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

2001 ◽  
Vol 281 (5) ◽  
pp. F975-F982 ◽  
Author(s):  
Maria T. Llinás ◽  
Ruth López ◽  
Francisca Rodríguez ◽  
Francisco Roig ◽  
F. Javier Salazar
Keyword(s):  
Sodium Intake ◽  
Hemodynamic Response ◽  
Hemodynamic Effects ◽  
Relative Contribution ◽  
Low Sodium ◽  
Renal Hemodynamic ◽  
Cox Inhibitor ◽  
Cox 2 ◽  
Excretion Rates

The objective of this study was to examine the role of cylcooxygenase (COX)-2-derived prostaglandins (PG) in modulating the renal hemodynamic effects of norepinephrine (NE) during low or normal sodium intake. The relative contribution of each COX isoform in producing the PG that attenuate the renal NE effects during normal sodium intake was also evaluated. The renal response to three doses of NE (50, 100, and 250 ng · kg−1 · min−1) was evaluated in anesthetized dogs pretreated with vehicle, a selective COX-2 inhibitor (nimesulide), or a nonselective COX inhibitor (meclofenamate). Intrarenal infusion of the two lower doses of NE in vehicle-pretreated dogs with normal sodium intake ( n = 8) elicited an increase in renal vascular resistance (RVR; 21 and 34%) without inducing changes in glomerular filtration rate (GFR). The highest dose of NE in this group induced a further increment in RVR (113%) and a decrease in GFR (33%). Pretreatment with nimesulide in dogs with normal sodium intake ( n = 7) did not modify the NE-induced increments in RVR but enhanced the decreases in GFR induced by the three NE doses (12, 26, and 64%). The renal hemodynamic response to NE in meclofenamate-pretreated dogs with normal sodium intake ( n = 7) was similar to that found in dogs pretreated with nimesulide. Infusion of the lowest dose of NE to vehicle-pretreated dogs with low sodium intake ( n = 6) did not modify GFR and elicited an increase in RVR (42%). Infusion of the second and third doses of NE led to a decrease in GFR (35 and 91%) and a rise in RVR (82 and 587%). Infusion of the first two doses of NE in nimesulide-pretreated dogs with low sodium intake ( n= 5) induced a fall in GFR (64 and 92%) and an increase in RVR (174 and 2,293%) that were greater ( P < 0.05) than those induced by NE in vehicle-pretreated dogs. The elevation in the urinary excretion rates of PGE2 and 6-keto-PGF1α elicited by NE was prevented in the nimesulide-pretreated dogs. Our results show that COX-2 inhibition potentiates the renal hemodynamic effects of NE and propose that the PG involved in modulating them are mainly derived from COX-2 activity.

Cyclooxygenase-2 plays a significant role in regulating the tone of the fetal lamb ductus arteriosus

1999 ◽  
Vol 276 (3) ◽  
pp. R913-R921 ◽  
Author(s):  
Ronald I. Clyman ◽  
Pierre Hardy ◽  
Nahid Waleh ◽  
Yao Qi Chen ◽  
Françoise Mauray ◽  
...  
Keyword(s):  
Significant Role ◽  
Ductus Arteriosus ◽  
Late Gestation ◽  
Relative Contribution ◽  
Cox Inhibitor ◽  
Fetal Lamb ◽  
Cox 2 ◽  
Cox 2 Inhibitors ◽  
Cox 1

