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Am J Physiol Renal Physiol 293: F860-F867, 2007. First published June 13, 2007; doi:10.1152/ajprenal.00510.2006
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Short-term ANG II produces renal vasoconstriction independent of TP receptor activation and TxA2/isoprostane production

Øyvind B. Vågnes,1 Bjarne M. Iversen,3 and William J. Arendshorst1,2

1Department of Cell and Molecular Physiology, 2Carolina Center for Vascular Biology and UNC Kidney Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and 3Renal Research Group, Institute of Medicine and Haukeland University Hospital, University of Bergen, Bergen, Norway

Submitted 20 December 2006 ; accepted in final form 10 June 2007


   ABSTRACT
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 ABSTRACT
METHODS
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 DISCUSSION
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 REFERENCES
 
The relative contributions of vasoconstrictor and of dilator systems are balanced in health. The balance is reset in disease, often favoring a predominant role of vasoconstrictors, perhaps due to positive interactions between constrictor systems. For example, in hypertension, chronic high levels of angiotensin II (ANG II) stimulate the production of thromboxane (TxA2/PGH2) and/or isoprostane that activate constrictor thromboxane prostanoid (TP) receptors in the vasculature. The present study evaluated a modest concentration of ANG II administered acutely into the renal artery on urinary excretion of TxB2 and isoprostane and possible renal TP receptor activation that might amplify ANG II-induced renal vasoconstriction. TP receptors were blocked with SQ29548 coinfused with ANG II. Results were compared with a time control group of continuous ANG II infusion (40 ng·min–1·kg body wt–1) over 90 min. TP receptor antagonism during 30–60 min had no effect on the reduction in renal blood flow (RBF) produced by ANG II (15.8 ± 2.8 vs. 13.2 ± 4.9%) (P > 0.6). Likewise, there was no difference between groups during ANG II-induced renal vasoconstriction between 60–90 min in presence or absence of TP receptor antagonist (RBF –8.6 ± 4.0 vs. –9.6 ± 4.5%) (P > 0.8). Systemic arterial pressure was stable throughout, so RBF changes reflected localized changes in renal vascular resistance. Urinary excretion of TxB2 and isoprostane were nearly doubled by ANG II. The present data indicate that short-term intrarenal infusion of ANG II rapidly increases renal production of TxA2 but that the ANG II-induced renal vasoconstriction is independent of TP receptor activation during the initial 90 min of local challenge with ANG II.

kidney; renal circulation; glomerular arterioles; renin-angiotensin system; prostanoids; oxidative stress; isoprostane

RENAL HEMODYNAMIC REGULATORY mechanisms play an important role in maintaining glomerular function, salt and water balance, and arterial pressure (AP). Renal vascular resistance (RVR) is controlled by a balance of vasoconstrictor and dilatory stimuli in health, with the vasoconstrictor agents predominating in many disease states. For example, in genetic hypertension in the spontaneously hypertensive rat (SHR), exaggerated renal vasoconstriction is seen in response to ANG II, a response primarily due to defective buffering of vasodilator prostanoids (12, 14, 24, 40). On the other hand, higher expression of a G protein-coupled receptor such as thromboxane prostanoid (TP) and vasopressin (V1) receptors can account for the ability of thromboxane A2 (TxA2) and vasopressin, respectively, to produce more pronounced renal vasoconstriction in young SHR (11, 13, 18, 48). In long-standing established hypertension, there are significant potentiating interactions among vasoconstrictor systems. In this regard, chronic increases in ANG II are known to stimulate production of TxA2/PGH2 with subsequent constriction-mediated TP receptors as well as angiotensin AT1 receptors. In ANG II-induced hypertension, ANG II increases urinary excretion of TxA2 and isoprostane that magnify the constrictor action of each other in the systemic and renal vasculature. After 2 wk of ANG II infusion, pharmacological inhibition of TxA2 synthesis or of TP receptors reduces a majority of the AP increase (34, 54, 55). A similar attenuated AP response to chronic ANG II is seen in TP receptor null mice (20, 28). Similarly, activation of TP receptors contributes to renal vasoconstriction in ANG II- and ANG II-salt-induced hypertension (33, 35). A similar systemic and renal interaction between ANG II and TP receptor activation is found in renovascular hypertension (6, 15, 23, 53). Such long-term interactions between ANG II and TxA2 appear to be involved in the exaggerated renal vasoconstriction resulting from tubuloglomerular feedback control of preglomerular vasomotor tone in SHR (7, 8).

