It is known that endothelin-1 stimulates the release of nitric oxide and prostaglandins in various vascular beds. We designed the present study to analyze the roles of prostaglandins and nitric oxide in the effect of endothelin-1 on the regulation of renal hemodynamics and renin release. We used Nω-nitro-l-arginine methyl ester (L-NAME) and meclofenamic acid to inhibit the production of nitric oxide and prostaglandins, respectively. With a nonfiltering kidney model, renal blood flow was reduced 21% in dogs treated with L-NAME and 18% in dogs treated with meclofenamic acid. Inhibition of nitric oxide and prostaglandins, however, produced opposite effects on estimated glomerular hydraulic pressure: L-NAME increased glomerular hydraulic pressure from 63.1±0.9 to 64.6±1.3 mm Hg (P<.01), and meclofenamic acid reduced glomerular hydraulic pressure from 63.3±1.4 to 59.8±1.6 mm Hg (P<.01). Endothelin-1 infusion produced a dose-dependent reduction in renal blood flow after blockade of nitric oxide and prostaglandins. The responses of glomerular hydraulic pressure were different in the two groups during endothelin-1 infusion. Endothelin-1 progressively reduced glomerular hydraulic pressure in a dose-dependent fashion in the meclofenamic acid group. However, endothelin-1 slightly increased glomerular hydraulic pressure until the infusion rate reached 5.0 ng/kg per minute. At that rate, endothelin-1 reduced glomerular hydraulic pressure from 63.3±1.4 to 47.0±1.4 mm Hg in the meclofenamic acid group (P<.01), a more than 25% reduction, whereas at the same dose, endothelin-1 reduced glomerular hydraulic pressure only less than 2% in the L-NAME group. In addition, blockade of nitric oxide and prostaglandins did not alter the inhibitory effect of endothelin-1 on renin release in the nonfiltering kidney. Therefore, the present study demonstrates that the release of nitric oxide and prostaglandins might modulate the effects of endothelin-1 on the renal circulation. The present findings suggest that the differential vasoconstrictive effects of endothelin-1 on preglomerular and postglomerular vessels are associated with its stimulation of nitric oxide and prostaglandin production.
As one of the most potent vasoconstrictors found in the body, ET-1 also elicits vasodilator responses from various vascular beds. In a previous study, ET-1 administration was reported to cause an initial endothelium-dependent vasodilation,1 2 which was related to release of endothelium-derived relaxing factors.3 Other studies also reported that inhibition of prostaglandin production by indomethacin enhanced the pressor response of ET-1 in the renal vasculature.4 5 Additionally, the initial vasodilation by ET-1 infusion was reported to be markedly attenuated with an inhibitor of NO production, suggesting that NO participates in causing the vasodilation and that ET-1 stimulates NO release.6 Therefore, the findings imply that these vasodilator endothelial products, NO and prostaglandins, may affect the magnitude of response of various vascular beds during ET-1 administration.
ET-1 has a potent effect on both RBF and GFR in dogs, rats, and rabbits,1 7 8 affecting both afferent and efferent arterioles. However, the effects of ET-1 on RBF and GFR are not parallel, particularly at low concentrations. Previous studies showed that with a low concentration of ET-1, renal plasma flow was reduced by more than 20%, whereas GFR was unchanged in rats and dogs.1 9 In addition, Denton and Anderson8 and King and Brenner10 reported that low doses of ET-1 increased the mean transglomerular capillary hydraulic pressure gradient in rats, suggesting that the increase in GHP is probably the reason that GFR was maintained despite reductions in RBF and filtration coefficient in rats. In our previous study with a nonfiltering kidney model,11 we demonstrated that at a dose of 1.0 ng/kg per minute, ET-1 reduced RBF 23% but did not alter GHP in dogs. These findings suggest that ET-1 may have a predominantly vasoconstrictive effect on efferent arterioles. However, since ET-1 stimulates the release of prostaglandins and NO, it is possible that the nonparallel vasoconstrictor effect of ET-1 on afferent and efferent arterioles may be related to differential vasodilator responses of the vessels leading to and away from the glomerulus. So far, little evidence to support this possibility has been presented.
