Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, Michigan 48202-2689
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ABSTRACT |
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Cyclooxygenase (COX)-2 is in the macula densa, cosegregating with neuronal nitric oxide synthase (nNOS). It is hypothesized that in response to acute inhibition of NOS, the influence of COX-2-derived prostanoids is exaggerated, compensating for renal vasoconstriction. Blood pressure (BP) and renal blood flow (RBF) were measured after selective COX-2 inhibition with NS-398 followed by NOS inhibition with L-nitro arginine methyl ester (L-NAME) or after L-NAME followed by NS-398. BP was 106 ± 4 mmHg and was unaffected by NS-398. L-NAME after NS-398 increased BP by 27 ± 2 mmHg, decreased RBF by one-half, and doubled renal vascular resistance (RVR; P < 0.001). Initial L-NAME increased BP by 26 ± 3 mmHg (P < 0.001) and decreased RBF by 44% (P < 0.001), doubling RVR. After L-NAME, NS-398 induced a further 7 ± 3-mmHg rise in BP (P < 0.05), decreased RBF by 20% (P < 0.025), and increased RVR by 23% (P < 0.01). The constrictor response to COX-2 inhibition after L-NAME could not be duplicated by either selective nNOS inhibition or NOS-independent renal vasoconstriction. Acute NOS inhibition unmasked renal vasoconstriction with COX-2 inhibition, suggesting that the influence of COX-2-derived vasodilator eicosanoids is exaggerated to maintain renal perfusion, compensating for the acute loss of NO.
renal blood flow; prostaglandins; neuronal nitric oxide synthase; endothelial nitric oxide synthase; renal vasoconstriction
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INTRODUCTION |
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VASODILATOR PROSTANOIDS, the products of cyclooxygenase (COX) metabolism of arachidonic acid, regulate renal hemodynamics and excretion (7, 10). There are two separate isoforms of COX, the constitutive prostaglandin (PG)H2/G2 synthase COX-1 and the inducible PGH2/G2 synthase COX-2 (6, 7). COX-1 exists in the cortex in glomerular epithelial and mesangial cells and vascular endothelium, but not in the macula densa (22). Although COX-2 is generally considered to respond to inflammatory stimuli, in the renal cortex it can be found in the thick ascending limb of the loop of Henle in and near the macula densa (9), suggesting that it might be involved in feedback regulation of renal resistance. Harris et al. (8), using in situ hybridization, reported that dietary sodium restriction stimulated cortical renin and induced COX-2 in the rat kidney. COX-2 exists constitutively in the macula densa, and sodium restriction induces greater COX-2 expression there and in adjacent epithelial cells of the thick ascending limb (7, 8). However, although COX-2 has been reported not to be found in the arterioles, glomeruli, or cortical or medullary collecting ducts (7), COX-2 has also been reported to be a major source of renal and vascular endothelial prostacyclin synthesis (16). On balance, the differential localization of COX isoforms in the cortical vasculature suggests that although COX-1 products are candidates for direct regulation of renal vascular tone, the role of COX-2-derived products in controlling vascular resistance, through macula densa feedback or, more directly, from the endothelial cells, is an area of controversy.
It has been suggested (18) that various vasodilator systems can compensate for the loss of endogenous vasodilator tone that results from the inhibition or deletion of nitric oxide (NO). Many of the same signals that stimulate COX production of endothelium-derived prostacyclin also stimulate endothelial NO synthase (eNOS). The similar dilator properties of NO and prostacyclin suggest some degree of interaction. However, the concurrent regulation of renal vascular tone by products of NOS and COX has not been well defined. Baylis et al. (1), using conscious rats, showed that a pressor dose of the nonselective NOS inhibitor L-nitro arginine methyl ester (L-NAME) provoked renal vasoconstriction, which was further amplified by COX inhibition. Blocking the thromboxane receptor had no effect on this response (1). Similarly, NOS inhibition with L-NAME for 5 wk also produced renal vasoconstriction, and this could be amplified further by indomethacin. Baylis et al. suggested that although there are no obvious interactions between COX products and NO under normal conditions, acute or chronic inhibition of NOS could cause significant renal vasoconstriction and lead to compensatory renal vasodilatation mediated by dilator COX products.
