(Hypertension. 1996;28:656-662.)
© 1996 American Heart Association, Inc.
Articles |
Change in Pressor Responsiveness to Angiotensin II as a Determinant of Blood Pressure After Unclipping in Two-Kidney, One Clip Hypertensive Rats
the Department of Pharmacology and Toxicology, Michigan State University, East Lansing.
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Abstract |
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The hypotensive effect of correction of renal artery stenosis in humans or experimental animals with renovascular hypertension is commonly attributed to decreasing renin secretion from the formerly stenotic kidney. However, plasma renin activity is normal in 50% of individuals with renovascular hypertension. We studied conscious, chronically instrumented two-kidney, one clip (2K1C) rats. The renal artery clip was removed and mean arterial pressure measured for 3 days. The majority of the fall in blood pressure occurred between 2 and 48 hours after unclipping. Measurement of water balance and urinary sodium excretion revealed no effect of unclipping. In another experiment, 2K1C hypertensive rats were chronically treated with enalapril and concomitant infusion of angiotensin II (3.8 pmol/min [4 ng/min] IV) to maintain blood pressure at hypertensive levels and prevent a fall in angiotensin II levels on unclipping. After 5 days, the clip was removed or sham removed, and treatment was continued. Blood pressure was recorded for 7 days. Blood pressure remained elevated in the sham unclipped rats. Unclipped rats exhibited a dichotomous response: blood pressure fell significantly within 48 hours in the majority of rats (responders) but remained elevated in a minority (nonresponders). All treatment was then withdrawn for 2 days. Sham unclipped rats remained hypertensive, and responders exhibited a further small decline in blood pressure. Blood pressure fell to normal in the nonresponders. Blood pressure falls after correction of renal artery stenosis in renovascular hypertension in part because of a decrease in pressor responsiveness to angiotensin II.
Key Words: angiotensin II • hypertension, renovascular • renal artery stenosis • blood pressure • kidney
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Introduction |
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In most cases of RVH in humans, correction of renal artery stenosis by percutaneous transluminal renal angioplasty or surgical intervention is effective, resulting in improvement or cure of the disease in as many as 90% of patients.1 2 Similarly, in the 2K1C rat, an experimental model of RVH, removal of the renal artery clip usually results in normalization of BP (for review, see Reference 3). The efficacy of percutaneous transluminal renal angioplasty or revascularization in lowering BP in RVH is generally attributed to the restoration of perfusion to the formerly stenotic kidney, which in turn causes a reduction in renin secretion. Indeed, there is considerable evidence in both humans4 5 6 and experimental animals3 7 8 that PRA falls after correction of renal artery stenosis. However, in as many as 50% of human patients with RVH, PRA is normal,9 10 yet angioplasty or surgery is nevertheless effective in lowering BP.6 11 12 Similar findings have been obtained after removal of the renal artery clip in rats with 2K1C hypertension.7 This result has led some investigators to doubt the renin dependence of the hypertension in such individuals.5 6 13 But it has been reported numerous times that blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors lowers BP in RVH even when PRA is normal, confirming that the hypertension remains dependent on an intact renin-angiotensin system.13 14 15
In a recent article,16 we reported that unilateral renal artery stenosis enhanced responsiveness to the SPE of Ang II in rats. The SPE is the phenomenon in which slight, initially nonpressor, increases in Ang II levels can, when maintained over a period of hours to days, raise BP.17 The SPE is mechanistically distinct from the fast pressor effect of Ang II, which requires large increases in Ang II levels.18 Several possible mechanisms for the SPE have been proposed. These include actions of Ang II on body fluid and sodium handling, potentiation of sympathetic nervous system activity, and promotion of structural changes in the vasculature (for review, see Reference 17). Our previous results16 suggested that enhanced responsiveness to the SPE could be the mechanism by which renin-dependent RVH is maintained without a large increase in PRA or Ang II levels. If this hypothesis is correct, correction of renal artery stenosis could lower BP in RVH by changing responsiveness to the SPE from an augmented state to a magnitude exhibited in normal individuals. We designed the present study to test this possibility in 2K1C hypertensive rats.