Therefore, we designed the present study to analyze the roles of prostaglandins and NO in the effect of ET-1 on the regulation of renal hemodynamics. Using a stop-flow technique plus a nonfiltering kidney model, we were able to determine how prostaglandin blockade and NO production inhibition affected GHP in response to ET-1 administration.
Experiments were performed on mongrel dogs of either sex obtained from the research animal facilities of the University of Mississippi Medical Center (body weight, 21.6±0.9 kg; n=14). The dogs were housed in the animal facilities before use and fed a standard laboratory diet. The food was removed from their cages 15 hours before surgery, but the dogs were given free access to water. The dogs were initially sedated with 10 mg acepromazine maleate IM. Ten minutes later, they were anesthetized with approximately 30 mg/kg sodium pentobarbital IV.
Surgical Procedure and Experimental Measurements
The surgical procedure and experimental measurements were similar to those described in our previous study.11 Via a left retroperitoneal flank incision, a portion of the aorta above the left renal artery was gently isolated so that a silicone rubber cuff occluder could be placed around the aorta. The occluder was connected to a servo-controlled device that was used for maintenance of arterial pressure below the occluder (ie, renal arterial pressure) at a constant level. The left renal artery was also isolated, and an electromagnetic flow probe was placed around it. An electromagnetic flowmeter (model FM-501, Carolina Medical Electronics) was used for measurement of RBF. The left ureter was cannulated with a PE-90 catheter for measurement of urinary pressure by a pressure transducer (Cobe). A 22-gauge L-shaped needle attached to a catheter was inserted into the renal vein for sampling of renal venous blood. Finally, a 23-gauge L-shaped needle was also inserted into the left renal artery for intrarenal infusion.
Blood gas measurements were made with a pH/blood gas analyzer (model 1304, Instrumentation Laboratories) for determination of the rate of the respirator.
For determination of GHP, a stop-flow pressure method was applied. The left kidney was acutely rendered nonfiltering by techniques described previously.12 13 14 First, an osmotic diuresis was established, and then the ureter was occluded to elevate its pressure until the filtration pressure was zero. GHP was estimated from the equation GHP=Pπ+Pt, where Pπ is plasma colloid osmotic pressure, which was calculated from the plasma protein concentration measured by a refractometer (AO Reichert Scientific Instruments) with a formula proposed by Navar and Navar.15 Pt stands for stopped-flow urinary pressure, which was directly measured by a pressure transducer and is assumed to be equal to the proximal tubular hydraulic pressure.16
After completion of surgery, a dose of 300 mL of 6.0% mannitol solution was intravenously infused over 10 minutes, followed by a sustaining infusion of 2.0 mL/min. After diuresis had occurred for approximately 10 minutes, the ureteral catheter was clamped and ureteral pressure was measured by a pressure transducer. The pressure reached a plateau in about 10 minutes. Absence of filtration was confirmed by measurement of arterial and renal venous [125I]iothalamate activities.
Preglomerular vascular resistance (RVRpre) and postglomerular vascular resistance (RVRpost) were calculated as RVRpre=(RAP−GHP)÷RBF and RVRpost=GHP÷RBF, where RAP is renal arterial pressure. Resistance is expressed as millimeters of mercury per milliliter per minute.
An index of renin release was determined from the difference in plasma renin activity between the renal venous and arterial plasma and the renal plasma flow. Blood samples for plasma renin activity measurements were collected in iced sodium-EDTA tubes and cold-centrifuged for more than 30 minutes. One milliliter of plasma was used for the assay with the use of the radioimmunoassay procedure of Haber et al.17 The renin release index (RR) from the left kidney was calculated as RR=(PRAv−PRAa)×RPF÷KW (g), where PRAv represents renin activity in the renal venous sample, PRAa is renin activity in the renal arterial sample, and RPF is renal plasma flow. One unit of renin release was taken to be equal to 1 ng angiotensin I/mL per hour, and the rate of renin release is expressed as units per minute per gram KW.
