Normal Plasma Renin Activity in Low Renin Hypertension ROBERT S. MODLINGER AND MICHAEL GUTKIN Hypertension Section, Department of Medicine, East Orange (New Jersey) Veterans Administration Hospital and the New Jersey Medical School, Newark, New Jersey ABSTRACT. Plasma renin activity (PRA) was measured every 4 h during a 24-h period of continuous recumbency in 10 patients with essential hypertension. All had maximum values at 12 midnight, 4 AM or 8 AM. Analysis of our data and that of others indicates that in some patients with "low renin" hypertension (LRH) these nocturnal peaks are of normal magnitude, occasionally exceeding values obtained after four hours of erect posture. Sleepinduced renin release in these patients is not
R
ENIN release is blunted in response to a variety of stimuli in patients with "low renin" essential hypertension (LRH) (1). However, it has not been determined whether the cumulative daily secretion of this enzyme is significantly lower in these patients than in others with "normal renin" hypertension (NRH). Although we are currently unable to measure either renin production or metabolic clearance rate, relevant information may be obtained by frequent determination of plasma renin activity (PRA) during prolonged recumbency and comparison of the area circumscribed by a curve of these values to that obtained in normals or NRH patients. We have obtained such information in five patients with LRH. To this we can now add the tabular data supplied but not emphasized by Grim et at. in their recent publication (2). The results support the conclusion that "renin" is not "low" in all patients with LRH under the conditions of continuous recumbency. Materials and Methods Peripheral venous blood was drawn into tubes containing Na EDTA and immediately placed in ice. The plasma was separated in a refrigerated centrifuge and frozen at - 2 0 C until the time of the assay. Samples were run in duplicate using 0.5 ml aliquots containing Received August 26, 1974.
suppressed despite blunted responses to other stimuli. This suggests that the ability to synthesize and release renin may be normal in these patients. Such peaks were not observed in all LRH subjects, however. The area enclosed by the recumbent PRA curve was also normal in some, but not all patients with LRH. Low renin hypertension may not be a homogeneous disorder. (J Clin Endocrinol Metab 40: 380, 1975)
phenylmethylsulfonylfluoride (3) and neomycin. The pH was not adjusted. The incubation (37 C, 3 h) was performed in a gyratory gas incubator in an atmosphere of 95% O2 and 5% CO2. All pipetting was done using a Micromedic Automated Pipetting Station. The intra- and interassay standard deviations for our method are 4.5% and 8.5%, respectively. These variations are essentially the same at 0.65, 2.2, and 5.7 ng/ml/h. Normal 12 noon erect values (based upon 27 subjects studied 38 times): 2.1-5.8 ng/ml/h (100 meq urinary Na+ per 24 h), > 4.7 ng/ml/h (10 meq urinary Na+ per 24 h). All samples from each patient were run at the same time. Patients were admitted to the Special Diagnostic: and Treatment Unit of the East Orange Veterans Administration Hospital. All had normal intravenous pyelograms, serum electrolytes, urine cultures, and 24-h urinary protein, VMA, aldosterone, 17-hydroxycorticoid and 17ketosteroid determinations. No patient had retinal hemorrhages or exudates. Antihypertensive agents were discontinued 2 weeks before hospital admission and no medications were administered during the study. No patient had received reserpine or guanethidine. Testing was begun after at least 5 days of constant salt intake (0.5, 1.0 or 2.5 g sodium). Patients were classified as "low renin" only if their 12 noon erect PRA was below the normal range relative to their urinary sodium. All subjects were in bed by 10 PM on the night preceding testing. At 8 AM a 19 gauge scalp vein needle was inserted in the forearm, the first PRA obtained, and 5% dextrose begun at 0.3 cc/min. Additional samples were obtained at four hour intervals without venipuncture.
