(Hypertension. 1995;25:288-293.)
© 1995 American Heart Association, Inc.
Articles |
Enhanced Slow Pressor Effect of Angiotensin II in Two-Kidney, One Clip Rats
From the Department of Pharmacology and Toxicology, Michigan State University, East Lansing.
Correspondence to Gregory D. Fink, PhD, Department of Pharmacology and Toxicology, Michigan State University, B-327 Life Sciences Bldg, East Lansing, MI 48824.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract Phase II of two-kidney, one clip (2K1C) Goldblatt hypertension in the rat is characterized by elevated blood pressure and near-normal plasma concentrations of angiotensin II (Ang II) but is reversed by inhibition of the renin-angiotensin system. We hypothesized that this angiotensin dependence is due to enhanced responsiveness to the slow pressor effect of Ang II caused by renal artery stenosis. To test this idea, we submitted rats to either renal artery clipping or sham operation. These groups were immediately subdivided; some animals received enalapril in their drinking water (508 µmol/L), and the rest drank distilled water only. After 10 to 14 days, catheters were inserted into the aorta and vena cava, and the rats were housed in metabolism cages. After 3 control days of measurement of mean arterial pressure and other variables, the enalapril-treated groups received an intravenous infusion of Ang II at a dose of 3.8 pmol/min (4 ng/min) for 14 days. Rats not drinking enalapril received only saline vehicle (2 mmol Na+ per day). After 3 days of Ang II infusion, the enalapril-treated 2K1C rats had attained a significantly higher level of mean arterial pressure than the enalapril-treated sham rats. At the end of the Ang II infusion, mean arterial pressure in enalapril-treated 2K1C rats was 151±6 mm Hg versus 107±7 mm Hg in enalapril-treated sham rats. Mean arterial pressure in the enalapril-treated sham rats after Ang II infusion was not significantly different from that of untreated sham rats (109±2 mm Hg). No significant differences in urinary sodium excretion or water balance were noted between the 2K1C and sham rats. These results support the hypothesis that 2K1C rats exhibit enhanced responsiveness to the slow pressor effect of Ang II.
Key Words: hypertension, renovascular • angiotensin II • rats
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The idea that two-kidney, one clip (2K1C) Goldblatt hypertension in rats evolves in a triphasic manner was first suggested in 1976 by Brown et al.1 Phase I is characterized by dramatic, parallel increases in blood pressure (BP), plasma renin activity, and circulating angiotensin II (Ang II) concentrations that occur in the period immediately following constriction of the renal artery. Removal of the renal artery clip or administration of an angiotensin-converting enzyme (ACE) inhibitor during this phase results in a prompt fall in plasma Ang II concentrations and BP. Over the course of 2 to 4 weeks, plasma renin activity and Ang II levels tend to fall back to near normal, whereas BP remains elevated or continues to increase.2 This scenario is characteristic of phase II 2K1C hypertension. Despite normal levels of renin and Ang II, the hypertension in phase II is still angiotensin dependent, because BP can be completely normalized by ACE inhibitors.3 If phase II 2K1C hypertension goes untreated for several months, there is a gradual progression to phase III, in which inhibition of the renin-angiotensin system (RAS) is no longer capable of completely reversing the hypertension.
The apparent dissociation between circulating Ang II concentrations and BP in phase II in the face of continued angiotensin dependence represents an interesting paradox: Why are ACE inhibitors effective antihypertensive agents when circulating renin and Ang II are not elevated? Several theories have been advanced to answer this question. One idea is that the antihypertensive effects of ACE inhibitors are due to pharmacological actions of these drugs not related to inhibition of Ang II formation. The fact that the vasodilator bradykinin is a substrate for ACE has led some investigators to postulate that ACE inhibitors lower BP by inhibiting the enzymatic breakdown of the peptide by ACE.4 According to this theory, during ACE inhibition, tissue bradykinin levels increase, causing vasodilation and a subsequent lowering of BP. This idea has been tested repeatedly but with inconclusive results.5 6 It has also been suggested that ACE inhibitors lower BP by increasing production of vasodilator prostanoids,7 by enhancing nitric oxide action,8 and, more recently, by blocking Ca2+ influx in vascular smooth muscle cells.9 None of these ideas have received wide acceptance.