ET-1 Infusion During Inhibition of NO Production
We designed this experiment to investigate the possible effect of NO on renal hemodynamics during ET-1 infusion. The experiment was begun after ureteral pressure had stabilized for at least 30 minutes. Measurements of blood flow and pressure were recorded on a MacLab/8 data recording system (MacLab MKIII, AD Instruments) and a polygraph (Grass Instrument Co). Average values for measured variables were determined for the last 5 minutes of each experimental period. Renal perfusion pressure was maintained at 80 mm Hg throughout the experiment with the servo-controlled device.18 L-NAME (Sigma Chemical Co) was administered by intrarenal infusion at a rate of 5 μg/kg per minute for 60 minutes before ET-1 (Sigma) infusion and was continuously infused after the ET-1 infusion. Four different doses (0.2, 1.0, 5.0, and 10.0 ng/kg per minute) of ET-1 solution were infused intrarenally, and each dose was maintained for approximately 15 minutes. Data were collected before ET-1 infusion and at 15-minute intervals during the infusion, including 3.0-mL blood samples obtained from the arterial and renal venous catheters for measurement of hematocrit, plasma protein concentration, plasma renin activity, and [125I]iothalamate activity. In addition, pH and blood gases were analyzed in the arterial blood samples.
ET-1 Infusion During Blockade of Prostaglandin Production
We designed these experiments to explore the possible effect of prostaglandins on renal hemodynamics during ET-1 infusion. The protocol was similar to that mentioned above. Meclofenamic acid (Sigma), used to block prostaglandin production in the kidney, was infused into the renal artery at a rate of 5 μg/kg per minute beginning 60 minutes before ET-1 infusion and continuing throughout the ET-1 infusion period. Four different doses were used (0.2, 1.0, 5.0, and 10.0 ng/kg per minute), and each was maintained for approximately 15 minutes. The measurements were similar to those described above.
After completion of the experiment, the ureteral clamp was released, and 45 minutes were allowed to permit fluid accumulated in the kidney during ureteral occlusion to be removed before the kidney was weighed.
Group means and SEM are presented in the text and figures. Statistical comparisons of all the data were performed with a single-factor ANOVA. The values in each group of the control, drug infusion, and different rates of the ET-1 infusion periods were compared. Dunnett's test was used for determination of the statistical probability of differences between groups. A probability value of less than 5% was accepted as a statistically significant difference. A probability value less than 1% is also indicated in the results.
Fig 1⇓ shows that in the present study, renal perfusion pressure was maintained at 80 mm Hg by the servo-controlled mechanism throughout the experiment. The filtration fraction of all dogs was 1.7±0.8%, which demonstrated that the kidney was in a nonfiltering state. Systemic arterial blood pressure was not different in the two groups before infusion of L-NAME and meclofenamate (129.2±2.3 versus 130.6±6.8 mm Hg, P>.05). However, in the L-NAME group, systemic arterial pressure increased to 142.0±2.2 mm Hg from 129.2±2.3 (P<.01) after L-NAME administration, whereas it was not different after meclofenamate infusion (130.6±6.8 versus 133.4±5.4 mm Hg, P>.05) in the meclofenamate group. Plasma protein concentration was not altered by infusion of L-NAME (6.09±0.17% versus 6.06±0.16%) or meclofenamic acid (6.07±0.10% versus 6.07±0.11%).
Fig 2⇓ shows RBF and GHP in response to L-NAME and meclofenamic acid infusions during 60 minutes of observation. L-NAME infusion increased GHP from 63.1±0.9 to 64.6±1.3 mm Hg (P<.01) and reduced RBF from 174.1±15.2 to 137.5±14.6 mL/min (P<.05). In the meclofenamic acid group, GHP decreased from 63.3±1.4 to 59.8±1.6 mm Hg (P<.01) and RBF fell from 204.1±39.0 to 166.4±33.4 mL/min (P<.05). Both agents elevated total renal vascular resistance, but their effects on preglomerular and postglomerular vessels were different (Fig 3⇓). L-NAME infusion (Fig 3A⇓) did not affect preglomerular resistance (0.11±0.01 versus 0.12±0.02 mm Hg/mL per minute, P>.05) but raised postglomerular resistance from 0.38±0.03 to 0.50±0.04 mm Hg/mL per minute (P<.01). Meclofenamic acid infusion (Fig 3B⇓) elevated preglomerular resistance from 0.09±0.01 to 0.14±0.02 mm Hg/mL per minute (P<.01) but had little effect on postglomerular resistance (0.38±0.06 versus 0.42±0.05 mm Hg/mL per minute, P>.05). Thus, L-NAME infusion mainly increased postglomerular resistance, and meclofenamic acid infusion predominantly raised preglomerular resistance.
