(Hypertension. 1995;26:460-464.)
© 1995 American Heart Association, Inc.
Articles |
Amylin Stimulates Plasma Renin Concentration in Humans
From the Department of Medicine, University of Melbourne, Austin & Repatriation Medical Centre, Heidelberg, Australia.
Correspondence to Dr M.E. Cooper, Department of Medicine, University of Melbourne, Austin & Repatriation Medical Centre (Repatriation Campus), W Heidelberg 3081,Vic, Australia. E-mail cooper@austin.unimelb.edu.au.
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Abstract |
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Abstract Although insulin resistance and hypertension are commonly associated, the underlying cause for this association remains unknown. Plasma concentrations of the recently described hormone amylin, which is cosecreted with insulin by the pancreatic ß cell, are reported to be elevated in various states of insulin resistance, including hypertension and obesity. Preliminary studies by our group have suggested that there are amylin binding sites in the kidney. In nine healthy humans an infusion of human amylin that resulted in steady state plasma amylin levels in the subnanomolar range led to significant increases in plasma renin and aldosterone concentrations. These changes occurred in the absence of significant changes in plasma electrolytes, catecholamines, vasopressin, total renin, or osmolality. Diastolic pressure at 30 minutes and plasma glucose at 60 minutes rose modestly. Since amylin has both metabolic and renal actions, this peptide may be an important link between hypertension, insulin resistance, and the renin-angiotensin system.
Key Words: renin • aldosterone • insulin resistance
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Introduction |
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Insulin resistance and hypertension are commonly associated in a clinical syndrome that has been called Syndrome X or the metabolic syndrome.1 2 It has been postulated that the elevation in insulin levels observed in insulin-resistant states may lead to hypertension, although recent studies suggest that insulin per se is unlikely to explain this phenomenon.3 It has recently been hypothesized, based on rodent studies, that amylin, which is cosecreted with insulin by the pancreatic ß cell, may be an important link between hypertension and insulin resistance.4 5 Amylin, also known as islet amyloid polypeptide, is a 37–amino acid peptide with significant homology to calcitonin gene–related peptide (CGRP).6 Amylin was initially purified from amyloid deposited in the pancreas of non–insulin-dependent diabetic patients.7 Known biological actions of amylin include effects on carbohydrate metabolism such as inhibition of glucose incorporation into glycogen in muscle,8 inhibition of insulin secretion by the pancreatic ß cell,9 and calcitonin-like effects on osteoclast function.10
Preliminary reports have indicated that amylin has binding sites in the rat renal cortex11 and increases plasma renin activity at least twofold in these animals.12 In the present study we explored the effects of human amylin on the renin-angiotensin-aldosterone axis in humans. Human amylin has been previously administered to humans, but the effects of this peptide on vasoactive hormones or blood pressure were not specifically investigated.13 14
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Methods |
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Study Protocol
Nine healthy male subjects (aged 18 to 35 years) were recruited after approval from the Austin Hospital Ethics Committee and gave written informed consent. Subjects were randomized to receive either placebo (110 mg mannitol plus 0.44 mg Tween 80) or amylin (1-37 human amylin; produced by solid-phase peptide synthesis, batch No. AC-0001, No. B262CO1FMW; purity >95% by high-performance liquid chromatography; Amylin Pharmaceuticals Inc) that was made up in water in a vial identical to that for placebo (4.4 mg per vial human amylin, 220 mg per vial mannitol, and 0.88 mg per vial Tween 80). Subjects initially received either placebo or amylin in a double-blind random order and received the other product 7 days later via an intravenous infusion. The amylin concentration was 1 mg/mL and was infused as a 0.1-mg bolus over 1 minute followed by a continuous infusion of 0.19 mg over 1 hour. The dose administered aimed to achieve a plasma amylin concentration of approximately 1 nmol/L, similar to the IC50 reported for the renal amylin binding site in the rat.11 Blood pressure and heart rate were measured every 30 minutes by an automated method (Dinamap, Critikon). Serial blood sampling was performed at -30, -15, 0, 15, 30, 60, 90, 120, and 180 minutes after commencement of the amylin or placebo infusion. Blood was collected and plasma separated immediately; a portion was placed in EDTA and another portion in 0.5 mg/mL EDTA, 0.5 µg/mL leupeptin, 25 µg/mL elastatinal, and 2 µg/mL antipain hydrochloride. The plasma was stored at -20°C for later biochemical analysis.