Endogenous TxA2 is thought to exert considerably less influence on AP and RVR in health, at least under basal conditions. In normotensive animals, TxA2 levels are low and their tonic influence on basal renal and systemic hemodynamics is negligible. This conclusion is based on findings that inhibition of TxA2 synthesis or blockade of TP receptors has little influence on AP and/or renal blood flow (RBF) in healthy normotensive rats, especially when plasma ANG II is normal or low (21, 22, 31, 33, 35, 58). Also, basal levels of TxA2 contribute little to tubuloglomerular feedback-induced renal vasoconstriction in normotensive rats (7). Furthermore, basal RBF and RVR are in the normal range in TP receptor null mice (5).

Under resting conditions, the acute renal vasoconstrictor actions of ANG II are normally buffered, in part, by the vasodilatory prostanoids PGE2 and PGI2. This is evidenced by enhanced ANG II-induced constriction during inhibition of cyclooxygenase (COX) with indomethacin (2, 12, 19, 21, 27, 37). Longer-term ANG II infusion appears to recruit the vasoconstrictor prostanoid TxA2 and perhaps isoprostanes, both acting through the TP receptor.

The dose and duration of short-term ANG II administration required to stimulate TxA2 synthesis and recruit the vascular actions of TxA2 in the kidney are poorly defined. The literature on these acute actions of ANG II in normal animals is mixed. It seems clear that acute (<30 min) ANG II stimulation of isolated arteries/arterioles and glomeruli can lead to increased TxA2 synthesis. In vivo, ANG II infusion at a pressor dose (500 ng·kg–1·min–1 iv for 30 min) increases TxA2 urinary excretion (15, 54). Less ANG II infused systemically (50 ng·kg–1·min–1) results in more variable, nonsignificant responses of absolute TxA2 excretion (56). The extent to which renal excretion of TxA2 is dependent on an increase in systemic AP is not known.

Whether the increased renal synthesis of TxA2 immediately contributes to the renal vasoconstriction produced by acute ANG II in vivo is not clear. Some studies report that inhibition of TxA2 synthesis or TP receptor blockade blunts renal vasoconstriction produced by short-term administration of ANG II infused (10–9 to 10–6 M for 10 min) (9, 10) or injected (10–7 M) (17) into the renal artery of isolated kidneys perfused with artificial solutions. Similar TP-mediated renal vasoconstriction has been reported for intact kidneys in response to pressor doses of ANG II given intravenously (54, 58). Other studies, however, provide more equivocal evidence that does not support a definitive interaction between ANG II and TxA2 in renal hemodynamic responses to ANG II given (10–50 ng·kg–1·min–1 iv for 140 min) in the acute setting in normal animals (15, 33, 35, 56). To our knowledge, no in vivo studies to date have investigated the possibility of interactions during physiological conditions in which ANG II selectively increases RVR independently of changes in systemic AP. We have recently shown that immediate renal vasoconstriction produced by intrarenal administration of ANG II is mediated, in part, by NADPH oxidase and superoxide production (26). Possible acute involvement of isoprostanes was not evaluated.

To this end, the purpose of our present study is to determine whether intrarenal administration of ANG II for durations of 60–90 min at doses that reduce RBF 10–15% of baseline stimulate urinary excretion of the stable TxB2 metabolite of TxA2 and whether TP receptor antagonism attenuates ANG II-induced renal vasoconstriction. An important aspect of our in vivo studies is ANG II infusion directly into the renal artery of normotensive rats to evaluate primary local renal actions independently of any confounding systemic effects. We postulate that short-term ANG II challenge would stimulate TxA2 excretion that, in turn, would cause consistent, discernable renal vasoconstrictor effects when actions are restricted to the kidney and a preparation designed to provide highly reproducible results with minimal variability. TP receptors are antagonized by coinfusion of SQ29548 into the renal artery.