380
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LOW RENIN HYPERTENSION
381
Patients remained completely supine except for 15-min periods immediately after the 8 AM and 12 noon samples and at 5 PM when the head of the bed was elevated to 30° to permit eating. At 8 AM on the following day, the dextrose infusion was discontinued and the patient arose. PRA was obtained at 12 noon after 4 h of erect posture and controlled ambulation. Sequential values for recumbent PRA were plotted longitudinally on graph paper. The area between them and the abscissa was cut out and weighed on a Mettler balance. Som I2noon 4pm 8pm I2midn. 4om 8am 12noon TIME The protocol followed by Grim et al. was slightly different. Their normal subjects (7) and FIG. 1. Diurnal variation of PRA in some patients with LRH patients (sufficient tabular data available LRH and NRH. in 9 of 12) consumed diets containing 2 meq/kg Na+. Although all retired at 10 PM after being PRA's at these times (4.6 ± 1.7 ng/ml/h) upright for 14 h, four-hourly sampling began at than his LRH group (2.7 ± 2.0 ng/ml/h), midnight and continued for 24 h. Because this four LRH patients had peaks within the first sample largely reflected the recent enforced normal range of 3.0, 3.4, 3.7, and 7.1 upright posture we did not include it in our ng/ml/h. This latter value was similar to the analysis of their data. Six values (4 AM thru 12 midnight) were plotted and the enclosed area highest peak of the normal group (8.0 determined. The interassay standard deviation ng/ml/h). of PRA obtained by these authors was 17%. Peak recumbent PRA's exceeded the 12 noon erect PRA in one of our five LRH patients (Dro) and 3 of the 9 LRH patients Results of Grim et al., but in none of their normal All of our LRH patients as well as 8 of or our NRH patients. Comparison of the the 9 LRH patients studied by Grim et al. areas enclosed by the PRA curves indihad their peak recumbent values at 12 cated a higher value for one of our LRH midnight, 4 AM, or 8 AM. Although the patients (Dro-2; area 772 mg) than for one normal group of Grim et al. had higher of our NRH patients (Zen-1; area 469 mg) E r 9 c t
TABLE 1. Summary of laboratory data Normal renin hypertension Recumbent PRA (ng/ml/h) IJrinp Msi"*"
Patient
(meq/24 h)
Maximum
(Time)
Minimum
Zen (1) (2)* (3) Kar Hea Mac (2)f Mil (l)t
112 166 27 21 56 23 21
1.51 0.51 3.04 5.83 5.23 5.39 4.06
8 AM
12 midnight
0.39 0.24 0.50 0.86 3.34 3.75 1.08
Wil Dro (1) (2) Gra Mac (l)t Mil (2)f
16 51 113 50 104 86
2.11 3.20 1.74 0.31 0.37 0.50
Low renin hypertension 4 AM 0.09 4 AM 1.96 12 midnight 0.73 12 midnight 0.15 8 AM 0.19 12 midnight 0.37
4 AM 4 AM 4 AM 8 AM 4 AM
(Time) 4 PM
12 noon 12 noon 4 PM 4 PM
12 noon 12 noon 4 PM
12 midnight 4 PM
12 noon 12 noon 12 noon
12 N Erect PRA ng/ml/h
Area (mg)
4.30 2.28 4.73 6.90 6.52 8.82 5.43
469 240 1,089 3,246 2,818 2,092 1,338
2.86 2.38 0.71 0.74 0.56 1.20
522 1,776 772 173 171 286
* Due to a dietary error patient received an excessive amount of salt. t Patients Mac and Mil demonstrated LRH on only one of the two testing dates.
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382
MODLINGER AND GUTKIN
JCE & M • 1975 Vol 40 • No 3
(Fig. 1, Table 1). Similarly, despite the first is not susceptible to "physiologic" higher mean area of Grim's normal subjects inhibition, such as that due to expanded (909 ± 243 mg; range: 573-1197 mg) com- extracellular fluid volume (1,8). Several pared to his LRH patients (455± 260 mg; LRH patients did not have normal nocturrange 167-901 mg), three of the latter nal spikes. These peaks were either missed patients (areas: 585, 754, and 901 mg) by the long interval between samples, or exceeded the area of one, three, and four of suppressed along with the response to the normals respectively (areas: 573, 715, other stimuli. The latter possibility would indicate the existence of at least two sub750, and 882 mg). Of the three LRH patients we studied groups among patients with suppressed twice, one was judged to have "low renin" PRA. We believe it is too simplistic to assign a on both occasions, one only on the first, and the other only on the second. The hypertensive to a "low renin" category on results obtained when renin was "normal" the relationship