Nonselective cyclooxygenase (COX) inhibitors are potent tocolytic agents but have adverse effects on the fetal ductus arteriosus. We hypothesized that COX-2 inhibitors may not affect the ductus if the predominant COX isoform is COX-1. To examine this hypothesis, we used ductus arteriosus obtained from late-gestation fetal lambs. In contrast to our hypothesis, fetal lamb ductus arteriosus expressed both COX-1- and COX-2-immunoreactive protein (by Western analysis). Although COX-1 was found in both endothelial and smooth muscle cells, COX-2 was found only in the endothelial cells lining the ductus lumen (by immunohistochemistry). The relative contribution of COX-1 and COX-2 to PGE2 synthesis was consistent with the immunohistochemical results: in the intact ductus, PGE2 formation was catalyzed by both COX-1 and COX-2 in equivalent proportions; in the endothelium-denuded ductus, COX-2 no longer played a significant role in PGE2 synthesis. NS-398, a selective inhibitor of COX-2, was 66% as effective as the selective COX-1 inhibitor valeryl salicylate and the nonselective COX inhibitor indomethacin in causing contraction of the ductus in vitro. At this time, caution should be used when recommending COX-2 inhibitors for use in pregnant women.

scholarly journals Enhanced Responses of Blood Pressure, Renal Function, and Aldosterone to Angiotensin I in the DD Genotype Are Blunted by Low Sodium Intake

2002 ◽  
Vol 13 (4) ◽  
pp. 1025-1033
Author(s):  
Frank G. H. van der Kleij ◽  
Paul E. de Jong ◽  
Rob H. Henning ◽  
Dick de Zeeuw ◽  
Gerjan Navis
Keyword(s):  
Renal Function ◽  
Vascular Resistance ◽  
Sodium Intake ◽  
Renal Vascular Resistance ◽  
Hemodynamic Parameters ◽  
Angiotensin I ◽  
Low Sodium ◽  
Renal Hemodynamic ◽  
Intake Level ◽  
Renal Vascular

ABSTRACT. Angiotensin-converting enzyme (ACE) activity is increased in the DD genotype, but the functional significance for renal function is unknown. Blunted responses of BP and proteinuria to ACE inhibition among DD renal patients during periods of high sodium intake were reported. It was therefore hypothesized that sodium status affects the phenotype in the ACE I/D polymorphism. The effects of angiotensin I (AngI) and AngII among 27 healthy subjects, with both low (50 mmol sodium/d) and liberal (200 mmol sodium/d) sodium intakes, were studied. Baseline mean arterial pressure (MAP) values, renal hemodynamic parameters, and renin-angiotensin system parameters were similar for all genotypes with either sodium intake level. With liberal sodium intake, the increases in MAP, renal vascular resistance, and aldosterone levels during AngI infusion (8 ng/kg per min) were significantly higher for the DD genotype, compared with the ID and II genotypes (all parameters presented as percent changes ± 95% confidence intervals), with mean MAP increases of 22 ± 2% (DD genotype), 13 ± 5% (ID genotype), and 12 ± 6% (II genotype) (P < 0.05), mean increases in renal vascular resistance of 100.1 ± 19.7% (DD genotype), 73.0 ± 16.3% (ID genotype), and 63.2 ± 16.9% (II genotype) (P < 0.05), and increases in aldosterone levels of 650 ± 189% (DD genotype), 343 ± 71% (ID genotype), and 254 ± 99% (II genotype) (P < 0.05). Also, the decrease in GFR was more pronounced for the DD genotype, with mean decreases of 17.9 ± 4.7% (DD genotype), 8.8 ± 3.4% (ID genotype), and 6.4 ± 5.9% (II genotype) (P < 0.05). The effective renal plasma flow, plasma AngII concentration, and plasma renin activity values were similar for the genotypes. In contrast, with low sodium intake, the responses to AngI were similar for all genotypes. The responses to AngII were also similar for all genotypes, with either sodium intake level. In conclusion, the responses of MAP, renal hemodynamic parameters, and aldosterone concentrations to AngI are enhanced for the DD genotype with liberal but not low sodium intake. These results support the presence of gene-environment interactions between ACE genotypes and dietary sodium intake.

