AJH
1990; 3:903 - 905
ORIGINAL CONTRIBUTIONS
Interaction of 1,25-Dihydroxyvitamin D and Plasma Renin Activity in High Renin Essential Hypertension Ellen D. Burgess, Ralph G. Hawkins, and Mamoru
Watanabe
Renin secretion by the kidney is inhibited by an in dietary sodium led to an increase in serum increase in free intracellular calcium concentration. 1,25-dihydroxyvitamin D concentration, which may This increase in free intracellular calcium content have contributed to an increase in intracellular cal may be augmented by serum 1,25-dihydroxy vitamin cium concentration, a decrease in renal secretion of D. In 10 subjects with high renin hypertension, an renin, and a fall in plasma renin activity. The re increase in dietary sodium intake resulted in an in sultant fall in PRA in part effected the change in crease in urinary calcium excretion (2.5 to 3.4 blood pressure to the increased sodium intake. mmol/L, Ρ = .011) and an increase in serum 1,25-di- Therefore, 1,25-dihydroxyvitamin D may be a medi hydroxyvitamin D (51.2 to 61.0 pmol/L, Ρ = .045). ator in the response of high renin hypertension to An inverse correlation existed between the change increased sodium intake. Am J Hypertens 1990;3:903in vitamin D and the change in plasma renin activ 905 ity (r = —0.765, Ρ = .01). An inverse correlation also existed between the change in plasma renin activity and the change in mean arterial blood pressure (r = K E Y W O R D S : Renin, calcium, vitamin D, hyperten - 0 . 7 5 7 , Ρ = .011). It is postulated that the increase sion.
P
rimary hypertension associated with high plasma renin activity has been felt to be a vaso constrictor form of hypertension. In this model, there is often a paradoxical effect of in creasing dietary sodium intake such that an increase in sodium intake results in a fall in blood pressure. The theory behind this paradoxical response is that plasma renin activity falls due to a relative volume expansion 1
and decreased renal renin release, thereby allowing va sodilatation. Although intracellular calcium is elevated in hyper tension, serum ionized calcium concentrations are var ied and differ with renin classification. Serum 1,25-dihy droxyvitamin D concentrations are accordingly altered, and an inverse correlation has been demonstrated be tween 1,25-dihydroxyvitamin D and plasma renin activ ity. Calcium plays a central role in the process of renin secretion. The secretory process is triggered by a lower ing of cytosolic calcium in the juxtaglomerular (J-G) cells, and is inhibited by an increase in cytosolic cal cium. The active form of vitamin D, 1,25-dihydroxy vitamin D, may effect an increase in cytosolic calcium concentration in renal tubular cells and may therefore decrease renal renin secretion. Inhibition of renal renin release with a subsequent fall in plasma renin activity 2
3
4
5
From the Department of Medicine, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada. Dr. Hawkins is currently at the Department of Medicine, University Hospital, University of Saskatchewan, Saskatoon, Canada. This article was presented in part at the Fourth Annual Meeting of the American Society of Hypertension, May 10 to 12, 1989. This work was funded by Foothills Hospital Foundation, Foothills Provincial General Hospital, Calgary, Alberta, Canada. Address correspondence and reprint requests to Ellen D. Burgess, MD, 1403-29 St NW, Calgary, Alberta, Canada, T2N 2T9.
6
7
TABLE 1. MEAN SERUM AND URINE MEASURES ON 10 AND 100 MMOL SODIUM DIETS Urinary calcium (mmol/day) 1,25-Dihydroxyvitamin D (pmol/L) Serum PTH (ng/L) Plasma renin activity (ng/L/sec) Mean arterial pressure (mm Hg) Data presented
as means, mean difference,
10 mmol
100 mmol
2.5 51.5 30.5 1.94 105.6
3.4 61.0 30.0 0.65 106.7
0.9 9.5 0.5 1.29 1.1
Ρ Value
±0.3 ±4.1 ±3.9 ±0.32 ±3.2
.011 .046 NS .003 NS
and SEM.
