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J Appl Physiol 104: 1080-1085, 2008. First published February 7, 2008; doi:10.1152/japplphysiol.01082.2007
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NT-pro-BNP during hypoglycemia and hypoxemia in normal subjects: impact of renin-angiotensin system activity

R. Due-Andersen,1 U. Pedersen-Bjergaard,1 T. Høi-Hansen,1 N. V. Olsen,2 C. Kistorp,3 J. Faber,3 F. Boomsma,4 and B. Thorsteinsson1

1Endocrinology Section, Division of Internal Medicine I, Hillerød Hospital, Hillerød; 2Department of Neuroanaesthesia, Neuroscience Centre, Copenhagen University Hospital, Copenhagen; 3Department of Endocrinology, Herlev University Hospital, Herlev, Denmark; and 4Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands

Submitted 10 October 2007 ; accepted in final form 5 February 2008


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Brain-derived natriuretic peptide (BNP) is a cardioprotective peptide released, together with the inactive NH2-terminal part of its prohormone (NT-pro-BNP), in response to different kinds of myocardial stress. Hypoglycemia and hypoxemia are conditions that threaten cellular function and hence potentially stimulate BNP release. BNP interacts with the renin-angiotensin system (RAS). The aim of this study was, therefore, to explore if basal RAS activity has an impact on NT-pro-BNP concentrations during myocardial stress induced by hypoglycemia and hypoxemia. From a cohort of 303 healthy young men, 10 subjects with high-RAS activity and 10 subjects with low-RAS activity (age 26 ± 1 yr; mean ± SE) were studied in a single-blinded, randomized, counterbalanced, crossover study on three occasions separated by at least 3 wk: 1) hypoglycemia (mean nadir plasma glucose 2.7 ± 0.5 mmol/l), 2) hypoxemia (mean nadir PO2 5.8 ± 0.5 kPa), and 3) normoglycemic normoxia (control). NT-pro-BNP was measured at baseline, during the stimuli, and in the recovery phase. Hypoxemia was associated with a 9% increase in NT-pro-BNP from 2.2 ± 1.5 pmol/l at baseline to 2.4 ± 1.5 pmol/l during hypoxemia (P < 0.001). Hypoglycemia did not affect the NT-pro-BNP level. RAS activity had no impact on NT-pro-BNP levels during hypoglycemia and hypoxemia. Hypoxemia, but not hypoglycemia, stimulates NT-pro-BNP. This indicates that cardiac defense mechanisms against hypoglycemia, if any, are probably different from those against hypoxemia. Basal RAS activity had no impact on NT-pro-BNP levels.

brain-derived natriuretic peptide; angiotensin II; cardiac repolarization

BRAIN-TYPE NATRIURETIC PEPTIDE (BNP) is synthesized by the heart in response to certain kinds of myocardial stress and is thought to possess cardioprotective functions. BNP is cleaved from prohormone BNP (pro-BNP) in a process that formerly was believed to release equimolar amounts of the inactive NH2-terminal part of pro-BNP (NT-pro-BNP). However, recently, it was shown that processing of pro-BNP may be far more complex. Thus several different posttranslational forms of pro-BNP [i.e., pro-BNP 1–108, NT-pro-BNP 1–76 (29, 30), BNP 1–32, and BNP 3–32 (1)] are found in the circulation. Furthermore, the pattern of pro-BNP processing may vary in acute and chronic heart failure (12).

The main stimulus for BNP release is increased myocardial wall stretch induced by raised cardiac filling pressure (17). This occurs in patients with acute or chronic heart failure, and, in the acute clinical setting, BNP and NT-pro-BNP can be used as rule-out markers of heart failure (4). BNP gene expression is also stimulated in response to acute and chronic cardiac ischemia (10, 11), just as a stimulatory effect of acute hypoxemia on BNP has been discussed (3, 13, 16). This suggests a role for BNP in the cellular (defense) response to lack of substrate. The impact of hypoxemia on NT-pro-BNP release is unknown, but is clinically highly relevant for the use of NT-pro-BNP as a marker of heart failure in patients with hypoxemic dyspnea.

Hypoglycemia, a common adverse effect to insulin therapy, represents an alternative form of substrate depletion. Hypoglycemia causes catecholamine release and affects the electrophysiological properties of the cardiac myocytes (37), and myocardial glucose deficiency may stimulate BNP (and NT-pro-BNP) release.

