Rapid Modulation of Renal and Adrenal Responsiveness to Angiotensin II
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1 832 Rapid Modulation of Renal and Adrenal Responsiveness to Angiotensin II Paul R. Conlin, Thomas J. Moore, Gordon H. Williams, Norman K. Hollenberg Reiproal hanges in adrenal and vasular responsiveness to angiotensin II (Ang II) are part of the normal adaptation to shifts in salt intake. When dietary salt intake is abruptly redued from high to low, enhanement in aldosterone seretion requires several days to develop. One established it is not known how quikly the enhanement is reversed with salt repletion. We investigated the time ourse and relative ontributions of salt, volume expansion, or both to this proess by studying IS normotensive subjets; 5 were studied during both high-salt and low-salt balane, and 10 were studied only in low-salt balane. For rapid volume expansion to reverse low-salt balane, 5 subjets reeived in random order an infusion of normal saline or dextran. The adrenal glomerulosa and renal vasular responses to Ang II were assessed after eah volume expansion maneuver. Saline and dextran infusions suppressed plasma renin ativity and aldosterone equally, although dextran ated more slowly. Both also inreased renal perfusion and renal vasular and pressor responses to Ang II, whih in 3 to 7 hours beame idential to responses seen during high-salt intake ("modulation"). Saline infusion also blunted adrenal responsiveness to Ang II during that same interval. Despite suppression of the renin-angiotensin system by dextran infusion, aldosterone responsiveness to Ang II remained enhaned. These observations suggest that the renal and vasular responses to Ang II are modulated rapidly by the effets of volume expansion per se. For the adrenal, modulation is also rapid, but a unique effet of saline (sodium and/or hloride), independent of plasma volume expansion, is responsible for the swift hange in aldosterone responsiveness to Ang II in salt-restrited normotensive subjets. (Hypertension. 1993;22: ) KEY WORDS adrenal glands angiotensin II aldosterone sodium, dietary A ngiotensin II (Ang II) has profound effets on the / \ adrenal zona glomerulosa and vasular smooth A. \. musle, produing stimulation of aldosterone seretion and vasoonstrition in a dose-dependent manner. The magnitude of these vasular and adrenal responses to Ang II is regulated also by shifts in salt intake, whih result in not only hanges in plasma Ang II onentration but also hanges in target tissue responsiveness determined by the level of dietary sodium. 1 With a high-sodium diet the vasular response to Ang II, espeially the renal vasular response, is enhaned and the adrenal response is redued. Conversely, when an individual onsumes a low-salt diet, adrenal responsiveness is inreased, and the vasular response is suppressed. The mehanisms responsible for normal modulation of adrenal and vasular smooth musle responsiveness to Ang II may differ. In the ase of vasular smooth musle, multiple studies have revealed a hange in Ang II reeptor number that appears to be adequate to aount for the hange in response with shifts in salt intake. 2-4 The hange in reeptor number also appears to reflet ambient Ang II onentrations. 2 In the ase of the adrenal Reeived January 13, 1992; aepted in revised form July 15, From the EndoTine-Hypertension Division and Departments of Mediine and Radiology, Brigham and Women's Hospital and Harvard Medial Shool, Boston, Mass. Correspondene to Paul R. Conlin, MD, Endorine-Hypertension Division, Brigham and Women's Hospital, 221 Longwood Ave, Boston, MA glomerulosa, there has been substantial ontroversy, with ambient Ang II onentrations appearing to have less of an influene. 4 In humans the studies have been neessarily more indiret, but the observations are in aord with the more diret animal studies: angiotensin onverting enzyme inhibition reverses the blunted renal vasular sensitivity to Ang II indued by restrition of salt intake but does not influene the response of the normal adrenal to Ang II. 5 ' 6 Dietary sodium restrition-indued hanges in adrenal responsiveness to Ang II require a period of time for their appearane. When salt-replete humans begin to restrit salt intake, the enhaned adrenal response to Ang II beomes apparent only after approximately 2 days and reahes its maximum at 4 to 5 days. 7 No data are available on how quikly these response patterns, one established by restrition of salt intake, an be reversed with a salt load. Rapid suppression of the irulating renin-angiotensin-aldosterone system an be indued by intravasular volume expansion with olloid and rystalloid infusions or head-out water immersion. Both saline infusion and immersion have been shown to suppress plasma renin ativity (PRA) and aldosterone in parallel. 8 Tuk et al 9 ompared the effets of saline- and dextran-indued volume expansion in salt-restrited normotensive subjets. Both maneuvers resulted in a similar nadir for PRA and aldosterone 6 hours after the start of the infusions; however, a temporal differene in the suppression pattern was seen, with dextran produing a slower suppression than saline.