may result in a lowering of blood pressure. Therefore, if these relationships remain intact in high renin hyper tension, dietary changes could elicit changes in serum 1,25-dihydroxyvitamin D concentration that would af fect cytosolic calcium content. If this occurred in J-G cells, changes in 1,25-dihydroxyvitamin D would be inversely correlated to changes in renal renin secretion and plasma renin activity. The resultant changes in plasma renin activity would be directly correlated to blood pressure responses. The objective of this study was to assess whether changes in dietary sodium intake could effect the changes described, and to validate the above hypoth esis. 8
METHODS All subjects had been referred for investigation to the Hypertension Clinic at Foothills Provincial General Hos pital. All subjects were studied using a longitudinal pro tocol of 5 days on a 10 mmol sodium diet and 5 days on a 100 mmol sodium diet. Subjects were randomized as to which segment initiated their protocol. Diet segments were isocaloric and supplemented with potassium 100
>
mmol/day and calcium 25 mmol/day. Each morning, patients were seen in the Hypertension Clinic for deter mination of blood pressure and given their dietary ra tion and supplements for the day. On the fourth day of each diet segment, a 24 h urine collection was obtained. On the morning of the fifth day, blood pressures were measured and blood samples obtained after overnight recumbency. Blood pressures were measured by the auscultatory method for indirect blood pressure determi nation using a mercury manometer by the same nurse on all occasions. Plasma renin activity (PRA) was measured by radio immunoassay. Serum and urine calcium concentrations were measured colorimetrically. Serum 1,25-dihydroxy vitamin D concentrations were measured using a com petitive protein binding receptor assay after phase sepa ration using a dextran-coated charcoal suspension. Crossreactivity with non-1-hydroxyvitamin D metabo lites was ^ 0 . 1 % . Normal range for our laboratory is 36.2 to 120 pmol/L. Serum parathyroid hormone (PTH) concentration was measured by N-tact IMRA (Incstar Corp., Stillwater, MN) immunoradiometric assay with a normal range being 10 to 55 n g / L . The percentage response of a measure was calculated as: 100 X
[^(100 mmol Na) A
> hΟ < LU DC
Difference
\\Q mmol Na]
(10mmolNa)
Comparison of measures between study segments was performed using Student's paired t test. Linear re gressions were made using least-squares method. Sta tistics were done using Medical Research-Time Ori ented Database, Retriever Data Systems, Seattle, Washington.
-30
CO
0.45 n g / L / s e c recumbent on 100 mmol so dium diet). There was a significant increase in urinary calcium excretion with the increase in dietary sodium, and 8
1,25-dihydroxyvitamin D (Table 1). No significant change in serum phosphate occurred (1.26 to 1.26 mmol/L, mean difference ± SEM 0.00 ± 0.03). To allow for the effect of changes in serum albumin con centration on changes in serum calcium concentration, a corrected value for the change in serum calcium was calculated. The corrected mean change in serum cal cium concentration was —0.01 ± 0 . 0 2 mmol/L (P = NS). As expected, there was a significant fall in mean PRA with the increase in dietary sodium. The change in mean arterial pressure (MAP) ranged from —16.7 to 19.4 mm Hg, with no difference in the mean MAP be tween the two diet segments. There was a significant positive correlation between the percentage change in PRA and the change in MAP (r = —0.757, Ρ = .011) consistent with that previously reported. The percentage change in PRA correlated in versely to the percentage change in 1,25-dihydroxyvita min D (r = 0.765, Ρ = .01) (Figure 1), consistent with the concept that the increase in 1,25-dihydroxyvitamin D would effect an increase in cytosolic calcium in J-G cells, with a subsequent fall in renal renin secretion and plasma renin activity. There was an inverse correlation between the change in MAP to the percentage changes in serum 1,25-dihydroxyvitamin D concentrations (r = — 0.650, Ρ = .042) and to the corrected changes in serum calcium concentrations (r = —0.778, Ρ = .008). These were likely secondary to the intercorrelations be tween the effects of 1,25-dihydroxyvitamin D on renal renin release, gut calcium absorption and urinary cal cium excretion, and, therefore, serum calcium concen tration. 9