   METHODS
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 METHODS
RESULTS
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Sixteen experiments in all were performed using male Sprague-Dawley rats (6–8 wk of age) from the local breeding colony in accordance with institutional guidelines for the care and use of research animals. The animals were fed a standard lab chow with free access to tap water. They were deprived of food the night before an experiment.

The surgical preparation is standard for acute RBF experiments (4, 13, 25). Briefly, an animal was anesthetized by injection of pentobarbital sodium (65 mg/kg body wt ip) and placed on a heating table that maintained body temperature at 37°C. To ensure free breathing, a tracheostomy was performed and a PE-205 tube was inserted. For measurement of AP and collection of blood, the right femoral artery was cannulated. AP was measured via a pressure transducer (Statham P23B). The right femoral vein was cannulated with catheters (PE-10) for administration of maintenance solutions. Isotonic bovine serum albumin (4.7 g/dl) was infused initially at a rate of 50 µl/min to replace losses associated with surgery (1.25 ml/100 g body wt) and then at 10 µl/min for the duration of an experiment to maintain hematocrit at presurgical levels. A tapered and curved PE-10 catheter was introduced into the left femoral artery and advanced through the aorta until the tip was positioned ~1 mm into the left renal artery. Placement of this catheter did not affect renal blood flow (RBF). A noncannulating flowprobe (1 RB; Transonic, Ithaca, NY) was placed around the left renal artery and filled with ultrasonic coupling gel (HR lubricating jelly; Carter-Wallace, New York, NY). The renal artery catheter was used for injection or infusion of ANG II, the TP receptor agonist U46619 [GenBank] , or the TP receptor antagonist SQ29548 (Cayman Chemical, Ann Arbor, MI).

ANG II was infused into the renal artery at 40 ng·kg–1·min–1 for intervals of 60 or 90 min in three groups of animals. RBF and AP were recorded continuously, using conventional methodology (4, 13, 25). During the final 30 min of ANG II infusion in the two experimental groups, the TP receptor antagonist SQ29548 (180 ng·kg–1·min–1) was coinfused into the renal artery (ira). Reported values were averaged over the final 10 min of each period. No SQ29548 was given to the time control group.

Preliminary studies established that this dose of SQ29548 could reverse ongoing renal vasoconstriction induced by continuous infusion of U46619 [GenBank] into the renal artery. SQ29548 infusion ira for either 30- to 60- or 60- to 90-min was effective in abolishing the renal vasoconstrictor of the TxA2 mimetic. Moreover, the effect was rapidly apparent, within the initial few minutes of SQ infusion. Thus intrarenal administration of the TP receptor antagonist should have been effective if TP receptors were activated during ANG II infusion.

To ensure complete blockade of TP receptors, at the end of an experiment the TP receptor agonist U46619 [GenBank] (400 ng/10 µl) was injected into the renal artery. In each group of the ANG II infusion studies, the lack of RBF change in response to U46619 [GenBank] (400 ng/10 µl ira) challenge after each SQ29548 infusion period was confirmed; the results consistently indicated >95% blockade. The employed infusion of SQ29548 into the renal artery is similar to that infused intravenously to block the renal vasoconstriction and reduced GFR produced by intravenous infusion of the TP receptor agonist U46619 [GenBank] (56).

The ureter of the left kidney was cannulated with a PE-10 tube to collect urine during control and experimental periods. Urine was assayed for the stable thromboxane metabolite TxB2, prostacyclin (stable 6-keto-PGF1{alpha}), and isoprostane (8-isoprostane F2{alpha}) EIA Kits (Cayman Chemical).

Data are presented as means ± SE. Statistical analyses of the hemodynamic data groups were performed using one-way and two-way ANOVA for repeated measures within and between groups, respectively. Urinary excretion data were analyzed using a paired Student's t-test.


   RESULTS
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The average age of the rats was 7.0 ± 0.2 wk; body wt averaged 230 ± 11 g. The mean AP was 117 ± 3 mmHg, and RBF averaged 3.9 ± 0.2 ml·min–1·g kidney wt–1. Arterial blood hematocrit was stable: 45 ± 1% at the start and 45 ± 1% at the end of an experiment.