ET-1 infusion produced similar dose-dependent reductions in RBF in the L-NAME and meclofenamic acid groups (Fig 4⇓). RBF in both groups was significantly reduced compared with the group without treatment, as we have published previously.11 However, the GHP responses to ET-1 in the L-NAME and meclofenamic acid groups were different. After blockade of NO production, ET-1 infusion increased GHP until the infusion rate reached 5.0 ng/kg per minute (Fig 5⇓). At 1.0 ng/kg per minute, ET-1 elevated GHP from 63.1±0.9 to 65.5±1.6 mm Hg (P<.01). With inhibition of prostaglandin production by meclofenamic acid, ET-1 progressively reduced GHP in a dose-dependent fashion. At 5.0 ng/kg per minute, ET-1 reduced GHP from 63.3±1.4 to 47.0±1.4 mm Hg (P<.01), a more than 25% reduction. At the same rate of ET-1 infusion, however, GHP was less than 2% below control in the group treated with L-NAME. GHP in dogs treated with L-NAME or meclofenamate is shown in Fig 6⇓ compared with GHP in control dogs, for which data were published previously.11 GHP was greater in the L-NAME–treated dogs than in the control dogs in response to ET-1 infusion, and it was remarkably reduced in the meclofenamate-treated group compared with control dogs.
Fig 7⇓ presents preglomerular and postglomerular vascular resistances during L-NAME and meclofenamic acid infusion as renal perfusion pressure was constantly maintained at 80 mm Hg. Preglomerular vascular resistance was increased in response to ET-1 infusion but was greater in the meclofenamic acid group than in the L-NAME group. During ET-1 infusion at 10 ng/kg per minute, preglomerular resistance was 0.14±0.02 mm Hg/mL per minute in the L-NAME group and 0.28±0.03 mm Hg/mL per minute in the meclofenamic acid group (P<.01), two times the L-NAME level. However, postglomerular vascular resistance appeared to be somewhat greater in the L-NAME group than in the meclofenamic acid group although the differences between the groups did not reach statistical significance.
Fig 8⇓ shows renin release in response to ET-1 infusion during inhibition of NO and prostaglandin production. The rate of renin release in the nonfiltering condition during control was not different in the two groups (53.1±11.2 [U/min]/g KW in the L-NAME group and 52.5±14.0 in the meclofenamic acid group). Furthermore, L-NAME and meclofenamic acid did not alter renin release during the 60-minute infusion (39.4±8.8 and 44.1±9.3 [U/min]/g KW, respectively; P>.05). However, ET-1 infusion significantly reduced renin release in both groups. At 1.0 ng/kg per minute, the rate of renin release was reduced to 28.3±7.1 (U/min)/g KW in dogs treated with L-NAME (P<.01) and 20.2±10.5 in dogs treated with meclofenamic acid (P<.05). Increases in the rate of ET-1 infusion further reduced the rates of renin release in both groups (Fig 8⇓).
Early studies demonstrated that ET-1 infusion caused initial vasodilation,1 2 which was believed to be associated with release of endothelium-derived relaxing factors. Since the initial vasodilation was markedly lessened with pretreatment of inhibitors of NO production and prostaglandin synthesis,2 6 19 it has been suggested that NO and prostaglandins participate in the vasodilation during ET-1 infusion. In addition, direct evidence has revealed that ET-1 stimulates release of endothelium-derived relaxing factors, including prostacyclin and NO, in intact animals and isolated kidneys.5 19 20 Furthermore, the vasodilator properties of ET-1 may exist throughout ET-1 administration since several studies demonstrated that indomethacin potentiated the vasoconstrictive effect of ET-1 on the renal vasculature.4 5 More recent evidence shows that endothelin-B receptors in endothelial cells are responsible for the stimulation of NO and prostacyclin production by ET-1.21 22 However, it should be noted that the vasodilator component seems to differ among species, such as rats, dogs, and rabbits. It appears that rats lack a vasodilator component in the renal vasculature, whereas dogs and rabbits have vasodilator elements in response to ET-1 administration.