8
DISCUSSION In subjects with high renin essential hypertension, an increase in dietary sodium intake may result in a fall in blood pressure. The response of MAP in these individu als is directly correlated to the changes in PRA. The proposed effector of the fall in renal renin release and PRA is the change in serum 1,25-dihydroxyvitamin D concentrations that occur secondary to changes in diet. The trigger for the changes in 1,25-dihydroxyvitamin D is unclear. Ultimately, however, there would be an in crease in cytosolic calcium concentration in renal cells which would result in a reduction in renal renin release. The associated fall in PRA would correlate directly with the changes in MAP. The lack of a significant change in serum calcium (when corrected for changes in serum albumin concen tration) and PTH concentration may be a result of a negative feedback of serum 1,25-dihydroxyvitamin D on PTH release, and the subsequent effects on calcium metabolism. The active form of vitamin D has been demonstrated to effect an increase in intracellular calcium concentra tion in vascular smooth muscle cells, and could be associated with an increased responsiveness to vaso
pressors in some models of hypertension. The blood pressure response to alterations in dietary intake is an integrated response. In the subjects with high renin hy pertension presented herein, the blood pressure re sponse was only partially determined by the fall in plasma renin activity, and may have been partially off set by the increase in vascular responsiveness to circu lating vasopressors. In summary, the proposed linkage between 1,25-di hydroxyvitamin D and plasma renin activity appears to be intact in subjects with high renin hypertension and contributes to the paradoxical blood pressure response to increased dietary sodium seen in this group of pa tients. ACKNOWLEDGMENTS The authors gratefully acknowledge Lorna Milkovich for her fine administration of the protocols, Terisa Wong for analyti cal assistance, and the members of the Hypertension Clinic, Foothills Provincial General Hospital and the University of Calgary Hypertension Research Group for their ongoing sup port. REFERENCES 1.
Laragh JH: Vasoconstriction-volume analysis for under standing and treating hypertension; the use of renin and aldosterone profiles. Am J Med 1973;55:261-274.
2.
Longworth DL, Drayer JIM, Weber MA, Laragh JH: Di vergent blood pressure responses during short-term so dium restriction in hypertension. Clin Pharmacol Ther 1980;27:544-546.
3.
Erne P, Bolli P, Burgisser E, Buhler FR: Correlation of platelet calcium with blood pressure: effect of antihyper tensive therapy. Ν Engl J Med 1984;310:1084-1088.
4.
Resnick LM: Calcium metabolism in the pathophysiol ogy and treatment of clinical hypertension. Am J Hyper tens 1989;2:179S-185S.
5.
Resnick LM, Muller FB, Laragh JH: Calcium-regulating hormones in essential hypertension-relation to plasma renin activity and sodium metabolism. Ann Intern Med 1986;105:649-654.
6.
Fray JCS, Park CS, Valentine AND: Calcium and the control of renin secretion. Endocr Rev 1987;8:53-93.
7.
Haussler MR, Donaldson CA, Kelly MA, et al: Functions and mechanism of action of the 1,25-dihydroxyvitamin D receptor, in Norman AW: Vitamin D. A Chemical, Biochemical and Clinical Update. Berlin, Walter de Gruyter & Co, 1985, pp 83-92.
8
10
3
8.
Burgess ED, Keane PM, Watanabe M: Blood pressure and serum calcium responses to altered sodium intake in high renin hypertension. Am J Hypertens 1989;2:182184.
9.
Agus ZS, Goldfarb S: Calcium metabolism; normal and abnormal, in Arieff Al, De Fronzo RA (eds): Fluid Elec trolyte and Acid Base Disorders. New York, Churchill Livingstone, 1985, ρ 511.
10.