2 Conlin et al Modulation of Angiotensin II Responsiveness 833 We have used the protool of Tuk et al 9 to asertain how quikly hanges in adrenal and renal vasular Ang II responsiveness an be indued by short-term salt and/or volume expansion after sodium restrition. Our first goal was to establish the rapidity with whih the renal and adrenal response patterns, one sensitized by sodium restrition, ould be reverted to that seen when the individual is salt- and/or volume-replete. Our seond goal was to identify the relative ontributions of salt and volume expansion to the regulation of vasular and adrenal responsiveness to Ang II. Methods Subjets We studied 15 normotensive subjets. Eah was admitted to the Clinial Researh Center of the Brigham and Women's Hospital for study. The study was approved by the Human Subjets Committee of the Brigham and Women's Hospital, and written, informed onsent was obtained from eah subjet before partiipation. All subjets onsumed an isoalori onstant diet during the study. Five subjets initially onsumed a diet of 0 mmol sodium and 100 mmol potassium for the first 2 days of study. Subsequently, their diet was hanged to one that ontained 10 mmol sodium and 100 mmol potassium, whih was ontinued for the duration of the study. Ten additional subjets were studied only on the diet ontaining 10 mmol sodium and 100 mmol potassium daily, whih was ontinued for the duration of the study. Daily 24-hour urine olletions were assessed for sodium and reatinine exretion to doument external sodium balane. Aute Volume Expansion After a low-sodium balane was ahieved, 5 subjets reeived an infusion of normal saline or dextran-40 (Rheomarodex, Pharmaia LKB Biotehnology, Pisataway, NJ) to expand intravasular volume rapidly. After a 5- to 6-day reequilibration on the low-salt diet, the alternate infusion was administered. Eah of the 5 subjets reeived both agents in random order. The first infusion was performed after an overnight fast and with subjets in the supine position beginning at 8 AM on the day after low-sodium balane had been ahieved. Saline was administered at 500 ml/h for 4 hours; dextran was infused at 250 ml/h and was aompanied by 250 ml/h of 5% dextrose in water (D5W) for a total of 500 ml/h over 4 hours. The doses of both the salt-ontaining and non-salt-ontaining solutions were designed to ahieve similar volume expansion. The smaller amount of dextran infused was hosen beause dextran-indued intravasular volume expansion ours in part by attrating fluid from extraellular and intraellular ompartments and results in an approximate doubling of the infused volume. 10 The additional D5W was oadministered to avoid this potential interstitial and intraellular spae volume ontration. During the infusion studies, blood samples for measurement of plasma aldosterone, PRA, ortisol, hematorit, and sodium and potassium onentrations were drawn at baseline and 15, 30, 60, 1, and 240 minutes after the start of the infusions. A total of 150 ml of blood was removed over the ourse of eah of the study days and was replaed by D5W provided through the intravenous tube used for blood drawing. Renal Vasular and Adrenal Responses to Angiotensin II For the measurement of renal plasma flow, infusion of para-aminohippurate (PAH; Merk, Rahway, NJ) was begun (8 mg/kg loading dose; 12 mg/min ontinuous infusion) 60 minutes before initiation of the Ang II infusion and was ontinued during the Ang II infusion. The subjets were supine from 12:30 PM, and the infusions were begun at 3 PM. For measurement of the vasular, renal blood flow, and adrenal responses to Ang II, the 5 subjets ompleting the high-salt and low-salt diets reeived Ang II infusions (3 ng/kg per minute for 45 minutes) on four separate oasions during the study: during high-salt balane, on ahieving low-salt balane, 3 hours after the saline infusion, and 3 hours after the dextran infusion. In the other 10 subjets, the infusion study (1, 3, and 10 ng/kg per minute for 45 minutes