of a single erect plasma are grouped with the NRH patients in renin activity to concurrent urinary sodium Table 1. A fourth patient, Gra, had sup- excretion. It has already been shown that pressed renin on repeat erect PRA deter- 22-33% of LRH patients do not have "low mination one month after completion of renin" upon retesting (1). The demonstration that the enclosed recumbent PRA area this study. in LRH overlaps with that of normals and Discussion NRH patients further weakens the validity of this method of classification. Low renin The circadian periodicity of PRA in conhypertension may not be a homogeneous tinuously recumbent normal individuals disorder. was first described by Gordon et al. (4). Although Liddle (5) feels that this is of cenAcknowledgments tral nervous system origin, it is possible that it arises from changes in blood pressure, The authors are grateful to the staff of the Special cardiac output, glomerular filtration rate, Diagnostic and Treatment Unit for their invaluable sodium excretion, or other unidentified cooperation and to Mrs. Alice Etienne for her skillful factors associated with the sleep-wake technical assistance. We wish to thank Dr. Norrnao Ertel for his useful advice and criticism. cycle. Weinberger et al. (6) and more recently References Vagnucci et al. (7) demonstrated marked fluctuation and significant elevations of 1. Dunn, M. J., and R. L. Tanner, Kidney Intl 5: 317, early morning PRA in normal subjects. We 1974. have noted both in our data and those of 2. Grim, C , J. Winnacker, T. Peters, and C. Gilbert, / Clin Endocrinol Metab 39: 247, 1974. Grim, that these nocturnal elevations also 3. Katz, F. H., and J. A. Smith, Clin Chem 18: 528, occur in patients with LRH. The fact that 1972. these spikes may be of normal amplitude 4. Gordon, R. D., L. K. Wolfe, D. P. Island, and G. indicates that renin release during sleep is W. Liddle, 7 Clin Invest 45: 1587, 1966. unimpaired in some LRH patients despite 5. Liddle, G. W., In Williams, R. H. (ed.), Textbook of Endocrinology, W. B. Saunders Co., Philadelblunted response to erect posture and phia, 1974, p. 242. sodium restriction. This would suggest that 6. Weinberger, M. H., D. R. Rosner, D. C. Kern, L. renin synthesis and release mechanisms in Joyner, and G. Foust, In Assaykeen, T. A. (ed.), some cases of LRH are intact and that the Control of Renin Secretion, Plenum Press, New York, 1972, p. 189. lack of response to other stimuli stems from disordered receptor or control mechanisms. 7. Vagnucci, A. H., R. H. McDonald, Jr., A. L. Drash, and A. K. C. Wong, / Clin Endocrinol Metab 38: It may be that sleep, sodium restriction, 761, 1974. and erect posture stimulate renin release 8. Jose, A., J. R. Crout, and N. M. Kaplan, Ann via different pathways and that only the Intern Med 72: 9, 1970. The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 November 2015. at 20:38 For personal use only. No other uses without permission. . All rights reserved.
R
ENIN release is blunted in response to a variety of stimuli in patients with "low renin" essential hypertension (LRH) (1). However, it has not been determined whether the cumulative daily secretion of this enzyme is significantly lower in these patients than in others with "normal renin" hypertension (NRH). Although we are currently unable to measure either renin production or metabolic clearance rate, relevant information may be obtained by frequent determination of plasma renin activity (PRA) during prolonged recumbency and comparison of the area circumscribed by a curve of these values to that obtained in normals or NRH patients. We have obtained such information in five patients with LRH. To this we can now add the tabular data supplied but not emphasized by Grim et at. in their recent publication (2). The results support the conclusion that "renin" is not "low" in all patients with LRH under the conditions of continuous recumbency. Materials and Methods Peripheral venous blood was drawn into tubes containing Na EDTA and immediately placed in ice. The plasma was separated in a refrigerated centrifuge and frozen at - 2 0 C until the time of the assay. Samples were run in duplicate using 0.5 ml aliquots containing Received August 26, 1974.
