(Hypertension. 1995;26:1089-1092.)
© 1995 American Heart Association, Inc.
Articles |
From the Hypertension Clinic, Hospital de Niños "Ricardo Gutierrez," Buenos Aires, Argentina.
Correspondence to Beatriz Grunfeld, La Pampa 3635, Buenos Aires 1430, Argentina.
| Abstract |
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Key Words: insulin hypertension, genetic sodium
| Introduction |
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It has been suggested that hyperinsulinemia could lead to hypertension by means of its known sodium-retaining effect, among other effects.5 6 In hypertensive patients adequate renal sodium excretion is achieved only at elevated blood pressures.7 This rightward shift of the pressure-natriuresis curve may be the consequence of alterations in renal hemodynamics, but it also could be due to abnormalities of renal tubule sodium reabsorption.8
We and others previously reported an increased sodium reabsorption in the proximal tubule of normotensive offspring of parents with essential hypertension.9 10 Thus, the aim of the present study was to evaluate the role of the insulin response to an intravenous glucose load in the increased proximal renal sodium reabsorption found in offspring of hypertensive parents.
| Methods |
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Blood pressure of parents was assessed personally by one of the authors. Procedures were explained carefully to both parents and children, and informed consent was obtained from parents.
All subjects came to the clinic after an overnight fast and after
receiving 300 mg/m2 of lithium carbonate at 10
PM the night before. At 6 AM subjects emptied
their bladders completely, and urine was collected until 9
AM for measurement of sodium, potassium,
creatinine, and lithium. At 9 AM a
butterfly-like needle was placed in an antecubital vein and a blood
specimen was obtained for measurement of glucose, insulin, lithium,
creatinine, sodium, and potassium. An
intravenous glucose load (0.25 g/kg, 25% solution) was
then infused over
2 minutes in a contralateral vein. Blood samples
were obtained at 1, 3, 5, and 7 minutes after glucose injection for
measurement of insulin and at 10, 20, 30, 40, 50, and 60 minutes for
insulin and glucose. A second urine collection was performed between 9
AM and noon for sodium, potassium, creatinine,
and lithium. Patients received an oral water load (20 mL/kg and
diuresis) throughout the study. Sodium, potassium, and
creatinine levels were measured by an automated method
(Beckman Instruments). Lithium was measured by atomic absorption
spectophotometry (Perkin Elmer), and insulin was measured by
radioimmunoassay.
For statistical analysis comparisons between and within groups were calculated by paired and unpaired t tests. Pearson correlation coefficients were used to assess relations between variables. A value of P<.05 was accepted as significant. Findings are expressed as mean±SEM.
| Results |
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Table 2 shows the calculated variables both before and after the IVGTT. FeLi was significantly lower in the F+ (16.1±1.8% in F+ versus 23.5±2.0% in F-; P<.02) and did not change after the intravenous glucose load in either group (14.7±1.3% in F+ versus 20.9±1.7% in F-, respectively; P=NS versus before IVGTT) (Fig 1). The IAUC was comparable in both groups (2815±499 µU/mL per hour in F+ versus 2290±418 µU/mL per hour in F-; P=NS). There was no correlation between FeLi and IAUC (Fig 2). FeNa was similar in both groups (0.99±0.1% F+ versus 0.99±0.1% in F-; P=NS) and decreased significantly after the intravenous glucose load to a comparable extent in both groups (0.77+0.13% in F+ versus 0.85±0.1% in F-; P<.01 versus before IVGTT) (Fig 3). No correlation was found between FeNa and IAUC. Fractional excretion of potassium was similar before and after intravenous glucose loading in both groups.
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When we segregated the F+ according to IAUC level (<2500 or >2500 U/mL per hour), on the basis of our previous findings in normotensive adolescents with normal BMI we could establish that FeNa decreased significantly in adolescents with the higher insulin levels (1.02±0.16 before IVGTT versus 0.67±0.19 after IVGTT; P<.005), whereas no change could be detected in adolescents with lower IAUC levels (0.95±0.14 before IVGTT and 0.88±0.17 after IVGTT; P=NS) (Fig 4).
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| Discussion |
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Although the sodium-retaining effects of insulin have been known for a long time11 the mechanisms involved and the site of insulin action both have been controversial matters.12 Several studies indicated that insulin may control sodium reabsorption along the whole nephron. The ability of insulin to increase sodium reabsorption in the proximal convoluted tubule has been established convincingly in in vitro studies.13 14 In contrast, in vivo studies in animals failed to demonstrate increased proximal tubule sodium reabsorption during insulin antinatriuresis,15 16 suggesting that the antinatriuretic effect of insulin is exerted predominantly in postproximal tubules.
Feraille et al17 showed time and dose dependence of insulin action in rats on sodium reabsorption along the different nephron segments. Thus, although the collecting ducts were less sensitive, they displayed an earlier response to insulin than the proximal tubules. Furthermore, the threshold concentrations of insulin on sodium reabsorption were found to lie in the proximal tubule and thick ascending limb within the fasting range, whereas it was within the range of postprandial stimulated plasma insulin concentrations in the collecting tubules. The above could in part explain our findings of an antinatriuretic effect of insulin distal to the proximal tubules. Finally, previous studies conducted in humans indicated that exogenous insulin increases sodium reabsorption despite either no changes or a slight decrease in proximal sodium reabsorption, again supporting a postproximal tubule site for insulin action.5 6 18 19
Although specific insulin-binding sites were demonstrated along the entire nephron the number of insulin binding sites and affinity constants varied significantly among different nephron segments, with the greatest number of insulin binding sites of high affinity found in proximal and distal convoluted tubule segments.20 Our present and past findings3 further support previous contentions21 22 that insulin resistance associated with essential hypertension is relatively selective for glucose metabolism in certain target tissues and that hyperinsulinemia may result in increased insulin effects in areas where insulin sensitivity is preserved such as the renal tubule.
Mean insulin levels and mean IAUC after an intravenous glucose challenge in the F+ included in the present study were similar to those of the F- at variance with our previous findings.3 This is explained by the fact that obese children were included in both groups because we were presently interested only in the role of endogenous insulin on sodium handling.
FeLi has been shown to accurately reflect proximal tubule sodium reabsorption in sodium-replete humans.23 The increased renal proximal sodium reabsorption found in offspring of hypertensive parents was related to the family history of hypertension and was independent of the BMI.
Renal blood flow has been shown to be lower and filtration fraction and renal vascular resistance higher in children of hypertensive parents at such an early age as 11 years old compared with children of normotensive parents.24 A rise in filtration fraction increases peritubular capillary oncotic pressure because more ultrafiltrate is formed and plasma proteins become more concentrated, thus enhancing the uptake of sodium and water.25
A diminished FeLi reflecting an increased renal proximal sodium reabsorption in these high-risk adolescents may indicate a physiological adaptive mechanism to the hemodynamic changes described in this population. An increased activity of the sympathetic nervous system26 and/or the renin-angiotensin system27 also could account for the increased proximal sodium reabsorption.
In summary normotensive adolescent offspring of hypertensive parents have an increased renal proximal sodium reabsorption that is not related to endogenous insulin levels. However, FeNa diminished after the insulin response to the intravenous glucose load. Therefore, our findings under physiological conditions in humans show that one possible role of insulin in the development of hypertension may be exerted through an antinatriuretic effect distal to the proximal tubule.
| Selected Abbreviations and Acronyms |
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| Acknowledgments |
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Received June 19, 1995; first decision August 1, 1995; accepted October 6, 1995.
| References |
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