Kaliuretic regulatory factors in the rat

1987 ◽  
Vol 253 (6) ◽  
pp. F1182-F1196 ◽  
Author(s):  
J. C. Rutledge ◽  
L. Rabinowitz
Keyword(s):  
Sodium Intake ◽  
Plasma Potassium ◽  
Urine Excretion ◽  
High Potassium ◽  
Regulatory Factors ◽  
Potassium Intake ◽  
Excretion Rates ◽  
Caloric Balance ◽  
Adrenalectomized Rats

To evaluate the role of aldosterone, plasma potassium, and sodium and urine excretion rates in controlling both total daily potassium excretion and the diurnal cyclic excretion of potassium, we performed experiments on unanesthetized, undisturbed rats kept in a 12-h light/12-h dark environment and fed a liquid diet. Independent variations were imposed on potassium intake, sodium intake, and, in groups of adrenalectomized rats, on aldosterone infusion rates. Potassium intake was 2.6, 10.6, and 18.7 meq/day. Sodium intake was 2.1, 6.7, and 17 meq/day. Aldosterone infusion was 0.1, 0.4, 1, and 10 times a basal rate of 1 microgram.day-1.100 g-1, with constant dexamethasone infusion at 1.43 micrograms.day-1.100 g-1. Twenty-four-hour excretion of potassium and sodium balanced 24-h intake of potassium and sodium regardless of the imposed combination of known regulatory factors. The amplitudes of potassium and sodium excretion during the diurnal cycle were each closely related to the ongoing levels of potassium and sodium intake. Plasma potassium was measured at the peak of the potassium cycle. It is suggested, based on analysis of the results, that when caloric balance was maintained, the amplitude of the diurnal potassium cycle was not importantly influenced by the rates of sodium and urine excretion, and, in addition to effects of aldosterone and plasma potassium concentration, the amplitude was importantly influenced by unspecified, homeostatically effective kaliuretic factors. Adrenalectomized rats receiving subbasal aldosterone replacement rejected the high potassium diet, were anuric, lost weight, and were severely hyperkalemic, observations indicating the necessity of adequate aldosterone for maintenance of potassium homeostasis.

scholarly journals Human intermittent hypoxia-induced respiratory plasticity is not caused by inflammation

2015 ◽  
Vol 46 (4) ◽  
pp. 1072-1083 ◽  
Author(s):  
Andrew E. Beaudin ◽  
Xavier Waltz ◽  
Matiram Pun ◽  
Katherine E. Wynne-Edwards ◽  
Sofia B. Ahmed ◽  
...  
Keyword(s):  
Intermittent Hypoxia ◽  
Sleep Apnoea ◽  
Double Blind ◽  
Healthy Humans ◽  
Cox Inhibitor ◽  
Obstructive Sleep ◽  
Tnf Α ◽  
Respiratory Plasticity ◽  
Cox 2

Ventilatory instability, reflected by enhanced acute hypoxic (AHVR) and hypercapnic (AHCVR) ventilatory responses is a fundamental component of obstructive sleep apnoea (OSA) pathogenesis. Intermittent hypoxia-induced inflammation is postulated to promote AHVR enhancement in OSA, although the role of inflammation in intermittent hypoxia-induced respiratory changes in humans has not been examined. Thus, this study assessed the role of inflammation in intermittent hypoxia-induced respiratory plasticity in healthy humans.In a double-blind, placebo-controlled, randomised crossover study design, 12 males were exposed to 6 h of intermittent hypoxia on three occasions. Prior to intermittent hypoxia exposures, participants ingested (for 4  days) either placebo or the nonsteroidal anti-inflammatory drugs indomethacin (nonselective cyclooxygenase (COX) inhibitor) and celecoxib (selective COX-2 inhibitor). Pre- and post-intermittent hypoxia resting ventilation, AHVR, AHCVR and serum concentration of the pro-inflammatory cytokine tumour necrosis factor (TNF)-α were assessed.Pre-intermittent hypoxia resting ventilation, AHVR, AHCVR and TNF-α concentrations were similar across all three conditions (p≥0.093). Intermittent hypoxia increased resting ventilation and the AHVR similarly across all conditions (p=0.827), while the AHCVR was increased (p=0.003) and TNF-α was decreased (p=0.006) with only selective COX-2 inhibition.These findings indicate that inflammation does not contribute to human intermittent hypoxia-induced respiratory plasticity. Moreover, selective COX-2 inhibition augmented the AHCVR following intermittent hypoxia exposure, suggesting that selective COX-2 inhibition could exacerbate OSA severity by increasing ventilatory instability.