Bukoski RD, Xue H, McCarron DA: Effect of l,25(OH) vitamin D and ionized CA on Ca uptake by primary cultures of aortic myocytes of spontaneously hyperten sive and Wistar Kyoto normotensive rats. Biochem Biophys Res Commun 1987;146:1330-1335. 2
3
2+
45
1990; 3:903 - 905
ORIGINAL CONTRIBUTIONS
Interaction of 1,25-Dihydroxyvitamin D and Plasma Renin Activity in High Renin Essential Hypertension Ellen D. Burgess, Ralph G. Hawkins, and Mamoru
Watanabe
Renin secretion by the kidney is inhibited by an in dietary sodium led to an increase in serum increase in free intracellular calcium concentration. 1,25-dihydroxyvitamin D concentration, which may This increase in free intracellular calcium content have contributed to an increase in intracellular cal may be augmented by serum 1,25-dihydroxy vitamin cium concentration, a decrease in renal secretion of D. In 10 subjects with high renin hypertension, an renin, and a fall in plasma renin activity. The re increase in dietary sodium intake resulted in an in sultant fall in PRA in part effected the change in crease in urinary calcium excretion (2.5 to 3.4 blood pressure to the increased sodium intake. mmol/L, Ρ = .011) and an increase in serum 1,25-di- Therefore, 1,25-dihydroxyvitamin D may be a medi hydroxyvitamin D (51.2 to 61.0 pmol/L, Ρ = .045). ator in the response of high renin hypertension to An inverse correlation existed between the change increased sodium intake. Am J Hypertens 1990;3:903in vitamin D and the change in plasma renin activ 905 ity (r = —0.765, Ρ = .01). An inverse correlation also existed between the change in plasma renin activity and the change in mean arterial blood pressure (r = K E Y W O R D S : Renin, calcium, vitamin D, hyperten - 0 . 7 5 7 , Ρ = .011). It is postulated that the increase sion.
P
rimary hypertension associated with high plasma renin activity has been felt to be a vaso constrictor form of hypertension. In this model, there is often a paradoxical effect of in creasing dietary sodium intake such that an increase in sodium intake results in a fall in blood pressure. The theory behind this paradoxical response is that plasma renin activity falls due to a relative volume expansion 1
and decreased renal renin release, thereby allowing va sodilatation. Although intracellular calcium is elevated in hyper tension, serum ionized calcium concentrations are var ied and differ with renin classification. Serum 1,25-dihy droxyvitamin D concentrations are accordingly altered, and an inverse correlation has been demonstrated be tween 1,25-dihydroxyvitamin D and plasma renin activ ity. Calcium plays a central role in the process of renin secretion. The secretory process is triggered by a lower ing of cytosolic calcium in the juxtaglomerular (J-G) cells, and is inhibited by an increase in cytosolic cal cium. The active form of vitamin D, 1,25-dihydroxy vitamin D, may effect an increase in cytosolic calcium concentration in renal tubular cells and may therefore decrease renal renin secretion. Inhibition of renal renin release with a subsequent fall in plasma renin activity 2
3
4
5
From the Department of Medicine, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada. Dr. Hawkins is currently at the Department of Medicine, University Hospital, University of Saskatchewan, Saskatoon, Canada. This article was presented in part at the Fourth Annual Meeting of the American Society of Hypertension, May 10 to 12, 1989. This work was funded by Foothills Hospital Foundation, Foothills Provincial General Hospital, Calgary, Alberta, Canada. Address correspondence and reprint requests to Ellen D. Burgess, MD, 1403-29 St NW, Calgary, Alberta, Canada, T2N 2T9.
6
7
TABLE 1. MEAN SERUM AND URINE MEASURES ON 10 AND 100 MMOL SODIUM DIETS Urinary calcium (mmol/day) 1,25-Dihydroxyvitamin D (pmol/L) Serum PTH (ng/L) Plasma renin activity (ng/L/sec) Mean arterial pressure (mm Hg) Data presented
as means, mean difference,
10 mmol
100 mmol
2.5 51.5 30.5 1.94 105.6
3.4 61.0 30.0 0.65 106.7
0.9 9.5 0.5 1.29 1.1
Ρ Value
±0.3 ±4.1 ±3.9 ±0.32 ±3.2
.011 .046 NS .003 NS
and SEM.