at eah dose level) was performed only with subjets on the low-salt diet. These subjets were studied onurrent with the 5 subjets ompleting the high-salt and low-salt diet studies and served to anhor the steep orrelation between Ang II and plasma aldosterone observed in subjets onsuming a low-salt diet. 7 This relation was to serve as a major point for omparison after eah of the volume expansion maneuvers. Blood samples were obtained for measurement of plasma aldosterone, PAH, ortisol, sodium, potassium, Ang II, and PRA at the beginning ( 10 and 0 minutes) and end of eah dose of Ang II. Blood pressure was measured every 2 minutes using an indiret reording sphygmomanometer (Dynamap, Critikon, Tampa, Fla). Laboratory Proedures All blood samples were olleted on ie and entrifuged at 4 C; plasma was stored at - C until the time of assay. Aldosterone and ortisol were measured by radioimmunoassay (Diagnosti Produts, Los Angeles, Calif), as were PRA and Ang II." Plasma and urinary eletrolytes were measured with an ion-seletive eletrode system and reatinine by autoanalyzer. Plasma and infusate PAH onentration was measured by a Tehnion autoanalyzer spetrophotometer. Clearane of PAH orreted for body surfae area was alulated as previously desribed. 12 Statistial Analysis Mean values are presented with SEM as the index of dispersion. Differenes between means of parameters within groups were tested for signifiane using the paired / test or analysis of variane; between-group differenes were assessed using the unpaired t test. Time-dependent variables were evaluated using twoway repeated-measures analysis of variane. Correlations of plasma Ang II and aldosterone levels from individuals in balane on high-salt and low-salt diets were assessed using linear regression. The Fisher Exat Test was used to ompare the distribution of data points representing the relation between Ang II and aldosterone levels after dextran and saline infusions, beause the nonhomogeneous distribution of these data preluded the use of linear regression. 13 The null hypothesis was rejeted at a level of f<.05.
3 834 Hypertension Vol 22, No 6 Deember 1993 TABLE 1. Clinial Charateristis of Study Subjets Charateristi n Age, y Weight, kg Male/female Admission BP (mm Hg) Systoli Dlastoll High- and Low-Salt Diets 5 35±6 75±3 3/2 109±3 66±4 BP indiates blood pressure. Values are mean±sem. Low-Salt Diet 10 34±3 72±2 10/0 111 ±3 68±2 A U a, D ^ Q) E m ^ I Pla 1 r Saline I I Results The baseline harateristis of the study subjets are shown in Table 1. The 5 subjets ompleting the highsalt and low-salt protools were similar in harateristis to the 10 subjets ompleting the low-salt diet alone. As expeted, low-salt intake led to ativation of the reninangiotensin system, with inreases in PRA and Ang II levels (Table 2). Likewise, salt restrition inreased plasma aldosterone levels when ompared with high-salt balane. Both saline and dextran infusions administered during low-salt balane resulted in a rapid fall in PRA and aldosterone levels. With saline infusion, aldosterone and PRA differed signifiantly (P<.05) from baseline levels after 60 and 1 minutes, respetively (Fig 1A and IB). In ontrast, dextran infusion aused a slower redution in both PRA and aldosterone, with signifiant differenes from baseline observed only after 240 minutes (P<.05). Despite this differene in suppression pattern, both agents resulted in similar values for PRA and aldosterone 240 minutes after the start of the infusion studies (Table 3). Hematorit fell signifiantly and in parallel during both the saline and dextran infusions, suggesting that similar amounts of volume expansion had ourred (Table 3). infusion resulted in a slightly greater derement in hematorit than saline infusion (P<.05). Likewise, serum sodium and potassium onentrations showed the antiipated fall (due to hemodilution) dur- TABLE 2. Baseline Measurements During High- and Low-Salt Balane Parameter 24-Hour urinary sodium, mmol/d Aldosterone, pmol/l Plasma renin ativity, ng L" 1 s- 1 Angiotensin II, pmol/l Cortisol, nmol/l Serum Na +, mmol/l Serum K +, mmol/l High-Salt (n=5) 225±22 2± ± ±3 190±30 139±1 4.2±0.1 Values are mean±sem. *P<.05 ompared with high-salt. Low-Salt (n=5) 15±4* 970+4* * 34+3* Low-Salt (n=15) 12±2* 9±110* 1.12±0.