Dietary sodium intake modulates renal excretory responses to intrarenal angiotensin (1–7) administration in anesthetized rats

2013 ◽  
Vol 304 (3) ◽  
pp. R260-R266 ◽  
Author(s):  
Julie O'Neill ◽  
Alan Corbett ◽  
Edward J. Johns
Keyword(s):  
Glomerular Filtration Rate ◽  
Glomerular Filtration ◽  
Filtration Rate ◽  
Sodium Intake ◽  
Dietary Sodium ◽  
High Sodium ◽  
Sodium Diet ◽  
Low Sodium Diet ◽  
Low Sodium ◽  
Renal Hemodynamic

Angiotensin II at the kidney regulates renal hemodynamic and excretory function, but the actions of an alternative metabolite, angiotensin (1–7), are less clear. This study investigated how manipulation of dietary sodium intake influenced the renal hemodynamic and excretory responses to intrarenal administration of angiotensin (1–7). Renal interstitial infusion of angiotensin (1–7) in anesthetized rats fed a normal salt intake had minimal effects on glomerular filtration rate but caused dose-related increases in urine flow and absolute and fractional sodium excretions ranging from 150 to 200%. In rats maintained for 2 wk on a low-sodium diet angiotensin (1–7) increased glomerular filtration rate by some 45%, but the diuretic and natriuretic responses were enhanced compared with those in rats on a normal sodium intake. By contrast, renal interstitial infusion of angiotensin (1–7) in rats maintained on a high-sodium intake had no effect on glomerular filtration rate, whereas the diuresis and natriuresis was markedly attenuated compared with those in rats fed either a normal or low-sodium diet. Plasma renin and angiotensin (1–7) were highest in the rats on the low-sodium diet and depressed in the rats on a high-sodium diet. These findings demonstrate that the renal hemodynamic and excretory responses to locally administered angiotensin (1–7) is dependent on the level of sodium intake and indirectly on the degree of activation of the renin-angiotensin system. The exact way in which angiotensin (1–7) exerts its effects may be dependent on the prevailing levels of angiotensin II and its receptor expression.

Endothelial COX-1 and -2 differentially affect reactivity of MVB in portal hypertensive rats

2002 ◽  
Vol 283 (3) ◽  
pp. G587-G594 ◽  
Author(s):  
M. A. Potenza ◽  
O. A. Botrugno ◽  
M. A. De Salvia ◽  
G. Lerro ◽  
C. Nacci ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
Hypertensive Rats ◽  
Mesenteric Blood Flow ◽  
Western Blots ◽  
Vascular Bed ◽  
Cox Inhibitor ◽  
Mesenteric Vascular Bed ◽  
Cox 2 ◽  
Cox 1

Expression of constitutive and inducible cyclooxygenase (COX-1 and COX-2, respectively) and the role of prostanoids were investigated in the aorta and mesenteric vascular bed (MVB) from the portal vein-ligated rat (PVL) as a model of portal hypertension. Functional experiments were carried out in MVB from PVL and sham-operated rats in the absence or presence of the nonselective COX inhibitor indomethacin or the selective inhibitors of COX-1 (SC-560) or COX-2 (NS-398). Western blots of COX-1 and COX-2 proteins were evaluated in aorta and MVB, and PGI2 production by enzyme immunoassay of 6-keto-PGF1α was evaluated in the aorta. In the presence of functional endothelium, decreased contraction to norepinephrine (NE) and increased vasodilatation to ACh were observed in MVB from PVL. Exposure of MVB to indomethacin, SC-560, or NS-398 reversed the hyporeactivity to NE and the increased endothelial vasodilatation to ACh in PVL, with NS-398 being more potent than the other two inhibitors. Upregulation of COX-1 and COX-2 expressions was detected in aorta and MVB from PVL portal hypertensive rats, and increased production of 6-keto-PGF1α was observed in aorta from portal hypertensive rats. These results suggest that generation of endothelial vasodilator prostanoids, from COX-1 and COX-2 isoforms, accounts for the increased mesenteric blood flow in portal hypertension.

