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(Hypertension. 1997;29:1014-1019.)
© 1997 American Heart Association, Inc.
Articles |
Insulin-Induced Hypertension in Rats Depends on an Intact Renin-Angiotensin System
Correspondence to Michael W. Brands, PhD, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 N State St, Jackson, MS 39216-4505.
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Abstract |
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Abstract This study tested the dependence of insulin-induced hypertension in rats on a functional renin-angiotensin system. Rats were instrumented with chronic artery and vein catheters and housed in metabolic cages. After acclimation, 10 rats began receiving the angiotensin-converting enzyme inhibitor (ACEI) benazepril at 1.8 mg · kg-1 · d-1 via a continuous intravenous infusion that was maintained throughout the study; 8 control rats received vehicle. Four days after starting ACEI or vehicle, all rats entered a 5-day control period that was followed by a 7-day insulin infusion at 1.5 mU · kg-1 · min-1. Glucose was coinfused at 22 mg · kg-1 · min-1 to prevent hypoglycemia. Insulin infusion in control rats increased mean arterial pressure (MAP; measured 24 h/d) from an average of 101±1 to 113±2 mm Hg on day 1; MAP averaged 110±1 mm Hg for the 7-day infusion period. Glomerular filtration rate decreased, although not significantly, from 2.7±0.1 to 2.1±0.2 mL/min on day 3. Chronic ACEI decreased baseline MAP from an average of 97±1 to 79±1 mm Hg and markedly attenuated the increase in MAP during insulin. MAP averaged 81±1 mm Hg for the 7-day period and increased significantly, to 85±2 mm Hg, only on day 3. Likewise, the tendency for glomerular filtration rate to decrease was blunted. These results indicate that insulin-induced hypertension in rats depends on angiotensin II and suggest that a reduction in glomerular filtration rate contributes to the shift in pressure natriuresis.
Key Words: insulin • blood pressure • angiotensin II • glomerular filtration rate
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Introduction |
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Because hyperinsulinemia generally is associated with hypertension in obesity,1 2 3 many investigators have speculated that increased insulin may contribute to the elevated BP.2 3 This possibility has been bolstered by additional reports correlating hyperinsulinemia with hypertension4 5 6 and by acute infusion studies suggesting that insulin might elevate BP through renal, neural, and/or secondary humoral mechanisms.7 8 9 10 11 Experiments that have evaluated directly the chronic hemodynamic actions of hyperinsulinemia have revealed a sustained, probably species-specific, pressor action of insulin,12 13 14 15 but the mechanisms have yet to be identified.
In rats, we have reported that hyperinsulinemia, in the absence of hypoglycemia, causes an increase in MAP that is maintained for at least 7 days.12 13 14 15 This insulin-induced hypertension is associated with a shift in pressure natriuresis, since the rats are in sodium balance at elevated BP12 13 14 15 16 17 ; however, the rise in BP is not accompanied by sodium retention and increased cardiac output.14 In fact, total peripheral resistance is increased,14 suggesting activation of a vasoconstrictor mechanism. The nature of this mechanism is not known. However, because the absence of insulin-induced hypertension in dogs suggests that there may be important species differences in the hemodynamic response to insulin,18 19 20 identification of the mechanism for the hypertension in rats is essential for determination of whether the conditions facilitating this response can, or do, exist in humans.
The renin-angiotensin system is one of the most powerful endogenous systems influencing the pressure-natriuresis relationship,17 and there is evidence that insulin and Ang II may potentiate each other's actions. For example, Rocchini et al21 reported that euglycemic hyperinsulinemia had a dose-related effect to exacerbate the BP rise caused by acute Ang II infusion, and insulin also has been reported to increase mesangial cell responsiveness to Ang II.22 Furthermore, hyperinsulinemic Zucker rats have been reported to have increased BP sensitivity to Ang II,23 and fructose-induced hyperinsulinemia and hypertension in rats are prevented by chronic Ang II receptor blockade.24 Therefore, this study was designed to test the dependence of the chronic, insulin-induced rise in BP in rats on a functional renin-angiotensin system.
