Sodium Intake Alters the Effects of Norepinephrine on the Renin System and the Kidney

Sodium Intake Alters the Effects of Norepinephrine on the Renin System and the Kidney Laura I. Rankin, M.D., David P. Henry, M.D., Myron H. Weinberger, M.D., Philip S. Gibbs, M.D., and Friedrich C. Luft, M.D. To examine the interactions between sodium intake and the sympathetic nervous system and their influences on the blood pressure control system we studied eight normotensive men after high (800 mEq/d) and low (10 mEq/d) sodium intake. We measured blood pressure, arterial, venous and urinary norepinephrine (NE), glomerular filtration rate (GFR), renal blood flow (RBF), plasma renin activity (PRA) and aldosterone (PA), and the fractional excretion of sodium (FENa) and potassium (FEK) before and during incremental infusion of norepinephrine. High salt intake influenced

the sensitivity to NE as well as subsquent pressor responses. The NE-induced decrease in RBF and GFR was not different on high and low sodium intakes. A significant decrease in FENa (p < 0.05) with NE infusion could only be seen during high sodium intake. A significant increase in PRA (p < 0.01) and PA (p < 0.05) was induced by NE only during the low sodium period. These observations reveal previously unrecognized qualitative and quantitative interactions between sodium homeostasis and norepinephrine which are capable of influencing blood pressure in man.

T

MATERIALS AND METHODS

flow rates during the study. After lunch a venous catheter was placed in the dominant arm and priming doses of inulin and para-aminohippurate were infused. Subjects were recumbent during the study. A solution of 5% dextrose in water (05 W) with sustaining amounts of inulin and P AH was then administered at a rate of 45 mllhr throughout the study. After I hr, a catheter was placed in the radial artery of the nondominant arm. A venous catheter for blood sampling was also placed in the nondominant arm. Eight consecutive 3D-min clearance periods were then conducted. The first two periods provided baseline data. L-Norepinephrine bitartrate (Levophed®. Winthrop Laboratories, New York. N.Y.) was infused in ~oW delivered by a Harvard infusion pump into the venous catheter in the dominant arm at rates of I, 2, 4, 8, and 16lLg/min during consecutive 3D-min periods. A final recovery period was also conducted. If mean arterial blood pressure increased more than 24 mm Hg from control, no subsequent increase in norepinephrine infusion rate was performed and the recovery period was conducted during the next 30 min. At 5. 15, and 25 min of each clearance period, blood pressure was recorded using a P23GB transducer (Statham Gould, Oxnard, Calif.) and an Electronics for Medicine recorder (model VR 12. White Plains , N.Y.) as described previously' At the midpoint of each period, venous blood was sampled for determination of plasma renin activity, sodium, potassium, inulin, PAH, venous norepinephrine, and aldosterone concen-

After due approval by the Indiana University Human Use and Clinical Research Center Committees, eight normotensive men ranging in age from 24 to 38 yr were recruited by advertisement. The protocol was conducted with each subject randomly assigned to low (7 days) and high (5 days) levels of sodium (Na) intake. The basic 10 mEq Na was constant throughout and has been described in detail elsewhere. 3 The high Na diet was identical with the exception that 290 mEq Na was added to the diet in the form of NaC!. An additional 500 mEq NaCI was given in bouillon between and with meals to attain a total Na intake of 800 mEq/day. On the study day. the subject ate breakfast and lunch as usual. Liberal fluid intake was provided to ensure rapid urine

From the Specialized Center of Research (SCOR) in Hypertension. the Lilly Laboratories for Clinical Research. and the Departments of Medicine and Anesthesiology, Indiana University School of Medicine, Indianapolis. Ind. Supported in part by USPHS Grant HL 14159. Specialized Center of Research (SCOR) in Hypertension and RR 00750, (General Clinical Research Celller). Reprilll requests should be addressed 10 Friedrich C. Luft, M.D. , Indiana Universitv Medical Center , Fesler Hall 110, 1100 W. Michigan Street, Indianapolis, Ind. 46223. © 1981 by The National Kidney Foundation, Inc. 0272-6386/81/030177-08$01.00/0

HE KIDNEY and its regulatory systems

influence arterial blood pressure primarily by modulating sodium homeostasis.1.2 Two renal regulatory systems, which are both influenced by sodium intake are the renin-angiotensinaldosterone system and the sympathetic nervous system. 3 -6 We previously examined the effects of extremes in sodium intake on the interrelationships among the renin system, sympathetic nervous system, renal hemodynamics and arterial blood pressure 3 - 5 as well as the effect of low and high sodium intake on the pressor responses and vascular compartmentalization of administered norepinephrine in normotensive man. 7 We now report the effect of low and high sodium intake on the responses of the renin system and on renal hemodynamics to administered norepinephrine in these same normotensive subjects. Our studies provide new information about the adaptive changes that occur following sodium restriction or loading.

