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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 4 1446-1450
Copyright © 2007 by The Endocrine Society

RAPID COMMUNICATION

Amylin and Hypertension: Association of an Amylin –G132A Gene Mutation and Hypertension in Humans and Amylin-Induced Endothelium Dysfunction in Rats

Anna Novials, Leocadio Rodriguez-Mañas, Ana Chico, Mariam El Assar, Sílvia Casas and Ramon Gomis

Institute of Diabetes (A.N., A.C., S.C.), Sardà Farriol Foundation, 08017 Barcelona, Spain; Research Unit and Department of Geriatrics (L.R.-M., M.E.A.), Hospital of Getafe, 28905 Madrid, Spain; and Laboratory of Experimental Diabetes (S.C., R.G.), Institut d’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clinic and University of Barcelona, 08036 Barcelona, Spain

Address all correspondence and requests for reprints to: Dr. Anna Novials, Sardà Farriol Foundation, Passeig Bonanova 69, 6th floor, 08017 Barcelona, Spain. E-mail: anovials{at}fsf.es.

Abstract

Context: Amylin has been linked to the development of hypertension in several pathological states related to hypertension and insulin resistance, although there is scant data regarding its potential mechanisms of action. The –132 G/A mutation located within an activator domain of the amylin gene’s promoter was first identified in a small cohort of Spanish patients with type 2 diabetes.

Objective: The objective of the study was to test the interference of amylin peptide with endothelium-dependent responses as an added potential mechanism for amylin-induced hypertension.

Design: A total of 384 patients with type 2 diabetes and 207 healthy controls were subjected to clinical analysis and genetic screening for the –132 G/A mutation of the amylin gene. The effect of amylin on endothelium-dependent responses was analyzed in aortic rings and mesenteric microvessels from nondiabetic rats.

Results: The prevalence of the mutation was 10.1 vs. 0.9% in the control population (P < 0.001). Hypertension was higher in a diabetic population carrying the mutation than in diabetic noncarriers (74 vs. 57%; P < 0.05). Diabetic carriers showed higher fasting amylin levels than diabetic noncarriers (11.4 ± 7 vs. 8.2 ± 3 pmol/liter; P < 0.05). Preincubation with 20 pmol/liter amylin impaired the relaxant responses induced by acetylcholine in rat aorta and mesenteric microvessels. This effect was abolished in both vascular beds in the presence of 100 µmol/liter NG-nitro-L-arginine methyl ester.

Conclusions: We propose that amylin levels and hypertension may be linked by a novel mechanism involving the capacity of amylin to induce endothelial dysfunction by interfering with nitric oxide-mediated responses.

AMYLIN HAS BEEN involved in the normal regulation of glucose metabolism. It is synthesized and coreleased (1) with insulin from pancreatic islet ß-cells and exerts its peripheral effects as an antagonist of insulin’s ability (2) to inhibit glucagon secretion (3) and by delaying gastric emptying (4). In addition, overexpression of this peptide has been implicated as one main factor involved in the process of pancreatic amyloidogenesis described in type 2 diabetes (DM2) (5). Amylin has also been linked to the development of hypertension (HBP). However, there are scant data regarding the potential mechanisms by which amylin might induce HBP. Although stimulation of the renin-angiotensin system is the best-known possibility (6, 7, 8), a relationship between amylin and this system has not been demonstrated in all studies (9), suggesting the existence of other potential mechanism(s).

The search for genetic defects would explain differences in phenotype. The –132 G/A mutation located within an activator domain of the amylin gene’s promoter was first identified in a small cohort of Spanish patients with DM2 (10). This same mutation was also described by other groups, with noted differences in prevalence probably attributable to distinct ethnic background (11, 12). Previous in vitro results demonstrated an increased transcriptional activity of the mutant compared with the wild-type amylin gene promoter (13). Taking this finding in account, we speculated that patients carrying the mutation could be prone to increase synthesis or amylin secretion, which could determine specific phenotypic traits. In the present population, the prevalence of the mutation was higher in DM2 patients than in controls (10.1% vs. 0.9%). Amylin fasting levels were higher in DM2 carriers (11.3 ± 7 pmol/liter) than in noncarriers (8.7 ± 3 pmol/liter). The most remarkable clinical feature was the higher prevalence of HBP in DM2 carriers than in noncarriers (74 vs. 57%). To determine possible explanations for this high prevalence of HBP in our population, the aim of this study was to test the interference of amylin peptide with endothelium-dependent responses as an added potential mechanism for amylin-induced HBP.