The present study hypothesized that in the absence of renal NO, the influence of COX-2-derived prostanoids in the kidney is exaggerated, blunting renal vasoconstriction. In the normal anesthetized rat, the COX-2-selective inhibitor NS-398 has no significant effect on blood pressure (BP) or renal blood flow (RBF) (5), suggesting that COX-2 products have no appreciable influence on renal hemodynamics. However, it is proposed that pretreatment with the nonselective NOS inhibitor L-NAME, which induces acute hypertension and renal vasoconstriction, changes the role of COX-2 so that it buffers the constrictor response to inhibition of NOS activity. Thus, under these conditions, COX-2 produces dilator PGs that compensate for renal vasoconstriction in the absence of NO. Thus selective inhibition of COX-2 after NOS inhibition should provoke further renal vasoconstriction.
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METHODS |
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Male Sprague-Dawley rats (250-400 g; Charles River Laboratory, Wilmington, MA) fasted overnight but were allowed free access to water. They were anesthetized with thiobutabarbital (125 mg/kg body wt ip; Inactin, Sigma, St. Louis, MO), placed on a heating pad to maintain constant body temperature, and given a tracheotomy with PE-240 tubing to facilitate spontaneous breathing of room air. The femoral vein was catheterized with PE-50 tubing for maintenance infusion of 40 µl/min of 0.9% NaCl. The femoral artery was catheterized with PE-50 tubing attached to a Statham pressure transducer (Viggo-Spectramed, Oxnard, CA) and a Gould recorder (Gould Instruments, Valley View, OH) for continuous monitoring of BP and heart rate (HR). The pressure transducer was calibrated with a mercury manometer.
A midventral incision was made in the abdominal cavity, the intestines
were wrapped in moist gauze and folded under the right ventral wall,
and the left renal vein and artery were dissected from the surrounding
tissues. A noncannulating electromagnetic flow probe with an internal
circumference of 1.5 mm (Carolina Medical Electronics, King, NC) was
placed on the renal artery. The probe was calibrated by direct
cannulation of the renal artery and by gravimetric determination of
blood flow over timed intervals. After surgery, the rats received a
bolus of 1.0 ml of 6% heat-inactivated BSA (Sigma) in normal saline
and were allowed to stabilize for 60 min. BP (mmHg) was derived from
the electronic integrated mean, although HR [beats/min (bpm)] was
recorded at timed intervals while the damping was turned off. RBF was
obtained from the flowmeter signal and normalized by dividing by kidney
weight (ml · min1 · g kidney
wt
1). Renal vascular resistance (RVR) was calculated by
dividing renal perfusion pressure by corrected RBF
(mmHg · ml
1 · min · g kidney
wt
1), hereafter referred to as resistance units (RU).
When the experiments were completed, the rats were killed by
pneumothorax and aortic transection, and the kidneys were
decapsulated, excised, and weighed for normalization of RBF.
The first protocol consisted of two sets of experiments (n = 9 rats/group), measuring BP and renal hemodynamics before and after a sequence of two drug challenges. The rats were treated with an acute blocking dose of the selective COX-2 inhibitor NS-398 (0.94 µg/kg body wt; Cayman, Ann Arbor, MI). Once values before and 30 min after COX-2 inhibition were established, the NOS inhibitor L-NAME (10 mg/kg body wt iv; Sigma) was administered and measurements were taken before and 15-20 min after treatment. In the second group of rats, the sequence was reversed; L-NAME was given first, followed 10-15 min later by NS-398.
In the second protocol, using six rats, the effects of COX-2 inhibition after NOS inhibition were tested to determine whether they are due specifically to interruption of neuronal NOS (nNOS)-derived NO. For this, a blocking dose was administered of the selective nNOS inhibitor 7-nitroindazole (7-NI; Biomol, Plymouth Meeting, PA) in a bolus (50 mg/kg body wt ip) suspended in peanut oil vehicle, a dose that has been shown to selectively inhibit nNOS activity without affecting eNOS (2, 17). After 45 min, NS-398 was administered and renal and systemic hemodynamics were measured before and 30 min after treatment.