American Journal of Kidney Diseases, Vol. I, No. 3 (November), 1981

177

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RANKIN ET AL.

trations. Arterial blood was obtained simultaneously for determination of norepinephrine concentration. Urine was obtained at the end of each period for determination of sodium, potassium, inulin, PAH, and norepinephrine excretion. Diuresis was maintained throughout the study by intravenous D" W infusion. Sodium and potassium were measured with a flame photometer (Instrumentation Laboratories, Boston, Mass.). Inulin and PAH concentrations were determined by an automated method (AutoAnalyzer, Technicon, Chauncey, N.Y.). Plasma renin activity and aldosterone concentrations were measured by previously reported radioimmunoassay methods. s The concentration of norepinephrine in plasma and urine was measured by a radioenzymatic assay. 9 Clearances and fractional excretion were calculated in the usual fashion 3 The data were analyzed using repeated measures analysis of variance, twoway analysis of variance, linear regression analysis, Student's t test or nonparametric approaches as appropriate. The 95% confidence limits were accepted as significant. Results are expressed as mean and standard error of the mean (SEM).

RESULTS

On the day prior to each study the subjects excreted 19.9 ± 4.6 mEq/24 hr of sodium on the 10 mEq Na intake, and 795.8 ± 28.6 mEq/24 hr on the 800 mEq Na intake. Potassium excretion at these times was 61.4 ± 6.6 and 159.4 ± 6.7 mEq124 hr, respectively. The plasma concentrations of sodium and potassium were unaltered by sodium intake or norepinephrine infusion. Table 1 illustrates the mean blood pressure values. All subjects received all five infusion rates of norepinephrine (l, 2, 4, 8, 16 JLg/min) when studied during the low Na phase. However, during the high Na period, six subjects developed an increase of > 25 mm Hg mean arterial pressure with infusion of 8 JLg norepinephrine/min. Thus only two subjects received 16 JLg/min norepinephrine during the high Na regimen. At the 800 mEq/d level of Na intake the basal blood pressure was modestly but significantly (p < 0.05) greater than at the 10 mEq/d level of the Na intake as determined by a one-tailed paired t test. As the infusion rate was increased, the blood pressure was greater for a given norepinephrine Table 1. Mean Arterial Blood Pressure Values (mm Hg) During Norepinephrine Infusion (Mean ± SEM) Period (infusion rate)

Basal 1 lJ,g/min 2 IJ,g/min 4 IJ,g/min 8 IJ,g/min 16 lJ,g/min

10 mEq Na Intake

92.2± 94.1 ± 95.5 ± 99.0± 106.8 ± 117.2±

2.8 2.7 2.3 2.2 1.5 2.0

800 mEq Na Intake

94.5± 3.6 101.2±3.9 104.6 ± 4.6 108.4± 4.6 123.2 ± 5.1 118.1 ± 4.9(n

=

2)

Table 2. Arterial and Venous Plasma Norepinephrine Concentrations (pg/ml) During Norepinephrine Infusion (Mean ± SEM) Period (infusion rate) Basal 1 ",g/min 2 ",g/min 4 ",g/min 8 ",g/min 16 ",g/min

10 mEq Na Intake 800 mEq Na Intake arterial venous arterial

venous arterial venous arterial venous arterial venous arterial venous

192± 264 ± 592 ± 612± 957± 643 ± 1946 ± 953± 3133 ± 1684 ± 8872 ± 3889 ±

35 63 79 181 79 69 124 95 275 226 592 351

86± 17 107± 16 381 ± 47 272 ± 27 773 ± 104 482± 60 1786 ± 229 899 ± 101 3512± 375 1634 ± 318 5896 ± 947 (n 3436 ± 1662 (n

= 2) = 2)

infusion rate after the high Na than the low Na diet (p < 0.01). In addition, the incremental increase in blood pressure at each of the four lower infusion rates (excluding 16 JLg/min) was greater after the high sodium diet (p < 0.05) than during the low sodium intake when compared by paired t test. Table 2 outlines both arterial and venous plasma norepinephrine values. During the basal state arterial and venous values were not different. With infusion there was an incremental increase. According to two-way analysis of variance the arterial levels were greater (p < 0.01) than the venous levels after the infusion of exogenous norepinephrine. The arterial norepinephrine concentration and its urinary excretion rate were highly correlated during both studies (r = 0.86, r = 0.89, P < 0.001). The slopes of this relationship, as illustrated in Fig. 1, were not different in the two studies. The infusion of norepinephrine affected renal hemodynamics. The clearances of inulin and PAH decreased (p < 0.01) in a stepwise fashion as the dose of norepinephrine was increased (Fig. 2), and this relationship was not altered by the sodium intake. As seen in Fig. 3, the clearance of P AH also decreased with norepinephrine infusion (p < 0.001). A rapid return to control levels was observed in the recovery period. As shown in Fig. 4, the basal fractional excretion of NA (FEN a) was higher after the high Na diet than the low Na diet (p < 0.001). With increasing doses of NE, the FEN a decreased (p < 0.05) when the subjects were on the high Na diet. No effect was detected on the low Na diet. No change in the fractional potassium excretion was observed during the norepinephrine infusions. The effect of increasing doses of exogenous norepinephrine upon plasma renin activity (PRA)