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Methods |
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All experiments were conducted in male Sprague-Dawley rats (weight approximately 350 g; Harlan Sprague Dawley, Madison, Wis); protocols were approved by the Institutional Animal Care and Use Committee at the University of Mississippi Medical Center. Anesthesia was induced with sodium pentobarbital (50 mg/kg), and atropine was administered (40 µg IP per rat) to minimize airway secretions. Under aseptic conditions, a laparotomy was performed, and a nonocclusive catheter was inserted in an orthograde manner into the abdominal aorta, caudal to the kidneys, via a stab incision in the aortic wall made with the tip of an 18-gauge needle. The catheter was constructed from medical vinyl tubing (BOLAB, size V/4 [20 gauge]), with one end formed into an S shape. Into this end was inserted a 5- to 6-mm segment of PE-90 tubing tapered over heat to approximately PE-30 size. Only the PE segment tip was inserted into the aorta.
The insertion point was sealed with cyanoacrylate adhesive, and the catheter was exteriorized through the lateral abdominal wall. A femoral vein catheter (BOLAB, size V/4 [20 gauge], with no modifications) was implanted through a separate incision and the tip maneuvered into the vena cava. All incisions were infiltrated with penicillin G and bupivacaine at closure, and the catheters were routed subcutaneously to the scapular region and exteriorized through a Dacron-covered stainless steel button sutured subcutaneously over the scapulae.
The rats were allowed to recover from surgery and then were placed in individual metabolic cages in a quiet, air-conditioned room with a 12-hour light/dark cycle. The catheters were passed though a stainless steel spring that was attached to the button, and the opposite end of the spring was connected to a dual-channel hydraulic swivel (Instech). The venous catheter was immediately connected, via the hydraulic swivel, to a syringe pump (Harvard Apparatus) that ran continuously throughout the study. All solutions contained antibiotic (25 000 U penicillin G per rat per day and 0.03 g mezlocillin per rat per day) and were infused through a filter (0.22 mm, Cathivex, Millipore Corp). The arterial catheter was filled with heparin solution (1000 USP U/mL) and connected, also via the swivel, to a pressure transducer (Cobe) mounted on the cage exterior at the level of the rat. The amplified pulsatile arterial pressure signals were sent to an analog-digital converter and analyzed by computer with customized software. The analog signals were sampled 4 seconds each minute 24 h/d.
Total sodium and potassium intakes throughout the experiment were maintained constant at approximately 2.9 and 4.5 mmol/d, respectively, by continuous intravenous infusion of 18 mL/d sterile 0.9% saline that also contained 18.6 mg KCl/mL, combined with sodium- and potassium-deficient rat chow (3.04x10-6 mmol sodium/g and 1.87x10-6 mmol potassium/g; Teklad). A diet deficient in sodium and potassium ensured that the daily intakes of these electrolytes were controlled precisely by the infusion. In addition, 23 mL sterile water was infused as vehicle for the insulin and glucose infusions during the experimental period, yielding a total volume of 41 mL/d in all rats. This infusion was begun immediately after placement of the rat in the metabolic cage, and 5 to 7 days were allowed for acclimation before control measurements were recorded.
Experimental Protocol
After it was determined that the rats were in sodium balance and
that MAP was stable, the ACEI benazepril was added to the infusate of
10 rats at a concentration that delivered 1.8
mg · kg-1 · d-1 IV. This 24 h/d
infusion was maintained throughout the remainder of the study, and 4
days were allowed before control measurements were made. After the
5-day control period, a 24 h/d intravenous infusion of
insulin (Regular Insulin, pork; Novo Nordisk) at 1.5
mU · kg-1 · min-1 was
started and maintained for 7 days. In addition, the sterile water
vehicle from the control infusate was replaced by 50% dextrose
solution that provided 22 mg
glucose·kg-1·min-1
to prevent hypoglycemia during insulin infusion. After the
insulin/glucose infusion period, recovery measurements were collected
for 6 days using the control infusion solution. In 8 control rats, the
identical protocol was followed except that benazepril was not added to
the infusate.
On day 2 of the control period, on day 3 of the experimental period, and at the end of the recovery period after a 4-hour fast, arterial blood was collected from each rat in chilled sodium-EDTA tubes for measurement of plasma insulin and glucose concentrations and for gamma counting. The sample was replaced with an equal volume of 0.9% saline.
