(Hypertension. 1997;29:678-682.)
© 1997 American Heart Association, Inc.
Articles |
1-Adrenergic Receptor Antibodies in Patients With Primary Hypertension
the Max Delbruck Center for Molecular Medicine (H.-P.L., G.W.) and the Franz Volhard Clinic (V.H.), Virchow Klinikum, Humboldt University, Berlin, Germany.
Correspondence to Gerd Wallukat, Max Delbruck Center for Molecular Medicine, Robert-Roessle-Str. 10, 13122 Berlin, FRG. E-mail gwalluk@orion.rz.mdc-berlin.de
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Abstract |
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Autoimmune mechanisms have been proposed to play a role in the pathogenesis of primary (essential) hypertension. Autoantibodies against the
1-adrenergic receptor have been described in patients with malignant and secondary hypertension. To investigate the incidence of autoantibodies against the 1-adrenoceptor in patients with primary hypertension, we examined the immunoglobulin fractions of sera from 54 patients with primary hypertension and 26 normotensive control subjects for the presence of autoantibodies against the 1-adrenoceptor. Sera from 24 patients (44%) and 3 subjects (12%) were positive. An epitope analysis of 16 autoantibody-positive immunoglobulin fractions revealed that in two thirds of the cases, the antibodies were directed against the first extracellular loop of the 1-adrenoceptor and in one third, against the second. The autoantibodies had a positive chronotropic effect on isolated neonatal rat cardiomyocytes, an effect that was blocked by 1-adrenergic antagonists. Since the functional characteristics of the autoantibodies showed no desensitization phenomena, they may play a role in elevating peripheral vascular resistance and promoting cardiac hypertrophy in patients with primary hypertension.
Key Words: hypertension, essential • sympathetic nervous system • immune system • receptors, adrenergic, alpha-1 • epitope mapping
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Introduction |
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Immune mechanisms are known to be important in diseases such as lupus erythematosus, systemic rheumatoid arthritis, Graves' disease, pernicious anemia, juvenile diabetes mellitus, and myasthenia gravis. However, the immune system is not frequently discussed in the pathophysiology of human primary (essential) hypertension. Nevertheless, there are some indications suggesting that primary or secondary alterations in the function of the immune system may play a role in both the initiation and maintenance of the hypertensive state.1 2 In addition, spontaneously hypertensive rats (SHR) have been reported to show signs of immunological dysfunction. For instance, the number of T lymphocytes decreases with age in SHR, in contrast to Wistar-Kyoto rats (WKY), which exhibit an increase in the number of T lymphocytes with age.3 Furthermore, SHR have a decreased delayed-type hypersensitivity immune response, a prolonged allograft rejection time,4 and a high incidence of periarteritis nodosa compared with WKY.5 Humans with primary hypertension show a delayed-type hypersensitivity to vascular antigens6 and enhanced activity of sensitized T lymphocytes.7 Furthermore, 20% to 40% of hypertensive patients have an elevated level of serum immunoglobulins compared with normotensive control subjects.8 9 10 11 12 The level of serum IgG is positively correlated with blood pressure in untreated hypertensive patients and in patients with poorly controlled hypertension.10 In addition, autoantibodies to nuclear structures and smooth muscle were found significantly more often, and in higher concentrations, in patients with essential hypertension compared with normotensive control subjects.13
Autoantibodies against receptors are known to be important in myasthenia gravis14 and Graves' disease. In Graves' disease, the antibodies exhibit agonist activity.15 Autoantibodies directed against the cardiac ß1-adrenergic receptor have been shown to be present in the sera of patients with dilatative cardiomyopathy.16 17 18 The serum 
-globulin fraction from patients with myocarditis and dilatative cardiomyopathy had a positive chronotropic effect on cultured neonatal rat heart myocytes.16 18 This effect could be blocked by ß1-selective antagonists but not by a ß2-selective antagonist.19 An epitope was detected by autoantibodies to the ß-adrenergic receptor with an amino acid sequence analogous to that of the second extracellular loop of the human ß1-adrenergic receptor.20 Autoantibodies against the 1-adrenergic receptor were previously described by Fu et al21 in patients with malignant and secondary hypertension. Our aim in the present investigation was to determine the incidence of agonistic 1-adrenergic autoantibodies in the sera of patients with primary hypertension and to investigate their possible role in raising systemic arterial resistance.