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Methods |
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Animals
Male Sprague-Dawley rats (n=31) weighing 199±1 g (Sasco, Madison, Wis) were used. On arrival at our facility, the rats were maintained according to protocols approved by the Michigan State University All-University Committee on Animal Use and Care. Before surgery, the rats were housed in clear plastic boxes and allowed free access to standard rat chow (Teklad) and tap water.
Surgical Procedures
All surgical procedures were performed after administration of pentobarbital sodium (Abbott Laboratories) (181.5 µmol/kg [45 mg/kg] IP). If necessary, anesthesia was supplemented during surgery with methohexital sodium (Eli Lilly) (17.6 to 35.2 µmol/kg [5 to 10 mg/kg] IV). Postoperative analgesia was provided by treatment with butorphanol tartrate (Bristol Laboratories) (1.1 µmol/kg [0.5 mg/kg] SC).
Induction of Renal Artery Stenosis
Renal artery stenosis (2K1C hypertension) was produced by the application of a 0.2-mm ID silver clip over the left renal artery via an abdominal incision. Postoperatively, the rats received one injection of penicillin G and dihydrostreptomycin (Pfizer) (0.2 mL IM) to prevent infection.
Arterial and Venous Catheterization
Four weeks after renal artery clipping, the rats were catheterized. Mean body weight at the time of catheterization was 361±6 g. The surgical procedures used have been described previously.16 Briefly, arterial and venous catheters were advanced through the left femoral artery and vein into the abdominal aorta and vena cava, respectively. The ends of the catheters were passed through a stainless steel spring attached to a plastic swivel. The rats, after regaining consciousness, were housed singly in stainless steel metabolism cages in a climate-controlled room with a 12-hour light/dark cycle for the remainder of the experimental protocol. Three to 5 days of recovery from surgery were allowed before experimentation was begun; tobramycin sulfate (Eli Lilly) (701.6 nmol [1.0 mg] IV) was given once daily during this period to prevent infection.
Reversal of 2K1C Hypertension (Unclipping)
For unclipping, rats were anesthetized with methohexital sodium (52.8 to 70.4 µmol/kg [15 to 20 mg/kg] IV). An incision was made on the left flank, the kidney exposed, and the clip removed with forceps, with care taken not to rupture the artery. Sham unclipped rats underwent flank incision and exposure of the clipped kidney, but the clip was not disturbed.
Chronic Rat Maintenance and Measurements
Once housed in metabolism cages, the rats were allowed access to sodium-deficient rat chow (Teklad) and distilled water ad libitum. Sodium intake was controlled by intravenous infusion of a sodium chloride solution (2 mmol Na+ per day) in a volume of 5 mL. Water intake and urine output were measured daily with the use of calibrated dispensers and collectors, respectively. Urinary concentrations of sodium and potassium were measured in daily samples with a flame photometer (model IL 943, Instrumentation Laboratories). UNaV and potassium excretion were calculated by multiplying electrolyte concentration by daily urine volume. WB was calculated as the difference between daily water intake and urine output. MAP and heart rate were recorded once daily for 10 to 20 minutes from the arterial catheter by connection to a pressure transducer (model P10EZ, Gould Instruments) attached to a digital BP monitor (model BP2, Stemtech) and polygraph (model 7B, Grass Instrument Co). All measurements were obtained between 8 AM and noon.
Experimental Protocols
Time Course of Changes in Measured Parameters After Unclipping
Rats were catheterized as described above, and experimentation was begun 5 days later. Experimental variables were recorded for 1 control day (C in Figs 1 through 3
). Only rats that had MAP greater than 130 mm Hg were included in the experiment. Immediately after measurements on the control day, the rats underwent either unclipping (n=7) or sham unclipping (n=6). Recovery of consciousness occurred 5 to 10 minutes after completion of the unclipping surgery. MAP was then recorded at 15 and 30 minutes and 1, 2, 4, 6, 24, 48, and 72 hours after unclipping. All experimental variables were measured at the 24-, 48-, and 72-hour time points.