suppressed despite blunted responses to other stimuli. This suggests that the ability to synthesize and release renin may be normal in these patients. Such peaks were not observed in all LRH subjects, however. The area enclosed by the recumbent PRA curve was also normal in some, but not all patients with LRH. Low renin hypertension may not be a homogeneous disorder. (J Clin Endocrinol Metab 40: 380, 1975)
phenylmethylsulfonylfluoride (3) and neomycin. The pH was not adjusted. The incubation (37 C, 3 h) was performed in a gyratory gas incubator in an atmosphere of 95% O2 and 5% CO2. All pipetting was done using a Micromedic Automated Pipetting Station. The intra- and interassay standard deviations for our method are 4.5% and 8.5%, respectively. These variations are essentially the same at 0.65, 2.2, and 5.7 ng/ml/h. Normal 12 noon erect values (based upon 27 subjects studied 38 times): 2.1-5.8 ng/ml/h (100 meq urinary Na+ per 24 h), > 4.7 ng/ml/h (10 meq urinary Na+ per 24 h). All samples from each patient were run at the same time. Patients were admitted to the Special Diagnostic: and Treatment Unit of the East Orange Veterans Administration Hospital. All had normal intravenous pyelograms, serum electrolytes, urine cultures, and 24-h urinary protein, VMA, aldosterone, 17-hydroxycorticoid and 17ketosteroid determinations. No patient had retinal hemorrhages or exudates. Antihypertensive agents were discontinued 2 weeks before hospital admission and no medications were administered during the study. No patient had received reserpine or guanethidine. Testing was begun after at least 5 days of constant salt intake (0.5, 1.0 or 2.5 g sodium). Patients were classified as "low renin" only if their 12 noon erect PRA was below the normal range relative to their urinary sodium. All subjects were in bed by 10 PM on the night preceding testing. At 8 AM a 19 gauge scalp vein needle was inserted in the forearm, the first PRA obtained, and 5% dextrose begun at 0.3 cc/min. Additional samples were obtained at four hour intervals without venipuncture.
380
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LOW RENIN HYPERTENSION
381
Patients remained completely supine except for 15-min periods immediately after the 8 AM and 12 noon samples and at 5 PM when the head of the bed was elevated to 30° to permit eating. At 8 AM on the following day, the dextrose infusion was discontinued and the patient arose. PRA was obtained at 12 noon after 4 h of erect posture and controlled ambulation. Sequential values for recumbent PRA were plotted longitudinally on graph paper. The area between them and the abscissa was cut out and weighed on a Mettler balance. Som I2noon 4pm 8pm I2midn. 4om 8am 12noon TIME The protocol followed by Grim et al. was slightly different. Their normal subjects (7) and FIG. 1. Diurnal variation of PRA in some patients with LRH patients (sufficient tabular data available LRH and NRH. in 9 of 12) consumed diets containing 2 meq/kg Na+. Although all retired at 10 PM after being PRA's at these times (4.6 ± 1.7 ng/ml/h) upright for 14 h, four-hourly sampling began at than his LRH group (2.7 ± 2.0 ng/ml/h), midnight and continued for 24 h. Because this four LRH patients had peaks within the first sample largely reflected the recent enforced normal range of 3.0, 3.4, 3.7, and 7.1 upright posture we did not include it in our ng/ml/h. This latter value was similar to the analysis of their data. Six values (4 AM thru 12 midnight) were plotted and the enclosed area highest peak of the normal group (8.0 determined. The interassay standard deviation ng/ml/h). of PRA obtained by these authors was 17%. Peak recumbent PRA's exceeded the 12 noon erect PRA in one of our five LRH patients (Dro) and 3 of the 9 LRH patients Results of Grim et al., but in none of their normal All of our LRH patients as well as 8 of or our NRH patients. Comparison of the the 9 LRH patients studied by Grim et al. areas enclosed by the PRA curves indihad their peak recumbent values at 12 cated a higher value for one of our LRH midnight, 4 AM, or 8 AM. Although the patients (Dro-2; area 772 mg) than for one normal group of Grim et al. had higher of our NRH patients (Zen-1; area 469 mg) E r 9 c t
TABLE 1. Summary of laboratory data Normal renin hypertension Recumbent PRA (ng/ml/h) IJrinp Msi"*"
Patient
(meq/24 h)
Maximum
(Time)
Minimum
Zen (1) (2)* (3) Kar Hea Mac (2)f Mil (l)t
112 166 27 21 56 23 21
1.51 0.51 3.04 5.83 5.23 5.39 4.06
8 AM
12 midnight
0.39 0.24 0.50 0.86 3.34 3.75 1.08
Wil Dro (1) (2) Gra Mac (l)t Mil (2)f
16 51 113 50 104 86
2.11 3.20 1.74 0.31 0.37 0.50
Low renin hypertension 4 AM 0.09 4 AM 1.96 12 midnight 0.73 12 midnight 0.15 8 AM 0.19 12 midnight 0.37
4 AM 4 AM 4 AM 8 AM 4 AM
(Time) 4 PM
12 noon 12 noon 4 PM 4 PM
12 noon 12 noon 4 PM
12 midnight 4 PM
12 noon 12 noon 12 noon
12 N Erect PRA ng/ml/h
Area (mg)
4.30 2.28 4.73 6.90 6.52 8.82 5.43
469 240 1,089 3,246 2,818 2,092 1,338
2.86 2.38 0.71 0.74 0.56 1.20
522 1,776 772 173 171 286
* Due to a dietary error patient received an excessive amount of salt. t Patients Mac and Mil demonstrated LRH on only one of the two testing dates.