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Methods |
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Cell Culture
Isolation and cultivation of neonatal heart cells were performed as previously described.16 Briefly, single cells were dissociated from the minced ventricles of 1- to 2-day-old Wistar rats with a 0.25% solution of crude trypsin and were cultured as monolayers with a density of 800/mm2 in Halle SM 20-I medium equilibrated with humidified air. The medium contained 10% heat-inactivated bovine neonatal serum and 2 µmol/L fluorodeoxyuridine (Serva), the latter to prevent proliferation of nonmuscle cells. On day 3 or 4, the cells were incubated for 2 hours in 2 mL fresh serum-containing medium. Seven to 10 selected cells or synchronously contracting cell clusters per flask were counted for 15 seconds. This procedure was repeated twice in different cultures to yield results representing a total of up to 30 cells for each sample of a given immunoglobulin fraction or drug, which were added cumulatively.
Preparation of Immunoglobulin Fraction
The immunoglobulin fraction was isolated from serum samples of about 2 mL by ammonium sulfate precipitation at a saturation of 40%. The precipitates were washed and dissolved in dialysis buffer (154 mmol/L NaCl, 10 mmol/L sodium phosphate, pH 7.2). The precipitation, washing, and dissolving procedure was repeated twice. Finally, the immunoglobulins were taken up in 2 mL phosphate-buffered saline (pH 7.2) and dialyzed at 4°C for 30 hours against 1 L dialysis buffer. The buffer was changed five times during dialysis. For detection of autoantibodies, the immunoglobulin fractions were added to the flasks at a dilution of 1:20. For the neutralization experiments, synthetic peptides corresponding to the sequence of the first extracellular loop (F-W-A-F-G-R-A-F-C-D-V-W-A), second extracellular loop (G-W-K-E-P-V-P-P-D-E-R-F-C-G-I-T-E-E-A-G-Y-A-V-F-S-S-V) of the human 1c-adrenoceptor (according to new nomenclature22 ), and third extracellular loop (G-S-L-F-S-T-L-K-P-P-D) of the human 1b-adrenoceptor were each added in excess (0.05 to 0.1 µg in 50 µL) to 50 µL of the immunoglobulin fraction. (In this article, the pharmacologically defined receptor subtypes are designated by uppercase subscripts and the cloned receptors by lowercase subscripts.) The mixtures were shaken and placed in a refrigerator for 1 hour. The 100-µL samples were then added to neonatal rat heart muscle cells cultured in 2 mL of medium to a final dilution of 1:40. The beating rate was counted for 15 seconds, 5 and 60 minutes after the addition of the peptide/immunoglobulin mixture.
Patients
Blood was obtained from 54 patients (30 women, 24 men) aged 28 to 72 years (mean, 55.4) with primary hypertension. None of the patients had been treated with an 1-blocker or 2-agonist during a period of at least 3 months before blood collection. Sixteen patients requiring three antihypertensive drugs for control of their blood pressure were classified as having severe hypertension. Thirty patients with an echocardiographically measured septal width of more than 12 mm were classified as having left ventricular hypertrophy. The control group included 10 healthy people (2 men, 8 women) and 16 individuals with coronary heart disease without any evidence of arterial hypertension (10 men, 6 women) aged 35 to 77 years (mean, 57.7). Blood samples for these tests were obtained after written permission from the participants; the protocol was approved by the university's ethics committee.
Chemicals
Prazosin and 2-([2,6-dimethoxyphenoxyethyl]aminomethyl)-1,4-benzodioxane (WB-4101) were purchased from Sigma-Aldrich Chemie, propranolol from Isis Chemie, phenylephrine from Serva Feinbiochemica, and chlorethylclonidine (CEC) from ICN Pharmaceuticals. All other chemicals were of analytical grade.
Statistics
Results are expressed as mean±SE. Student's t test was used for comparison of variables between groups. Values of P<.05 were considered to denote statistical significance; values of P<.001 were considered as highly significant. Significance of incidence was checked by the 
2 test.
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Results |
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Incidence of Autoantibodies Against the
1-AdrenoceptorWe investigated sera from 54 patients with primary hypertension and 26 control subjects for the presence of autoantibodies directed against the
1-adrenoceptor. Sera from 24 patients (44%) and 3 control subjects (12%) were positive, as shown in Fig 1
. Two of the positive normotensive control subjects had coronary heart disease. One of the positive control subjects was completely healthy. The prevalence of autoantibodies in hypertensive patients was numerically higher in the subgroup of patients with left ventricular hypertrophy (53%); however, the difference was not statistically significant. The patients classified as having severe hypertension had no higher prevalence (37%) than patients with milder hypertension. Sera of 7 autoantibody-positive hypertensive patients and 2 patients without autoantibodies were reinvestigated after an intervening period of 1 to 2 years. The positive patients remained positive. One of the previously negative patients was slightly positive 2 years later.
