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...

Role of COX-2-derived metabolites in regulation of the renal hemodynamic response to norepinephrine. Am J Physiol Renal Physiol 281: F975-F982, 2001.-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 ng⅐kg Ϫ1 ⅐min Ϫ1) 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 ϭ 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 ϭ 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 ϭ 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 ϭ 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 ϭ 5) induced a fall in GFR (64 and 92%) and an increase in RVR (174 and 2,293%) that were greater (P Ͻ 0.05) than those induced by NE in vehicle-pretreated dogs. The elevation in the urinary excretion rates of PGE 2 and 6-keto-PGF1␣ 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. renal function; glomerular filtration rate; renal vascular resistance; prostaglandins; cyclooxygenase-2 IT IS WELL KNOWN THAT ENDOGENOUS prostaglandins (PG) play an important role in regulating renal function when vasoconstrictor levels are elevated (1-3, 6, 14, 15, 18, 22). This notion is supported by studies showing that norepinephrine (NE) infusion induces an increment in renal synthesis of PG (5, 15) and that the renal vasoconstriction induced by NE is significantly potentiated when synthesis of PG is reduced (1, 2, 15). Finally, it has been reported that PGI 2 infusion reduces the renal vasoconstriction elicited by NE (3,14).Several studies have shown that both cyclooxygenase (COX) isoforms are constitutively expressed in the kidney and that the intrarenal loc...

. Role of nitric oxide and cyclooxygenase-2 in regulating the renal hemodynamic response to norepinephrine. Am J Physiol Regul Integr Comp Physiol 284: R488-R493, 2003. First published September 19, 2002 10.1152/ajpregu.00449.2002We have reported that the renal hemodynamic effects of norepinephrine (NE) are modulated by cyclooxygenase-2 (COX-2)-derived metabolites. Our main objective was to examine whether there is an interaction between nitric oxide (NO) and COX-2 in modulating the renal hemodynamic effects of NE. NE was infused at three doses to anesthetized dogs pretreated with vehicle (n ϭ 8), a selective COX-2 inhibitor (nimesulide) (n ϭ 6), an NO synthesis inhibitor [N G -nitro-L-arginine methyl ester; L-NAME] (n ϭ 8), or with nimesulide and L-NAME (n ϭ 5). During NE infusion, PGE 2 excretion increased (125%) in the control group and did not change in the L-NAME-treated dogs. The simultaneous inhibition of NO and COX-2 potentiated to a greater extent the NE-induced renal vasoconstriction than inhibition of either NO or COX-2. The NE-induced renal vasoconstriction during NO and COX-2 inhibition was reduced (P Ͻ 0.05) by infusing an AT 1 receptor antagonist (n ϭ 6). These results suggest that there is an interaction between NO and COX-2 in protecting the renal vasculature from the NE effects and that angiotensin II partly mediates the NEinduced renal vasoconstriction when NO synthesis and COX-2 activity are reduced. renal adrenergic system; cyclooxygenases; AT 1 receptors antagonist; kidney THE RENAL VASOCONSTRICTION elicited by norepinephrine (NE) seems to be modulated by nitric oxide (NO) and 12,14,20). The role of PG is supported by studies showing that NE infusion led to an increment in renal PG synthesis (12,14) and that the NE-induced renal vasoconstriction is potentiated when PG synthesis is reduced (6,12,14,20). It has been proposed that the PGs involved in modulating the renal effects of NE are mainly derived from cyclooxygenase-2 (COX-2) (14). The importance of NO has been indicated in studies demonstrating that the renal vasoconstriction elicited by NE is significantly enhanced when NO production is reduced (7,8). On the other hand, it has been suggested that NO enhances COX-2 activity (3,11,24,26). Taking together the studies previously mentioned, it may be proposed that the NE increment in COX-2 activity is mediated by NO. However, it remains to be examined whether this hypothesis is correct.This study evaluates whether NE enhances the production of COX-2-derived metabolites through an NOdependent mechanism and whether the simultaneous inhibition of NO synthesis and COX-2 potentiates the renal hemodynamic effects of NE to a greater extent than the inhibition of either NO synthesis or COX-2 activity. The hypotheses were that 1) NO is involved in the NE-induced increase in COX-2 activity and 2) the simultaneous inhibition of NO synthesis and COX-2 will potentiate more the NE-induced renal vasoconstriction than the inhibition of either NO synthesis or COX-2. If the second hypothesis is correct, t...