Subjects and Methods

Subjects, clinic, and genetic analyses

We recruited 384 unrelated patients with DM2 and 207 healthy controls without DM2 obtained from patient’s spouses and hospital staff. Informed consent was obtained from each individual and approved by the Hospital Ethical Committee. Clinical data included sex, age, body mass index (BMI), diabetes duration, and treatment and presence of microvascular and macrovascular complications related to diabetes. HBP and dyslipidemia were defined according to the American Diabetes Association criteria (14).

Blood samples were obtained after overnight fasting for the next determinations. Plasma glucose was measured using automated glucose oxidase method, and glycosylated hemoglobin by HPLC. Cholesterol, triglycerides, and high-density lipoprotein cholesterol were measured using enzymatic methods (Advia Autoanalyzer 1650; Bayer Diagnostics, Leverkusen, Germany), and low-density lipoprotein cholesterol was calculated by the Friedewald formula. Plasma amylin levels were determined by RIA (Phoenix Pharmaceuticals Inc., Belmont, CA; intraassay and interassay coefficients of variation, 6 and 13%, respectively). Genomic DNA was extracted from peripheral blood leukocytes using the saline precipitation method. Single-strand conformational polymorphism analysis and electrophoretic conditions were previously described (15). The variants detected by single-strand conformational polymorphism were sequenced on ABI392 automated sequencer (Perkin-Elmer/Applied Biosystems Inc., Foster City, CA).

Studies of vascular reactivity

To analyze the effect of amylin on vascular responses, 16-wk-old nondiabetic male Sprague Dawley rats were used according to the previously described method (16). Drug effects on the vascular tone of aortic isolated rings were as follows. The aorta was divided into cylindrical segments 4 to 5 mm in length. For isometric tension recordings, each vascular cylinder was set up in an organ bath according to the previously described method (17). The vessels were exposed to 75 mmol/liter K+ to verify their functional integrity. After wash, segments were contracted with the concentration of noradrenaline (NA) (10–30 nmol/liter) required to induce a contractile response equivalent to 55–65% of that induced by K+. Drug effects on vascular tone of mesenteric microvessels were as follows. The mesentery was removed and third branch mesenteric arteries were dissected and mounted on a small vessel myograph. Arteries were then contracted with 125 mmol/liter K+ (KKHS; equimolar substitution of KCl for NaCl in Krebs-Henseleit solution) for 2 min. The bath was then washed three times with KHS, and a further 30-min wash was performed before the arteries were contracted with the concentration of NA (1–2 µmol/liter) required to produce approximately 80% of the maximum response to KKHS.

Relaxations to acetylcholine (ACh) were subsequently assessed in both experimental approaches by adding increasing concentrations of the drugs at 2-min intervals (final bath concentrations 10 nmol/liter to 10 µmol/liter in aorta; 1 nmol/liter to 10 µmol/liter in mesenteric arteries). Segments with relaxant responses to 10 µmol/liter ACh of greater than 50% were considered to have an intact endothelium (16). In some cases, the curve to the ACh was performed after incubating the segments for 15 min with r-amylin (5 and 20 pmol/liter) and/or 100 µmol/liter NG-nitro-L-arginine methyl ester (L-NAME). In other sets of experiments we evaluated the contractile responses to NA by adding cumulative concentrations (final bath concentrations 1 nmol/liter to 10 µmol/liter in aorta; 10 nmol/liter to 30 µmol/liter in mesenteric arteries), as well as their potential modification by the 15-min preincubation with r-amylin (20 pmol/liter).

Drugs used were NA hydrochloride, ACh chloride, L-NAME (all obtained from Sigma, St Louis, MO), and synthetic rat amylin (r-amylin) (Bachem, Bubendorf, Switzerland). Drug solutions were made in distilled water, except NA, which was prepared in saline (0.9% NaCl) ascorbic acid (0.01% wt/vol).

Statistical analysis

Calculations were performed with software SPSS V.11.5.1 (SPSS GmbH., Munich, Germany). Data are presented as the mean ± SD. Comparisons between groups were performed by the t test except when variables were nonnormally distributed, in which case the Mann-Whitney U test was used. The Kruskal-Wallis test was used when more than two groups were compared. Correlations were performed by linear regression. In regard to curves to the ACh, deviations from the mean were analyzed using factorial two-way ANOVA. Significance was considered at P < 0.05.