may result in a lowering of blood pressure. Therefore, if these relationships remain intact in high renin hyper tension, dietary changes could elicit changes in serum 1,25-dihydroxyvitamin D concentration that would af fect cytosolic calcium content. If this occurred in J-G cells, changes in 1,25-dihydroxyvitamin D would be inversely correlated to changes in renal renin secretion and plasma renin activity. The resultant changes in plasma renin activity would be directly correlated to blood pressure responses. The objective of this study was to assess whether changes in dietary sodium intake could effect the changes described, and to validate the above hypoth esis. 8
METHODS All subjects had been referred for investigation to the Hypertension Clinic at Foothills Provincial General Hos pital. All subjects were studied using a longitudinal pro tocol of 5 days on a 10 mmol sodium diet and 5 days on a 100 mmol sodium diet. Subjects were randomized as to which segment initiated their protocol. Diet segments were isocaloric and supplemented with potassium 100
>
mmol/day and calcium 25 mmol/day. Each morning, patients were seen in the Hypertension Clinic for deter mination of blood pressure and given their dietary ra tion and supplements for the day. On the fourth day of each diet segment, a 24 h urine collection was obtained. On the morning of the fifth day, blood pressures were measured and blood samples obtained after overnight recumbency. Blood pressures were measured by the auscultatory method for indirect blood pressure determi nation using a mercury manometer by the same nurse on all occasions. Plasma renin activity (PRA) was measured by radio immunoassay. Serum and urine calcium concentrations were measured colorimetrically. Serum 1,25-dihydroxy vitamin D concentrations were measured using a com petitive protein binding receptor assay after phase sepa ration using a dextran-coated charcoal suspension. Crossreactivity with non-1-hydroxyvitamin D metabo lites was ^ 0 . 1 % . Normal range for our laboratory is 36.2 to 120 pmol/L. Serum parathyroid hormone (PTH) concentration was measured by N-tact IMRA (Incstar Corp., Stillwater, MN) immunoradiometric assay with a normal range being 10 to 55 n g / L . The percentage response of a measure was calculated as: 100 X
[^(100 mmol Na) A
> hΟ < LU DC
Difference
\\Q mmol Na]
(10mmolNa)
Comparison of measures between study segments was performed using Student's paired t test. Linear re gressions were made using least-squares method. Sta tistics were done using Medical Research-Time Ori ented Database, Retriever Data Systems, Seattle, Washington.
-30
CO
0.45 n g / L / s e c recumbent on 100 mmol so dium diet). There was a significant increase in urinary calcium excretion with the increase in dietary sodium, and 8
1,25-dihydroxyvitamin D (Table 1). No significant change in serum phosphate occurred (1.26 to 1.26 mmol/L, mean difference ± SEM 0.00 ± 0.03). To allow for the effect of changes in serum albumin con centration on changes in serum calcium concentration, a corrected value for the change in serum calcium was calculated. The corrected mean change in serum cal cium concentration was —0.01 ± 0 . 0 2 mmol/L (P = NS). As expected, there was a significant fall in mean PRA with the increase in dietary sodium. The change in mean arterial pressure (MAP) ranged from —16.7 to 19.4 mm Hg, with no difference in the mean MAP be tween the two diet segments. There was a significant positive correlation between the percentage change in PRA and the change in MAP (r = —0.757, Ρ = .011) consistent with that previously reported. The percentage change in PRA correlated in versely to the percentage change in 1,25-dihydroxyvita min D (r = 0.765, Ρ = .01) (Figure 1), consistent with the concept that the increase in 1,25-dihydroxyvitamin D would effect an increase in cytosolic calcium in J-G cells, with a subsequent fall in renal renin secretion and plasma renin activity. There was an inverse correlation between the change in MAP to the percentage changes in serum 1,25-dihydroxyvitamin D concentrations (r = — 0.650, Ρ = .042) and to the corrected changes in serum calcium concentrations (r = —0.778, Ρ = .008). These were likely secondary to the intercorrelations be tween the effects of 1,25-dihydroxyvitamin D on renal renin release, gut calcium absorption and urinary cal cium excretion, and, therefore, serum calcium concen tration. 9