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Effects of Unclipping in Setting of Fixed Ang II
Rats were catheterized as described above. Three days later, experimentation was begun. MAP and other variables were measured for 3 control days (days C1 through C3). Only rats that had MAP greater than 130 mm Hg during this period were selected for inclusion in the experiment. Immediately after measurements on day C3, the rats began receiving the angiotensin-converting enzyme inhibitor enalapril maleate (Sigma Chemical Co) in the drinking water (508 µmol/L [250 mg/L]) and concomitant intravenous infusion of Ang II at a rate of 3.8 pmol/min (4 ng/min) to inhibit endogenous production of Ang II and to fix levels of the peptide, respectively. Previous results from this laboratory19 have shown that this combination maintains stable hypertension in 2K1C rats. Treatment with enalapril and Ang II was continued for 12 days (days T1 through T5 and U1 through U7). Rats underwent either unclipping (n=12) or sham unclipping (n=6) immediately after measurements on day T5. Recovery of consciousness occurred 5 to 10 minutes after completion of the unclipping surgery. MAP was recorded 6 hours after unclipping or sham unclipping and for the next 7 days (days U1 through U7). This was followed by a 2-day recovery period (days R1 and R2) during which no treatment was given.
Statistical Analysis
Results are expressed as mean±SE. For all data, within- and between-group differences were analyzed by ANOVA. If statistically significant differences were detected by ANOVA, post hoc between-group comparisons were performed by testing simple main effects, and analysis of contrasts was used for post hoc within-group comparisons. A value of P<.05 was the criterion for statistical significance in all tests. All analyses were performed with a computer software package for statistics (Crunch Version 4).
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Results |
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Time Course of Changes in Measured Parameters After Unclipping
Fig 1
presents data relating to the effect of unclipping or sham unclipping on MAP in 2K1C hypertensive rats. Measurements made on the control day confirmed that the rats were hypertensive (MAP: 143±9 mm Hg in subsequently unclipped rats versus 150±10 in subsequently sham unclipped rats). Unclipping resulted in a small, acute fall in MAP. After the initial depressor response, MAP remained stable until 2 hours after unclipping. It then decreased over the remainder of the experiment, reaching a nadir 24 to 72 hours after unclipping (72 hours after unclipping: 107±3 mm Hg). MAP in the unclipped rats was significantly lower than the control measurement from 2 hours after unclipping to the end of the protocol. Sham unclipped rats exhibited variable MAP throughout the experiment, but no decrease was significant compared with control. At all time points tested, MAP was significantly lower in the unclipped group than in the sham unclipped rats.
Daily WB data are shown in Fig 2. WB was similar in both groups on the control day (9±3 mL in subsequently unclipped rats versus 7±2 in subsequently sham unclipped rats). Unclipping or sham unclipping resulted in a transient fall in WB (on day U1: 0±3 mL in unclipped rats versus 1±2 in sham unclipped rats) that stabilized after the first day of measurement (on day U2: 10±2 mL in unclipped rats versus 11±1 in sham unclipped rats). Differences in WB were not significant between groups at any time during the experiment.
Fig 3 shows UNaV data. All rats were on a fixed sodium intake of 2 mmol/d. Unclipping and sham unclipping did not cause any changes in UNaV. Differences in this parameter were not significant between groups at any time during the experiment. Other analyses (data not shown) revealed no significant differences between groups in heart rate or urinary potassium excretion at any time throughout the protocol.