scholarly journals Differential contribution of COX-1 and COX-2 derived prostanoids to cortical spreading depression—Evoked cerebral oligemia

2016 ◽  
Vol 37 (3) ◽  
pp. 1060-1068 ◽  
Author(s):  
Helaine Gariepy ◽  
Jun Zhao ◽  
Dan Levy
Keyword(s):  
Cortical Spreading Depression ◽  
Spreading Depression ◽  
Selective Inhibition ◽  
Doppler Flowmetry ◽  
Relative Contribution ◽  
Cox Inhibitor ◽  
Cox 2 ◽  
Synthase Inhibitor ◽  
Later Phase ◽  
Cox 1

Cortical spreading depression (CSD) is considered a significant phenomenon for human neurological conditions and one of its key signatures is the development of persistent cortical oligemia. The factors underlying this reduction in cerebral blood flow (CBF) remain incompletely understood but may involve locally elaborated vasoconstricting eicosanoids. We employed laser Doppler flowmetry in urethane-anesthetized rats, together with a local pharmacological blockade approach, to test the relative contribution of cyclooxygenase (COX)-derived prostanoids to the oligemic response following CSD. Administration of the non-selective COX inhibitor naproxen completely inhibited the oligemic response. Selective inhibition of COX-1 with SC-560 preferentially reduced the early reduction in CBF while selective COX-2 inhibition with NS-398 affected only the later response. Blocking the action of thromboxane A2 (TXA2), using the selective thromboxane synthase inhibitor ozagrel, reduced only the initial CBF decrease, while inhibition of prostaglandin F2alpha action, using the selective FP receptor antagonist AL-8810, blocked the later phase of the oligemia. Our results suggest that the long-lasting oligemia following CSD consists of at least two distinct temporal phases, mediated by preferential actions of COX-1- and COX-2-derived prostanoids: an initial phase mediated by COX-1 that involves TXA2 followed by a later phase, mediated by COX-2 and PGF2alpha.

Renal hemodynamic response to l-arginine in uncomplicated, type 1 diabetes mellitus: the role of buffering anions and tubuloglomerular feedback

2012 ◽  
Vol 303 (5) ◽  
pp. F648-F658 ◽  
Author(s):  
Alberto Montanari ◽  
Almerina Biggi ◽  
Aderville Cabassi ◽  
Irene Pelloni ◽  
Filippo Pigazzani ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Filtration Rate ◽  
Critical Role ◽  
Hemodynamic Response ◽  
Tubuloglomerular Feedback ◽  
Critical Determinant ◽  
Renal Hemodynamic ◽  
Type 1 Dm