To verify effective, nearly complete SQ29548 blockade of TP receptors, the TxA2 agonist U 46619 (400 ng) was injected before (ira) and during SQ29548 infusion (180 ng·kg–1·min–1 ira) for 3 min. As is shown in Fig. 1, U46619 [GenBank] caused a maximum decrease in RBF of 22.8 ± 4.3% of baseline flow. Intrarenal infusion of SQ29548 did not change basal RBF or MAP, but it inhibited 97% the constrictor response to TP receptor stimulation by U46619 [GenBank] injection (0.8 ± 0.7% decrease in RBF, P < 0.001) (Fig. 1).


Figure 1
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  		Fig. 1. Maximum renal blood flow (RBF) response to injection of the thromboxane prostanoid (TP) receptor agonist U46619 into the renal artery before and during concurrent infusion of the TP receptor antagonist (SQ29548). **P < 0.001.

 
Infusion of ANG II ira (40 ng·kg–1·min–1) for 60 or 90 min reduced RBF and increased RVR, while MAP was unchanged in each group. The temporal changes in continuous recordings of RBF and MAP produced by ANG II before and during SQ29548 (180 ng·kg–1·min–1) are shown in Fig. 2. In the time control group, infusion of ANG II alone caused sustained renal vasoconstriction over the 90 min of observation as RBF was similar statistically as analyzed by ANOVA for repeated measures (P > 0.8). RBF was reduced at 30 and 60 min by 11.2 ± 3.6 and 13.2 ± 4.9% of basal RBF, respectively. MAP was stable at preinfusion levels at both time periods (1.5 ± 2.8 and –1.1 ± 3.5% changes, respectively). This degree of constriction was maintained over the 90-min period of recording.


Figure 2
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  		Fig. 2. Average data for continuous recordings of RBF and mean arterial pressure (MAP) during infusion of ANG II into the renal artery during control conditions and during coinfusion of SQ29548 to block TP receptors. ANG II was infused into 3 groups of rats for durations of 60 and 90 min.

 
SQ29548 was tested to determine whether ANG II led to renal vasoconstriction mediated by TP receptors. The RBF results analyzed by ANOVA for repeated measures within a group indicate that the ANG II-induced renal vasoconstriction was stable over time in all three groups of animals (P > 0.3–0.8). A major finding was that SQ29548 did not alter the degree of constriction produced by ANG II within either experimental group when infused during the 30- to 60-min time block (P > 0.3) or during the 60- to 90-min period of continued ANG II infusion (P > 0.8). The data in Fig. 3 clearly show that coinfusion of ANG II+SQ29548 between 30 and 60 min caused the same amount of renal vasoconstriction as did ANG II in time control studies. RBF was reduced by 15.8 ± 2.8% of baseline in this group (vs. –13.2% in time controls), indicating little effect of TP receptor antagonism under these conditions. Similarly, essentially the same RBF values were recorded when the TP receptor antagonist was infused between 60 and 90 min during longer-term ANG II infusion (–8.6 ± 4.0% RBF) compared with ANG II-induced constriction in the 60- to 90-min time control group (–9.6 ± 4.5% RBF). MAP was unchanged in all groups.


Figure 3
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  		Fig. 3. Group averages for the responses of RBF and MAP to continuous infusion of ANG II into the renal artery during a control ({circ}) and an experimental period in which the TP receptor antagonist SQ29548 was infused along with ANG I during (bullet) a 30- to 60-min or 60- to 90-time period (n = 6 and 5, respectively). In a time control group, ANG II was infused continuously in the absence of the TP receptor antagonist (n = 5).

 
Urinary excretion of TxB2 and 6-keto-PGF1 was measured in the control period before ANG II infusion and then during 30–60 min of ANG II infusion in a paired manner. There was roughly a twofold increase in TxB2 excretion (253 ± 24 vs. 406 ± 48 pg/30 min, P < 0.005) while 6-keto-PGF1 (a nonenzymatic degradation product of PGI2) excretion was unchanged (P > 0.8) (Fig. 4). Renal excretion of isoprostane (8-isoprostane F2{alpha}) doubled (from 178 ± 33 to 379 ± 54 pg/30 min, P < 0.03).