Recently, a new hypothesis has been advanced to explain the antihypertensive effects of ACE inhibitors in situations in which the circulating RAS is not overtly activated. It was proposed that in 2K1C hypertension, various tissue RASs are activated whose products act in a primarily paracrine fashion and thus are not detectable in plasma.10 11 Inhibition of such local Ang II formation by ACE inhibitors could be responsible for their antihypertensive effect. The contribution of these local RASs to 2K1C hypertension remains controversial.12 13
Another possibility is that phase II 2K1C hypertension is a manifestation of an augmentation of the pressor actions of circulating Ang II. It is well documented that blood-borne Ang II can raise arterial pressure through two distinct mechanisms. Larger doses of the peptide (>29 pmol/kg per minute) increase BP acutely over seconds to minutes. This is the direct, or fast, pressor effect of Ang II. The fast pressor effect is thought to be mainly caused by the vasoconstrictor actions of the peptide. The other mechanism by which circulating Ang II can increase BP is the "slow pressor effect." The slow pressor effect, first characterized by Dickinson and Lawrence14 in 1963, is the phenomenon by which infusion of low doses of Ang II that do not cause an acute (seconds to minutes) pressor response, when maintained over hours to days, produces sustained hypertension. The slow pressor effect was extensively studied by Brown et al.15 From their work, it is evident that barely detectable increases in plasma Ang II can over time elicit significant chronic hypertension in normal rats. It is possible that in 2K1C hypertension, the effects of one or both of these pressor mechanisms may be enhanced and may thus maintain elevated BP. Despite the occurrence of structural vascular changes in 2K1C rats, causing an increase in the reactivity of resistance vessels in vitro, previous reports16 have demonstrated that the fast pressor effect of Ang II is not increased in 2K1C hypertension. However, the contribution of the slow pressor effect in this model has not been adequately assessed.
We hypothesize that renal artery stenosis brings about enhanced responsiveness to the slow pressor effect of circulating Ang II and that this explains the paradoxical angiotensin dependence of phase II 2K1C hypertension when circulating Ang II concentrations are normal or only slightly elevated. The idea that 2K1C hypertension is associated with enhanced responsiveness to the slow pressor effect of Ang II is not entirely new. Other investigators3 17 18 19 have published data suggesting an increased sensitivity to slow pressor mechanisms of Ang II in 2K1C hypertension. Nevertheless, this hypothesis has never been directly tested. Therefore, in the present study, we examined the slow pressor effect of circulating Ang II in 2K1C rats.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Animals
Male Sprague-Dawley rats (Sasco, Madison, Wis) weighing 250 to 350 g 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 were allowed access to standard rat chow (Teklad) and tap water ad libitum.
Surgical Procedures
All surgical procedures were performed after the administration
of pentobarbital sodium (181.5 µmol/kg [45 mg/kg] IP, Abbott
Laboratories). If necessary, anesthesia was supplemented during surgery
with methohexital sodium (17.6 to 35.2 µmol/kg [5 to 10 mg/kg] IV,
Eli Lilly). Postoperative analgesia was provided by a single injection
of butorphanol tartrate (1.1 µmol/kg [0.5 mg/kg] SC, Bristol
Laboratories).
Induction of Renal Artery Stenosis
Renal artery stenosis was produced by the application of a
0.2-mm internal diameter silver clip over the left renal artery via an
abdominal incision. Rats treated in this manner were termed 2K1C.
Sham-operated rats underwent abdominal incision and left renal artery
isolation, but no clip was placed. Postoperatively, the rats received a
single injection of penicillin G and dihydrostreptomycin (0.2 mL IM,
Pfizer) to prevent infection.
Arterial and Venous Catheterization
Ten to 14 days after renal artery clipping or sham operation,
rats were catheterized. Body weights at the time of catheterization
were 369±12 g for enalapril-treated 2K1C rats, 379±11 g for
enalapril-treated sham rats, 404±16 g for vehicle-treated sham rats,
and 365±12 g for vehicle-treated 2K1C rats. Differences between groups
were not significant. Arterial and venous catheters, constructed of
polyvinyl chloride (Norton Performance Plastics) with
silicone rubber tips (Dow Corning), were advanced through the left
femoral artery and vein into the abdominal aorta and vena cava,
respectively. The ends of the catheters were tunneled subcutaneously to
the head, where they were anchored to the skull using jeweler's screws
(Small Parts) and dental acrylic (Dentsply). The ends of the catheters
were then passed through a stainless steel spring (McGuire Spring Corp)
attached to a plastic swivel, through which infusions were given. After
regaining consciousness, rats 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 days of
recovery from surgery were allowed before experimentation was begun;
tobramycin sulfate (701.6 nmol [1.0 mg] IV, Eli Lilly) was given once
daily during this period to prevent infection.
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 obtained daily from 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). Sodium and
potassium excretions were calculated by multiplying electrolyte
concentration by daily urinary volume. Water balance was calculated as
the difference between daily water intake and urine output. Mean
arterial pressure (MAP) and heart rate were recorded daily from the
arterial catheter by connection to a pressure transducer (model P10EZ,
Gould Instruments) attached to a digital BP monitor (model BP2,
Stemtech) and a polygraph (model 7B, Grass Instrument Co). All
measurements were obtained between 8 AM and noon.