The natriuretic system seems to be involved in a systemic antagonistic interplay with the renin-angiotensin system (RAS) in maintenance of electrolyte and fluid homeostasis, blood pressure control, and autonomic neuronal balance (2, 34). In addition, local cardiac interactions seem to take place, as BNP prevents acute hypertrophic actions of angiotensin II, and angiotensin II stimulates BNP gene expression in vitro (28, 33). Like BNP, the RAS may also be involved in the cellular response to substrate depletion. In elite endurance athletes (20) and during hypoglycemia in patients with Type 1 diabetes (21–24, 36), low spontaneous RAS activity seems to be associated with superior functional capacity. If BNP has cardioprotective functions in periods with acute lack of substrate, subjects with unfavorable high-RAS activity may, therefore, have compensatory higher BNP (and NT-pro-BNP) levels.

The aims of this study were to explore if hypoxemia and hypoglycemia affect the NT-pro-BNP level, and if spontaneous RAS activity has an impact on NT-pro-BNP concentrations during hypoglycemia and hypoxemia.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Subjects.   A total of 303 healthy young men participated in a screening procedure involving a venous blood sample and a health screening questionnaire. Blood samples were analyzed for angiotensin-converting enzyme (ACE) activity, angiotensinogen concentration, and the angiotensin II subtype 2 (AT2) receptor 1675A/G polymorphism, as these three RAS parameters are associated with risk of severe hypoglycemia in Type 1 diabetes (21–24, 36). Based on these parameters and a scoring system, we selected the 20 subjects (26 ± 1 yr; mean ± SE), who differed most in terms of particularly high or low-RAS activity. By screening 300 subjects, 19 out of 20 participants had RAS activity scores beyond the "mean ± 2 SD" of the cohort, improving the a priori probability of detecting a difference grossly. The high-RAS activity group was characterized by ACE activity and angiotensinogen concentration in the highest quartile and the AT2 receptor genotype AA corresponding to low AT2 receptor expression and, consequently, maximum stimulation via the angiotensin II subtype 1 (AT1) receptor (32). The low-RAS activity group was characterized by ACE activity and angiotensinogen concentration in the lowest quartile and the AT2 receptor genotype GG, corresponding to high AT2 receptor expression (minimum stimulation via the AT1 receptor) (32).

Design.   The study was a single-blinded, randomized, counterbalanced, crossover study. Each subject was studied at three occasions separated by at least 3 wk: at hypoglycemia, at hypoxia, and on a normoglycemic, normoxemic control day. All participants gave written, informed consent to participate, and the study was approved by the Regional Ethics Committee.

Experimental setup.   Subjects were studied after an overnight fast. Two cannulas for blood sampling were placed in the antecubital vein and in the radial artery of the nondominant arm. Baseline blood samples were drawn at time 15 and 45 min. Hereafter, hypoglycemia, hypoxia, or euglycemia/normoxia (placebo) was induced. The stimulus period lasted 60 min. Blood was sampled at 100 (only plasma glucose), 115, 130 (only plasma glucose), and 145 min. Samples at the recovery phase were drawn at 215 min.

Hypoglycemia was induced by subcutaneously fast-acting human insulin [Actrapid; Novo Nordisk, Bagsvaerd, Denmark, 0.2 U/kg, administered twice separated by 30 min: a dosage scheme that resulted in stable hypoglycemia within the target range (plasma glucose 2.5–2.9 mmol/l in pilot studies)]. This regimen was used to avoid the administration of any exogenous substrate (glucose) during the hypoglycemic phase of the experiments and thereby any possible interference with natural glucose fluxes. Compared with conventional hyperinsulinemic hypoglycemic clamping, this method is associated with a slightly less constant hypoglycemic level. Euglycemia was restored by ingestion of a small meal consisting of 400 ml of apple juice and a slice of brown bread (55 g). Hypoxemia was induced with a gas mixture containing 12% oxygen administered on a soft facial mask. On the control day, the subjects were given two placebo injections with an insulin pen without insulin and atmospheric air on the mask. During the study, plasma glucose and oxygen saturation were measured regularly using bed-side plasma glucose measurements (HemoCue, HemoCue, Angelholm, Sweden) and a pulse oxymeter (N-180, Nellcor; Tyco Healthcare, Pleasanton, CA), respectively.