Analytic Methods
Plasma insulin concentration was measured by radioimmunoassay
(Diagnostic Products), and plasma glucose was
determined with a glucose analyzer (Yellow Springs Instrument
Co). Urinary sodium and potassium concentrations were determined with
ion-sensitive electrodes (Nova). GFR and effective renal plasma flow
were measured with a 4-hour fasted plasma sample after a 24-hour
intravenous infusion of 125I-iothalamate
(Glofil) and 131I-iodohippuran. Steady state was achieved
after 24 hours of intravenous isotope infusion in this
protocol; therefore, a sample of the infusate was counted, and the
infusion rate of isotope was substituted for the urinary excretion rate
of isotope for calculation of clearance.25 The
effectiveness of ACEI was determined by comparing the responses to
intra-arterial bolus infusion of Ang I (1 µg/kg) 2 days
before the ACEI period was started and during the control period.
Results are presented as mean±SE. Experimental data were compared with control data using two-factor ANOVA with repeated measures on one factor (time) and Dunnett's test for testing within-group effects.26 Statistical significance was considered at a value of P<.05.
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Results |
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Fig 1
shows the effects of 7 days of insulin
infusion on MAP in the 8 control (top) and 10 ACEI-infused (bottom)
rats. Both groups began with similar arterial pressures,
averaging 99±2 and 97±1 mm Hg in the control and ACEI groups,
respectively, and benazepril lowered arterial pressure
approximately 18 mm Hg, to an average of 79±1 mm Hg for
the 5-day ACEI control period. Insulin infusion increased MAP in the
control rats to an average of 110±1 mm Hg for the 7-day period,
approximately 11 mm Hg above preinsulin levels, and the increase
was statistically significant from day 1. In marked contrast, MAP in
the ACEI rats averaged 81±1 mm Hg during the 7-day period,
2 mm Hg above preinsulin levels, and only day 3 was elevated
significantly above control. After the insulin infusion was stopped,
arterial pressure returned to levels not different from
preinsulin levels in the control rats; and stopping benazepril infusion
in the ACEI rats caused a rapid rise in arterial pressure
to normal levels. Bolus testing with intra-arterial Ang I
revealed that chronic ACEI administration reduced the area under the BP
curve for 4 minutes after Ang I infusion from 134±9 to 28±8
mm Hg·min.
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Fig 2 shows that both groups of rats were in sodium
balance at similar levels of sodium excretion before the insulin
infusion was started. Sodium excretion decreased on day 1 of insulin in
both groups, but the decrease was statistically significant only in the
ACEI rats. Sodium balance was reachieved in both groups of rats,
although a significant overshoot in sodium excretion was measured in
the control rats, in which BP increased significantly.
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GFR averaged 2.7±0.1 mL/min in the control and ACEI rats before
insulin infusion. A tendency for GFR to decrease in the control rats,
to 2.1±0.1 mL/min, was measured on day 3 of the insulin infusion, and
this response was attenuated in the ACEI rats (Fig 3);
however, the decrease in GFR in the control rats was not statistically
significant. Renal plasma flow also tended to decrease during insulin
infusion, but no significant changes were measured in either group.
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Baseline insulin levels tended to be higher in the ACEI rats, but
similar plasma concentrations were achieved during the insulin infusion
in both groups (Table). The Table also shows that
supplemental glucose prevented hypoglycemia during insulin infusion,
and slight increases actually occurred in each group. However, the
changes were not different between groups, and the rise in BP in the
control rats was similar to that measured in our previous
studies,12 13 14 which used the same infusion doses without a
rise in plasma glucose. Chronic ACEI markedly elevated plasma renin
activity, which tended to decrease in both groups during insulin
infusion. Plasma protein concentration and hematocrit did not change
significantly in either group during insulin, nor did food intake
differ between groups (data not shown). Twenty-four-hour averaged heart
rates were 390±6 and 395±7 beats per minute before insulin in the
control and ACEI rats, respectively. As in our previous studies, heart
rate tended to increase, to 404±5 and 400±7 beats per minute,
respectively, during insulin infusion and averaged 382±7 and 386±7
beats per minute, respectively, during the recovery period. However,
there were no significant between- or within-group differences.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study revealed that a functional renin-angiotensin system is required for full expression of insulin-induced hypertension in rats. Similar Ang II dependence has been reported for the increase in BP,24 27 left ventricular weight,27 28 and plasma insulin24 27 associated with feeding rats a diet high in simple sugar content, and the work of Verma et al29 in metformin-treated, fructose-fed rats provides additional support for the hypothesis that fructose-induced hypertension is insulin mediated. However, high-sugar diets also have been reported to raise BP without changing insulin,30 31 32 to raise insulin without changing BP,28 and to have no effect on either variable, when arterial pressure was measured 24 h/d throughout the study33 or after 23 weeks of feeding.34 Thus, a consistent cause-and-effect link between high-sucrose or -fructose diets, insulin, and BP has not been established, and it remains unclear how the high-sugar feeding models relate to the model used in the present and previous studies from our laboratory.12 13 14 15 This is because dietary manipulation has the potential to exert multiple systemic effects in addition to possibly raising insulin, and in the present study, plasma insulin was increased by direct manipulation of a continuous intravenous insulin infusion.