Effects of Unclipping in Setting of Fixed Ang II
MAP data in the setting of fixed Ang II are shown in Fig 4. When unclipping was performed, a dichotomous response was obtained: MAP fell in eight rats (responders) but remained elevated in four (nonresponders). Therefore, the data are presented in such a way as to distinguish between the two response patterns. During the control period, MAP was consistently higher in rats that went on to become nonresponders than in rats that became responders (this difference was significant only on day C3). Enalapril treatment with concomitant infusion of Ang II (3.8 pmol/min [4 ng/min] IV) was effective in maintaining MAP at levels not different from control during days T1 through T5 of the treatment period, in agreement with our previous results.19 MAP in the sham unclipped rats was stable throughout the entire treatment period. Unclipping was not associated with a significant decrease in MAP at 6 hours in responders (145±3 mm Hg before unclipping versus 136±6 at 6 hours after unclipping) or nonresponders 140±9 mm Hg before unclipping versus 141±8 6 hours after unclipping). In the responders, the difference in MAP compared with sham unclipped rats was significant from the first day after unclipping to the end of the experiment (on day U1: 120±6 mm Hg in responders versus 139±4 in sham unclipped rats; on day U7: 120±4 mm Hg in responders versus 143±3 in sham unclipped rats). Likewise, MAP values were significantly different between the responders and nonresponders on days U1 through U7, with MAP in nonresponders virtually indistinguishable from that of sham unclipped rats. Withdrawal of enalapril plus Ang II (days R1 and R2) had no effect on MAP in the sham unclipped group (on day R2: 144±9 mm Hg) but caused a further decline in MAP in the responders (on day R2: 104±1 mm Hg). However, withdrawal of treatment resulted in a large, significant fall in MAP in the nonresponders (on day U7: 147±9 mm Hg; on day R2: 115±5). MAP did not differ significantly between responders and nonresponders during the recovery period.
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Fig 5 shows the daily WB data obtained in this experiment. Overall, WB was highly variable in all rat groups throughout the protocol. Sham unclipped rats had consistently higher WB values than either unclipped group, but this is unlikely to be related to surgical treatment because no changes in this parameter were significant and these differences were evident before unclipping or sham unclipping (days T1 through T5). Unclipping did not result in a dichotomous outcome in responders versus nonresponders; no differences between these groups were significant.
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Daily UNaV data are presented in Fig 6. All rats were on a fixed sodium intake of 2 mmol/d. Accordingly, UNaV values were stable (1.5 mmol/d) throughout the experiment. Unclipping did not appear to cause any changes in sodium handling: UNaV did not differ significantly between any groups during the entire experiment. Other data (not shown) revealed no significant differences between groups in heart rate and urinary potassium excretion.
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Discussion |
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Identification of the mechanism or mechanisms responsible for the decrease in BP after correction of a renal artery stenosis in humans or experimental animals with RVH has been the subject of much research over the past few decades.3 Traditional theory states that the restoration of adequate perfusion to the stenotic kidney removes the stimulus for accelerated renin secretion, thus lowering PRA, which leads to lessened Ang II–induced vasoconstriction.5 20 21 This schema appears to be valid in cases of RVH in which PRA is markedly elevated5 20 22 but does not satisfactorily explain the ability of stenosis correction to lower BP in the common instance in which PRA is within the normal range. It is therefore logical to conclude that factors in addition to a decline in Ang II production also are involved. Some investigations implicate increases in sodium and water balance or diminished sympathetic nervous system activity, but other studies fail to support these possibilities.3 Several lines of evidence point to depressor substances released from the renal medulla as contributors to the fall in BP after unclipping in rats and rabbits,3 especially within the first 24 hours. The aim of the present experiments, however, was to investigate the role of changes in pressor responsiveness to Ang II in the effect of unclipping. Vascular responses to Ang II can be roughly assayed in intact animals by measurement of the fast pressor effect (peaking in 10 to 20 seconds) to intravenous injections of relatively large doses of the peptide. Such responses are actually decreased in 2K1C rats and increase to normal within 24 hours after unclipping.3 Thus, changes in vascular reactivity to Ang II probably are not a factor in the fall in BP after unclipping. Mechanisms other than direct vascular contraction are involved in the SPE of Ang II,17 and increased responsiveness to the SPE may occur in 2K1C rats.16 23 Thus, our specific goal in the current experiment was to test the hypothesis that unclipping would decrease the pressor response to chronic, low-dose infusion of Ang II, ie, reduce the SPE. We speculated that this could be a mechanism by which reversal of renal artery stenosis lowers BP.
