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Fructose-induced hyperuricemia in essential hypertension
Fructose-induced Hyperuricemia in Essential Hypertension E. A
Fiaschi, B. Baggio, S. Favaro, A. Antonello, E. Camerin, S. Todesco, and A. Borsatti rapid
given
intravenous to
nine
fructose
load
normouricemic
hypertensive
and
eight
increase
probably
uric acid
of preformed
purine
gested
essential
increase was
significantly
in plasma
hypertensives
than
in controls.
no significant
difference
in
urinary
tion
between
the
two
higher There
in
tients
was excre-
brought
in
subjects.
control
The following
urate
the
tion
concentration
of
Since
was
essential
about
uric by
acid
due to an increased that
have
of purine
concentra-
fructose
nucleotides,
a higher
is
it is sug-
hypertensive than
most
metabolism
normal
pa“pool”
nucleotides.
groups.
A
LTHOUGH HYPERURICEMIA has been associated with diverse hypertensive states,lm4 the underlying mechanism remains obscure. Many authors have suggested a diminished urate clearance by the kidney, but studies of purine biosynthesis and turnover are lacking.5*6 Since it is well known that an intravenous fructose load increases plasma urates, most probably through an increased metabolism of preformed purine nucleotides,’ ” we decided to compare the effect of an acute fructose load given intravenously (i.v.) in normouricemic essential hypertensives and normal subjects. MATERIAL
AND
METHODS
The study hypertensives,
was performed on nine essential hypertensive and eight control subjects. The five males and four females aged 20-50 yr, had a mean blood pressure of 178 (+ 20.6, SD)/1 13 (+ 7.5) mm Hg. None of the patients had been treated with diuretic or antihypertensive drugs. In all the patients, BUN, plasma creatinine. creatinine clearance, plasma urate. plasma renin activity, plasma and urinary aldosterone. plasma and urinary electrolytes. urinary catecholamines. intravenous pyelogram, and renal angiography were normal. The controls were five males and three females 15-48 yr of age. All the experiments were performed at the same time each morning with the subject fasting and resting quietly in bed. For urine collection sterile indwelling catheters were used. After taking basal plasma and urinary samples, a fructose load (0.3 g/kg body weight) was injected i.v. at a rate of 5 ml/min (in about IO min). Blood samples for urate determinations were taken at 15, 30, 60. and 120 min after the end of the infusion. At 15, 30, 60, and 120 min after the end of the infusion urines were collected in plastic containers (with toluene as a preservative) maintained at room temperature; they were immediately assayed. Plasma and urinary uric acid was estimated by the spectrophotometric method using purified uricase.12 For the statistical analysis the differences between the mean values obtained in the same subjects during the study period were compared utilizing the Student’s t test for paired variables; the differences between the mean values obtained in the two groups of subjects were compared by the Student’s t test for unpaired variables. A change or difference was termed significant if the p value was < 0.05.
From the Institute of Clinical Medicine I, University oj’Padua. Padua. 1tai.v. Received for publication February 2. 1977. Reprint requests should be addressed to Dr. A. Borsatti, Clinica Medica sitario, 35100 Padua. Italy. K)I977 bv Grune & Stratton, Inc. ISSN 0026-0495.
Metabolism, Vol. 26, No. 11 (November),
1977
I. Policlinico
Univer-
1219
FIASCHI ET Al.
1220
Table 1. Effect of Fructose Infusion on Plasma Uric Acid Concentration and Urinary Uric Acid Excretion (Mean f SEM) Controls 0 min Plasma
uric acid
Concentration Urinary
4.2 (mg/lOO
ml) +0.26
uric acid
Excretion
15 min 5.0 10.32
0.99 h-o.21
(mg/min)
0.99 ho.12
30th
Essential 60min
4.8 ho.33
4.8 10.30
I .Ol 10.16
0.98 zkO.17
120min
Omin
4.9
4.5
10.33
10.27
0.99
0.83
ho.12
10.16
15min 6.3 ho.45 1.90 ho.26
Hypertensives 30 min 6.2 ztO.43 1.42
ho.16
60min 6.1 ztO.49 1.24 ztO.10
120min 5.5 zto.41 1.01 zto.13
RESULTS
Plasma uric acid concentration and urinary uric acid excretion in hypertensive and control subjects are summarized in Table 1. Both groups showed a significant, although not homogeneous, increase in plasma uric acid concentration after fructose load. This increase was significantly higher in hypertensive patients at 15, 30, and 60 min (Fig. 1). Normal controls did not demonstrate any significant change in urinary uric
-I/-i 0s
,&I465 t.55574 p
‘”
jj,,
p
t.53103 p
t:5.1596 pa005
,
,
::
a u 06
2
!2 45 5
I
,/’
L-----L________L___________-____--______I t.2.7313 PROas
t.33683 peO.02
1 60
TIME
(MIN.)