Laboratory analyses.   All biochemical analyses were performed blinded to the other results. Plasma concentrations of NT-pro-BNP were measured using a highly sensitive and specific immunoassay (ELECSYS 2010, Roche Diagnostics, Mannheim, Germany; lower detection limit: 5 pg/ml; coefficient of variation at this range: 3%). The median (interquartile range) NT-pro-BNP concentration in young healthy subjects is 2.5 (1.3) pmol/l [corresponding to 20 (10.3) pg/ml] (19). Angiotensinogen was determined as the maximal quantity of angiotensin I generated during incubation of plasma in the presence of excess recombinant human renin, as described previously (6). Serum ACE activity was determined by a commercial kinetics-based assay (Sigma Diagnostics, St. Louis, MO). DNA was extracted from peripheral blood leukocytes using a standard salting-out method. The ACE insertion/deletion variant and the AT2 receptor 1675G/A polymorphism were determined by polymerase chain reaction. Renin was determined by a radioimmunoassay of generated angiotensin I (7).

Glucose, potassium, and blood gases were analyzed immediately by the local laboratory. Plasma glucose concentrations were measured enzymatically (COBAS INTEGRA, Roche, Basel, Switzerland), PO2 by amperometry, and plasma potassium using a standard ion-selective electrode.

Statistics.   Test for normality was done using Kolmogorov-Schmirnov's model. An independent-samples T-test, or when appropriate the Mann-Whitney test, was used to compare baseline values in the two groups. To evaluate both the impact of RAS group and of intervention (hypoglycemia or hypoxia vs. placebo) on the outcome variables, a mixed linear model (analysis of covariance) was applied. Hypoglycemia and hypoxia data were analyzed separately. "RAS group" and "intervention" were defined as fixed factors, and "number of participant" as a random factor. To correct for minor baseline differences between RAS groups, the baseline value of the particular variable being investigated was included in the model as a covariate. The mixed model was applied on data obtained in the stimulus period and the recovery period. To meet the requirement of normal distribution, NT-pro-BNP was log transformed before entering the model. An additional comparison between RAS groups was done on all 3 study days using a general linear model exploiting the principal of repeated measures. Correlations were evaluated using Pearson correlation coefficient. A level of significance <5% (P < 0.05; two-sided) was considered significant. Statistical analyses were performed using SPSS (version 13.0). Values are given as means ± 1 SE.

A power calculation (power = 80%, level of significance = 5%) revealed that a total of 20 highly selected participants would enable us to detect a difference between RAS activity groups of 17 pg/ml NT-pro-BNP.


   RESULTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
RAS parameter baseline characteristics for the groups are listed in Table 1. Neither NT-pro-BNP nor blood pressure differed between RAS groups at baseline (Table 2) or during the control day (Fig. 1C).


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  		Table 1. RAS parameter baseline characteristics

 

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  		Table 2. NT-pro-BNP, BP, and renin during hypoglycemia and hypoxemia in normal subjects with high or low RAS activity

 

Figure 1
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  		Fig. 1. NH2-terminal part of prohormone brain-type natriuretic peptide (NT-pro-BNP) profiles during hypoglycemia (A), hypoxemia (B), and control study (C) in normal subjects with high (dashed line) or low (solid line) renin angiotensin system (RAS) activity. n.s., Not significant.

 
Hypoglycemia.   The hypoglycemic stimulus was similar in the RAS groups, with mean plasma glucose in the stimulus period of 2.8 ± 0.3 mmol/l and nadir plasma glucose of 2.7 ± 0.5 mmol/l. Hypoglycemia did not affect NT-pro-BNP levels during the stimulus period (Table 3, Fig. 1A). There was, however, a nonsignificant increase in NT-pro-BNP in the low-RAS activity group (P = 0.33) during recovery. This increase was not correlated to mean plasma glucose during the hypoglycemic stimulus (P = 0.29). Diastolic blood pressure was significantly decreased in the recovery phase, whereas systolic blood pressure did not change during the experiment (Table 3). Basal RAS activity had no significant impact on NT-pro-BNP levels, diastolic blood pressure, or systolic blood pressure. However, there was a tendency toward higher spontaneous NT-pro-BNP levels in the high-RAS group (P = 0.14) and a nonsignificant NT-pro-BNP increase in the low-RAS group. When analyzing the same three outcome variables, the possible interaction between "RAS" and "intervention" did not enter the mixed model significantly. Plasma renin increased by 43%, P < 0.001, and was correlated to neither NT-pro-BNP nor ln(NT-pro-BNP) during the hypoglycemic period.


