Acute Effects of Cyclooxygenase-2 Inhibition on Renal Function in Heterozygous Ren-2-Transgenic Rats on Normal or Low Sodium Intake

Abstract

Background/Aims: Since there are no data available so far on the role of renal cyclooxygenase-2 (COX-2) in hypertensive Ren-2-transgenic rats (TGR), in the present study we evaluated renal cortical COX-2 protein expression and prostaglandin E₂ (PGE₂) concentrations as well as renal functional responses to acute COX-2 inhibition in male heterozygous TGR and in normotensive Hannover Sprague-Dawley (HanSD) rats fed either a normal-sodium (NS) or a low-sodium (LS) diet. Methods: In rats fed either the NS or the LS diet for 12 days and prepared for clearance experiments with left ureteral catheterization, the renal functional responses of the left kidney were evaluated after intrarenal COX-2 inhibition with DuP-697 or NS-398. In renal cortical tissue, COX-2 protein expression was assessed by immunoblotting, and the concentration of PGE₂ as a marker of COX-2 activity was determined by enzyme immunoassay. Mean arterial pressure in the right femoral artery was monitored by means of a pressure transducer. Results: In heterozygous TGR, to our surprise, the LS diet normalized the mean arterial pressure. Despite significantly higher renocortical expression of COX-2 and PGE₂ concentrations as well as urinary PGE₂excretion in TGR as compared with HanSD rats kept on the NS diet, selective intrarenal COX-2 inhibition did not influence renal function either in TGR or in HanSD rats. The LS diet increased renocortical COX-2 expression and PGE₂ concentrations as well as urinary PGE₂excretion significantly stronger in TGR than in HanSD rats. Regardless of these increases, the intrarenal COX-2 inhibition caused comparable decreases in glomerular filtration rate, in absolute and fractional sodium excretion, as well as in urinary PGE₂excretion in TGR and HanSD rats kept on the LS diet. Conclusions: The present data show that a LS diet normalizes the mean arterial pressure in heterozygous male TGR. This first study on the role of renal COX-2 in TGR also demonstrates that COX-2-derived vasodilatory prostanoids do not act as renal compensatory vasodilator and natriuretic substances in this model of hypertension.

Effects of changes in sodium balance on plasma and kidney angiotensin II levels in anesthetized and conscious Ren-2 transgenic rats

“…Furthermore, we found that severe sodium depletion substantially attenuated BP in TGR at all ages, but did not alter plasma or kidney ANG II levels in TGR. These findings are in good agreement with our recent observation that long-term treatment with LS diet immediately after the weaning period (starting at 28 days of age) markedly reduced BP in heterozygous TGR almost to normotensive levels [37,38].…”

“…Moreover, previous studies have proved that the activity of the RAS is inversely related to the level of salt intake, and that the increased activity of RAS during sodium restriction is a compensatory mechanism capable of maintaining normal sodium balance, stable extracellular fluid volume and BP across a wide range of sodium retention [22,[57][58][59][60]. It has been shown that heterozygous TGR respond to increased dietary salt intake by exacerbation of their hypertension [35,36] and that sodium restriction resulted in marked attenuation of the development of hypertension in heterozygous male TGR [37,38]. These findings indicate that TGR carry an important salt-sensitive component of hypertension.…”

“…Given the importance of plasma and tissue ANG II in the development of salt-sensitive hypertension in rats [29][30][31][32][33][34] and in the view of findings that TGR also show a saltsensitive component of hypertension [35][36][37][38], a second objective of this study was to determine the effects of high salt diet and salt depletion on blood pressure and plasma and kidney ANG II levels in TGR and HanSD rats.…”

Effects of Dietary Salt Load and Salt Depletion on the Course of Hypertension and Angiotensin II Levels in Male and Female Heterozygous Ren-2 Transgenic Rats

“…Nevertheless, our method was previously validated in this laboratory by Heller and Hellerova [unpublished observation], who demonstrated a very good correlation between indirect tail-cuff measurements and direct measurements of BP simultaneously obtained through an arterial catheter. Since the time of this validation we have employed the tail-cuff method routinely in our laboratory [28,29,35,36] .…”

“…Since an emerging body of evidence indicates that TGR exhibit a salt-sensitive component of hypertension [27][28][29][30] , and since we have recently demonstrated that this salt sensitivity in male heterozygous TGR is associated with a loss of the normal regulatory effect of changes in dietary salt intake on ANG II production [17] , the second aim of the present study was to delineate the effects of oral salt loading and salt depletion on BP and plasma and kidney ANG II levels in female heterozygous TGR and age-matched female HanSD rats and to compare these responses to changes in sodium balance with those in male TGR and HanSD rats.…”