I20
I I20
I 60 wtE
(MIN.)
Fig. 1. Effect of a rapid intravenous infusion of fructose (0.3 g/kg body weight) on plasma uric acid concentration in hypertensive and control (broken line) subjects. The lower port gives the differences in behavior of the two groups.
FRUCTOSE-INDUCED
1221
HYPERURICEMIA
2
:n___:
2’
J
t=3.4m peGa
$ %O F ti
KG979 p
1
I
trooooo p=ns
A”’
t = 2.0746 p=n.s
tz2.7716 P’om5
tzM964 p=n.a
I
1
IS
30
tr0.0200 p=nr.
t=ao136 p=n.L). I 60
1 I20 TIME
Fig. 2. Effect of o rapid intravenous infusion of fructose (0.3 g/kg body weight) on urinary uric acid excretion in hypertensive and control (broken line) subjects. The lower part gives the differences in behavior of the two groups.
(MIN.)
~=~~~~ t Cl5672
td30621 t-l.7725
t .L2355
kO.0956 pzn.s I 120 TlMf
(MIN.)
.__________
t-O.6442 p=n.s
tz2.0503 p=lIs.
kO5542 p=n.s.
I
1
15
30
t :0.0601 p=n.s
t .0.1816 p=n.s.
I
1
120
60 TIME
(MIN.)
Fig. 3. The ratios between urinary uric acid excretion and plasma uric acid concentration in hypertensive and control (broken line) subjects after a rapid intravenous infusion of fructose (0.3 g/kg body weight).
1222
FIASCHI
ET AL.
acid excretion, while a significant increase at 15, 30, and 60 min was found in hypertensive subjects. Making a comparison between the two groups, hypertensive patients demonstrated a significantly higher urinary uric acid excretion only at 15 min (Fig. 2). To check whether the amount of excreted uric acid was proportional to the plasma uric acid increase in both groups, we have taken into consideration the ratio between urinary uric acid excretion and plasma uric acid concentration. This index did not show any significant difference between control and hypertensive subjects (Fig. 3). DISCUSSION
Our data confirm the previously described increase in plasma uric acid concentration after an acute fructose load in normal subjects.9~‘0~‘3 The increase we observed in our controls was lower than that reported by other investigators. This discrepancy may be explained by considering the different dosages of fructose used (0.3 g instead of 0.5 g/kg body weight). In fact, it has been demonstrated that the increase in plasma urate brought about by fructose is dose dependent. I4 Our data also demonstrate that the increase in plasma uric acid concentration is significantly higher in normouricemic essential hypertensive patients. This observation cannot be explained by a lower than normal urinary uric acid excretion. In fact, in addition to a higher plasma uric acid concentration, hypertensive subjects also showed a higher urate excretion, Furthermore, the ratio between urinary uric acid excretion and plasma uric acid concentration, which roughly appraises the ability of the kidney to excrete the increased amount of plasma urate, did not show any significant difference between control and hypertensive subjects. To try to explain our findings, it is worthwhile to consider the mechanism of action of fructose. A rapid infusion of fructose brings about an increased production of uric acid not through an acceleration of the de novo synthesis, but most probably through an increased metabolism of preformed purine nucleotides.‘s8,” Therefore, we could conclude that hypertensive patients must have a greater than normal “pool” of purine nucleotides. Whether this is due to the hypertensive disease itself or is a part of an inborn metabolic error of which arterial hypertension is another expression is open to investigation. REFERENCES 1. Breckenrige A: Hypertension and hyperuricaemia. Lancet 1:15, 1966 2. Cannon PJ, Stason WB, Demartini FE, et al: Hyperuricemia in primary and renal hypertension. N Engl J Med 275:457, 1966 3. Kinsey D, Walther R, Sise HS, et al: Incidence of hyperuricemia in 400 hypertensive patients. Circulation 24:972, 1961 4. Lagrue G, Ryckewaert A: L’uricCmie au tours des hypertensions artCrielles. Coeur Med Intern 7:507, 1968