Contrary to the important role of COX-2 in the long-term regulation of renal haemodynamics, the metabolites derived from COX-2 seem to be only involved in the acute regulation of renal excretory function.

The aim of the present study was to assess the role of vascular alpha 1D-adrenoceptors in the sympathetic vasopressor response in vivo. Specifically, we evaluated the effect of a selective alpha 1D-adrenoceptor antagonist, BMY 7378 (8-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-8-azaspiro(4,5)dec ane-7,9- dione 2HCl), on the vasopressor response induced by preganglionic (T7-T9) sympathetic stimulation in the pithed rat. The vasopressor response was dose-dependently sensitive to inhibition by intravenous BMY 7378 (0.1, 0.31, 1 and 3.1 mg/kg), doses of 1 and 3.1 mg/kg being equally effective. Like BMY 7378, 5-methylurapidil (0.1, 0.31, 1 and 3.1 mg/kg) antagonized the vasopressor response to spinal stimulation; doses of 1 and 3.1 mg/kg were also equally effective. In combination experiments, BMY 7378 (1 mg/kg, i.v.) and the alpha 1A-adrenoceptor antagonist, 5-methylurapidil (1 mg/kg, i.v.), showed an additive effect. The present results demonstrate that the alpha 1D-adrenoceptor subtype plays an important role in the pressor response to sympathetic nerve stimulation in the pithed rat, and confirm the participation of the alpha 1A-adrenoceptor subtype in the same response.

In this study, we aimed to elucidate whether the daily hypertensive dose of long-term N(G)-nitro-l-arginine methyl ester (l-NAME) treatment, could make a difference between endothelial and smooth muscle functions in rat thoracic aorta. We test the hypothesis that high-dose, long-term l-NAME treatment has a depressive effect on vascular smooth muscle contractile activity which is not related with nitric oxide (NO) synthesis inhibition. After 14 days of treatment, isometric tension and (45)Ca(2+) influx were measured in aortic tissues isolated from l-NAME(10) and l-NAME(100) hypertensive (10 and 100 mg/kg/day, systolic blood pressures 167 +/- 7 and 172 +/- 10 mmHg, respectively) and control normotensive rats (132 +/- 7 mmHg). In l-NAME(10)- and l-NAME(100)-treated rats, acetylcholine-induced relaxation in aortic rings was suppressed with no significant difference between the treatments. l-NAME(100) (but not l-NAME(10)) treatment, significantly inhibited contractile responses to phenylephrine, angiotensin II, and K(+) (80 mm) in endothelium-intact tissues. The effect of l-NAME(100) on phenylephrine-induced contractile responses was not observed after 3 days of treatment. In endothelium-denuded aortic tissues of l-NAME(100) (but not l-NAME(10))-treated rats, phenylephrine (1 x 10(-6) m)- and K(+) (80 mm)-induced contractions and (45)Ca(2+) influxes were significantly reduced. In Ca(2+)-free medium (0.1 mm EDTA), on the contrary, the transient contractions obtained by either phenylephrine (1 x 10(-6) m) or caffeine (1 x 10(-2) m), or the sustained contractions induced by 12-o-tetradecanoylphorbol-13-acetate (1 x 10(-6) m; a protein kinase C activator) in endothelium-denuded aortic rings, were not modified by both l-NAME treatments. These results indicate that in aortic rings from l-NAME hypertensive rats, low and high doses, long-term l-NAME administration may be associated with equivalent inhibition in NO-dependent vasodilator tone (corresponding to equivalent hypertension values); whereas only high-dose, long-term l-NAME administration produces an endothelium-independent decrease in vasocontrictor activity, at least partly explained by a reduction in extracellular Ca(2+) influx.