Figure 4
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  		Fig. 4. Urinary excretion of thromboxane B2 (TxB2), isoprostane, and 6-keto-PGF1{alpha} before and during infusion of ANG II into the renal artery. Urine was collected between 30 and 60 min of ANG II infusion. *P < 0.03, **P < 0.01.

 

   DISCUSSION
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The present study provides new information firmly establishing that the immediate renal vasoconstriction elicited by intrarenal infusion of ANG II, at a dose that selectively reduces RBF 10–15%, for 30–90 min, occurs independently of TP receptor activation and recruitment of the TxA2/PGH2 or isoprostane systems. This occurs at a time when ANG II stimulates renal synthesis and urinary excretion of TxB2 during the initial 30–60 min of intrarenal ANG II. The most likely explanation for this apparent paradox is that TxA2 synthesis takes place in the renal medulla or another site remote from the major resistance arterioles: afferent and efferent arterioles in the renal cortex. The decrease in RBF after 60 and 90 min of intrarenal infusion was similar in animals infused with ANG II alone or in combination with SQ29548. Although no hemodynamic participation a TP receptor agonist was unmasked, urinary excretion of TxB2 and isoprostane doubled, whereas urinary excretion of 6-keto-PGF1 was unchanged. These findings for acute experiments performed in normal animals indicate that renal hemodynamics are not influenced by TxA2 during intrarenal infusion of modest amounts of ANG II over a relatively short time period The present study is the first to demonstrate the lack of hemodynamic effects of TxA2 in vivo during acute intrarenal ANG II infusion.

The relationship between systemic infusion of ANG II and TxA2 effects has been studied for nearly two decades, with mixed results. Differences in results appear to depend on design of the studies, which includes the dose of ANG II, duration of administration, route of administration, and background activity of the renin-angiotensin system. Acute infusion of ANG II may or may not lead to increased renal production of TxA2 and/or TP-mediated renal vasoconstriction. All in vivo rat studies to date have been performed using iv infusion of ANG II that increases systemic AP, and the importance of extrarenal influences on renal responses has not been rigorously tested. High-dose iv infusion of ANG II (500 ng·kg–1·min–1 for 30 min) is reported to increase the excretion of prostanoids, with PGE2 and 6-keto-PGF1{alpha} increasing more than TxB2 (55). In these studies, ANG II increased AP 35 mmHg, a systemic effect that was reversed by ANG II receptor antagonism with saralasin, as was the case with urinary prostanoid excretion. The pressor response was reduced in part by the TP receptor antagonist SQ29548 given iv. In a subsequent study, a lower dose of ANG II given iv (50 ng·kg–1·min–1 for 45 min) increased AP 12 mmHg without significantly affecting RBF or GFR or urinary excretion of TxB2 (56). In this follow-up study, high-dose ANG II infused iv (500 ng·kg–1·min–1 for 45 min) increased AP 15 mmHg and reduced RBF ~60%, responses that were not significantly attenuated by either TxA2 synthesis inhibition or TP receptor blockade. TxB2 excretion was apparently not measured in these animals. Other investigators report that, although the TxA2/TP system is quiescent during basal resting conditions, iv infusion of pressor amounts of ANG II (10 ng·kg–1·min–1 for 120 min) produces renal vasoconstriction, responses that could be reversed by systemic pharmacological inhibition of TxA2 synthesis or blockade or of TP receptors (3). In this regard, it would be of interest to evaluate intrarenal infusion of ANG II for durations beyond the tested 90 min in the current study.

We recently observed that systemic infusion of ANG II (50 ng·kg–1·min–1 for 30 min) reduced RBF to a similar degree in wild-type and TP receptor null mice, suggesting an acute renal action of ANG II independent of an endogenous TP receptor agonist (J. J. Boffa and W. J. Arendshorst, unpublished observations). Also, RBF and RVR are in the normal range in TP receptor null mice (5).