5. De Wardener HE: The Kidney. An Outline of Normal and Abnormal Structure and function. London, Churchill, 1967, p 356 6. Scott JT, Arnott R, Glass HJ: C,, studies of uric acid turnover. Ann Rheum Dis 27:476. 1968 7. Bode CH, Schumacher HR. Goebel H, et al: Fructose-induced depletion of liver adenine nucleotides in man. Horm Metab Res, 3:289, 1971 8. Fox IH, Kelley WN: Studies on the mech-
FRUCTOSE-INDUCED
HYPERURICEMIA
anism of fructose induced hyperuricemia man. Metabolism 21:713, 1972
1223
in
9. Narins RG, Weisberg JS, Myers AR: Effects of carbohydrates on uric acid metabolism. Metabolism 23:455, 1974 10. Perheentupa J, Raivio K: Fructose induced hyperuricaemia. Lancet 2:528. 1967 11, Raivio KI, Kekomlki MP, MIenpal PH: Depletion of liver adenine nucleotides induced by D-fructose. Biochem Pharmacol 18:2615, 1969
12. Thefeld W, Hoffmeister H, Busch EW. et al: Normalwerte der Serumharnsaure in Abhlngigkeit van Alter und Geschlecht mit einen neuen enzymatischen. Dtsch Med Wochenschr 98:380, 1973 13. Marcolongo R, Marinello E. Combucci G, et al: The role of xanthine oxidase in hyperuricemic states. Arthritis Rheum 17:430. I974 14. Heuckenkamp QU, Zollner N: Fructose induced
hyperuricaemia
Lancet
1:808. 1971
Fiaschi, B. Baggio, S. Favaro, A. Antonello, E. Camerin, S. Todesco, and A. Borsatti rapid
given
intravenous to
nine
fructose
load
normouricemic
hypertensive
and
eight
increase
probably
uric acid
of preformed
purine
gested
essential
increase was
significantly
in plasma
hypertensives
than
in controls.
no significant
difference
in
urinary
tion
between
the
two
higher There
in
tients
was excre-
brought
in
subjects.
control
The following
urate
the
tion
concentration
of
Since
was
essential
about
uric by
acid
due to an increased that
have
of purine
concentra-
fructose
nucleotides,
a higher
is
it is sug-
hypertensive than
most
metabolism
normal
pa“pool”
nucleotides.
groups.
A
LTHOUGH HYPERURICEMIA has been associated with diverse hypertensive states,lm4 the underlying mechanism remains obscure. Many authors have suggested a diminished urate clearance by the kidney, but studies of purine biosynthesis and turnover are lacking.5*6 Since it is well known that an intravenous fructose load increases plasma urates, most probably through an increased metabolism of preformed purine nucleotides,’ ” we decided to compare the effect of an acute fructose load given intravenously (i.v.) in normouricemic essential hypertensives and normal subjects. MATERIAL
AND
METHODS
The study hypertensives,
was performed on nine essential hypertensive and eight control subjects. The five males and four females aged 20-50 yr, had a mean blood pressure of 178 (+ 20.6, SD)/1 13 (+ 7.5) mm Hg. None of the patients had been treated with diuretic or antihypertensive drugs. In all the patients, BUN, plasma creatinine. creatinine clearance, plasma urate. plasma renin activity, plasma and urinary aldosterone. plasma and urinary electrolytes. urinary catecholamines. intravenous pyelogram, and renal angiography were normal. The controls were five males and three females 15-48 yr of age. All the experiments were performed at the same time each morning with the subject fasting and resting quietly in bed. For urine collection sterile indwelling catheters were used. After taking basal plasma and urinary samples, a fructose load (0.3 g/kg body weight) was injected i.v. at a rate of 5 ml/min (in about IO min). Blood samples for urate determinations were taken at 15, 30, 60. and 120 min after the end of the infusion. At 15, 30, 60, and 120 min after the end of the infusion urines were collected in plastic containers (with toluene as a preservative) maintained at room temperature; they were immediately assayed. Plasma and urinary uric acid was estimated by the spectrophotometric method using purified uricase.12 For the statistical analysis the differences between the mean values obtained in the same subjects during the study period were compared utilizing the Student’s t test for paired variables; the differences between the mean values obtained in the two groups of subjects were compared by the Student’s t test for unpaired variables. A change or difference was termed significant if the p value was < 0.05.