Experimental Protocol
Two groups of 2K1C rats and two groups of sham rats were
studied. Immediately after renal artery clipping or sham operation, one
group of 2K1C rats (n=8) and one group of sham rats (n=8) drank
enalapril maleate (Sigma Chemical Co) at a concentration of 508
µmol/L (250 mg/L) in their drinking water until the end of the
experiment. This was done to prevent the development of hypertension in
the 2K1C rats and to ensure that both groups began the experiment with
similar MAP levels. The two remaining rat groups (2K1C, n=11; sham,
n=8) drank distilled water only throughout the experiment.
Ten to 14 days after initial surgery, rats were catheterized as described above and placed in metabolism cages. After 3 days of recovery from surgery, experimentation was begun. Three control days of measurements were taken (days C1 through C3). Then the two groups of animals drinking enalapril received an intravenous infusion of Ang II (Sigma) at 3.8 pmol/min (4 ng/min) for 14 days (days E1 through E14). This infusion rate was chosen because previous data showed that it produces a gradual rise in MAP when given chronically while not affecting MAP acutely.20 The two groups not drinking enalapril were catheterized but did not receive Ang II. All measurements were taken daily throughout the protocol. In addition, at three times during the experiment (days C3, E4, and E11), the acute pressor response to a 38.6 pmol (50 ng) bolus of Ang I (Sigma) was recorded. This was done to ensure adequate ACE inhibition in the enalapril-treated rats.
Statistical Analysis
Results are expressed as mean±SEM. For all data, within- and
between-group differences were analyzed by mixed-design ANOVA. Post hoc
between-group comparisons were performed by testing simple main
effects. The criterion for statistical significance was a probability
level of less than .05. All analyses were performed with a computer
software package for statistics (CRUNCH Version 4).
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Chronic enalapril treatment (508 µmol/L drinking water) was effective in preventing the development of hypertension during the control period in the 2K1C rats (Fig 1). In fact, this enalapril dose resulted in significant hypotension (MAP on day C2, 88±6 mm Hg) in these rats compared with vehicle-treated sham rats (MAP on day C2, 109±2 mm Hg). Likewise, pretreatment with enalapril resulted in significant hypotension (MAP on day C2, 88±5 mm Hg) in the sham rats receiving the drug compared with vehicle-treated shams. MAP on day C2 in vehicle-treated 2K1C rats was 124±6 mm Hg (data not shown). Fig 1 shows that Ang II infusion at a dose of 3.8 pmol/min in 2K1C rats treated with enalapril caused them to attain a significantly higher MAP level (MAP on day E14, 151±6 mm Hg) than enalapril-treated sham rats (MAP on day E14, 107±7 mm Hg) also receiving 3.8 pmol/min Ang II. The greater hypertensive response to Ang II in 2K1C rats treated with enalapril did not occur rapidly. Differences in MAP between these groups were not significant until the third day of the infusion period. After this time, the differences were significant until the end of the experiment, with the exception of day 5 of the Ang II infusion period. Fig 1 also demonstrates that Ang II infusion increased MAP in enalapril-treated sham rats (MAP on day E14, 107±7 mm Hg) only to a level not significantly different from MAP in vehicle-treated sham rats (MAP on day E14, 109±2 mm Hg), suggesting that 3.8 pmol/min was a reasonable physiological dose of the peptide. MAP of vehicle-treated 2K1C rats on day E14 was 121±6 mm Hg (versus 124±6 mm Hg on day C2), indicating that this rat group had stable hypertension throughout the protocol.
|
Fig 2 presents water balance data for 2K1C rats receiving enalapril, enalapril-treated sham rats, and vehicle-treated shams. No statistically significant differences in water balance between 2K1C rats on enalapril and sham rats on enalapril were seen during the control period. On day C2, water balance for 2K1C enalapril-treated rats was 11±2 mL and was 8±2 mL for enalapril-treated sham rats. Likewise, water balance in vehicle-treated sham rats (8±3 mL on day C2) was not different from that seen in either enalapril-treated group during the first 2 days of the control period. However, there was a statistically significant difference in water balance between enalapril-treated shams and vehicle-treated shams on day C3 only. Ang II infusion did not result in significant differences in water balance between groups receiving the peptide, with the exception of day 7 of the infusion period, when water balance in 2K1C rats (14±3 mL) was higher than that of the shams (8±4 mL). At the end of the experiment, on day E14, water balance was 10±2 mL for enalapril-treated 2K1C rats, 11±2 mL for enalapril-treated shams, and 9±1 mL for vehicle-treated shams. Differences between groups were not statistically significant. In vehicle-treated 2K1C rats, water balance during the control period (day C2) was 8±3 mL, and at the end of the experiment (day E14) water balance was 12±1 mL (data not shown).