Results

Prevalence of mutation and clinical analyses

The prevalence of the –132 G/A mutation in the group with diabetes was 10.1 vs. 0.9% in the control population (P < 0.001) (odds ratio, 6.5; 95% confidence interval, 5.8–7.3). Tables 1Go and 2Go show the clinical and biochemical characteristics of patients with DM2 carrying or lacking the mutation. The main difference was the higher prevalence of HBP in diabetic carriers than diabetic noncarriers (74 vs. 57%; P < 0.05). Fasting amylin levels were measured in 35 carriers and 50 noncarriers matched for age, sex, and BMI, showing higher values for carriers than for noncarriers (11.4 ± 7 vs. 8.2 ± 3 pmol/liter; P < 0.05).


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  		TABLE 1. Features and biochemical measurements of patients with DM2 carrying or not carrying the –132 G/A mutation in the amylin gene

 

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  		TABLE 2. Pharmacological treatments for diabetes, HBP, and dyslipidemia of patients with DM2 with or without the –132 G/A mutation in the amylin gene

 
Vascular reactivity

In experiments with rat aorta, preincubation with r-amylin (5 or 20 pmol/liter) did not change the basal tone of the vascular segments or the sensitivity or the maximal response to NA of vessels (Fig. 1AGo). This was not the case for the responses evoked by ACh. ACh-induced relaxant responses were significantly impaired by the preincubation of the rat aorta with 20 pmol/liter r-amylin. This effect was not observed when vessels were preincubated with lower (5 pmol/liter) concentrations of r-amylin (Fig. 1BGo).


Figure 1
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  		FIG. 1. Vascular responses in rat aorta. A, Contractile responses to NA in untreated control segments and in the presence of amylin 5 pmol/liter and 20 pmol/liter. B, Relaxant responses to ACh in untreated control segments and in the presence of amylin 5 pmol/liter and 20 pmol/liter. C, Relaxant responses to ACh in untreated control segments and in segments preincubated with amylin 20 pmol/liter, L-NAME 100 mmol/liter, and L-NAME 100 mmol/liter plus amylin 20 pmol/liter. Data are expressed as percentage of the contraction elicited by 75 mmol/liter KCl (A) and by 10–30 nmol/liter NA (B and C). n, Number of vascular segments used for each curve. *, P < 0.05 vs. control segments.

 
To evaluate the participation of nitric oxide as a target for amylin by determining its effect on the relaxant responses to ACh, we tested whether preincubation with r-amylin added any significant effect to that obtained by preincubating the vessels with L-NAME; 100 µmol/liter L-NAME totally abolished the relaxant responses induced by ACh. Preincubation with L-NAME plus r-amylin (20 pmol/liter) did not add any effect to the preincubation with L-NAME alone (Fig. 1CGo).

Similar to that observed in rat aorta, preincubation of the mesenteric microvessels with r-amylin caused no effect on the basal tone. The contractile responses elicited by NA were not modified by any of the two concentrations (5 or 20 pmol/liter) of r-amylin used in these experiments (Fig. 2AGo). In contrast, 20 pmol/liter of r-amylin, although not 5 pmol/liter, impaired the relaxant responses induced by cumulative concentrations of ACh in microvessels (Fig. 2BGo). In contrast to that observed in the aorta, preincubating the vessels with L-NAME (100 µmol/liter) did not abolish the relaxant responses evoked by ACh but did impair them in a significant way, proportionally, close to that produced by 20 pmol/liter r-amylin. This inhibitory effect of L-NAME or r-amylin on the vascular relaxation induced by ACh did not increase when the microvessels were preincubated with L-NAME plus r-amylin (Fig. 2CGo). In any of the vessels studied (aortic rings or mesenteric branches), r-amylin (1 pmol/liter-1 µmol/liter) exerted an effect on the vascular tone.


Figure 2
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  		FIG. 2. Vascular responses in mesenteric microvessels. A, Contractile responses to NA in untreated control segments and in the presence of amylin 5 pmol/liter and 20 pmol/liter. B, Relaxant responses to ACh in untreated control segments and in the presence of amylin 5 pmol/liter and 20 pmol/liter. C, Relaxant responses to ACh in untreated control segments and in segments preincubated with amylin 20 pmol/liter, L-NAME 100 mmol/liter, and L-NAME 100 mmol/liter plus amylin 20 pmol/liter. Data are expressed as mean ± SEM of the percentage of the contraction elicited by 125 mmol/liter KCl (A) and by 1–2 µmol/liter NA (B and C). n, Number of vascular segments used for each curve. *, P < 0.05 vs. control segments.