* 30±3* 250 ±30 138±1 4.3± Time (min) FIG 1. Line graphs show plasma renin ativity (A) and aldosterone (B) responses to saline and dextran infusions plotted as perent of baseline values (see Table 3). Saline ( ) produed a prompt suppression of both plasma renin ativity and aldosterone, whereas the response to dextran (o) was slower. *P<.05 ompared with baseline. ing dextran infusion and differed signifiantly from postsaline values. Three hours after ompletion of the saline and dextran administrations, basal levels of both plasma aldosterone and renal plasma flow differed from those seen during low-salt intake but did not differ from levels obtained during high-salt balane (Fig 2). Ang II was then infused (3 ng/kg per minute for 45 minutes) to determine whether hanges in target tissue responsiveness had ourred as a result of the rapid extraellular fluid and/or plasma volume expansion. There was a rapid shift in renal vasular and pressor responsiveness to Ang II. The fall in renal plasma flow and rise in mean blood pressure indued by Ang II beame equivalent to the responsiveness seen during a high-salt diet. Likewise, in the 3 hours after dextran infusion, the shift in renal vasular and pressor responses to Ang II infusion were essentially idential to those seen after saline (Fig 3). Plasma aldosterone and Ang II onentrations orrelated both during a high-salt (r=.68, P<.01) and low-salt (r=.52, P<.001) diet. As antiipated, the relation between plasma Ang II and plasma aldosterone showed substantial enhanement during the low-salt diet (Fig 4A). The influene of the two volume expansion infusions on adrenal responsiveness was omplex. Saline infusion rapidly suppressed adrenal responsiveness to Ang II (Fig 4B). The individual points were symmetrially distributed about the regression line relating Ang II and aldosterone onentrations during a high-salt
4 TABLE 3. Biohemial and Hematortt Responses to Volume Expansion Conlin et al Modulation of Angiotensin II Responsiveness 835 Saline Parameter Hematorit Serum Na +, mmol/l Serum K +, mmol/l Plasma renln ativity, ng L~ 1 s" 1 Angiotensin II, pmol/l Aldosterone, pmol/l Before 0.42± ± ±0. 32±2 1330±500 After 0.38±0.01* 141 ±1 4.3± ±0.08* 18±2* 280±60* Before ± ±4 1030±470 After 0.35±0.01* 136+1*t t 0.74±0.14* +4* * Values are mean±sem. *P<.05 vs before. tp<.05 vs after. diet (8 above and 7 below). All but one of the data points were below the line defined by steady-state low-salt balane relations. infusion, on the other hand, did not influene the aldosterone response to Ang II despite suppression of the basal levels: indeed, 6 of the 14 data points were on or above the line relating Ang II and aldosterone relations during a low-salt diet. As the range of plasma Ang II onentrations ahieved was relatively narrow, the postsaline Ang II-aldosterone relation was partiularly sensitive to one data point, and the postdextran data was more widely sat- * A 700 O(v, E 650 o D 600 I 550 Si CL ^500 B J. "I 1I I 1 I 50 r 4-0 o i ^ I is 1 i ~ L HS LS SAL DEX FIG 2. Bar graphs show para-aminohippurate (PAH) learane (A) and aldosterone levels (B) obtained 3 hours after ompletion of saline and dextran infusions (n=5). High-salt diet (HS) signifiantly inreased renal blood flow and dereased aldosterone levels ompared with low-salt intake (LS). Both saline (SAL) and dextran (DEX) infusions administered during low-salt balane led to similarly enhaned renal blood flow and redued aldosterone levels ompared with levels seen during low-salt balane. *P<.05 vs LS. tered and nonhomogeneously distributed. Thus, we ompared the responses to saline and dextran by nonparametri analysis. The distributions of data