|
Fig 3 shows data on urinary sodium excretion. No significant differences in sodium excretion were noted between any groups studied. All rats were on a fixed sodium intake of 2.0 mmol/d. Accordingly, on day C2, sodium excretion was 2.05±0.30 mmol for enalapril-treated 2K1C rats, 1.65±0.14 mmol for enalapril-treated shams, and 1.51±0.12 mmol for vehicle-treated sham rats. Ang II infusion did not result in any significant differences in urinary sodium excretion between the experimental groups. The only exception to this was on the seventh day of the infusion, when differences in sodium excretion between enalapril-treated groups were significant. At the end of the experiment, on day E14, urinary sodium excretion was 1.62±0.20 mmol for enalapril-treated 2K1C rats, 1.39±0.17 mmol for enalapril-treated shams, and 1.65±0.23 mmol for vehicle-treated sham rats. In the vehicle-treated 2K1C rats, urinary sodium excretion on day C2 was 1.73±0.25 mmol, and on day E14 it was 1.22±0.21 mmol (data not shown).
|
At three times during the course of the experiment (days C3, E4, and E11), the acute pressor response to a 38.6 pmol IV bolus of Ang I was measured in all rat groups. This was done to make certain that enalapril was effective in causing ACE inhibition in rats receiving the drug. Fig 4 shows the results. At all three times tested, during both the control period and Ang II infusion, rats treated with enalapril (2K1C and shams) showed a significantly attenuated acute pressor response to Ang I compared with the vehicle-treated group. The acute response to Ang I in vehicle-treated 2K1C rats (data not shown) did not differ from that of the vehicle-treated sham rats at any time throughout the protocol.
|
Other results revealed no significant differences in heart rate between the enalapril-treated groups during either the control period or Ang II infusion. On day C2, heart rate was 417±16 beats per minute (bpm) in enalapril-treated 2K1C rats and 387±13 bpm in enalapril-treated sham rats. On day E14, these values were 406±13 and 380±19 bpm, respectively. Likewise, heart rate did not differ between the two vehicle-treated groups at any time throughout the experiment. On day C2, heart rate was 407±12 bpm in vehicle-treated 2K1C rats and 404±13 bpm in vehicle-treated sham rats. On day E14, these values were 396±11 and 372±24 bpm, respectively. Measurement of daily urinary potassium excretion yielded no significant differences between any groups in the study. Potassium excretion on day C2 was 4.05±0.38 mmol in enalapril-treated 2K1C rats, 3.57±0.40 mmol in enalapril-treated sham rats, 2.99±0.33 mmol in vehicle-treated 2K1C rats, and 3.36±0.32 mmol in vehicle-treated sham rats. On the last day of the experiment (day E14), urinary potassium excretion was 4.90±0.35 mmol in enalapril-treated 2K1C rats, 4.08±0.26 mmol in enalapril-treated sham rats, 3.74±0.37 mmol in vehicle-treated 2K1C rats, and 3.82±0.34 mmol in vehicle-treated sham rats.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Speculation that renal artery stenosis causes increased sensitivity to circulating Ang II was originally put forth in articles in which the BP response to reclipping a recently unclipped renal artery was studied. Skulan and coworkers17 found that unclipping the renal artery in 2K1C hypertensive rats in phase II resulted in a rapid normalization of BP. When they reapplied the clip to the same renal artery 2 days after unclipping, BP rose to pre-unclipping levels within 2 hours. However, when the rats were left unclipped for 21 days and then reclipped, the increase in BP was delayed and took days to reach pre-unclipping levels. In the same article, these authors reported that the arterial pressure response to short-term infusions of exogenous renin or Ang II was exaggerated in the 2-day unclipped rats compared with naive control rats. From these data, the authors concluded that the 2-day unclipped rats exhibited a reversibly increased sensitivity to Ang II caused by some unknown physiological change. Several years later, many of the experiments performed by Skulan et al were repeated by ten Berg and de Jong,18 and their results confirmed those reported by Skulan et al. They too suggested that renal artery stenosis causes increased sensitivity to Ang II.
The idea that the increased sensitivity to Ang II seen in phase II of 2K1C hypertension is related to the slow pressor effect of the peptide was addressed by other investigators in experiments using the ACE inhibitor captopril.3 19 It was found that long-term (12 to 20 days) administration of captopril to 2K1C hypertensive rats during phase II prevented any further rise in BP.3 Untreated 2K1C rats exhibited a large increase in BP over the same time course, yet plasma renin and Ang II levels were within the normal range. The authors concluded that the rise in MAP during phase II was due to Ang II acting through its slow pressor effect. In a later article,19 this same group compared the short- and long-term effects of captopril in phase II 2K1C hypertensive rats. They found that long-term captopril administration lowered MAP to a greater extent than short-term treatment with the drug. This greater response was postulated to reflect reversal of the slow pressor effect of the peptide.