We compared the effect of unclipping in untreated 2K1C rats and in 2K1C rats in which hypertension was maintained by treatment with the angiotensin-converting enzyme inhibitor enalapril and concomitant intravenous infusion of Ang II at 3.8 pmol/min (4 ng/min). In untreated 2K1C rats, unclipping was associated with a small, immediate (within 15 minutes) decline in MAP followed by a slowly developing, larger fall. It is not possible to determine from our study how much of this initial depressor response was due to the effects of surgery, anesthesia, and the postsurgical analgesic, but a large role is unlikely because sham unclipped rats actually demonstrated an increase in pressure during this early period. MAP was not significantly lower than control in unclipped rats until 2 hours after surgery. After this time, pressure continued to drop, reaching its nadir about 24 hours after unclipping. It has been shown previously that the time course of the reversal of Ang II–dependent hypertension differs depending on whether the fast pressor effect (due to direct vascular contraction) or the SPE predominates. Only a few minutes are required for recovery from the fast pressor effect, whereas 45 minutes to several hours are needed when the SPE is operative.18 24 25 The protracted nature of the fall in MAP after unclipping in the untreated 2K1C rats is consistent with reversal of the SPE.25
The key test of our hypothesis was conducted in the second experiment. 2K1C hypertensive rats were maintained for 12 days on a combination of enalapril and Ang II infusion (3.8 pmol/min [4 ng/min] IV). We have shown this infusion rate to be the minimum necessary to sustain BP at hypertensive pretreatment levels in enalapril-treated 2K1C rats but to produce only normal BP in enalapril-treated intact rats.19 We designed this treatment regimen to minimize reductions in blood and tissue Ang II concentrations normally expected to occur after unclipping. In this setting, reversal of renal artery stenosis still caused a large and statistically significant decrease in MAP in the majority (8 of 12) of rats (the 4 unclipped rats in which MAP did not fall will be discussed in detail below). What is the evidence that this fall in BP was related to a decline in the pressor activity of Ang II? We have shown26 that angiotensin-converting enzyme inhibition with enalapril normalizes MAP in hypertensive 2K1C rats prepared identically to those used in the current study. Thus, in rats in the present study receiving enalapril plus Ang II infusion, BP was supported at a hypertensive level (an approximate 35 mm Hg increment) solely by Ang II. After unclipping in the responders, continuing Ang II infusion appeared to contribute only about 10 mm Hg to the overall MAP level (based on the fall in MAP after the infusion was terminated; see Fig 4). Thus, reversal of renal artery stenosis appeared to reduce the chronic pressor effect in response to Ang II by nearly 70%, a magnitude in agreement with our previous findings in 2K1C rats.16 Earlier studies support the conclusion that Ang II infusion at a rate of 3.8 pmol/min increases BP in rats primarily via the SPE,16 25 and the delayed time course of the hypotensive effect of unclipping in responders in the present study suggests that it also resulted from a reduction in the SPE of Ang II. Overall, then, the results are consistent with our hypothesis that a component of the hypotensive response to unclipping in 2K1C rats is caused by reduced responsiveness to the SPE of Ang II.