The elevated state of the renin-angiotensin system in chronic studies appears to recruit the potentiating constrictor role of TxA2 (or PGH2 or isoprostanes) in the regulation of renal hemodynamics. In studies assessing the role of TxA2 in renal vasoconstriction in hypertension, a consistent finding is that TxA2 and TP receptors have very little tonic influence on basal RBF and RVR in normotensive control rats (3, 22, 31, 33, 35, 43, 56). SQ29548 does not reduce the pressor response to iv injection of ANG II in conscious rats (34). However, when activity of the renin-angiotensin system is elevated in normal rats, TP receptor antagonism increases basal RBF without affecting systemic AP, suggesting a preferential action on the renal microvasculature (58). In contrast, TP receptors exert little control of RBF or RVR when endogenous ANG II levels are reduced acutely by angiotensin-converting enzyme inhibition. However, in rats pretreated with captopril and the plasma concentration of ANG II kept constant at elevated levels (5–80 ng/min iv for 90–180 min), administration of the TP receptor antagonist SQ29548 reduces renal vascular resistance and the pressor response to ANG II.

In our study, intrarenal infusion of SQ29548 for 30 min between 30 and 60 or 60 and 90 min of ANG II infusion did not modify the renal vascular response to such a short-term ANG II infusion. Our animals are likely in a euvolemic volume state in which plasma renin activity approximates that in conscious animals, considerably lower than normally seen in anesthetized rats not receiving a constant replacement solution of albumin that maintains plasma protein concentration and hematocrit at presurgical levels (13, 22, 49).

It is noteworthy that the 15-mmHg systemic pressor response to acute ET-1 iv infusion in rats is prevented by TP receptor blockade, whereas a concurrent ~15% reduction of RBF is not significantly affected by SQ29548 (57). In another study, acute TP receptor antagonism did not affect ET-1-induced vasoconstriction for 30 min evidenced by a 15-mmHg increase in AP and a 40% reduction in RBF (36). Similar to our findings for ANG II in vivo, norepinephrine acutely increases prostanoid excretion (PGE2 > TxB2 > 6-keto-PGF1{alpha}), while the induced renal vasoconstriction of isolated perfused rat kidneys is unaffected by TP receptor blockade (30).

Ex vivo studies of isolated rat kidneys perfused with erythrocyte- and colloid-free saline solutions have employed administration of ANG II into the renal artery. Some reveal involvement of TP receptors, whereas others do not. In one study, acute injection of ANG II (100 ng) produces renal vasoconstriction that is potentiated by cyclooxygenase (COX) inhibition, indicating preferential synthesis of vasodilator prostanoids. The degree of ANG II-induced renal vasoconstriction was not influenced by the TP receptor blocker SQ29548 (15). Interestingly, as we observed in vivo, the lack of a functional contribution of TxA2 on TP receptors in the vasculature of their isolated kidneys was observed at a time when ANG II increased urinary excretion of TxB2, fourfold in their studies. Another laboratory reported that intrarenal injection of ANG II produces renal vasoconstriction of isolated kidneys that is not modified by SQ29548, at a concentration that inhibited constriction elicited by the TP receptor agonist U46619 [GenBank] (39). On the other hand, other studies of isolated kidneys perfused with artificial solutions find involvement of TP receptors when ANG II produces intense renal vasoconstriction. ANG II administration into isolated, perfused Wistar-Kyoto kidneys perfused with Krebs solution devoid of erythrocytes and colloid that produces near-maximum renal vasoconstriction is reported to be mediated in part by TP receptors (10). In the isolated rabbit kidney perfused with Krebs solution, intrarenal injection of ANG II (1–1,000 nM), but not norepinephrine, is reported to produce an increase in RVR that is attenuated by 20-min inhibition of TxA2 synthesis or TP receptors (17).

The role of the arachidonate/COX system has been studied in chronic experiments of different models of hypertension. Studies on the isolated, perfused kidney from an animal with renin-dependent hypertension induced by aortic coarctation show that the ANG II-induced increase in RVR is reversed by the COX inhibitor indomethacin, implying a COX metabolite is responsible for renal vasoconstriction in a chronic high-ANG II state (15). Furthermore, SQ29548 prevented the effect of ANG II in the hypertensive kidney, whereas no response was seen in the normotensive controls, indicating a more dominant role of a TP receptor agonist in long-term ANG II infusion studies. The findings indicate that the increased participation of TxA2/PGH2 and/or isoprostanes differ in chronic diseases associated with chronic stimulation of the renin-angiotensin system compared with control animals with minimal activation of the renin-angiotensin system.