In the third protocol, the mechanical reduction in RBF seen after L-NAME administration was tested to determine whether it could account for the hemodynamic changes seen after COX-2 inhibition, independent of NOS inhibition. To do this, renal perfusion was reduced to a level comparable to L-NAME treatment in six rats (RBF 30-40% below the resting baseline) by using a suprarenal aortic occluding loop made of 3-0 silk contained in a sleeve made of PE-160 flame-flared tubing. Blood flow was reduced for 10 min before administration of NS-398 and maintained for 30 min afterward. A carotid arterial line was monitored to measure BP above the occluding loop so that both renal perfusion pressure and suprarenal systemic BP could be monitored. A comparison was made of hemodynamic measurements before and 30 min after administration of NS-398 while RBF was reduced.
Paired Student's t-tests were used to evaluate treatment-induced changes (with NS-398 or vehicle) within each group, and protocol groups were compared by using an unpaired Student's t-test. P < 0.05 was considered significant.
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RESULTS |
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Response to COX-2 inhibition before L-NAME.
Basal BP in nine untreated rats was 106 ± 4 mmHg. Treatment with
NS-398 had no significant effect on BP (Fig.
1). Basal RBF was 8.70 ± 0.77 ml · min1 · g kidney
wt
1. NS-398 treatment marginally increased RBF by 7 ± 2% (P < 0.05). Basal RVR was 12.89 ± 1.10 RU
and was unchanged by NS-398 (Fig. 1). Basal HR of 329 ± 7 bpm was
unchanged by NS-398. Subsequent treatment with L-NAME
(after NS-398) increased BP by 27 ± 2 mmHg (P < 0.001) to 131 ± 5 mmHg and decreased RBF by one-half to 5.24 ± 0.37 ml · min
1 · g kidney
wt
1 so that RVR more than doubled (25.90 ± 1.79 RU,
P < 0.001), and it also reduced HR by 41 bpm
(P < 0.01). These values were not changed further by
an additional 30 min of vehicle infusion (Fig. 1).
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Response to COX-2 inhibition after L-NAME.
Basal BP in nine untreated rats was 100 ± 2 mmHg. Treatment with
L-NAME (Fig. 1) increased BP by 26 ± 3 mmHg
(P < 0.001), reduced HR by 60 ± 12 bpm
(P < 0.01), and reduced RBF by 44% [from 9.43 ± 0.62 to 5.31 ± 0.41 ml · min1 · g kidney wt
1
(P < 0.001)] so that RVR more than doubled (from
10.91 ± 0.80 to 24.60 ± 1.80 RU, P < 0.001). These changes were all similar to the changes induced by
L-NAME after rats were treated with NS-398.
Response to COX-2 inhibition after 7-NI.
Basal BP was unchanged 45 min after 7-NI administration (101 ± 4 mmHg), HR was 295 ± 10 bpm, RBF was 6.81 ± 0.24 ml · min1 · g kidney wt
1,
and RVR was 15.11 ± 0.69 RU. Thirty minutes after NS-398
administration, none of these parameters had changed significantly
(Fig. 2). BP was 95 ± 4 mmHg, HR
was 277 ± 10 bpm, RBF was 6.34 ± 0.35 ml · min
1 · g kidney wt
1,
and RVR was 15.26 ± 0.92 RU. Thus selective nNOS inhibition did
not provoke any of the hemodynamic responses to NS-398 seen after
nonselective NOS inhibition with L-NAME.
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Response to COX-2 inhibition after reduced RBF.
BP was 100 ± 3 mmHg, HR was 297 ± 9 bpm, RBF was 9.01 ± 0.73 ml · min1 · g kidney
wt
1, and RVR was 11.57 ± 1.03 RU. Aortic
constriction reduced RBF by 37% to 5.64 ± 0.25 ml · min
1 · g kidney wt
1.
BP above the occluder rose by 19 ± 3 mmHg (P < 0.005), but renal perfusion pressure was reduced to 62 ± 2 mmHg
by the suprarenal aortic constriction. RVR was unchanged by
constriction (11.02 ± 0.58 RU). Addition of NS-398 had no further
effect (Fig. 2) on BP (116 ± 5 mmHg), RBF (5.72 ± 0.28 ml · min
1 · g kidney wt
1),
or RVR (10.40 ± 0.68 RU). HR was unchanged by any of these manipulations (300 ± 14 bpm). Thus reducing renal perfusion and increasing systemic BP to the same degree as with L-NAME
did not unmask any similar pressor or renal vasoconstrictor response to subsequent COX-2 inhibition.