However, an important caveat to the above conclusion is that responsiveness can be fully evaluated only with simultaneous measurements of response and peptide concentration in the relevant biophase. We did not attempt to evaluate Ang II concentrations in either cardiovascular tissues or plasma. Instead, our experimental design was based on two assumptions. First, we assumed that chronic high-dose enalapril treatment reduces endogenous Ang II formation to functionally insignificant levels. It is clear, however, that even chronic high-dose treatment with converting enzyme inhibitors does not cause the disappearance of immunoreactive Ang II from blood and tissues (eg, Reference 27). Nonetheless, we have shown that our enalapril treatment regimen abolishes the normal BP responses of rats to acute and chronic treatment with losartan,28 suggesting that whatever endogenous Ang II formation remains is functionally insignificant. Our second critical assumption was that unilateral renal artery stenosis does not alter the metabolic clearance of Ang II. Available evidence indicates that Ang II clearance in RVH is reduced in the stenotic kidney but increased in the contralateral kidney.29 Thus, it is unclear whether total body clearance of Ang II is significantly affected by clipping or unclipping. Lacking additional evidence on these two important assumptions, we cannot rule out the possibility that the fall in Ang II–related pressor activity apparent in this experiment after unclipping was the result of a fall in Ang II concentration in blood and/or tissue secondary to either diminished endogenous formation or increased metabolic clearance.
The idea that changes in the pressor responsiveness to Ang II are a determinant of BP in RVH is certainly not new.10 30 31 Several investigators have studied pressor sensitivity to Ang II after unclipping in 2K1C rats.3 22 32 33 Skulan et al32 as well as ten Berg and de Jong22 reported an exaggerated BP response to Ang II in recently unclipped 2K1C rats. Very low infusion rates of renin or Ang II were sufficient to restore hypertension in the early phase after clip removal. Conversely, Kumar et al33 found that supraphysiological infusion rates of Ang II were needed to maintain hypertension after unclipping. The results observed in responders in the present experiments are consistent with the findings of the latter study. BP fell rapidly in most 2K1C rats after unclipping, even when we attempted to maintain Ang II levels relatively constant using enalapril and a very low infusion rate of the peptide—the same rate that preserved hypertension before unclipping. Thus, we would predict that a much higher infusion rate of Ang II would be necessary for restoration of hypertension in the majority of unclipped rats.
As mentioned above, unclipping resulted in a dichotomous response in 2K1C rats maintained hypertensive by treatment with enalapril and Ang II. In 4 of 12 rats that underwent unclipping, termed nonresponders, MAP remained elevated as long as Ang II was infused. When treatment was withdrawn, MAP fell to normotensive levels overnight. This dichotomy in the response to unclipping was unexpected but quite dramatic. Given this clear division in responses, we felt accurate representation of the data required separate display and analysis of the two groups. Interpretations based on such post hoc divisions, however, must be made with caution. How are nonresponder rats different from those in which BP fell after unclipping (ie, responders)? One possibility is that the nonresponders had a more malignant form of hypertension that resulted in altered vascular structure, thereby amplifying the vasoconstrictor action of Ang II.34 More malignant forms of hypertension might result from variability in clip placement, internal diameter, or both. Indeed, MAP was consistently higher in the nonresponders during the control period. However, the fact that MAP fell within 24 hours after cessation of Ang II infusion argues against a role for altered vascular structure in the nonresponders, because reversal of structural changes has been shown to require a much longer time period.35 A more likely explanation for the dichotomy observed in this experiment can be found in other results from this laboratory. We have reported that 2K1C rats that do not become hypertensive exhibit an augmented slow pressor response to Ang II when given exogenous peptide, suggesting that there is a degree of renal artery stenosis insufficient to raise arterial pressure alone that can nevertheless enhance responsiveness to the SPE of Ang II.23 Based on these observations, we speculate that unclipping did not result in the complete relief of the renal artery stenosis in the nonresponders. Although we did not obtain histological data to confirm this point, it is possible that sufficient occlusion of the renal artery, presumably caused by fibrosis (or other structural abnormalities) at the site of the clip, remained to maintain enhanced responsiveness to the SPE as long as exogenous Ang II was present. Once Ang II levels were allowed to fall (when the infusion was stopped), BP normalized as well. Furthermore, we contend that the findings of Skulan et al32 and ten Berg and de Jong22 (see above) also can be explained by incomplete restoration of adequate flow to the unclipped kidney.