 
Discussion

High amylin levels have been noted in obese (18), lean gestational diabetes (19), and hypertensive populations (9). This observation has likewise been made during our study of diabetic patients carrying the –132 G/A amylin mutation, in which the prevalence of HBP and fasting amylin levels were higher than in noncarrier patients. Several reports claim a relationship between amylin and hypertension. It appears that the infusion of human amylin in healthy humans led to significant increases in plasma renin and aldosterone concentrations with a slight effect on diastolic blood pressure (BP) after amylin infusion, and no significant changes in systolic BP. Amylin plasma concentrations observed in this study (6) were considerably higher than those observed in healthy individuals or in individuals with HBP (9) or insulin resistance (20). Although the exact mechanism by which amylin stimulates plasma renin activity remains unknown, there are interesting data pointing to a direct effect of the peptide on high-affinity amylin binding sites detected in the renal cortex and/or central nervous system (7, 8, 21).

Another potential mechanism explaining the relationship between amylin and HBP is through direct interference on the vascular tone. To address this possibility, we evaluated the effect of amylin at concentrations detectable in humans (5 and 20 pmol/liter) on the responses elicited by NA and ACh in rat vessels. Our findings support a direct effect of amylin on the vascular responses in both great aorta vessels and microvessels. This effect seems to be mediated by the interference of amylin with the nitric oxide released by the endothelium. In fact, the effect of amylin and L-NAME in microvessels was similar and there was an additive effect when both substances were used jointly. Although 100 µmol/liter of L-NAME totally abolished the relaxant response in the aorta, indicating that it is completely mediated by nitric oxide, amylin also impaired these relaxant responses. Although our experimental approach does not allow us to reach firm conclusions about the mechanism, amylin had no direct vasoconstrictor effects or enhanced NA-mediated vasoconstriction, thus indicating that basal nitric oxide release is not affected. In this regard, some authors (22) have raised the possibility of amylin inducing oxidative stress.

Few studies have previously evaluated the effect of amylin on vascular reactivity. Moreover, they have found a direct, not endothelium-dependent, vasodilator effect on both the aorta (23) and microvessels (24). A possible role for the calcitonin gene-related peptide receptor in mediating this vasodilator response to amylin has been demonstrated (25). The apparent discrepancy with our findings could be related to the different concentrations of amylin. The authors used higher concentrations than usually found in human plasma and detected a significant response with concentrations ranging from 10–100 nmol/liter. Findings supporting the requirement of supraphysiological amylin concentrations to induce some change in vascular tone have been reported (6). In their study, when high amounts of amylin were infused to healthy volunteers, their plasma amylin levels increased from less than 8 pmol/liter to nearly 1000 pmol/liter, leading to significant increases in plasma renin, but a modest effect on diastolic BP. In our study, however, we produced an inhibitory effect on nitric oxide-mediated responses at a concentration of 20 pmol/liter amylin, although no effect was noted with concentrations of 5 pmol/liter or lower. In this regard, a previous report on the distribution of amylin plasma levels in normotensive people based on their genetic risk for developing HBP is noteworthy (9). They found a bimodal distribution of plasma amylin with family history-positive individuals clustered in the stratum of high plasma levels, in contrast to those individuals without such family history, which were clustered in the stratum of low plasma levels.

In summary, we have identified a new hyperamylinemic state in a subpopulation of patients with DM2 carrying a mutation in the activator domain of the amylin gene, which can lead to a high incidence of HBP. In addition, we describe in a rat model a new mechanism linking amylin and HBP. In conclusion, high amylin levels may induce endothelial dysfunction by interfering with nitric oxide-mediated responses. Whether this mechanism can contribute to the development of HBP in all hyperamylinemic states remains to be elucidated.

Footnotes

This study was supported by FIS (PI02/0931, PI04/1955, PI05/1215, and PI05/1920), RGDM (G03/212) and RETIC (RD06/0015) grants from Ministerio de Sanidad y Consumo (Spain). S.C. acknowledges the receipt of a Juan de la Cierva contract from Ministerio de Educación y Ciencia (Spain).

Disclosure statement: The authors have nothing to disclose.

First Published Online January 9, 2007

Abbreviations: ACh, Acetylcholine; BMI, body mass index; BP, blood pressure; DM2, type 2 diabetes; HBP, hypertension; L-NAME, NG-nitro-L-arginine methyl ester; NA, noradrenaline.

Received September 8, 2006.

Accepted January 3, 2007.

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