pK) and plasma aldosterone concentration (PAC) has been demonstrated in studies showing that pK and PAC are modified during the prolonged administration of...

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Role of COX-2-derived metabolites in regulation of the renal hemodynamic response to norepinephrine

Cited by 29 publications

References 30 publications

Role of COX-2 in the Enhanced Vasoconstrictor Effect of Arachidonic Acid in the Diabetic Rat Kidney

Role of COX-2 in the Enhanced Vasoconstrictor Effect of Arachidonic Acid in the Diabetic Rat Kidney

Renal Hypoxia and Dysoxia After Reperfusion of the Ischemic Kidney

Role of Cyclooxygenase-2 in the Prolonged Regulation of Renal Function

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