Additional evidence for differences in fructose feeding versus insulin-induced hypertension is that fructose feeding was reported to raise plasma Ang II levels in a study in which insulin increased but BP did not.28 In the present study, the effect of insulin infusion to raise MAP depended on Ang II despite the absence of elevated plasma renin activity. One possible explanation for this relationship is that the insulin infusion raised BP by enhancing Ang II sensitivity. Evidence that insulin may enhance Ang II sensitivity comes from studies in which the addition of Ang II has yielded a greater response in the presence of elevated insulin levels. Rocchini et al21 reported that euglycemic hyperinsulinemia had a dose-related effect to exacerbate the BP rise caused by acute Ang II infusion, and Ling et al22 reported that insulin increased mesangial cell responsiveness to Ang II. In the present study, plasma renin activity actually decreased during insulin infusion, suggesting lower Ang II levels. This also could be viewed as evidence that Ang II sensitivity was enhanced; however, it is difficult to explain the rise in BP through these changes. Thus, even if Ang II sensitivity did increase, with the decrease in plasma renin activity measured, this mechanism probably does not explain the increase in BP during insulin infusion.
Another possible explanation for the Ang II dependence of the pressor response is that Ang II modulates responsiveness to insulin. Insulin has been reported to enhance Na,K-ATPase activity,35 and Santoro et al36 have reported that chronic ACE inhibition impaired the ability of hyperinsulinemia to lower plasma potassium, a response that depends at least partly on enhanced Na,K-ATPase activity.37 Early studies also revealed an antinatriuretic action of insulin,7 8 and Sechi et al38 reported that insulin receptor number and mRNA levels in rat kidney were decreased significantly by high salt diet, which markedly lowered plasma renin activity. This suggests that the effects of insulin on renal sodium transport may depend to some degree on the presence of Ang II. Thus, although Ang II may not mediate insulin-induced hypertension in rats, a certain minimal level of Ang II may be required for full expression of the renal actions of insulin.
This evidence for interaction between insulin and Ang II within the kidney also is consistent with a shift of the renal pressure-natriuresis relationship with hyperinsulinemia, which is prevented by inhibition of Ang II production.16 17 Neither cumulative sodium balance nor cardiac output increases with sustained insulin infusion,14 but the maintenance of sodium balance in the face of the elevated arterial pressure is evidence that renal sodium excretory capability has shifted to a more antinatriuretic state.16 17 If pressure natriuresis was not shifted, the elevated BP would induce natriuresis until enough volume was lost to return BP to normal.16 17 Thus, the maintenance of sodium balance during chronic insulin infusion is due to a balance between the antinatriuretic effect of hyperinsulinemia and the natriuretic effect of the increased arterial pressure and also indicates that the renal pressure-natriuresis relationship has shifted to a higher pressure.
The antinatriuretic effect of insulin could be due
to either increased tubular sodium reabsorption or decreased GFR. There
is considerable evidence from acute insulin infusion studies that
insulin increases tubular sodium chloride reabsorption,7 8
and this could be the mechanism for the decrease in sodium excretion on
day 1 of insulin infusion. We have not measured GFR on day 1 to
determine the role of tubular reabsorption, but by day 3 of the
infusion, GFR is decreased in insulin-induced hypertensive
rats,14 15 and a similar tendency was noted during insulin
infusion in the present study. In addition, decreased GFR during
insulin infusion is linked closely with increased BP. For example, we
have reported that chronic 
/ß-adrenergic blockade had no effect on
the hypertensive response to sustained
hyperinsulinemia, and the decrease in GFR was
statistically significant and nearly identical in blockade and
vehicle-infused rats.15 In contrast, the tendency for
reduced GFR during insulin infusion in the control rats in the
present study was noticeably attenuated in the ACEI rats, in which
the increase in BP was almost completely blocked. These findings
therefore suggest that the shift in pressure natriuresis with chronic
hyperinsulinemia in rats may be linked to the
antinatriuretic effect of decreased GFR.