According to the “tubulocentric” hypothesis of the glomerular hyperfiltration of diabetes mellitus (DM), tubuloglomerular feedback (TGF) is the critical determinant of the related renal hemodynamic dysfunction. To examine the role of TGF in human type 1 DM, 12 salt-replete healthy (C) and 11 uncomplicated DM individuals underwent measurements of glomerular filtration rate (GFR), renal blood flow (RBF), and lithium-derived absolute “distal” sodium delivery (DDNa). Measurements were made during two 3-h infusions of 0.012 mmol·kg−1·min−1 l-arginine (ARG) buffered with either equimolar HCl (ARG.HCl) or citric acid (ARG.CITR). Our hypothesis was that changes in TGF signaling would be directionally opposite ARG.HCl vs. ARG.CITR according to the effects of the ARG-buffering anion on DDNa. Similar changes in C and DM followed ARG.CITR, with declines in DDNa (−0.26 ± 0.07 mmol/min C vs. −0.31 ± 0.07 mmol/min DM) and increases in RBF (+299 ± 25 vs. +319 ± 29 ml·min−1·1.73 m−2) and GFR (+6.6 ± 0.8 vs. +11.6 ± 1.2 ml·min−1·1.73 m−2). In contrast, with ARG.HCl, DDNa rose in both groups ( P = 0.001), but the response was 73% greater in DM (+1.50 ± 0.15 mmol/min C vs. +2.59 ± 0.22 mmol/min DM, P = 0.001). RBF also increased ( P = 0.001, +219 ± 20 ml·min−1·1.73 m−2 C, +105 ± 14 DM), but ΔRBF after ARG.HCl was lower vs. ARG.CITR in both groups ( P = 0.001). After ARG.HCl, ΔRBF also was 50% lower in DM vs. C ( P = 0.001) and GFR, unchanged in C, declined in DM (−7.4 ± 0.9 ml·min−1·1.73 m−2, P = 0.02 vs. C). After ARG.HCl, unlike ARG.CITR, DDNa increased in C and DM, associated with less ΔRBF and ΔGFR vs. ARG.CITR. This suggests that the renal hemodynamic response to ARG is influenced substantially by the opposite actions of HCl vs. CITR on DDNa and TGF. In DM, the association of ARG.HCl-induced exaggerated ΔDDNa, blunted ΔRBF, and the decline in GFR vs. C shows an enhanced TGF dependence of renal vasodilatation to ARG, in agreement with a critical role of TGF in DM-related renal hemodynamic dysfunction.

Interaction of renal prostaglandins with the renin-angiotensin and renal adrenergic nervous systems in healthy subjects during dietary changes in sodium intake

1985 ◽  
Vol 68 (4) ◽  
pp. 387-393 ◽  
Author(s):  
Herbert J. Kramer ◽  
Bruno Stinnesbeck ◽  
Georg Klautke ◽  
Jochen Kipnowski ◽  
Dietrich Klingmueller ◽  
...  
Keyword(s):  
Nervous System ◽  
Renal Function ◽  
Urinary Excretion ◽  
Healthy Subjects ◽  
Sodium Intake ◽  
Renin Angiotensin ◽  
Low Sodium ◽  
Renal Prostaglandins ◽  
Adrenergic Nervous System

1. In six healthy subjects the role of renal prostaglandins (PG) in modulating the actions of the renin-angiotensin and renal adrenergic nervous systems on renal function was investigated. 2. During high dietary sodium intake (350 mmol/day) for 4 days no changes in urinary excretion of PGE2, PGF2α, noradrenaline or adrenaline were noted, whereas plasma renin activity (PRA) and urinary aldosterone excretion were suppressed. 3. After 4 days of low sodium intake (35 mmol/day) urinary excretion of PGE2, aldosterone and noradrenaline, as well as PRA, had significantly increased. 4. Inhibition of PG synthesis with indomethacin (2 mg/kg body weight) had no effects on renal function on day 5 of high sodium intake. Despite suppression of PRA and urinary aldosterone, indomethacin significantly reduced p-aminohippurate (PAH) clearance, glomerular filtration rate (GFR) and urinary sodium excretion on day 5 of low sodium intake, when urinary noradrenaline excretion remained high. 5. The results point to the crucial role of the renal adrenergic nervous system in controlling renal vascular resistance and sodium conservation in healthy subjects during low sodium intake, which is unmasked when renal PG synthesis is blocked by indomethacin. Enhanced renal PG synthesis during sodium restriction therefore not only attenuates the vascular and tubular effects of the renin-angiotensin system but, more importantly, also those of the highly stimulated renal adrenergic nervous system.

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