From the Institute of Clinical Medicine I, University oj’Padua. Padua. 1tai.v. Received for publication February 2. 1977. Reprint requests should be addressed to Dr. A. Borsatti, Clinica Medica sitario, 35100 Padua. Italy. K)I977 bv Grune & Stratton, Inc. ISSN 0026-0495.
Metabolism, Vol. 26, No. 11 (November),
1977
I. Policlinico
Univer-
1219
FIASCHI ET Al.
1220
Table 1. Effect of Fructose Infusion on Plasma Uric Acid Concentration and Urinary Uric Acid Excretion (Mean f SEM) Controls 0 min Plasma
uric acid
Concentration Urinary
4.2 (mg/lOO
ml) +0.26
uric acid
Excretion
15 min 5.0 10.32
0.99 h-o.21
(mg/min)
0.99 ho.12
30th
Essential 60min
4.8 ho.33
4.8 10.30
I .Ol 10.16
0.98 zkO.17
120min
Omin
4.9
4.5
10.33
10.27
0.99
0.83
ho.12
10.16
15min 6.3 ho.45 1.90 ho.26
Hypertensives 30 min 6.2 ztO.43 1.42
ho.16
60min 6.1 ztO.49 1.24 ztO.10
120min 5.5 zto.41 1.01 zto.13
RESULTS
Plasma uric acid concentration and urinary uric acid excretion in hypertensive and control subjects are summarized in Table 1. Both groups showed a significant, although not homogeneous, increase in plasma uric acid concentration after fructose load. This increase was significantly higher in hypertensive patients at 15, 30, and 60 min (Fig. 1). Normal controls did not demonstrate any significant change in urinary uric
-I/-i 0s
,&I465 t.55574 p
‘”
jj,,
p
t.53103 p
t:5.1596 pa005
,
,
::
a u 06
2
!2 45 5
I
,/’
L-----L________L___________-____--______I t.2.7313 PROas
t.33683 peO.02
1 60
TIME
(MIN.)
I20
I I20
I 60 wtE
(MIN.)
Fig. 1. Effect of a rapid intravenous infusion of fructose (0.3 g/kg body weight) on plasma uric acid concentration in hypertensive and control (broken line) subjects. The lower port gives the differences in behavior of the two groups.
FRUCTOSE-INDUCED
1221
HYPERURICEMIA
2
:n___:
2’
J
t=3.4m peGa
$ %O F ti
KG979 p
1
I
trooooo p=ns
A”’
t = 2.0746 p=n.s
tz2.7716 P’om5
tzM964 p=n.a
I
1
IS
30
tr0.0200 p=nr.
t=ao136 p=n.L). I 60
1 I20 TIME
Fig. 2. Effect of o rapid intravenous infusion of fructose (0.3 g/kg body weight) on urinary uric acid excretion in hypertensive and control (broken line) subjects. The lower part gives the differences in behavior of the two groups.
(MIN.)
~=~~~~ t Cl5672
td30621 t-l.7725
t .L2355
kO.0956 pzn.s I 120 TlMf
(MIN.)
.__________
t-O.6442 p=n.s
tz2.0503 p=lIs.
kO5542 p=n.s.
I
1
15
30
t :0.0601 p=n.s
t .0.1816 p=n.s.
I
1
120
60 TIME
(MIN.)
Fig. 3. The ratios between urinary uric acid excretion and plasma uric acid concentration in hypertensive and control (broken line) subjects after a rapid intravenous infusion of fructose (0.3 g/kg body weight).