We reported in a previous study11 that ET-1 had profound effects on renal hemodynamics and renin release in a nonfiltering kidney preparation. The findings in the present study have demonstrated that stimulation of NO and prostaglandin production by ET-1 infusion may be involved in these effects on the renal circulation. These two endothelium-derived factors appear to have differential effects on preglomerular and postglomerular vessels in response to ET-1 infusion, with NO primarily affecting the postglomerular vessels and prostaglandins mainly the preglomerular vessels.
To determine GHP in the present study we used a stop-flow technique plus the nonfiltering kidney model, which has been used previously by many investigators.12 13 23 Like many other methods used for measurement of GHP, the nonfiltering model has its limitations. Data from the previous studies suggested that GHP measured with this model was comparable to that measured with the direct-puncture method in the rat; however, in the dog, the readings from this model could be greater than those made with the direct-puncture method because the dog is characterized by filtration pressure disequilibrium.23 24 It is most likely that GHP in this model is overestimated compared with that in the normal physiological condition. Several factors may contribute to this elevation of GHP. First, the increase in GHP is at least partly due to the fact that this model renders the kidney in a nonfiltering condition so that a cessation of NaCl delivery to the macula densa region activates the tubuloglomerular feedback mechanism. This activation causes preglomerular vasodilation25 26 via a mediator that is still unidentified. Some evidence indicates that activation of renal prostaglandins may be responsible for the preglomerular vasodilation,27 which suggests that renal prostaglandin production may be at a relatively high state in this model. It is possible that this high level of prostaglandin production in kidney may result in hypersensitivity to inhibitors of prostaglandin production. Second, when glomerular filtration reaches complete cessation in this model, it can alter the filtration pressure disequilibrium of the normal condition to an equilibrium state, which can raise GHP via some mechanisms, such as increases in blood flow through the glomerular capillary. Third, the renin-angiotensin system is also activated in this model because of the cessation of NaCl delivery to the macula densa, which may influence GHP via the action of angiotensin II. Angiotensin II was reported to affect predominantly efferent arterioles in vivo,13 and an increase in its activity could raise glomerular pressure. In addition, a rise in tubular and interstitial pressures in this model can impair autoregulation of RBF via a myogenic response, which may affect renal vascular resistance in response to ET-1. Therefore, these limitations can to some extent alter the normal physiological state of renal hemodynamics that may attenuate or potentiate endogenous mediators in response to ET-1 infusion. However, because all the experimental procedures and measurements were conducted under the same conditions and renal perfusion pressure was maintained at the same level in all the experiments, the data from this experimental model should provide useful information about the roles of NO and prostaglandins in response to ET-1 infusion.
Furthermore, this model also has some unique features. First, it is relatively easy to determine the estimated GHP with little surgical trauma. Second, it determines GHP in the whole kidney, unlike the micropuncture technique, which mainly measures superficial nephrons. Third, it is easy to use a servo-controlled device to control renal perfusion pressure, which is essential for the present study. Fourth, GHP is relatively stable during the experiment, as was shown in our previous study.11 To overcome the weakness of this model and maintain GHP in a normal range, we used a servo-controlled system to reduce renal perfusion pressure to 80 mm Hg and maintain it throughout the experiment. GHP in the present study was approximately 65 mm Hg during the control period and was not different in the two groups.
In the present study, we started administering L-NAME and meclofenamic acid 60 minutes before ET-1 infusion to inhibit renal NO and prostaglandin production through an intrarenal infusion. During this observation period, L-NAME infusion reduced RBF from 174.1±15.2 to 137.5±14.6 mL/min (P<.05) but raised GHP from 63.1±0.9 to 64.6±1.3 mm Hg (P<.01). In contrast, the data from our previous study11 indicated that RBF was not decreased (148±17 versus 163±25 mL/min) and GHP was not altered (67.3±2.0 versus 67.3±2.1 mm Hg) during a 60-minute observation with saline infusion. These data suggest that NO plays a significant role in controlling renal circulation and that it mainly affects postglomerular vessels in the present conditions. This effect may be attributed to the fact that NO release in the present conditions reduces efferent arteriolar sensitivity to angiotensin II, directly relaxes postglomerular vessels, or both. However, meclofenamic acid infusion produced different results compared with L-NAME infusion. GHP was reduced from 63.3±1.4 to 59.8±1.6 mm Hg (P<.01), and RBF was decreased from 204.1±39.0 to 166.4±33.4 mL/min (P<.05). In addition, the prostaglandin synthesis inhibitor significantly raised preglomerular vascular resistance but only slightly changed postglomerular vascular resistance, resulting in a decrease in GHP. This raises the possibility that prostaglandins were active and at least partly responsible for reducing preglomerular vascular resistance in the nonfiltering condition.