represent- B I s JL 0 HS LS SAL DEX FIG 3. Bar graphs show derement in para-aminohippurate (PAH) learane (A) and inrement in mean blood pressure (B) with angiotensin II infusion (3 ng/kg per minute for 45 minutes) (n=5). Low-salt diet (LS) led to a signifiant redution in angiotensin II responsiveness of the renal blood supply ompared with high-salt balane (HS). Both saline (SAL) and dextran (DEX) infusions administered during low-salt balane rapidly restored this responsiveness to that seen during high-salt balane. These hanges in renal blood flow were assoiated with baseline measurements of 561 ±41 (HS), 526±48 (LS), 601 ±42 (SAL), and 653±37 (DEX) ml (min 1.73 m 2 )" 1, respetively. Vasular responsiveness to angiotensin II (B) paralleled renal blood flow hanges. These hanges in mean blood pressure ourred from baseline measurements of 76±3 (HS), 82+4 (LS), 77±3 (SAL), and 79±4 (DEX) mm Hg, respetively. *P<.05 vs HS.
5 836 Hypertension Vol 22, No 6 Deember 1993 A Oioo 0) o <U < V) O Low solt High salto o O D Post-Saline Post Ang II (pg/ml) FIG 4. Plots show semilog regression relations of plasma angiotensin II (Ang II) and aldosterone levels for individuals in balane on a high-salt diet (HS) and low-salt diet (LS). Ang II infusion for subjets on HS diet (n=5) was 3 ng/kg per minute for 45 minutes; data points from baseline and after Ang II infusion are shown ( ). For subjets on LS diet, Ang II was infused at 3 ng/kg per minute for 45 minutes (n=5) and 1, 3, and 10 ng/kg per minute for 45 minutes at eah dose level (n=10); data from baseline and during Ang II infusion are shown (o). A: LS diet led to enhanement in aldosterone responsiveness to Ang II ompared with HS diet. B: Regression relations between Ang II and aldosterone depited in A are reprodued as dashed lines. Note that aldosterone responsiveness after saline infusion ( ) beame similar to that seen during HS balane, whereas after dextran infusion ( ) the data representing aldosterone-ang II relations were more distributed about the line representing LS balane. The differene in this distribution was signifiant (P<.05). ing Ang II-aldosterone relations after saline and dextran (based on the number of data points that were on or above the regression line derived from individuals on O HS HS LS a low-salt diet) were statistially signifiant (P=.O3, Fisher Exat Test). These different response patterns ould not be attributed to hanges in other regulators of aldosterone seretion. Plasma sodium and potassium were atually lower during Ang II infusion in the dextran-treated subjets, and ortisol levels (as a marker of ortiotropin seretion) did not differ between the two groups (Table 4). Disussion In this study, rapid saline and/or volume expansion had the antiipated effet on the irulating reninangiotensin-aldosterone system. PRA and aldosterone levels that were raised by a low-salt diet were redued by both saline- and dextran-indued volume expansion to levels appropriate to a high-salt intake. Three hours after ompletion of the aute volume expansion maneuvers, whih indued similar falls in hematorit, basal renal plasma flow and its response to Ang II infusion shifted to levels seen during high-salt intake. The adrenal glomerulosa response was more omplex. Saline treatment returned aldosterone responsiveness to a level appropriate to a high-salt intake, whereas dextran infusion did not have the same effet, despite an idential influene on basal onentration. As demonstrated in Fig 4A, the slopes of the relations between Ang II and aldosterone levels were markedly different when individuals onsumed a low-salt versus a high-salt diet. Over the range of Ang II levels ahieved, aldosterone responsiveness on a high-salt diet was shallow, whereas with salt restrition the relation beame more steep. To learly define this relation under saltrestrited onditions required that a full dose response to Ang II be obtained. Therefore, a subset of subjets was studied only during low-salt balane