The studies cited above provided evidence that the slow pressor effect was instrumental in phase II of 2K1C hypertension in the rat, but they did not evaluate that mechanism directly. Li and Jackson21 proposed that the slow pressor effect of Ang II could also play an important part in the hypertension of the spontaneously hypertensive rat (SHR) and designed experiments to test this idea in a more straightforward fashion. Both SHR and their normotensive control strain, Wistar-Kyoto rats (WKY), were treated with captopril from 4 weeks of age to prevent hypertension development in the SHR. Then, infusions of Ang II or norepinephrine were begun and continued for 2 weeks. The SHR showed a much greater rise in arterial pressure in response to Ang II than the WKY, whereas the response to norepinephrine did not differ. The authors attributed the differential response to an enhanced slow pressor effect of Ang II in the SHR.
The purpose of our study was to quantitate directly the slow pressor effect of circulating Ang II in chronically instrumented conscious rats with unilateral renal artery stenosis using a design modeled on that of Li and Jackson.21 The data indicate that Ang II, when infused at a dose of 3.8 pmol/min (4 ng/min), caused 2K1C rats maintained normotensive by drinking enalapril to attain a much higher level of MAP than identically treated sham rats. Differences in the pressor responses to Ang II became significant only after 3 days of infusion but continued to be so for the remainder of the experiment. These results show clearly that rats with unilateral renal artery stenosis exhibit an enhanced slow pressor response to Ang II. Assuming that Ang II infusion produced similar plasma peptide concentrations in enalapril-treated sham and 2K1C rats, the data indicate that renal artery stenosis increases responsiveness to the slow pressor effect of Ang II. That the rate of Ang II infusion we chose (3.8 pmol/min) provides a reasonable physiological plasma concentration of the peptide is suggested by the finding that this rate restored a normal MAP level in sham rats chronically treated with enalapril. In addition, Brown et al15 reported that an intravenous dose of Ang II approximately twice that which we used produced only marginal increases in plasma concentrations of the peptide when infused for 7 days. Taken together, these results may explain the apparent dissociation between plasma Ang II and BP noted in phase II of 2K1C hypertension in the rat, when a decline to near-normal plasma concentrations of Ang II occurs despite maintained or steadily increasing BP.
Possible mechanisms to explain the slow pressor effect of Ang II have been reviewed by Lever22 : actions of Ang II on sodium and water handling, augmentation of neurogenic pressor systems, and promotion of structural alterations in the vascular wall. Our experiment suggests that the increase in MAP brought about by Ang II infusion was not caused by water or electrolyte retention because no significant differences in these parameters were seen between rats receiving Ang II and vehicle-infused controls. But normal values for urinary sodium excretion in hypertensive rats receiving Ang II infusion confirm the recent demonstration that long-term Ang II infusion shifts the pressure-natriuresis relation in rats.23
The current experiments were not designed to examine the mechanism of the enhancement of the slow pressor effect of Ang II caused by renal artery stenosis. However, studies from other laboratories offer some possibilities. One potential mechanism is positive modulation of peripheral sympathetic nervous system activity, mediated by sensory afferents from the clipped kidney.24 25 Second, hormones released from the stenotic kidney in 2K1C hypertension may act in the contralateral kidney26 27 or elsewhere in the body27 to alter responsiveness to Ang II. A third mechanism that could contribute to the enhanced slow pressor effect in 2K1C rats is sodium retention. It is well known that the hypertension caused by Ang II infusion is sodium dependent.28 29 In addition, there have been reports of sodium retention in the development of 2K1C hypertension,30 31 although this subject remains controversial.32 If sodium retention were greater in 2K1C rats than in sham rats during the time between renal artery clipping and catheterization, this likely would have played a role in augmenting the slow pressor effect in the 2K1C group. However, we did not assess body fluid status during this period in our rats. Further experiments are needed to uncover the mechanism or mechanisms underlying our results.
An enhanced slow pressor effect of Ang II in 2K1C hypertension has important implications for current theories relating MAP and RAS activity in renal hypertension. Recently, increased local production of Ang II was demonstrated in specific tissues in 2K1C hypertension.10 11 33 Most tissue-generated Ang II acts in a paracrine fashion and does not enter the general circulation.34 There is evidence that locally produced Ang II may be responsible for the maintenance of hypertension when circulating levels of the peptide are normal, such as in phase II of 2K1C hypertension.33 35 Also, the ability of ACE inhibitors and Ang II receptor antagonists to normalize BP in phase II could be attributed to inhibition of local production or actions of the peptide, respectively.36 37 38 39 Our results suggest, however, that increased tissue Ang II formation may not be required to explain the RAS dependence of phase II 2K1C hypertension, because only a small increment in circulating Ang II completely restored BP in enalapril-treated 2K1C rats, in which most local tissue formation of Ang II was presumably blocked.37 38 39 Thus, in the face of increased responsiveness, even a normal circulating concentration of Ang II may be a major determinant of arterial pressure in 2K1C hypertension.