The GHP responses to ET-1 infusion in the L-NAME and meclofenamic acid infusion groups were different. GHP in the L-NAME group was elevated at low rates of ET-1 infusion and maintained at relatively high levels. However, ET-1 infusion produced a dose-dependent reduction in GHP in dogs treated with meclofenamic acid. At the rate of 5.0 ng/kg per minute, ET-1 reduced GHP to 47.0±1.4 mm Hg in the meclofenamic acid group, but it caused only a slight reduction in GHP to 62.3±2.9 mmHg in the L-NAME group. This difference between the two groups reflects the fact that NO and prostaglandins may be important mediators in the modulation of renal hemodynamics in response to ET-1 infusion.
It is still unclear why L-NAME and meclofenamate, which can block the release of NO and prostacyclin by ET-1, respectively, have different consequences on the renal circulation in response to ET-1 administration. One possible explanation is that NO and prostaglandins may selectively act on different vascular sites in the kidney. The evidence in the present study appears to suggest the NO most likely affects postglomerular vessels and prostaglandins may mainly influence preglomerular vessels. A previous study has demonstrated that prostaglandins effectively prevented the vasoconstrictive effect of angiotensin II on preglomerular vessels and had little effect on postglomerular vessels.28 To some extent, such a phenomenon may exist in the interaction between the inhibition of prostaglandins and ET-1 because meclofenamate increased the vasoconstrictive effect of ET-1 on preglomerular vessels in the present study. On the other hand, when L-NAME blocked NO production, ET-1 infusion maintained or slightly elevated GHP even at moderate doses, suggesting two possibilities: First, the stimulation of prostacyclin release by ET-1 may attenuate the vasoconstrictive effect of ET-1 on preglomerular vessels; second, the lack of NO release during the ET-1 infusion may enhance the vasoconstrictive effect of ET-1 on postglomerular vessels. Therefore, the present data show that NO and prostaglandins play significant roles in the effect of ET-1 on the renal circulation and that they affect different sites in the renal circulation.
We demonstrated in our previous study that ET-1 infusion produced an inhibitory effect on renin release in the nonfiltering kidney.11 The present data further support these previous findings. In addition, the present study showed that the inhibition of NO and prostaglandin production had no significant effect on renin release in the nonfiltering kidney and did not contribute to the effect of ET-1 on renin release. This evidence suggests that the inhibitory effect of ET-1 infusion on renin release is independent of its vasodilator components.
In summary, the present study suggests that the release of NO and prostaglandins may modulate the effect of ET-1 on the renal circulation. Prostaglandins appear to mainly affect preglomerular vessels, and NO most likely influences postglomerular vessels during ET-1 administration. These endothelin-induced vasodilator factors in some degree help to attenuate the potent vasoconstrictive effect of ET-1. More importantly, through selectively affecting different vessels, they modulate the effect of ET-1 on the renal circulation. The stimulation of prostaglandins may be beneficial for maintaining normal glomerular filtration through dilating preglomerular vessels, whereas the release of NO may ameliorate the potent vasoconstrictive effects of ET-1 on postglomerular vessels. Therefore, the present findings suggest that the differential vasoconstrictive effect of ET-1 on preglomerular and postglomerular vessels is at least partly related to its stimulation of prostaglandin and NO production. In addition, the inhibitory effect of ET-1 infusion on renin release is independent of its stimulation of prostaglandins and NO production.
Selected Abbreviations and Acronyms
|L-NAME||=||Nω-nitro-l-arginine methyl ester|
|GFR||=||glomerular filtration rate|
|GHP||=||glomerular hydraulic pressure|
|RBF||=||renal blood flow|
This work was supported by grants HL-21435 and HL-51971 from the National Heart, Lung, and Blood Institute, National Institutes of Health.
- Received November 28, 1995.
- Revision received January 9, 1996.
- Accepted May 8, 1996.
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