and with a range of doses of Ang II. The pratiality of performing this multiple dose study in the individuals after saline and dextran infusions was preluded by our desire to identify, within the shortest time possible, whether hanges in adrenal and renal responsiveness to Ang II had ourred. Additionally, the limitations on blood drawing imposed by the rigorousness of the study days prevented us from testing more than one Ang II infusion rate. Clearly, the renal blood supply and peripheral vasular responses had shifted during the 7-hour time interval separating the start of the volume expansion and the Ang II infusions. The observation that saline likewise shifted adrenal responsiveness to Ang II during that same time period, whereas dextran administration did not, does not imply that a new steady state had been TABLE 4. Biohemial Responses to Anglotensin II Infusion After Volume Expansion Saline Parameter Serum Na +, mmol/l Serum K +, mmol/l Cortiso), nmol/l Plasma renin ativity, ng L" 1 s" 1 Anglotensin II, pmol/l Before Ang II 4.2± ± ± ±2 After Ang II 4.3± ± ± ±4 Before Ang II 137±1* 3.9±0.1* 170± ± ±4 After Ang II 137±1* 4.0±0.1* 140± ± ±7 Ang II indiates angiotensin II. Values are mean±sem. *P<.05 vs saline Infusion.
6 Conlin et al Modulation of Angiotensin II Responsiveness 837 ahieved. It is very possible that further study at a later time point may have revealed similar shifting in adrenal responsiveness by dextran. Indeed, the apparent satter of the postdextran Ang II-aldosterone relations may reflet the evolution of this proess. The mehanisms responsible for sensitization of the adrenal glomerulosa by restrition of salt intake are inompletely understood. A potentially important lue arose from the time ourse for this ativation in humans: an inrease in responsiveness first beame evident only 48 hours after dietary salt restrition, with full expression present after several days. 7 In rats, this enhaned responsiveness is likewise time dependent, ourring within 48 hours, 14 and an be related to indution of the enzyme involved in the late pathway of aldosterone synthesis (onversion of ortiosterone to aldosterone by aldosterone synthetase) Although all aldosterone seretagogues autely enhane seretion by inreasing the rate of the early pathway (synthesis of pregnenolone from holesterol), 17 it is the inreased ativity of aldosterone synthetase that appears to aount for most, if not all, of the effet of salt restrition on adrenal sensitivity. The slow onset of adrenal sensitization is ompatible with the indution of this biosyntheti pathway rather than hanges in Ang II reeptor density, as ours in the vasulature. Indeed, adrenal Ang II reeptors have been noted to be redued by sodium restrition in primates. 18 The asymmetry in the onset and offset (hysteresis) of adrenal responsiveness suggests that other regulated steps might be affeted by saline infusion: it seems unlikely that the inreased aldosterone synthetase levels reruited gradually by a low-salt diet were reversed during the short period of time that followed saline volume expansion. How does information on the state of sodium balane reah the adrenal glomerulosa? The results of this study support earlier studies whih suggest that omponents of the renin-angiotensin system do not provide ruial information Other suggested andidates as a soure of information to the adrenal have inluded fators suh as atrial natriureti hormone (ANH), dopamine, or digitalis-like fators. Levels of ANH have been shown to trak with the level of sodium intake. Likewise, ANH has potent inhibitory effets on both renin and aldosterone seretion, partiularly in sodiumrestrited subjets Shenker 21 has shown that ANH infusion into sodium-restrited normotensive subjets promptly redued both PRA and aldosterone to levels similar to high-salt balane. However, Tuhelt et al, 23 using similar maneuvers, showed that adrenal responsiveness to Ang II during low-sodium balane was not signifiantly different