Finally, since ACE inhibitors lower MAP in individuals with normal circulating RAS activity, many investigators have suggested that these drugs may act primarily by potentiating the effects of bradykinin,5 promoting the release of vasodilator prostanoids,7 enhancing nitric oxide action,8 or altering vascular smooth muscle Ca2+ influx.9 Our finding and earlier reports21 40 that a low-dose infusion of Ang II alone was sufficient to rapidly overcome the antihypertensive effect of long-term ACE inhibitor treatment suggest that inhibition of Ang II production is a critical part of the ability of ACE inhibitors to lower BP. Furthermore, if enhanced responsiveness to blood-borne Ang II maintains elevated BP in phase II of 2K1C hypertension, merely decreasing the concentration of the peptide in the circulation with ACE inhibitors should be effective in normalizing BP.
In summary, we have reported that renal artery stenosis causes enhanced responsiveness to the slow pressor effect of circulating Ang II in rats. Our results suggest that such enhanced responsiveness may explain the apparent dissociation between plasma Ang II concentrations and BP seen in phase II of 2K1C hypertension in the rat, when normal plasma levels of the peptide are capable of maintaining hypertension. Further experiments are needed to elucidate the mechanism or mechanisms responsible for this phenomenon.
|
Acknowledgments |
|---|
This work was supported by grant HL-24111 from the National Heart, Lung, and Blood Institute. Matthew G. Melaragno is supported by a Pharmaceutical Manufacturers Association Foundation Fellowship for Advanced Predoctoral Training in Pharmacology and Toxicology.
|
Footnotes |
|---|
Portions of this work were presented in poster form at the 47th Annual Fall Conference of the American Heart Association Council for High Blood Pressure Research, San Francisco, Calif, September 28-October 1, 1993.
Received May 23, 1994; first decision July 27, 1994; accepted October 26, 1994.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
- Brown JJ, Cuesta V, Davies DL, Lever AF, Morton JJ, Padfield PL, Robertson JIS, Trust P. Mechanism of renal hypertension. Lancet. 1976;1:1219-1221. [Medline] [Order article via Infotrieve]
- Morton JJ, Wallace ECH. The importance of the renin-angiotensin system in the development and maintenance of hypertension in the two-kidney, one-clip hypertensive rat. Clin Sci. 1983;64:359-370. [Medline] [Order article via Infotrieve]
- Wallace ECH, Morton JJ. Chronic captopril infusion in two-kidney, one-clip rats with normal plasma renin concentration. J Hypertens. 1984;2:285-289. [Medline] [Order article via Infotrieve]
-
Swartz SL, Williams GH, Hollenberg NK, Moore TJ, Dluhy RG.
Converting enzyme inhibition in essential hypertension: the hypotensive
response does not reflect only reduced angiotensin II formation.
Hypertension. 1979;1:106-111.
[Abstract/Free Full Text] -
Bao G, Gohlke P, Qadri F, Unger T. Chronic kinin receptor
blockade attenuates the antihypertensive effect of ramipril.
Hypertension. 1992;20:74-79.
[Abstract/Free Full Text] - Carretero OA, Scicli AG. Local hormonal factors (intracrine, autocrine, and paracrine) in hypertension. Hypertension. 1991;18(suppl I):I-58-I-69.
- Schrör K. Role of prostaglandins in the cardiovascular effects of bradykinin and angiotensin-converting enzyme inhibitors. J Cardiovasc Pharmacol. 1992;20(suppl 9):S68-S73.
-
Goldschmidt JE, Tallarida RJ. Pharmacological evidence that
captopril possesses an endothelium-mediated component
of vasodilation: effect of sulfhydryl groups on
endothelium-derived relaxing factor. J Pharmacol
Exp Ther. 1991;257:1136-1145.
[Abstract/Free Full Text] -
Zhu Z, Tepel M, Neusser M, Mehring N, Zidek W. Effect of
captopril on vasoconstriction and Ca2+ fluxes in
aortic smooth muscle. Hypertension. 1993;22:806-811.
[Abstract/Free Full Text] -
Nishimura M, Milsted A, Block CH, Brosnihan KB, Ferrario CM.
Tissue renin-angiotensin systems in renal hypertension.
Hypertension. 1992;20:158-167.
[Abstract/Free Full Text] -
Okamura T, Miyazaki M, Inagami T, Toda N. Vascular
renin-angiotensin system in two-kidney, one clip hypertensive rats.
Hypertension. 1986;8:560-565.
[Abstract/Free Full Text] -
von Lutterotti N, Catanzaro DF, Sealy JE, Laragh JH. Renin is
not synthesized by cardiac and extrarenal tissues: a review of
experimental evidence. Circulation. 1994;89:458-470.
[Abstract/Free Full Text] -
Dzau VJ, Re R. Tissue angiotensin system in cardiovascular
medicine: a paradigm shift? Circulation. 1994;89:493-498.