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181

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is displayed in Fig. 5. The stimulated PRA noted in control periods during the low Na diet increased further with infu sion of 16 j.tg/min (p < 0.01) . In contrast, the high Na diet suppressed control renin levels (p < 0.01 ) and the subsequent infusion of norepinephrine did not result in a detectable change in PRA. A correlation between ANE and PRA was seen only during the low Na intake ( r = 0.25, p < 0.05) . However , urinary norepinephrine excretion and PRA were correlated at both levels of Na intake (r = 0.31, r = 0.25, p < 0.05). The effect of norepinephrine upon plasma aldosterone concentration (PA) is seen in Fig. 6. Similarly to PRA , the control PA was higher on the 10 mEq Na diet (p < 0.001) and increased further with NE infusion (p < 0.05) but only at the highest dose . During the 800 mEq Na intake, control PA was suppressed and did not change with NE infusion .

giotensin II and norepinephrine in experimental animals . 10. 12 The present study demonstrates that sodium intake influences the blood pressure response to norepinephrine and the sensitivity to that neurohumor as well. 7 In addition it provides important information about the effect of sodium intake on renal hemodynamics , renal sodium regulation, and the renin-angiotensin-aldosterone system . Guyton has proposed that the kidney 's ability to excrete salt and water is a major determinant of blood pressure response. \,2 Thus, observations of renal hemodynamics and function formed the basis for the present study. We observed dosedependent decreases in glomerular filtration rate and renal plasma flow with norepinephrine infusion which were not influenced by salt intake. In experimental animals receiving norepinephrine infusions, most investigators have reported a decrease in renal blood flow but the changes in glomerular filtration rate have been less con sistenL l3 . 20 Renal nerve stimulation has been reported to have variable effects on renal hemodynamics,20-22 but it is known that alpha adrenergic blockade prevents the change in

DISCUSSION

Sodium intake plays an important role in the control of arterial blood pressure even in the normotensive state. 3 Sodium intake influences the responsiveness to vasoactive materials such as an-

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hemodynamics induced by norepinephrine infusion or renal nerve stimulation. 20 In human studies single dose infusion of norepinephrine reduced renal blood flow but not glomerular filtration rate . 23.25 However, this result may have been due to the fact that norepinephrine concentrations were not high enough to cause a discernible change in glomerular filtration . Mills, using two doses of norepinephrine,26 was able to document a decrease in glomerular filtration rate only at a higher dose. The sympathetic nervous system is known to be involved in renal sodium handling. However, the mechanism by which sympathetic stimulation induces sodium reabsorption is not completely clear.14.17.19,22,27-29 In the present studies we were able to detect a change in fractional excretion of sodium only after the high sodium diet, perhaps because the basal level of sodium excretion after the low sodium intake period was too low to per-

Fig. 6. The effect of NE infusion on PA concentrations.

mit detection of a further decrease. To our knowledge the influence of salt intake on norepinephrine induced sodium reabsorption is a unique observation . The second component responsible for renal sodium handling, the renin-aldosterone system, demonstrated virtually complete suppression by a high sodium intake and was not detectably increased by norepinephrine infusion . We cannot, of course, exclude the participation of unexamined factors also thought to influence renal sodium handling. Thus, it would appear that the observed decrease in sodium excretion during high sodium intake was due to a direct effect of norepinephrine on the renal tubule 22 or to decreases in renal blood flow and filtration rate . During sodium depletion, apparent maximal sodium reabsorption prevented the detection of an increase in reabsorption induced by norepinephrine infusion , despite similar decreases in renal blood flow and glomerular filtration rate.