in the presene or absene of ANH infusion. Also, appropriate interpretation of the effets of ANH may need to take into aount hanges in ANH or yli GMP metabolism that might our during shifts in salt intake. Plasma and urinary dopamine are likewise inreased with sodium loading, and dopamine has been shown to have inhibitory effets on aldosterone seretion both in vivo and in vitro However, short-term dopamine blokade with metalopramide inreases basal aldosterone levels in salt-replete individuals but does not hange aldosterone responsiveness to Ang II. 26 Likewise, levels of endogenous digitalis-like fators have been noted to inrease in response to short-term volume expansion with saline. 27 Although the identity of endogenous Na + -K + pump inhibitors remains ontroversial, it is intriguing that inreasing doses of ouabain have been shown to inhibit aldosterone seretion in vitro. 28 Therefore, the ontributions of ANH, dopamine, and digitalis-like fators to adrenal modulation are unresolved. Despite its major role in autely regulating aldosterone seretion, the state of ativation of the reninangiotensin system is probably not involved in the shifts in responsiveness of the adrenal glomerulosa. Adrenal responsiveness to Ang II during salt restrition does not hange when irulating Ang II levels are redued by either onverting enzyme inhibition 519 or /3-bloker treatment, 29 whih also redues PRA and plasma angiotensin I onentrations. Thus, the physiologial determinants of sodium-regulated hanges in adrenal responsiveness remain obsure. When individuals shift from a very low-salt to a high-salt intake, the kinetis of the natriureti response are omplex There is a onsistent and substantial delay in the natriureti response so that positive sodium balane and weight gain our during the first 24 hours. We had antiipated that the very slow onset of adrenal sensitization during salt restrition would be mathed by a similar slow offset. This lag in suppression of aldosterone seretion thus might ontribute to a delay in natriuresis, as has been observed autely after saline infusion 32 or hronially when dietary sodium is altered In our study the adrenal response to Ang II shifted within hours of saline administration, making it unlikely that aldosterone ontributes more than a small amount to the previously desribed delayed natriuresis. In the short period of time after the suppression of PRA and Ang II levels by saline and dextran infusion, the responsiveness of PAH learane and mean blood pressure to Ang II infusion had reverted to that seen when the subjets were onsuming a high-salt diet. This ourred despite the fat that dextran suppressed PRA more slowly and aused a slightly smaller derement in PRA and Ang II levels than saline. These observations are in keeping with available data from animals and humans that suggest that ambient Ang II levels, ating through a modulation of Ang II reeptor density, determine the vasular smooth musle responsiveness to Ang II. 24 Most intriguing about the present observations is the rapidity of this reeptor modulation. Although we observed similar degrees of volume expansion with the two agents saline and dextran, the present results suggest that the sodium and/or hloride ontent of the infusion solution provided a speifi signal responsible for modulation of adrenal glomerulosa responsiveness. In ontrast, the volume signal provided by saline and dextran was suffiient to inhibit renin seretion and modulate the renal and vasular responses to Ang II. Aknowledgments Supported by grant AGO0599 and Speialized Center of Researh in Hypertension (SCOR) grant HL from the National Institutes of Health (NIH), Bethesda, Md. Dr Conlin is supported by a Clinial Assoiate Physiian award from the National Center for Researh Resoures (RR02635). The study was arried out in a Clinial Researh Center (NIH grant RR02635), and the statistial analyses were performed in a CLINFO faility supported by the same grant. We wish to