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DISCUSSION |
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This study hypothesized that acute inhibition of NOS with L-NAME would unmask compensatory renal vasodilatation by COX-2 prostanoid products so that selective COX-2 inhibition would result in renal vasoconstriction. Similar to a previous report from this laboratory (5), it was found that NS-398 did not alter BP in the controls and that there was no significant effect on RVR. However, if NOS was first blocked with L-NAME, a significant systemic pressor and renal vasoconstrictor response to selective COX-2 inhibition was unmasked, which is similar to previous reports employing nonselective COX inhibition (1). From this, one might conclude that the primary compensatory vasodilator effects buffering L-NAME-induced renal vasoconstriction are COX-2-derived prostanoids.
The interactions between NO and COX are a topic of considerable controversy. On one hand, NO could inhibit the production of dilator prostanoids. Kosonen et al. (12) found that NO donors inhibited lipopolysaccharide-stimulated COX-2 production of prostacyclin from endothelial cells without affecting the level of COX-2 expression, suggesting that NO may be an important regulator of endothelial COX-2 activity. McAdam et al. (16) reported that selective COX-2 inhibition in normal volunteers resulted in reduced circulating and excreted metabolites of prostacyclin and suggested that COX-2 is a major source of systemic and renal vasodilator prostacyclin biosynthesis in normal humans. Baylis et al. (1) suggested that NO inhibition could "lead to a permissive increase in synthesis of vasodilatory COX products" either as a direct effect of removing NOS or, more generally, in response to reduced renal perfusion, which would be reflected in the additional constrictor effect seen with inhibition of, first, NOS and then COX.
On the other hand, NO could stimulate COX (19) and the synthesis of dilator PGs. In contrast to the renal response to selective COX-2 inhibition reported in the present study, chronic NOS inhibition has been found to enhance production of the endothelium-derived vasodilator prostacyclin in coronary arteries through upregulation of COX-1 (3). Similarly, enhanced release of PGs contributes to flow-induced arteriolar dilatation in eNOS knockout mice (23). Using in vitro preparations of either macrophages or fibroblasts from COX knockout mice, Clancy et al. (4) found that exogenous NO stimulated COX-1-mediated PGE2 production, but NO tended to inhibit COX-2-mediated PGE2 synthesis. They suggested that NO might exert selective and different (stimulatory and inhibitory) effects on the activity of either COX isoform. These responses may also differ depending on the length of the studies involved. However, overall the data presented above suggest that NO may tend to stimulate COX-1 activity but inhibit COX-2, findings generally in keeping with our results. Therefore, if NO is removed from the scheme, one might expect the dilator effects of COX-2-derived PGs on RVR and even BP would be enhanced.
Is there physiological evidence for enhanced activity of COX-derived prostanoids in response to reducing NO? COX-related adaptive compensation for diminished NO synthesis has been documented (26). Acetylcholine-induced dilatation of the coronary circulation, normally attributed to endothelium-derived NO, is preserved in the eNOS knockout model by apparent compensatory upregulation of both COX products and nNOS-derived NO (27). Compensatory vasodilator adaptation induced by PGs and endothelium-derived hyperpolarizing factor has been reported to accommodate normal blood flow in the coronary resistance vessels of the eNOS knockout mouse, as well as dilatation of mesenteric and skeletal muscle arterioles induced by endothelium-derived hyperpolarizing factor and dilator PGs (23). These reports suggest that dilator PGs can compensate for the loss of NO-mediated vasodilatation, which is presumably regulated by eNOS. In the present data, the hemodynamic responses to COX-2 inhibition seen after nonselective NOS blockade could not be duplicated by selective nNOS inhibition, supporting the likelihood that eNOS is responsible for this interaction.