In humans, acute ANG II infusion iv at a pressor dose that increases AP and decreases RBF stimulates renal production of prostanoids in the following descending order: PGF2{alpha} > PGE2 = PGI2 > TxA2 (29). Slightly different urinary excretion is seen in response to a similar pressor dose of norepinephrine (PGF2{alpha} > 6-keto-PGF1{alpha} > PGE2 = TxB2). In the rat, short-term ANG II infusion iv is reported to stimulate greater renal production of PGE2 in the medulla than the cortex (32).

Renal TP receptors have been localized to vascular smooth muscle cells of renal arteries and arterioles, glomeruli, and various tubular segments including proximal and distal convoluted tubules, thick ascending limb of Henle's loop, and collecting ducts (1, 47). Administration of a TP receptor agonist produces renal vasoconstriction by primarily increasing afferent arteriolar resistance (45). Similarly, exogenous 8-iso-prostane PGF2{alpha} preferentially constricts the afferent arteriole (46). It is possible that postglomerular production may not affect renal resistance arterioles acutely.

The source of TxA2 that is excreted in urine as TxB2 is not known. It may reflect a combination of filtered plasma and renal production. Urinary prostanoids probably mainly reflect renal synthesis (16). Our studies of increased urinary excretion of TxB2 and isoprostane during intrarenal infusion of ANG II in the absence of a change in systemic AP are consistent with this conclusion. In the mouse, ANG II infusion iv (150 pM·kg–1·min–1 for 120 min) increases AP and renal cortical and medullary production of the vasodilator prostanoids PGE2 and PGI2 predominantly via COX-2 (38). Based on location of mRNA for synthetic enzymes, PGE2 appears to be generated mainly by collecting duct cells, with production of PGI2 and TxA2 localized to the vasculature (51). In the dog renal artery, ANG II stimulates PGI2 production by the endothelium and PGE2 release from vascular smooth muscle cells (41). Normal rat glomeruli synthesize prostanoids acutely at different rates: PGF2{alpha} > PGE2 > PGI2 = TxA2 (42). Acute ANG II challenge leads to preferential stimulation of PGE2 by glomeruli. Under basal conditions, rat renal cortical tubules produce PGE2 > TxA2 > PGI2. Medullary tubules produce more prostanoids than cortical tubules (59). COX-1 and COX-2 are expressed in both the renal cortex and medulla. Renal medullary interstitial cells are rich in COX-2. ANG II stimulates renal cortical tubular cells to produce PGE2 > PGF2{alpha} and no PGI2, while vascular smooth muscle cells produce PGI2 (50). In terms of regional heterogeneity, it is interesting to note that the immediate contraction of isolated rabbit cortical afferent arterioles produced by ANG II is independent of TP receptor activation (52). On the other hand, TxA2 may be involved in acute responses of postglomerular outer medullary descending vasa recta (44). Changes in medullary perfusion may be small relative to total kidney blood flow.

In summary, the present study demonstrates that short-term intrarenal infusion of ANG II reduces RBF 10–15% over the initial 90 min of administration in the rat. ANG infusion into the renal artery rapidly increases renal production of TxA2 and urinary excretion of TxB2 and isoprostane, an index of oxidative stress. Nevertheless, the ANG II-induced renal vasoconstriction is unaffected by coinfusion of SQ 29548, indicating that renal vasomotor tone is independent of detectable TP receptor activation during the initial 90 min of local challenge with ANG II.


   GRANTS
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This work was supported by National Heart, Lung, and Blood Institute Grant HL-02334 and by The Western Norway Regional Health Authority.


   FOOTNOTES
 

Present address of Ø. B. Vagnes: Renal Research Group, Institute of Medicine and Haukeland University Hospital, University of Bergen, Bergen, Norway

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.

Address for reprint requests and other correspondence: W. J. Arendshorst, Dept. of Cell and Molecular Physiology, 6341-B Medical Biomolecular Research Bldg., CB #7545, School of Medicine, Univ. of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7545 (e-mail: arends{at}med.unc.edu).


   REFERENCES
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B. Ponnuchamy and R. A. Khalil
Cellular mediators of renal vascular dysfunction in hypertension
Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2009; 296(4): R1001 - R1018.
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