The current experiments offer limited insight into the mechanism by which renal artery stenosis enhances responsiveness to the SPE. Since the magnitude of the SPE in normal animals is known to be largely determined by body fluid and sodium status36 37 and there is evidence of sodium retention in RVH,38 we assessed WB and UNaV in these experiments. If water or sodium retention secondary to renal artery stenosis is responsible for the altered responsiveness to Ang II seen in RVH, we expected that unclipping would result in diuresis, natriuresis, or both. We did not observe an effect of unclipping on WB or UNaV in either experiment. These results are in agreement with those of other investigators in 2K1C hypertension of a duration similar to that in our studies.7
Although not assessing responsiveness to the SPE directly, research from other laboratories suggests other possible mechanisms by which renal artery stenosis could enhance the SPE. It has been reported that sensory afferents from the clipped kidney can modulate peripheral sympathetic nervous system activity in 2K1C rats.39 40 It is possible that activation of these afferent nerves could affect the well-characterized41 interaction between the renin-angiotensin and sympathetic nervous systems. Alternatively, hormones released from the clipped kidney may act in the nonclipped kidney or elsewhere in the body20 to alter responsiveness to Ang II. Recent evidence, for example, shows that bradykinin modulates the SPE of Ang II.42 43 Although treatment with a bradykinin antagonist did not modify the BP response to unclipping in 2K1C rats,44 this peptide could have played a more important role in our studies in which continuous treatment with enalapril would be expected to impair bradykinin metabolism. We plan further experiments to determine the contribution of these mechanisms to the enhancement of the SPE caused by unilateral renal artery stenosis.
A rather large body of evidence supports the existence of a hormonal system in the renal medulla that liberates vasodilator lipids (medullipins) in response to increased medullary interstitial pressure.3 45 46 Many studies have suggested that a major part of the depressor response to unclipping in 2K1C rats is due to release of these lipids.3 33 The theory states that after unclipping, the sudden exposure to elevated arterial pressure in the formerly stenotic kidney serves as a stimulus for release of medullipins, thus causing a decrease in systemic pressure.3 33 The current experiments are suggestive of a role for these lipids in the early phase after unclipping in RVH rats. In the untreated 2K1C hypertensive rats, unclipping was associated with a small, acute decrease in MAP. Other studies have attributed this decrement in BP to medullary lipids.3 33 In contrast, no fall in MAP was observed over the first 6 hours in 2K1C rats in which MAP was maintained at a hypertensive level by enalapril plus Ang II. The observation that Ang II infusion abolished any early depressor response to unclipping is consistent with data33 45 47 showing inhibition of medullipin release by Ang II. Taken together, these results are supportive of a role for medullipin release in the early response to unclipping in 2K1C rats but also suggest that medullary lipids are not required for the chronic depressor effect of correction of renal artery stenosis.
In summary, we have shown that unclipping the renal artery in angiotensin-dependent 2K1C hypertensive rats can result in a normalization of BP within 48 hours, even in a setting of constant low-dose infusion of Ang II. The depressor response to unclipping was not associated with diuresis or natriuresis. These results suggest that the fall in BP after correction of renal artery stenosis in RVH is in part due to a decrease in responsiveness to the SPE of Ang II.
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Acknowledgments |
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This work was supported by grant HL-24111 from the National Heart, Lung, and Blood Institute. Matthew G. Melaragno is a recipient of a Pharmaceutical Research and Manufacturers of America Foundation Fellowship for Advanced Predoctoral Training in Pharmacology and Toxicology.
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Footnotes |
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Reprint requests to Gregory D. Fink, PhD, Department of Pharmacology and Toxicology, Michigan State University, B-440 Life Sciences Bldg, East Lansing, MI 48824-1317. E-mail finkg@pilot.msu.edu.
Received January 10, 1996; first decision February 9, 1996; accepted June 17, 1996.
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References |
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