This laboratory has previously reported that neither acute nor chronic NS-398 treatment (over a period of 14 days) in rats given either normal sodium or a sodium-restricted diet had any effect on BP, HR, RBF, or RVR (5). The present data support those earlier observations. Baylis et al. (1) reported that nonselective COX inhibition produced acute renal vasoconstriction only after acute or chronic NOS inhibition with L-NAME but had no effect under control conditions. Although subpressor doses of L-NAME did not unmask any hemodynamic effects of indomethacin, after a full blocking (pressor) dose of L-NAME, they found that subsequent nonspecific COX inhibition with indomethacin produced a further 8-mmHg increase in BP and exaggerated the increase in RVR, which is similar to what is reported here. On the basis of this, they suggested that enhanced prostanoid-mediated renal dilatation occurred only in the absence of NO (1). The present data with NS-398 are similar and support this observation, but they further demonstrate that the responses can be attributed to COX-2. Ichihara et al. (9) found that in a blood-perfused juxtaglomerular nephron preparation, COX-2 inhibition had no effect on afferent arteriolar diameter, whereas acetazolamide [which enhances tubuloglomerular feedback (TGF)-mediated changes] unmasked afferent vasoconstriction of 17% after COX-2 inhibition. They suggested that when TGF vasoconstriction is enhanced, COX-2 is upregulated to buffer this activity, possibly accompanied by changes in TGF function and regulation of afferent arteriolar resistance. Rodriguez et al. (20) reported that selective COX-2 inhibition had no effect on renal hemodynamics in normal dogs but, after 6 days of sodium restriction, selective inhibition of COX-2 increased BP by 10 mmHg and decreased both RBF and GFR by 22%. Because of the location of COX-2 in the macula densa, it could be assumed that the neuronal isoform of NOS in the macula densa might be responsible for NO interaction with COX-2. However, selective COX-2 inhibition lowers (endothelium-derived) circulating prostacyclin levels, suggesting a vascular origin. The present findings with selective nNOS inhibition do not support a role for a macula densa-mediated response and suggest that COX-2 most likely interacts with NO from eNOS.
Vasodilator COX products can be rapidly activated in response to renal vasoconstriction (26). Decreased renal perfusion is a strong signal for COX induction, because COX-2 is upregulated in the (ischemic) clipped kidney of two-kidneys, one-clip renovascular hypertensive rats but downregulated in the contralateral, perfused kidney (15, 25). It is not clear whether the increased vasodilator influence of COX-2 products seen after NOS inhibition is due to the removal of an endogenous inhibitory NO signal or merely to the reduction in renal perfusion seen after L-NAME administration. However, when the decrease in RBF was duplicated and systemic pressure was increased without inhibiting NOS, NS-398 did not elicit any pressor or renal vasoconstrictor responses, suggesting that the increase in COX-mediated vasodilatation is likely due to interaction with NO rather than just an adaptive hemodynamic response to mechanically reduced perfusion.
These data suggest that removal of eNOS-derived NO is permissive for increased activity or influence of COX-2-generated dilatory PGs, possibly endothelium-derived prostacyclin (16). Neither the pathway by which this occurs, by disinhibiting COX-2 or by stimulating increased PG synthesis as a result of NOS inhibition, nor the mechanism by which NO and COX-2 interact can be derived from the present studies.
In summary, the present data suggest that under resting conditions, COX-2 products have no measurable influence over basal renal hemodynamics or BP, but elimination of the vasodilator influence of NO results in a consistently and significantly compensatory vasodilator response by COX-2 products, which buffers the vasoconstrictor tone resulting from the absence of NOS activity. Furthermore, the present data do not support a specific effect of nNOS but rather imply that the dilator effect of COX-2-derived prostanoids (likely from the vasculature) is in response to the loss of eNOS-derived NO and its intrinsic dilator tone.
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ACKNOWLEDGEMENTS |
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The author acknowledges the technical assistance of D'Anna Potter.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grant HL-28982.
Address for reprint requests and other correspondence: W. H. Beierwaltes, Hypertension and Vascular Research Division, 7121 E & R Bldg., Henry Ford Hospital, 2799 West Grand Blvd., Detroit, MI 48202-2689 (E-mail: wbeierw1{at}hfhs.org).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published February 12, 2002;10.1152/ajprenal.00364.2001
Received 13 December 2001; accepted in final form 8 February 2002.
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