8
DISCUSSION In subjects with high renin essential hypertension, an increase in dietary sodium intake may result in a fall in blood pressure. The response of MAP in these individu als is directly correlated to the changes in PRA. The proposed effector of the fall in renal renin release and PRA is the change in serum 1,25-dihydroxyvitamin D concentrations that occur secondary to changes in diet. The trigger for the changes in 1,25-dihydroxyvitamin D is unclear. Ultimately, however, there would be an in crease in cytosolic calcium concentration in renal cells which would result in a reduction in renal renin release. The associated fall in PRA would correlate directly with the changes in MAP. The lack of a significant change in serum calcium (when corrected for changes in serum albumin concen tration) and PTH concentration may be a result of a negative feedback of serum 1,25-dihydroxyvitamin D on PTH release, and the subsequent effects on calcium metabolism. The active form of vitamin D has been demonstrated to effect an increase in intracellular calcium concentra tion in vascular smooth muscle cells, and could be associated with an increased responsiveness to vaso
pressors in some models of hypertension. The blood pressure response to alterations in dietary intake is an integrated response. In the subjects with high renin hy pertension presented herein, the blood pressure re sponse was only partially determined by the fall in plasma renin activity, and may have been partially off set by the increase in vascular responsiveness to circu lating vasopressors. In summary, the proposed linkage between 1,25-di hydroxyvitamin D and plasma renin activity appears to be intact in subjects with high renin hypertension and contributes to the paradoxical blood pressure response to increased dietary sodium seen in this group of pa tients. ACKNOWLEDGMENTS The authors gratefully acknowledge Lorna Milkovich for her fine administration of the protocols, Terisa Wong for analyti cal assistance, and the members of the Hypertension Clinic, Foothills Provincial General Hospital and the University of Calgary Hypertension Research Group for their ongoing sup port. REFERENCES 1.
Laragh JH: Vasoconstriction-volume analysis for under standing and treating hypertension; the use of renin and aldosterone profiles. Am J Med 1973;55:261-274.
2.
Longworth DL, Drayer JIM, Weber MA, Laragh JH: Di vergent blood pressure responses during short-term so dium restriction in hypertension. Clin Pharmacol Ther 1980;27:544-546.
3.
Erne P, Bolli P, Burgisser E, Buhler FR: Correlation of platelet calcium with blood pressure: effect of antihyper tensive therapy. Ν Engl J Med 1984;310:1084-1088.
4.
Resnick LM: Calcium metabolism in the pathophysiol ogy and treatment of clinical hypertension. Am J Hyper tens 1989;2:179S-185S.
5.
Resnick LM, Muller FB, Laragh JH: Calcium-regulating hormones in essential hypertension-relation to plasma renin activity and sodium metabolism. Ann Intern Med 1986;105:649-654.
6.
Fray JCS, Park CS, Valentine AND: Calcium and the control of renin secretion. Endocr Rev 1987;8:53-93.
7.
Haussler MR, Donaldson CA, Kelly MA, et al: Functions and mechanism of action of the 1,25-dihydroxyvitamin D receptor, in Norman AW: Vitamin D. A Chemical, Biochemical and Clinical Update. Berlin, Walter de Gruyter & Co, 1985, pp 83-92.
8
10
3
8.
Burgess ED, Keane PM, Watanabe M: Blood pressure and serum calcium responses to altered sodium intake in high renin hypertension. Am J Hypertens 1989;2:182184.
9.
Agus ZS, Goldfarb S: Calcium metabolism; normal and abnormal, in Arieff Al, De Fronzo RA (eds): Fluid Elec trolyte and Acid Base Disorders. New York, Churchill Livingstone, 1985, ρ 511.
10.
Bukoski RD, Xue H, McCarron DA: Effect of l,25(OH) vitamin D and ionized CA on Ca uptake by primary cultures of aortic myocytes of spontaneously hyperten sive and Wistar Kyoto normotensive rats. Biochem Biophys Res Commun 1987;146:1330-1335. 2
3
2+
45