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382
MODLINGER AND GUTKIN
JCE & M • 1975 Vol 40 • No 3
(Fig. 1, Table 1). Similarly, despite the first is not susceptible to "physiologic" higher mean area of Grim's normal subjects inhibition, such as that due to expanded (909 ± 243 mg; range: 573-1197 mg) com- extracellular fluid volume (1,8). Several pared to his LRH patients (455± 260 mg; LRH patients did not have normal nocturrange 167-901 mg), three of the latter nal spikes. These peaks were either missed patients (areas: 585, 754, and 901 mg) by the long interval between samples, or exceeded the area of one, three, and four of suppressed along with the response to the normals respectively (areas: 573, 715, other stimuli. The latter possibility would indicate the existence of at least two sub750, and 882 mg). Of the three LRH patients we studied groups among patients with suppressed twice, one was judged to have "low renin" PRA. We believe it is too simplistic to assign a on both occasions, one only on the first, and the other only on the second. The hypertensive to a "low renin" category on results obtained when renin was "normal" the relationship of a single erect plasma are grouped with the NRH patients in renin activity to concurrent urinary sodium Table 1. A fourth patient, Gra, had sup- excretion. It has already been shown that pressed renin on repeat erect PRA deter- 22-33% of LRH patients do not have "low mination one month after completion of renin" upon retesting (1). The demonstration that the enclosed recumbent PRA area this study. in LRH overlaps with that of normals and Discussion NRH patients further weakens the validity of this method of classification. Low renin The circadian periodicity of PRA in conhypertension may not be a homogeneous tinuously recumbent normal individuals disorder. was first described by Gordon et al. (4). Although Liddle (5) feels that this is of cenAcknowledgments tral nervous system origin, it is possible that it arises from changes in blood pressure, The authors are grateful to the staff of the Special cardiac output, glomerular filtration rate, Diagnostic and Treatment Unit for their invaluable sodium excretion, or other unidentified cooperation and to Mrs. Alice Etienne for her skillful factors associated with the sleep-wake technical assistance. We wish to thank Dr. Norrnao Ertel for his useful advice and criticism. cycle. Weinberger et al. (6) and more recently References Vagnucci et al. (7) demonstrated marked fluctuation and significant elevations of 1. Dunn, M. J., and R. L. Tanner, Kidney Intl 5: 317, early morning PRA in normal subjects. We 1974. have noted both in our data and those of 2. Grim, C , J. Winnacker, T. Peters, and C. Gilbert, / Clin Endocrinol Metab 39: 247, 1974. Grim, that these nocturnal elevations also 3. Katz, F. H., and J. A. Smith, Clin Chem 18: 528, occur in patients with LRH. The fact that 1972. these spikes may be of normal amplitude 4. Gordon, R. D., L. K. Wolfe, D. P. Island, and G. indicates that renin release during sleep is W. Liddle, 7 Clin Invest 45: 1587, 1966. unimpaired in some LRH patients despite 5. Liddle, G. W., In Williams, R. H. (ed.), Textbook of Endocrinology, W. B. Saunders Co., Philadelblunted response to erect posture and phia, 1974, p. 242. sodium restriction. This would suggest that 6. Weinberger, M. H., D. R. Rosner, D. C. Kern, L. renin synthesis and release mechanisms in Joyner, and G. Foust, In Assaykeen, T. A. (ed.), some cases of LRH are intact and that the Control of Renin Secretion, Plenum Press, New York, 1972, p. 189. lack of response to other stimuli stems from disordered receptor or control mechanisms. 7. Vagnucci, A. H., R. H. McDonald, Jr., A. L. Drash, and A. K. C. Wong, / Clin Endocrinol Metab 38: It may be that sleep, sodium restriction, 761, 1974. and erect posture stimulate renin release 8. Jose, A., J. R. Crout, and N. M. Kaplan, Ann via different pathways and that only the Intern Med 72: 9, 1970. The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 November 2015. at 20:38 For personal use only. No other uses without permission. . All rights reserved.