183

SODIUM INTAKE

The effect of norepinephrine on plasma renin activity was also influenced by the state of sodium balance. We detected a significant increase in PRA with norepinephrine infusion after the low sodium period but not while on a high sodium intake. This observation suggests that when renin release is suppressed by high sodium intake sympathetic stimulation of renin release cannot be achieved. It is of interest to note, however, that urinary norepinephrine excretion correlated with plasma renin activity at both levels of sodium intake. This relationship implies that urinary norepinephrine excretion may be a better indicator of renal sympathetic nerve activity than plasma concentrations. 29 - 32 The differential effect of sodium intake on renin release has also been noted with angiotensin II by Williams and colleagues who observed that they could only detect suppression of PRA by angiotensin II infusion when subjects were receiving a low sodium diet, but not after a more liberal (200 mEq/d) sodium intake. 33 Renin release is thought to be mediated by decreases in renal blood flow or pressure (baroreceptor), changes in ion transport by the tubule (macula densa) or direct adrenergic stimulation. 34 Studies utilizing alpha adrenergic blockade 19 or the denervated, nonfiltering kidnef5 have demonstrated sympathetic influences on renin release without alternations in flow, pressure, or sodium handling. The infusion of epinephrine has also been shown to cause dose-related degrees of renin release even though norepinephrine plasma concentrations did not change. 36 In that study sodium intake was not determined. In the present studies,

blood pressure increased with norepinephrine infusion, which would be expected to reduce renin release by the baroreceptor mechanism. In addition, we have previously demonstrated betaadrenergic stimulation of renin release 37 as well as the potential of juxtaglomerular nerves to stimulate renin release38 in isolated kidney slices devoid of hemodynamic and metabolic influences. The failure to detect a significant increase in renin activity during the high sodium phase of the study may have resulted from the technical limitations of assay measurements at low levels or to an interaction between the state of sodium balance and sympathetic-mediated renin release. It is likely that the physiologic role of the renin system has undergone drastic revision with the ever-increasing sodium ingestion of acculturated man. 39 ,40 From that standpoint our studies conducted at the 10 mEq/day level of sodium intake confirm an important interrelationship of the renin system and sympathetic nervous system during sodium depletion. However, hyperactivity of the sympathetic nervous system during periods of high sodium intake may be especially deleterious because of the impact of that system on arterial blood pressure and an even greater tendency toward sympathetic-mediated sodium retention. ACKNOWLEDGMENTS The authors wish to acknowledge the valuable contributions of several individuals to these studies. Mr. David Mannia, Ms. Rebecca Sloan. Mr. Charles Dinwiddie, Mr. Charles Hancock, Mrs. Ann Haddix, and Ms. Mary Wade provided expert technical assistance. Dr. Naomi Fineberg performed the complex statistical analysis. Mrs. Pat Feller assisted in the preparation of the manuscript.

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RANKIN ET AL. 26. Mills LC , Moyer JH, Skelton JM: The effect of norephinephrine and epinephrine on renal hemodynamics. Am J Med Sci 226:653-663, 1953 27. Bello-Reuss E, Trevino DL, Gottschalk CW: Effect of renal sympathetic nerve stimulation on proximal water and sodium reabsorption. J Clin Invest 57: 1104-1108, 1976 28. DiBona GF: Neural control of renal tubular sodium reabsorption in the dog. Fed Proc 37:1214-1217,1978 29. Boren KR, Henry DP, Selkurt EE, et al: Renal modulation of urinary catecholamine excretion during volume expansion in the dog. Hypertension 2:383-389, 1980 30. Henry DP, Dentino M, Gibbs PS, et al: Vascular compartmentalization of plasma norepinephrine in nonnal man. J Lab Clin Med 94:429-437, 1979 31. Luft FC, Weinberger MH, Grim CE, et al: Nocturnal electrolyte excretion and its relationship to the renin system and sympathetic activity in normal and hypertensive man. J Lab Clin Med 95:395-406, 1980 32. Beretta-Piccoli C, Weidmann P, Meier A, et al: Effect of short term norepinephrine infusion on plasma catecholamines, renin and aldosterone in normal and hypertensive man. Hypertension 2:623-630, 1980 33. Williams GH, Hollenberg NK, Moore n, et al: Failure of renin suppression by angiotensin II in hypertension. Circ Res 42:46-52, 1978 34. Kotchen T A, Guthrie GP: Renin-angiotensinaldosterone and hypertension. Endocrine Rev 1:78-99, 1980 35. Johnson JA, Davis JO, Witty RT: Effects of catecholamines and renal nerve stimulation on renin release in the nonfiltering kidney. Circ Res 29:646-653, 1971 36. Fitzgerald GA, Barnes P, Hamilton CA, et al: Circulating adrenaline and blood pressure: The metabolic effects and kinetics of infused adrenaline in man. Eur J Clin Invest 10:401-406, 1980 37. Weinberger MH, Aoi W, Henry DP: The direct effect of beta-adrenergic stimulation on renin release by rat kidney slices in vitro. Circ Res 37:318-324, 1975 38. Aoi W, Henry DP, Weinberger MH: Evidence for a physiological role of renal sympathetic nerves in adrenergic stimulation of renin release in the rat. Circ Res 38:123-226, 1976 39. Freis ED: Salt, volume, and the prevention of hypertension. Circulation 53:589-595, 1976 40. Brunner HR, Gavras H: Is the renin system really necessary? Am J Med 69:739-745, 1980