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Characterization of Autoantibodies
The 1-agonist phenylephrine showed dose-dependent stimulation of the contraction frequency in spontaneously beating rat cardiomyocytes that was blocked by the 1-adrenergic receptor antagonist prazosin, as shown in Fig 2. A maximal stimulatory effect was observed at a phenylephrine concentration of 100 µmol. Similarly, the autoantibodies exerted a positive chronotropic effect that was dose dependent (up to a dilution of 1:200). These results are depicted in Fig 3, which shows the application of three separate immunoglobulin fractions containing autoantibodies at a range of dilutions. An increase in the spontaneous contraction rate of the cells was evident with all three fractions.
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The pharmacological characterization is shown in Fig 4. Fig 4A shows the chronotropic effects of 1-adrenoceptor autoantibody on isolated neonatal rat cardiomyocytes. Both Fig 4A and 4B illustrate a similarity between the chronotropic effects of the autoantibody and phenylephrine given in 4B. As shown in Fig 4A, autoantibody-containing immunoglobulin increased the spontaneous beating rate of the cell by 40 beats per minute. A nonselective ß-antagonist (0.1 µmol propanolol) showed no effect. The functional response of the cardiomyocytes was abolished by the addition of prazosin (1 µmol/L). However, the blocking potency of selective 1-antagonists was different. The 1A-selective blocker WB-4101 (1 µmol/L) was able to antagonize approximately 80% of the autoantibody-induced chronotropic effect, whereas the 1B-antagonist CEC (10 µmol/L) was not effective. Fig 4B shows a pharmacological characterization of the effects mediated by phenylephrine in comparison. The antagonistic properties of the blockers are given.
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Fig 5A shows another characterization of the autoantibody-induced chronotropic effect. Addition of the 1-selective agonist phenylephrine to 1-autoantibody–prestimulated cardiomyocytes resulted in no further increase in the autoantibody-stimulated beating rate, which was maximal at 3 hours. The effect of the IgG fractions was not reversed by removing the medium and washing the cardiomyocytes with phosphate-buffered saline. In contrast, the addition of prazosin antagonized the antibody-mediated effect completely. No desensitization phenomena of the effector system occurred within 3 hours after antibody stimulation, whereas the effect of phenylephrine was desensitized during this period, as shown in Fig 5B.
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To localize the possible binding sites of the autoantibodies, we performed epitope analysis in 16 autoantibody-positive immunoglobulin fractions. It was possible to neutralize the positive chronotropic effect by preincubation of the immunoglobulin fraction with peptides corresponding either to the first (11 sera) or second (5 sera) extracellular loop of the 1-adrenoceptor, as shown in Fig 6. The peptide with an amino acid sequence of the third extracellular loop had no effect on the autoantibody-stimulated beating rate. The peptides had no chronotropic effects of their own (data not shown).
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Discussion |
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We showed that autoantibodies directed against the
1-adrenoceptor were present in 44% of sera from patients with primary hypertension. The human antibodies exhibited a cross-reactivity with 1-adrenoceptors of neonatal rat cardiomyocytes and also behaved as agonists in vitro, with a positive chronotropic effect similar to that of the 1-adrenoceptor agonist phenylephrine. The specificity of this effect was shown by blocking either with peptides corresponding to the sequence of the first or second extracellular loop of the 1c-adrenoceptor or pharmacologically with 1-adrenoceptor antagonists. The nonspecific 1-antagonist prazosin abolished the autoantibody-induced effect. The 1A-selective antagonist WB-4101 blocked the autoantibody-mediated effects to a major extent but not completely, whereas the effect of the 1B-selective antagonist CEC was not significant. This apparent specificity of the autoantibodies for the 1A-subtype of the -adrenoceptor is likely due to the obvious transmission of the chronotropic effect of -adrenergic agonists by the 1A-adrenoceptor subtype in our system. The data show the preference of WB-4101 compared with CEC in antagonizing the phenylephrine-induced chronotropic effect. Because of the small ß1-adrenergic agonistic activity of phenylephrine, propranolol showed a slight, insignificant blocking effect.