The mechanism for the reduction in GFR is not known; however, the tendency for renal plasma flow to change in parallel14 15 suggests a role for increased afferent arteriolar resistance, although a decrease in the glomerular filtration coefficient cannot be ruled out. The potential role of afferent constriction is consistent with our previous finding that insulin-induced hypertension in rats is not salt sensitive13 as well as with the report by Juncos and Ito39 that physiological levels of insulin constricted isolated rabbit afferent arterioles. Another possibility is that if the effect of insulin on renal sodium chloride transport extends to the macula densa, insulin could affect afferent resistance by enhancing tubuloglomerular feedback. This potential mechanism also opens the possibility that the Ang II dependence observed could be linked to the dependence of tubuloglomerular feedback sensitivity on Ang II.40 41 In addition, the reported effects of insulin on endothelin11 and thromboxane42 suggest that a second factor could mediate the effects of insulin on GFR and BP in rats. In fact, we have reported preliminary evidence that insulin-induced hypertension in rats requires a normal ability of the rat to synthesize thromboxane.43
The potential involvement of a second factor is intriguing because it is consistent with the direct vasodilator effect of insulin on isolated vascular smooth muscle44 45 and also may explain why acute insulin infusions have not been reported to decrease GFR. In addition, it may provide a mechanism for the significant increase in BP we have observed on day 1 of insulin in the present study and previously,46 a response difficult to ascribe to renal antinatriuretic effects alone. Furthermore, a second, mediating, factor may explain why hyperinsulinemia does not cause hypertension in dogs18 19 20 if this factor responds differently among species.
Thus, the mechanism for the shift in pressure natriuresis with insulin infusion in rats and the precise role of reduced GFR still are not clear, but the results from the present study indicate that a functional renin-angiotensin system is required for full expression of insulin-induced hypertension in rats. Ang II appears to function as a permissive factor rather than an actual mediator of the pressure increase, possibly through its important role in maintaining normal tubuloglomerular feedback sensitivity. Further study will be required to confirm the potential importance of decreased GFR and the mechanism for this effect of chronic insulin infusion in rats.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This research was supported by grants HL-39399, HL-23502, and HL-51971 from the National Institutes of Health. We thank CIBA-Geigy for supplying the benazepril.
Received September 5, 1996; first decision September 30, 1996; accepted October 18, 1996.
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J. Song, X. Hu, S. Riazi, S. Tiwari, J. B. Wade, and C. A. Ecelbarger Regulation of blood pressure, the epithelial sodium channel (ENaC), and other key renal sodium transporters by chronic insulin infusion in rats Am J Physiol Renal Physiol, May 1, 2006; 290(5): F1055 - F1064. [Abstract] [Full Text] [PDF]
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J. J. Kuo, O. B. Jones, and J. E. Hall Chronic cardiovascular and renal actions of leptin during hyperinsulinemia Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2003; 284(4): R1037 - R1042. [Abstract] [Full Text] [PDF]
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M. W. Brands, A. E. Hailman, and S. M. Fitzgerald Long-Term Glucose Infusion Increases Arterial Pressure in Dogs With Cyclooxygenase-2 Inhibition Hypertension, February 1, 2001; 37(2): 733 - 738. [Abstract] [Full Text] [PDF]
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C. R. Claxton, M. W. Brands, S. M. Fitzgerald, and J. A. Cameron Inhibition of Nitric Oxide Synthesis Potentiates Hypertension During Chronic Glucose Infusion in Rats Hypertension, January 1, 2000; 35(1): 451 - 456. [Abstract] [Full Text] [PDF]
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K. Kamide, M. T. Hori, J.-H. Zhu, J. D. Barrett, P. Eggena, and M. L. Tuck Insulin-Mediated Growth in Aortic Smooth Muscle and the Vascular Renin-Angiotensin System Hypertension, September 1, 1998; 32(3): 482 - 487. [Abstract] [Full Text] [PDF]
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T.-C. Fang and W.-C. Huang Angiotensin Receptor Blockade Blunts Hyperinsulinemia-Induced Hypertension in Rats Hypertension, August 1, 1998; 32(2): 235 - 242. [Abstract] [Full Text] [PDF]
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H. L. Keen, M. W. Brands, M. J. Smith Jr, and J. E. Hall Maintenance of Baseline Angiotensin II Potentiates Insulin Hypertension in Rats Hypertension, February 1, 1998; 31(2): 637 - 642. [Abstract] [Full Text] [PDF]
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