1222
FIASCHI
ET AL.
acid excretion, while a significant increase at 15, 30, and 60 min was found in hypertensive subjects. Making a comparison between the two groups, hypertensive patients demonstrated a significantly higher urinary uric acid excretion only at 15 min (Fig. 2). To check whether the amount of excreted uric acid was proportional to the plasma uric acid increase in both groups, we have taken into consideration the ratio between urinary uric acid excretion and plasma uric acid concentration. This index did not show any significant difference between control and hypertensive subjects (Fig. 3). DISCUSSION
Our data confirm the previously described increase in plasma uric acid concentration after an acute fructose load in normal subjects.9~‘0~‘3 The increase we observed in our controls was lower than that reported by other investigators. This discrepancy may be explained by considering the different dosages of fructose used (0.3 g instead of 0.5 g/kg body weight). In fact, it has been demonstrated that the increase in plasma urate brought about by fructose is dose dependent. I4 Our data also demonstrate that the increase in plasma uric acid concentration is significantly higher in normouricemic essential hypertensive patients. This observation cannot be explained by a lower than normal urinary uric acid excretion. In fact, in addition to a higher plasma uric acid concentration, hypertensive subjects also showed a higher urate excretion, Furthermore, the ratio between urinary uric acid excretion and plasma uric acid concentration, which roughly appraises the ability of the kidney to excrete the increased amount of plasma urate, did not show any significant difference between control and hypertensive subjects. To try to explain our findings, it is worthwhile to consider the mechanism of action of fructose. A rapid infusion of fructose brings about an increased production of uric acid not through an acceleration of the de novo synthesis, but most probably through an increased metabolism of preformed purine nucleotides.‘s8,” Therefore, we could conclude that hypertensive patients must have a greater than normal “pool” of purine nucleotides. Whether this is due to the hypertensive disease itself or is a part of an inborn metabolic error of which arterial hypertension is another expression is open to investigation. REFERENCES 1. Breckenrige A: Hypertension and hyperuricaemia. Lancet 1:15, 1966 2. Cannon PJ, Stason WB, Demartini FE, et al: Hyperuricemia in primary and renal hypertension. N Engl J Med 275:457, 1966 3. Kinsey D, Walther R, Sise HS, et al: Incidence of hyperuricemia in 400 hypertensive patients. Circulation 24:972, 1961 4. Lagrue G, Ryckewaert A: L’uricCmie au tours des hypertensions artCrielles. Coeur Med Intern 7:507, 1968
5. De Wardener HE: The Kidney. An Outline of Normal and Abnormal Structure and function. London, Churchill, 1967, p 356 6. Scott JT, Arnott R, Glass HJ: C,, studies of uric acid turnover. Ann Rheum Dis 27:476. 1968 7. Bode CH, Schumacher HR. Goebel H, et al: Fructose-induced depletion of liver adenine nucleotides in man. Horm Metab Res, 3:289, 1971 8. Fox IH, Kelley WN: Studies on the mech-
FRUCTOSE-INDUCED
HYPERURICEMIA
anism of fructose induced hyperuricemia man. Metabolism 21:713, 1972
1223
in
9. Narins RG, Weisberg JS, Myers AR: Effects of carbohydrates on uric acid metabolism. Metabolism 23:455, 1974 10. Perheentupa J, Raivio K: Fructose induced hyperuricaemia. Lancet 2:528. 1967 11, Raivio KI, Kekomlki MP, MIenpal PH: Depletion of liver adenine nucleotides induced by D-fructose. Biochem Pharmacol 18:2615, 1969
12. Thefeld W, Hoffmeister H, Busch EW. et al: Normalwerte der Serumharnsaure in Abhlngigkeit van Alter und Geschlecht mit einen neuen enzymatischen. Dtsch Med Wochenschr 98:380, 1973 13. Marcolongo R, Marinello E. Combucci G, et al: The role of xanthine oxidase in hyperuricemic states. Arthritis Rheum 17:430. I974 14. Heuckenkamp QU, Zollner N: Fructose induced
hyperuricaemia
Lancet
1:808. 1971