Phenylephrine was not able to induce its expected positive chronotropic effect in cardiomyocytes preincubated with 1-adrenergic antibodies, indicating that the 1-adrenoceptors were already occupied or activated. The effect was resistant to the washing procedure, which suggests that antibody-antigen binding is an important step in the receptor-mediated reaction cascade. The capability of receptor-specific antagonists to block the effect of the antibodies seems to be typical for autoantibodies directed against adrenergic receptors, since the same effect was seen in the case of autoantibodies directed against the ß1-adrenoceptor.19 These antibodies may recognize an epitope on the receptor that is not accessible when the receptor is occupied by an antagonist.23 The functional characteristics of the antibody described here correspond to those of an antibody obtained by immunizing rabbits with the peptide of the second extracellular loop of the 1c-adrenoceptor. The positive chronotropic effect evoked by this peptide antibody could be antagonized by prazosin and by preincubation with the peptide of the second extracellular loop.24
Fu and coworkers21 reported that autoantibodies directed against the 1-adrenoceptor were present in 3 of 20 patients with malignant essential hypertension and in 7 of 11 patients with secondary hypertension. In their study, the peptide of the second extracellular loop of the 1-adrenoceptor was used as an antigen in an enzyme-linked immunosorbent assay. This difference in technique may explain the greater prevalence of antibodies directed against the first extracellular loop in our study. We found antibodies directed against the first extracellular loop in two thirds of our patients and against the second extracellular loop in one third. The definitive role of autoantibodies against the 1-adrenoceptors in the pathogenesis of primary hypertension is unclear. 1-Adrenergic stimulation is known to cause a contraction of vascular smooth muscle cells in blood vessels. Therefore, autoantibodies to 1-adrenergic receptors may play a role in elevating peripheral vascular resistance. In addition, since 1-adrenergic stimulation has a hypertrophy-inducing effect on cardiomyocytes,25 the autoantibodies could play a role in the pathogenesis of cardiac hypertrophy. However, the prevalence of the autoantibodies was numerically higher (but not statistically significant) in the subgroup of hypertensive individuals with cardiac hypertrophy than in the total group of hypertensive patients. Further studies will be necessary to show the possible hypertrophy-inducing effect of the antibodies or those of autoantibodies found against the ß1- but not the 1-adrenoceptor in SHR.26 No autoantibodies against the ß1-adrenoceptor were detected in hypertensive patients in either our study or in that of Fu and coworkers.27
We can only hypothesize as to the origin of autoantibodies against the 1-adrenoceptor in our patients. It is not clear whether the occurrence of autoantibodies in hypertension may be a consequence of tissue damage. Severe, spontaneous increases in blood pressure, which are a common event in patients with insufficient treatment or with malignant hypertension, may result in vascular lesions. Such peripheral vascular damage could lead to a significant increase in total peripheral vascular resistance, additional vascular and renal damage, and subsequently, the release of immunogenic parts of the receptor. Selective manipulations of the immune system by drugs or surgery can cause significant decreases in arterial blood pressure in SHR.28 Thus, it is possible that the immunological abnormalities we describe in our patients with primary hypertension could become therapeutically relevant.
We observed that 3 of 26 normotensive control subjects had 1-adrenoceptor autoantibodies even though they were normotensive. We have not yet had the opportunity to follow such individuals long term to determine whether they develop hypertension at a later date, nor do we have sufficient data to implicate genetic factors in that regard. We intend a long-term follow-up of such individuals. In addition, one might expect that 1-adrenoceptor autoantibody–positive individuals might have an increase in heart rate. We have not been able to document a resting tachycardia thus far. The hypertensive subjects were frequently being treated with ß-blocking drugs. It is conceivable that the hyperdynamic nature of the prehypertensive state is related to 1-adrenoceptor autoantibodies.29 Finally, the presence of 1-adrenoceptor autoantibodies raises the tantalizing notion that immunosuppressive therapy might be of value in lowering blood pressure. This idea is provocative, and there are some very preliminary experimental animal data to this effect.28 We have no direct clinical experience and regard our present findings as too preliminary to make such a suggestion.
In conclusion, we found that nearly half of our patients with primary hypertension had autoantibodies directed against the 1-adrenoceptor. Since the autoantibodies were shown to exhibit pharmacological activity in vitro, they may play a role in the elevation of peripheral vascular resistance throughout the entire body and in the development of cardiac hypertrophy in patients with primary hypertension. The detection of such autoantibodies may also assist in subclassifying this heterogeneous group of patients. We recognize the fact that our findings are preliminary and provocative and require additional confirmation. Furthermore, a series of detailed mechanistic studies must be done. Nonetheless, we wish to suggest a possible role for immunological mechanisms in the pathogenesis of primary hypertension.
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Acknowledgments |
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We thank Albert Wollenberger and Friedrich Carl Luft for critically reading the manuscript as well as Karin Karczewski, Monika Wegener, and Holle Schmidt for technical assistance.
Received June 18, 1996;
first decision July 19, 1996;
first decision August 27, 1996;
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