In rat aorta, the presence of functional alpha(2)-adrenoceptors (alpha(2)-AR) was investigated in ring preparations preconstricted with alpha(1)-adrenergic and non- alpha(1)-adrenergic agonists. Particularly, the hypothetical interference of alpha(2)-AR agonists with alpha(1)-AR-mediated vasoconstriction was evaluated. Relaxant and contractile responses to alpha(2)-AR agonists were obtained. In endothelium-intact and endothelium-denuded aortic rings preconstricted with phenylephrine (1 x 10(-6) m), the imidazoline derivatives, clonidine and UK14304, induced relaxations with similar order of potencies (-log EC(50)) and maxima relaxant effects respectively. Pretreatment with the NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME) had no effect on the relaxant responses to clonidine and UK14304. In phenylephrine-constricted rings with endothelium, relaxations to clonidine and UK 14304 were not antagonized by the selective alpha(2)-AR antagonist, rauwolscine (< or =1 x 10(-6) m). Clonidine and UK 14304 induced only contractions on endothelium-intact and endothelium-denuded aortic rings contracted with prostaglandin F(2alpha) (3 x 10(-7) m). Moreover, clonidine and UK 14304-induced relaxation of endothelium-denuded arteries precontracted with methoxamine but not with serotonin. Finally, the concentration-contraction curves to clonidine and UK 14304 in endothelium-denuded aortic rings were significantly shifted to the right by the alpha(1D)-AR selective antagonist, BMY 7378, and rauwolscine. The pA(2) and pK(B) values for BMY 7378 and rauwolscine, respectively, against endothelium-independent actions of clonidine and UK 14304 were characteristic of an effect on the alpha(1D)-AR. The other selective alpha(2)-AR agonist tested BHT 933 (an azepine derivative), lacks considerable relaxant and contractile effects in rat aorta. The results provide no evidence for the presence of functional alpha(2)-AR in rat aorta. Respectively, the relaxant and contractile effects of the imidazoline derivatives, clonidine and UK 14304, may be due to an adjustable (in relation to the agonist-dependent active state of the alpha(1)-AR), inhibitory and excitatory, interaction with alpha(1)-ARs.

The mechanism whereby an infusion of amino acids (AA) leads to increments in glomerular filtration rate (GFR) and renal plasma flow (RPF) is incompletely understood. Dopamine (DA) is a catecholamine in which known actions at low doses include the ability to increase both GFR and RPF. Furthermore, urinary DA excretion has been shown to be augmented after an oral protein load. We therefore studied the renal hemodynamic response to intravenous infusion of a 10% mixed AA solution in anesthetized euvolemic Wistar-Furth rats in the presence or absence of specific DA1 [Sch 23390 (SCH)] and DA2 [S-sulpiride (S-SP)] receptor antagonists. Infusion of AA in vehicle-pretreated rats resulted in a 28 +/- 8% increase in GFR and a 29 +/- 6% increase in effective ERPF over baseline values. Administration of AA in the presence of SCH also resulted in elevations in both GFR and ERPF by 23 +/- 3% and 26 +/- 6%, respectively. In contrast, when AA were given in the presence of S-SP, the rise in both GFR and ERPF was completely prevented. To examine whether the AA-induced hyperfiltration was due to DA release from renal nerves or enhanced renal tubule DA synthesis, we administered AA to rats in which the left kidney had been chronically denervated while the right kidney remained intact. Infusion of AA led to significant increments in GFR (33 +/- 4%) and ERPF (34 +/- 7%) only in the intact control kidney, whereas GFR and ERPF remained unaltered in the denervated kidney.(ABSTRACT TRUNCATED AT 250 WORDS)