[Free Full Text] - Dickinson CJ, Lawrence JR. A slowly developing pressor response to small concentrations of angiotensin: its bearing on the pathogenesis of chronic renal hypertension. Lancet. 1963;1:1354-1356. [Medline] [Order article via Infotrieve]
-
Brown AJ, Casals-Stenzel J, Gofford S, Lever AF, Morton JJ.
Comparison of fast and slow pressor effects of angiotensin II in the
conscious rat. Am J Physiol. 1981;241:H381-H388.
[Abstract/Free Full Text] -
Brown JJ, Casals-Stenzel J, Cumming AMM, Davies DL, Fraser R,
Lever AF, Morton JJ, Semple PF, Tree M, Robertson JIS. Angiotensin II,
aldosterone and arterial pressure: a quantitative approach.
Hypertension. 1979;1:159-179.
[Free Full Text] -
Skulan TW, Brousseau AC, Leonard KA. Accelerated induction of
two-kidney hypertension in rats and renin-angiotensin sensitivity.
Circ Res. 1974;35:734-741.
[Abstract/Free Full Text] -
ten Berg R, de Jong W. Mechanism of enhanced blood pressure
rise after reclipping following removal of a renal artery clip in rats.
Hypertension. 1980;2:4-13.
[Abstract/Free Full Text] - Wallace ECH, Balmforth AJ, Morton JJ. Effect of acute and chronic captopril infusion on blood pressure in the two-kidney, one-clip hypertensive rat. J Hypertens. 1985;3:607-612. [Medline] [Order article via Infotrieve]
- Gorbea-Oppliger VJ, Fink GD. Clonidine reverses the slowly developing hypertension produced by low doses of angiotensin II. Hypertension. 1994;23(part 2):844-847.
-
Li P, Jackson EK. Enhanced slow-pressor response to
angiotensin II in spontaneously hypertensive rats. J Pharmacol
Exp Ther. 1989;251:909-921.
[Abstract/Free Full Text] - Lever AF. The fast and slowly developing pressor effect of angiotensin II. In: Robertson JIS, Nicholls MG, eds. The Renin-Angiotensin System. London, UK: Gower Medical Publishing; 1993:28.1-28.9.
- Van der Mark J, Kline RL. Altered pressure natriuresis in chronic angiotensin II hypertension in rats. Am J Physiol. 1994;266: R739-R748.
- Katholi RE, Whitlow PL, Winternitz SR, Oparil S. Importance of renal nerves in established two-kidney, one-clip Goldblatt hypertension. Hypertension. 1982;4(suppl II):II-166-II-174.
-
Kopp UC, Buckley-Bleiler RL. Impaired renorenal reflexes in
two-kidney, one-clip hypertensive rats.
Hypertension. 1989;14:445-452.
[Abstract/Free Full Text] -
Von Thun AM, Vari RC, El-Dahr SS, Navar LG. Augmentation of
intrarenal angiotensin II levels by chronic angiotensin II infusion.
Am J Physiol. 1994;266:F120-F128.
[Abstract/Free Full Text] -
Martinez-Maldonado M. Pathophysiology of renovascular
hypertension. Hypertension. 1991;17:707-719.
[Abstract/Free Full Text] -
Cowley AW, DeClue JW. Quantification of baroreceptor influence
on arterial pressure changes seen in primary angiotensin-induced
hypertension in dogs. Circ Res. 1976;39:779-787.
[Abstract/Free Full Text] -
DeClue JW, Guyton AC, Cowley AW, Coleman TG, Norman RA, McCaa
RE. Subpressor angiotensin infusion, renal sodium handling, and
salt-induced hypertension in the dog. Circ Res. 1978;43:503-512.
[Abstract/Free Full Text] - Leenen FHH, de Jong W. Plasma renin and sodium balance during development of moderate and severe renal hypertension in rats. Circ Res. 1975;36-37(suppl I):I-179-I-186.
- Möhring J, Möhring B, Näumann HJ, Philippi A, Homsy E, Orth H, Danda G, Kazda S, Gross F. Salt and water balance and renin activity in renal hypertension of rats. Am J Physiol. 1975;228: 1847-1855.
- McAreavey D, Brown WB, Robertson JIS. Exchangeable sodium in rats with Goldblatt two-kidney one-clip hypertension. Clin Sci. 1982;63:271-274. [Medline] [Order article via Infotrieve]
-
Shiota N, Miyazaki M, Okunishi H. Increase of angiotensin
converting enzyme gene expression in the hypertensive aorta.
Hypertension. 1992;20:168-174.
[Abstract/Free Full Text] -
Admiraal PJJ, Danser AHJ, Jong MS, Pieterman H, Derkx FHM,
Schalekamp MADH. Regional angiotensin II production in essential
hypertension and renal artery stenosis.