Assay Methods
Plasma electrolytes, glucose, lactate, and
creatinine concentrations and osmolality were measured with
standard laboratory methods. Plasma aldosterone
concentration was measured by radioimmunoassay. Plasma arginine
vasopressin concentration was measured with the use of acetone and
petroleum ether extraction and measured by radioimmunoassay with a
specific rabbit arginine vasopressin antiserum.15 Plasma
renin concentration, which represents active renin, was
measured by radioimmunoassay.16 The concentration of total
renin, which comprises both active and inactive renin, was measured by
an immunoradiometric assay17 with two epitope-specific
monoclonal antibodies (R 3-27-6 and R 3-36-16, Ciba-Geigy). The
interassay coefficient of variation was 6.7%, and the detection limit
was 2 mIU/L. Plasma atrial natriuretic peptide
concentration was measured by radioimmunoassay as previously
described.18 Plasma catecholamines were
measured by electrochemical detection after high-performance
liquid chromatographic extraction. Plasma amylin
concentrations were measured by a two-site immunoradiometric assay with
the use of monoclonal antibodies to human amylin.19 The
minimal detectable concentration of the assay was 8 pmol/L, and the
intra-assay and interassay coefficients of variation were 2.8% and
9.0%, respectively.
Statistical Analysis
Plasma prorenin (inactive renin) concentration was calculated as
the difference in total and active renin. Data for active renin, total
renin, and prorenin were analyzed after logarithmic
transformation because these variables were positively skewed.
Analyses were performed with the statistical program StatView
SE and graphics (Brainpower). Statistical analysis of the data
was by one-way ANOVA after calculation of the differences between
values from the placebo and amylin study periods. Correction for
multiple tests was performed with Fisher's least significant
difference method. A value of P<.05 was viewed as
statistically significant.
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Results |
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Human amylin infusion led to a rapid rise in plasma amylin levels (Fig 1). Transient nausea, ranging in duration from 10 to 20 minutes, developed in three subjects immediately after the bolus injection of amylin. Plasma amylin concentrations were less than 8 pmol/L, the minimal detectable concentration of the assay, when placebo was administered. Amylin infusion led to an increase in plasma active renin concentration, peaking at 60 minutes (0 minutes, 28±4 mIU/L; 60 minutes, 125±46 mIU/L; P<.01); this was not observed with placebo (Fig 2). The rise in plasma renin concentration was associated with an increase in plasma aldosterone levels at 60 minutes (Table). Total renin concentration did not differ between groups at any time. Prorenin, calculated as the difference in total and active renin, was significantly decreased at 60 minutes after amylin treatment (Table). The amylin infusion was not accompanied by changes in systolic pressure (Table) or heart rate (data not shown). Diastolic pressure increased slightly with amylin after 30 minutes (P<.05). Vasopressin concentration did not change over the duration of the study with either placebo or amylin. Plasma atrial natriuretic peptide concentrations were higher with amylin treatment at 30 and 60 minutes (Table). Plasma glucose increased modestly at 60 minutes in the group receiving amylin (P<.01). Plasma lactate, sodium, potassium, calcium, creatinine, osmolality, norepinephrine, and epinephrine did not change (data not shown).
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) or placebo infusion (
).
Data are shown on y axis (logarithmic scale) for plasma
renin concentration as mean±SEM. *P<.05,
P<.01 vs baseline.
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Discussion |
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This study indicates that the pancreatic ß cell hormone amylin increases the concentration of active renin at least fourfold in humans. This increase is much larger than that seen with physiological challenges such as erect posture or with vasodilators that do not directly interrupt the renin-angiotensin system. The rise in plasma renin concentration does not appear to be associated with hypovolemia because subjects were supine, blood pressure rose, plasma vasopressin concentrations did not change, and plasma atrial natriuretic peptide concentrations tended to increase. Since the study had a duration of fewer than 4 hours, it is possible, albeit unlikely, that extracellular fluid volume shifted between compartments without detectable changes in plasma vasopressin or atrial natriuretic peptide levels. It is of interest that active renin rose despite the small increase in atrial natriuretic peptide and rise in diastolic pressure, maneuvers known to inhibit renin secretion.20
Preliminary data from our group11 indicate that in addition to amylin binding to rat renal cortex this hormone also increases the production of renal cAMP, a well-described intracellular messenger for renin secretion.21 These previous findings and the effects of amylin to increase active renin are consistent with the presence of a receptor for amylin in the kidney. Pilot studies by our group using emulsion in vitro autoradiography have localized amylin binding in the monkey kidney to the juxtaglomerular apparatus (P. Sexton, S.Y. Chai, M.E.C., unpublished data, 1995), the predominant source of plasma renin.22 However, the technique used did not have adequate resolution for determination of whether the precise localization of amylin binding was to the renin-producing or the non–renin-producing cells of the juxtaglomerular apparatus. CGRP and salmon calcitonin have been shown to have similar affinity to amylin in rat forebrain23 24 and rat kidney.25 CGRP and salmon calcitonin have also been reported to increase plasma renin,26 27 although the mechanism for these effects is unknown. Since amylin can also interact with CGRP binding sites,28 though at 1/100 the affinity of CGRP, one cannot exclude the possibility that amylin stimulated plasma renin via CGRP-induced renal vasodilation without concomitant assessment of renal vascular resistance. However, the amylin concentration achieved in these individuals was at least 50-fold lower than the concentration required to induce renal vasodilation.29 In preliminary studies with the isolated perfused rat kidney, our group has also noted that the amylin concentration required to induce renal vasodilation via CGRP receptors was higher than that achieved in the present study.30 Furthermore, if amylin had induced renal vasodilation, one might have anticipated a significant reduction rather than the modest increase in blood pressure, as was observed with the human amylin infusion.