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  		Table 3. Estimated effect of hypoglycemia on ln NT-pro-BNP, BP, and plasma renin in normal subjects with high or low RAS activity

 
Hypoxemia.   The hypoxemic stimulus was similar in both groups, with mean PO2 in the stimulus period of 5.9 ± 0.6 kPa and nadir PO2 of 5.8 ± 0.5 kPa (corresponding to a mean saturation of 82 ± 1% and a nadir saturation of 81 ± 1%). NT-pro-BNP increased by 9% during the hypoxemic stimulus (P < 0.001) (Table 4, Fig. 1B). The effect was not maintained in the recovery phase (P = 0.25). Diastolic and systolic blood pressure were unaffected by hypoxemia (Table 4).


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  		Table 4. Estimated effect of hypoxemia on NT-pro-BNP, BP, and plasma renin in normal subjects with high or low RAS activity

 
The diastolic blood pressure was significantly lower in the low-RAS activity group during recovery, whereas RAS activity had significant impact neither on NT-pro-BNP levels nor on systolic blood pressure. Again, there was a tendency toward higher spontaneous NT-pro-BNP levels in the high-RAS group (P = 0.30). No interactions entered significantly in the mixed model, particularly no interaction between "RAS group" and "intervention" was found for any of the three outcome variables. Plasma renin decreased by 18% (P = 0.01), but was correlated to neither NT-pro-BNP nor ln(NT-pro-BNP).


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
NT-pro-BNP was stimulated modestly by hypoxemia. Previous studies of BNP responses to hypoxemia are scarce. A rat study demonstrated that subacute hypoxia (arterial oxygen saturation 90%) and endurance training in hypoxic conditions led to a twofold increase in BNP mRNA levels, but not in BNP concentrations (26). A study in 10 healthy humans confirmed that hypoxemia (arterial oxygen saturation 75–80%) has no effect on BNP concentrations (3). The disagreement between ours and these previous studies may be explained by the fact that Cargill et al. (3) only measured BNP after 30 min of hypoxemia. Since BNP is only prestored in limited amounts and increased release, therefore, requires de novo synthesis, this period may be too short to detect changes (18). Alternatively, Cargill et al. (3) may have used an assay with a lower sensitivity than we did in the present study. In addition, we measured NT-pro-BNP, whereas Cargill et al. measured BNP directly. The NT-pro-BNP molecule has been suggested to have a half-life of 25 (14) to 70 min (25), whereas the half-life of BNP approximates 5 min (25). The lower elimination rate for NT-pro-BNP may facilitate detection of small changes in release patterns.

Supporting a direct stimulatory effect of hypoxemia on BNP expression is the reporting of a hypoxia-inducible factor 1{alpha} responsive element (16) in the promoter sequence of the BNP gene. Hypoxia-inducible factor 1{alpha} is a transcription factor involved in the regulation of several genes. It is stabilized under hypoxic conditions and is a primary regulator of the physiological response to hypoxia. Furthermore, patients with stable myocardial ischemia, without ventricular dysfunction, have increased BNP levels (10), just as experimentally induced myocardial ischemia stimulates BNP gene expression in pigs (11). These results indicate that BNP may play a protective role in the cardiac defense against acute and chronic ischemic injury. In accordance with this, administration of exogenous BNP protected isolated, perfused rat hearts when subsequently exposed to acute ischemic injury (5).

Whether the increase in NT-pro-BNP during hypoxemia found in our study is a result of a direct effect on the myocytes, or indirectly triggered by hypoxemia-induced changes in hemodynamic parameters, is uncertain. The systemic systolic and diastolic blood pressure did not change as a function of hypoxemia. However, we did not measure the pulmonary arterial pressure, which may affect right ventricular function and thereby, to some degree, NT-pro-BNP release. Speaking against this are echocardiographic studies revealing that acute hypoxia has no impact on myocardial function at rest (15).