Hypertension. 1993;21:173-184.
[Abstract/Free Full Text] -
Guan S, Fox J, Mitchell KD, Navar LG. Angiotensin and
angiotensin converting enzyme tissue levels in two-kidney, one clip
hypertensive rats. Hypertension. 1992;20:763-767.
[Abstract/Free Full Text] -
Inada Y, Wada T, Shibouta Y, Ojima M, Sanada T, Ohtsuki K,
Itoh K, Kubo K, Kohara Y, Naka T, et al. Antihypertensive effects of a
highly potent and long-acting angiotensin II subtype-1 receptor
antagonist, (±)-1-(cyclohexylocarbonyloxy)ethyl
2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate
(TCV-116), in various hypertensive rats. J Pharmacol Exp
Ther. 1994;268:1540-1547.
[Abstract/Free Full Text] -
Campbell DJ, Kladis A, Duncan AM. Effects of converting enzyme
inhibitors on angiotensin and bradykinin peptides.
Hypertension. 1994;23:439-449.
[Abstract/Free Full Text] - Weber MA, Neutel JM, Smith DHG. Circulatory and extracirculatory effects of angiotensin-converting enzyme inhibition. Am Heart J. 1992;123:1414-1420. [Medline] [Order article via Infotrieve]
- Lee MAE, Paul M, Böhm M, Ganten D. Effects of angiotensin-converting enzyme inhibitors on tissue renin-angiotensin systems. Am J Cardiol. 1992;70:12C-19C. [Medline] [Order article via Infotrieve]
-
Hall JE, Mizelle HL, Brands MW, Hildebrandt DA. Pressure
natriuresis and angiotensin II in reduced kidney mass, salt-induced
hypertension. Am J Physiol. 1992;262:R61-R71.
[Abstract/Free Full Text]
This article has been cited by other articles:
 |
|
 |
|
  E. K. Jackson and W. A. Herzer Renal Extraction of Angiotensin II J. Pharmacol. Exp. Ther., December 1, 2003; 307(3): 1001 - 1006. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Ballew and G. D. Fink Role of ETA receptors in experimental ANG II-induced hypertension in rats Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2001; 281(1): R150 - R154. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. Ballew, S. W. Watts, and G. D. Fink Effects of Salt Intake and Angiotensin II on Vascular Reactivity to Endothelin-1 J. Pharmacol. Exp. Ther., April 13, 2001; 296(2): 345 - 350. [Abstract] [Full Text]
|
|
|
|
 |
|
 C.-T. Wang, S. Y. Chin, and L. G. Navar Impairment of pressure-natriuresis and renal autoregulation in ANG II-infused hypertensive rats Am J Physiol Renal Physiol, August 1, 2000; 279(2): F319 - F325. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Haas, J. D. Krier, R. J. Bolterman, L. A. Juncos, and J. C. Romero Low-Dose Angiotensin II Increases Free Isoprostane Levels in Plasma Hypertension, October 1, 1999; 34(4): 983 - 986. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Hocher, I. George, J. Rebstock, A. Bauch, A. Schwarz, H.-H. Neumayer, and C. Bauer Endothelin System–Dependent Cardiac Remodeling in Renovascular Hypertension Hypertension, March 1, 1999; 33(3): 816 - 822. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. F. Dillon, R. S. Root-Bernstein, and D. D. Holsworth Augmentation of Aortic Ring Contractions by Angiotensin II Antisense Peptide Hypertension, March 1, 1998; 31(3): 854 - 860. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Collister and J. W. Osborn Area postrema lesion attenuates the long-term hypotensive effects of losartan in salt-replete rats Am J Physiol Regulatory Integrative Comp Physiol, February 1, 1998; 274(2): R357 - R366. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. S. Potter, R. J. Johnson, and G. D. Fink Role of Endothelin in Hypertension of Experimental Chronic Renal Failure Hypertension, December 1, 1997; 30(6): 1578 - 1584. [Abstract] [Full Text]
|
|
|
|
|
|
A. Ichihara, E. W. Inscho, J. D. Imig, R. E. Michel, and L. G. Navar Role of Renal Nerves in Afferent Arteriolar Reactivity in Angiotensin-Induced Hypertension Hypertension, January 1, 1997; 29(1): 442 - 449. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. G. Melaragno and G. D. Fink Change in Pressor Responsiveness to Angiotensin II as a Determinant of Blood Pressure After Unclipping in Two-Kidney, One Clip Hypertensive Rats Hypertension, October 1, 1996; 28(4): 656 - 662. [Abstract] [Full Text]
|
|
|
|
|
|
J. P. Collister, B. J. Hornfeldt, and J. W. Osborn Hypotensive Response to Losartan in Normal Rats : Role of Ang II and the Area Postrema Hypertension, March 1, 1996; 27(3): 598 - 606. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||