The present study has not delineated the exact mechanism responsible for amylin increasing plasma renin concentration. The presence of a binding site in the juxtaglomerular apparatus may indicate a direct action of amylin via its receptor on renin-producing cells. In vitro studies with isolated juxtaglomerular cells are required to identify such a mechanism. However, the stimulation of renin could be via an alternative mechanism. The actions of this peptide on baroreceptor function, renal tubular ion transport, other potential hormonal mediators, or sympathetic activity have not been reported and warrant investigation. The rapid increase in active renin in response to amylin infusion suggests release of stored renin from juxtaglomerular cells. However, another possibility that needs to be considered is that amylin increased the conversion of prorenin to active renin. The reduction in plasma prorenin in the present study in response to amylin is consistent with the latter hypothesis.
The amylin concentration achieved in the present study was higher than that observed in healthy individuals or in individuals with hypertension or insulin resistance.31 32 Plasma amylin levels are less than 20 pmol/L in healthy individuals.19 In insulin-resistant subjects, including those with essential hypertension, plasma amylin levels are elevated, with concentrations up to 100 pmol/L reported.5 33 In insulin-resistant rodents plasma amylin levels of up to 600 pmol/L have been reported.34 However, the large rise in renin in the present study suggests that lower doses of amylin would also stimulate plasma renin activity.
Competitive amylin antagonists have been developed and shown to displace amylin from its binding site in brain24 and to retard amylin actions, including inhibition of insulin-mediated glucose uptake by skeletal muscle.35 More recently, we have shown that these antagonists displace amylin from the renal binding site.11 These antagonists have also recently been reported to prevent amylin-induced increases in plasma renin activity in rats.12 The presence of a range of amylin antagonists will now allow further investigation of a role for amylin in renal physiology and in the genesis of cardiovascular disorders such as hypertension.
Recent studies stimulated by the current interest in the relationships of hypertension, obesity, and insulin resistance have explored the role of hyperinsulinemia and the renin-angiotensin system in obesity-related hypertension. In an animal model of obesity-induced hypertension in dogs, the development of obesity caused by fat feeding was associated with an increase in blood pressure and concomitant increases in plasma renin activity and insulin.36 It appears unlikely that insulin per se could explain the development of hypertension because experimental evidence also in dogs demonstrates that insulin has no intrinsic hypertensive properties.37 In a recent study plasma renin activity in young, obese hypertensive subjects was higher compared with that in appropriately matched lean normotensive individuals.38 These hypertensive subjects also had increased levels of plasma insulin, a peptide whose serum levels are often paralleled by changes in amylin levels.31 A review of a large population of insulinoma patients did not indicate an increased prevalence of hypertension in this group or that surgical removal resulted in any blood pressure change.39 It is of interest that insulinoma patients do not in general have increases in plasma amylin levels.40 However, a recent report described a patient with a pancreatic islet tumor associated with very high serum amylin levels who presented with hypertension.41 Raised plasma amylin concentrations in hypertensive individuals have recently been reported.32 The hypothesis linking amylin to the genesis of hypertension and glucose intolerance would be strengthened by evidence of changes in amylin levels before rather than after Syndrome X was clinically apparent. Studies in children of Pima Indians, a group with a very high incidence of glucose intolerance, have shown that in these children systolic pressure and insulin levels were correlated before the development of frank diabetes.42 All these studies provide indirect support for a link between amylin, renin, insulin resistance, and hypertension.
Amylin has been previously reported to have important actions on fuel homeostasis and in particular on carbohydrate metabolism and has been postulated as a mechanism for the development of insulin resistance.8 The present report of an effect of this peptide on plasma renin and aldosterone concentrations in humans is consistent with amylin having an important function in cardiovascular and renal physiology and potentially a role in vascular disorders such as hypertension. Since amylin has both metabolic and renal actions, this peptide may be an important link between glucose intolerance, the renin-angiotensin system, and hypertension.
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Acknowledgments |
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This study was supported by grants from the National and Central Health and Medical Research Councils of Australia and Amylin Pharmaceuticals Inc. The authors wish to thank Mark Fineman for measurement of plasma amylin levels and Andrew Young and Orville Kolterman for helpful discussion and advice.
Received March 20, 1995; first decision April 13, 1995; accepted June 6, 1995.
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References |
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