7 838 Hypertension Vol 22, No 6 Deember 1993 express our gratitude to Elliot Fishman, RN, and the nursing and dietary staff of the Clinial Researh Center for their expert assistane during the performane of these studies. We also appreiate the advie on statistial analyses provided by Ray Gleason, PhD. Referenes 1. Hollenberg NK, Chenitz WR, Adams F, Williams GH. Reiproal influene of salt intake on adrenal glomrulosa and renal vasular responses to angiotensin II in normal man. J CUn Invest. 1974;54: Gunther S, Gimbrone MA Jr, Alexander RW. Regulation by angiotensin II of its reeptors in resistane blood vessels. Nature. 1980;287: Williams GH, Hollenberg NK, Braley LM. Influene of sodium intake on vasular and adrenal angiotensin II reeptors. Endorinology. 1976;98: Devynk MA, Pernollet GG, MDonald DJ, Mathews PG, Raisman RS, Meyer P. Alterations of adrenal and uterine angiotensin II reeptors during variations of sodium intake and/or experimental hypertension. 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Regulation of aldosterone synthetase ytohrome P-450 in rat adrenals by angiotensin II and potassium. Endorinology. 1991;128: Shiebinger RJ, Braley LM, Menahery A, Williams GH. Unique alium dependenies of the ativating mehanisms of the early and late aldosterone biosyntheti pathways in the rat. J Endorinol. 1986;110: Platia MD, Catt KJ, Hodges GD, Aguilera G. Regulation of primate angiotensin II reeptors during altered sodium intake. Hypertension. 1986;8: Rogaz S, Hollenberg NK, Williams GH. Role of angiotensin II in the hormonal, renal and eletrolyte response to sodium restrition. Hypertension. 1987;9: Sagnella GA, Markandu ND, Shore AC, MaGregor GA. Effets of hanges in dietary sodium intake and saline infusion on immunoreative atrial natriureti peptide in human plasma. Lanet. 1985;2: Shenker Y. Atrial natriureti hormone effets on renal funtion and aldosterone seretion in sodium depletion. Am J Physiol. 1988; 255:R867-R Oelkers W, Kleiner S, Bahr V. Etfets of inremental infusions of atrial natriureti fator on aldosterone, renin, and blood pressure in humans. Hypertension. 1988; 12: Tuhelt H, Eshenhagen G, Bahr V, Shwietzer G, Thiede HM, Oelkers W. Role of atrial natriureti fator in hanges in the responsiveness of aldosterone to angiotensin II seondary to sodium loading and depletion in man. Clin Si 1990;79: Drake CR Jr, Ragsdale NV, Kaiser DL, Carey RM. Dopaminergi suppression of angiotensin II-indued aldosterone seretion in man: differential responses during sodium loading and depletion. Metabolism. 1984;33:6% Carey RM. Aute dopaminergi inhibition of aldosterone seretion is independent of angiotensin II and adrenoortiotropin. J Clin Endorinol Metab. 1982^4: Gordon MB, Moore TJ, Dluhy RG, Williams GH. Dopaminergi modulation of aldosterone responsiveness to angiotensin II with hanges in sodium intake. J Clin Endorinol Metab. 1983;56: Borghi C, Boshi S, Munarini A, Mussi A, Costa FV, Ambrosioni E. Short-term plasma renin ativity suppression by saline and release of a plasma endogenous Na/K ATPase inhibitor in essential hypertension. Am J Hypertens. 1990,3: Braley LM, Williams GH, Menahery AI. The effets of ouabain on steroid prodution by rat adrenal ells stimulated with angiotensin II, ol-24 adrenoortiotropin, and potassium. Endorinology. 1978;103: Gordon MS, Williams GH, Hollenberg NK. Renal and adrenal responsiveness to angiotensin II: influene of beta adrenergi blokade. Endor Res. 1992;18: Wedler B, Brier ME, Wiersbitzky M, Gruska S, Wolf E, Kalhvellis R, Aronoff GR, Luft FC. Sodium kinetis in salt-sensitive and salt-resistant normotensive and hypertensive subjets. J Hypertens. 1992;10: Sagnella GA, Markandu ND, Singer DRJ, MaGregor GA. Kinetis of renal sodium exretion during hanges in dietary sodium intake in man: an exponential proess? Clin Exp Hypertens A. 1990;12: Singer DRJ, Shirley DG, Marandu ND, Miller MA, Bukley MG, Sugden AL, Sagnella GA, MaGregor GA. 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