The magnitude of the NT-pro-BNP increase during hypoxemia is of relevance for the use of NT-pro-BNP as a rule-out marker of heart failure in the acute clinical setting (35), as many patients with acute dyspnea are likely to suffer from hypoxemia. However, the modest impact of hypoxemia on NT-pro-BNP found in the present study suggests that hypoxemia is not likely to affect the diagnostic performance of NT-pro-BNP.

There do not seem to be any published studies on the effect of hypoglycemia on NT-pro-BNP or BNP. We found no changes in NT-pro-BNP levels during mild hypoglycemia, even though hypoglycemia is known to stress cardiac myocytes (27), to induce catecholamine release, and to induce hemodynamic changes, which also may stimulate BNP release (9). However, in the recovery period after hypoglycemia, the NT-pro-BNP level increased nonsignificantly in the low-RAS activity group. Whether this trend represents a delayed response to hypoglycemia, masked by a high variability in the NT-pro-BNP response, is unclear. The power to detect the observed increase was 72% (level of significance 0.05). However, mean plasma glucose in the hypoglycemic stimulus period was not correlated to the NT-pro-BNP concentration in the recovery phase, which speaks against a delayed response. The lack of correlation also indicates that the slightly larger variation in the hypoglycemic stimulus associated with inducing hypoglycemia with subcutaneously administered insulin (compared with using a hyperinsulinemic hypoglycemic clamp), did not cause the high variability in the NT-pro-BNP response.

The concentration of the other cardiac natriuretic peptide, atrial natriuretic peptide, is reportedly unaffected by hypoglycemia (duration 45 min, nadir plasma glucose 2 mmol/l) in normal men (8, 31). However, since atrial natriuretic peptide and BNP gene transcription are differently regulated (18), a direct comparison is inappropriate. Taken together, the findings tentatively indicate that BNP is not involved in the cellular defense against hypoglycemia.

BNP and RAS.   Spontaneous RAS activity had no significant impact on NT-pro-BNP levels during neither hypoglycemia nor hypoxemia. Both hormonal systems seem to be of importance for the cellular defense response in periods with acute substrate depletion, where high-RAS activity seems to be associated with reduced functional capacity and high levels of BNP may provide cellular protection. However, high-RAS activity tended to be associated with a higher spontaneous NT-pro-BNP concentration. The trend was generalized and observed consistently and might represent a compensatory increased basal level of NT-pro-BNP in the high-RAS activity group. Including more subjects would presumably have allowed us to detect a difference between the RAS groups. The reason why a larger study was not conducted was the fact that the participants were highly selected and represented the two extremes in the RAS activity spectrum to optimize the chances of finding a difference. Detecting a difference of 5 pg/ml NT-pro-BNP between the groups (with 80% power and a level of significance of 5%) would have required over 200 participants and screening over 3,200 potential participants, a number so large that a statistically significant effect of RAS group on NT-pro-BNP most likely would have been regarded as clinically irrelevant.

In conclusion, acute hypoxemia, but not acute hypoglycemia, stimulates NT-pro-BNP release in healthy subjects. The hypoxemia-induced rise in NT-pro-BNP is modest compared with baseline levels and supports the use of NT-pro-BNP as a rule-out marker of heart failure in the emergency care unit, as hypoxemia in itself, if present, only influences NT-pro-BNP concentrations modestly.

NT-pro-BNP responses were not dependent on basal RAS activity, even though high-RAS activity tended to be associated with higher spontaneous NT-pro-BNP concentrations.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
ACKNOWLEDGMENTS
 REFERENCES
 
The study was funded by grants from The Foundation of Harald Jensen and wife, The Foundation of Olga Bryde Nielsen, The Danish Pharmacy Foundation of 1991, The Foundation of Region 3, and The Research Foundation of Frederiksborg Amt.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
REFERENCES
 
We thank research nurses Pernille Banck and Tove Larsen, Endocrinology Section, Division of Internal Medicine I, Hillerød Hospital, for skillful technical assistance during the experiments. Also thanks to associate professor Lene Theil Skovgaard, Department of Biostatistics, University of Copenhagen for statistical guidance and assistance.


   FOOTNOTES
 

Address for reprint requests and other correspondence: R. Due-Andersen, Endocrinology Section, Division of Internal Medicine I, Hillerød Hospital, Helsevej 2, DK-3400 Hillerød, Denmark (e-mail: rsa{at}noh.regionh.dk)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 

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