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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 55:B390-B395 (2000)
© 2000 The Gerontological Society of America

Increased Bioactivity of Rat Atrial Extracts

Relation to Aging and Blood Pressure Regulation

Ping Laia, Stanley J. Naziana,c, William R. Gower, Jr.b, Carol S. Landona and John R. Dietza,c

a Departments of Physiology and Biophysics, University of South Florida, College of Medicine, Tampa
b Departments of Biochemistry and Molecular Biology, University of South Florida, College of Medicine, Tampa
c The University of South Florida Institute on Aging, Tampa

John R. Dietz, Department of Physiology and Biophysics, University of South Florida, College of Medicine, Box 8, Tampa, FL 33612 E-mail: jdietz{at}hsc.med.usf.edu.

Decision Editor: Jay Roberts, PhD


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
The purpose of this study was to evaluate the possible role of atrial factor(s) in the regulation of cardiovascular homeostasis and their relationship to aging. Rats were anesthetized and received jugular vein, carotid artery, and bilateral ureteral catheterization. After a half-hour equilibration period, the rats received 0.5 ml of atrial extract with a concentration of proANP (atrial natriuretic peptide) of 150 µg/ml prepared from either aged (18–20 month, "aged extract group", ) or young (2–3 month, "young extract group", ) rats. Mean arterial pressure (MAP) and renal function were monitored over five 20-minute periods. The atrial extract caused MAP to fall significantly in the aged extract group ( p < .05) but MAP was unchanged in young extract group. There was a significant difference in MAP between the two groups ( p < .05). Urine output increased significantly in both groups after extract infusion ( p < .05 in both cases). Sodium and potassium excretion showed similar responses. However, the diuresis, natriuresis, and kaliuresis after extract infusion would have been expected to be relatively lower in the aged extract group compared to the young extract group considering the significantly lower MAP in the aged extract group. High performance gel permeation chromatography (HP-GPC) analysis of the atrial extract showed an increased quantity of a large molecular weight C-terminal peptide in atrial extracts from aged rats compared to young rat atria. Plasma levels of ANP and proANP 1-30 both increased significantly after extract infusion in both aged and young groups, and there was no significant difference in ANP concentration between the two groups. However, the concentration of proANP 1-30 was significantly increased in the aged group compared to the young group after extract infusion. These results suggest that changes in the structure or processing of proANP in aging may contribute to the different hemodynamic responses.

SINCE deBold and colleagues (1) first described the natriuretic action of atrial extracts in 1981, numerous studies have provided evidence suggesting that atria play an important endocrine role in the regulation of blood pressure and kidney function (2). One important peptide secreted by the heart, atrial natriuretic peptide (ANP) is released primarily in response to atrial stretch (3)(4) and plays an important role both in blood volume homeostasis (5) and normal regulation of arterial blood pressure (6). Overexpression of the ANP gene results in natriuresis and hypotension, whereas a reduction in gene expression leads to sodium retention and hypertension (7)(8).

It is well known that aging is associated with cardiovascular and endocrine disorders (9). With advanced age, the plasma concentration of ANP has been reported to increase in both rats (10) and humans (11). The source of the increased plasma ANP levels appears to result from an increased cardiac secretion (12)(13). However, other studies suggest that the higher ANP levels in the elderly subjects may be attributable to a decrease in the total body clearance of ANP (14)(15). Also, studies by Tummala and associates (16) have shown that ANP secretion in response to adrenergic stimulation is also increased, and these secretory responses may contribute to the increased plasma levels of ANP that occur during aging. ANP secretion in response to volume expansion (17) and the natriuretic response to exogenous ANP (18)(19) appear to decrease with aging. The hypotensive response to ANP also seems to be attenuated (20), which could contribute to increased blood pressure during the aging process.

Although there is clear evidence that ANP is involved in body fluid balance, it is also evident that ANP cannot be solely responsible for the natriuresis resulting from atrial distention. It is reported that atrial distention-induced natriuresis could be superimposed on a falling level of ANP (21). Some investigators (22) have observed that acute volume expansion leads to a diuresis and natriuresis with no change in plasma ANP concentration. However, the natriuretic response to volume expansion is clearly attenuated in atrial appendectomized rats (18)(23). These results raise the possibility that the heart may release natriuretic and hypotensive factor(s) other than immunoreactive ANP.

The major storage form of ANP is proANP 1-126 (24). Both the C-terminal and the N-terminal fragments of this prohormone are released into the circulation by stimuli such as atrial distention (4) and increased sodium intake (25). Similar to ANP, the three N-terminal peptides consisting of proANP 1-30, proANP 31-67, and proANP 79-98 have vasodilator, natriuretic, and/or kaliuretic effects (26)(27)(28).

In this study, we compared the effects of atrial extracts from both aged and young rats on arterial pressure as well as sodium and potassium excretion in order to evaluate possible changes in rat atria that might occur with aging, and their potential contributions to blood pressure regulation and electrolyte balance during the aging process.


   Materials and Methods
Top
 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Atria from either young (2–3 months old) or aged (18–20 months old) rats (male Sprague-Dawley) were extracted as reported previously (24). The samples from young and aged rats were each pooled separately and assayed (4)(24) for proANP content. The sample of the atrial extract from the aged rats had a higher proANP concentration and was diluted with 0.9% saline so that each group had the same concentration of proANP. A concentration of 150 µg/ml of proANP was chosen for our experiments because 0.5 ml of this atrial extract from aged rats with this concentration of proANP caused prominent cardiovascular and renal effects in our preliminary studies.

Two groups of male Sprague-Dawley rats ( of each group) weighing 250–350 g (2–4 months of age) were anesthetized with sodium pentobarbital (50 mg/kg) given intraperitoneally. Supplemental anesthetic was given intravenously, when necessary, to maintain an appropriate level of anesthesia. The animals were placed in the supine position on a temperature-controlled pad to maintain body temperature between 37–38°C. Following tracheotomy, a polyethylene catheter (PE-50) was placed in the right external jugular vein for infusions, and a similar catheter was placed in the right carotid artery for arterial blood pressure monitoring and blood sampling. Both ureters were also catheterized (PE-10) for the collection of timed urine samples.

Following the surgical procedures, the rats were prehydrated with 2 ml of 0.9% saline, and a half-hour equilibration period was allowed for recovery from the preparatory procedures. Data were gathered over five 20-minute periods. At 40 minutes into the experiment, each rat was infused with 0.5 ml of atrial extract with a concentration of 150 µg/ml of proANP from either aged ("aged extract group," ) or young ("young extract group," ) rats. Blood samples of 2 ml each were drawn from the carotid artery 5 minutes before and 5 minutes after the extract infusions as well as at the end of the final urine collection. The first two blood samples withdrawn were simultaneously replaced by an equal volume of 6% albumin in Krebs buffer given intravenously. All blood samples were placed immediately in prechilled tubes containing 5% ethylenediamine tetraacetate to prevent proteolytic breakdown. Plasma obtained after centrifugation was frozen at -20°C until extraction and assay.

Plasma ANP and proANP 1-30 levels were measured by radioimmunoassay (RIA) using our laboratory methods previously described (4)(24). Arterial blood pressure was continuously monitored throughout the experiment using a pressure transducer. The data were recorded and displayed using Windaq Analysis Software (DATAQ Instruments, Akron, OH) and averaged for each 20-minute period. Urine was collected in preweighed tubes during five 20-minute periods (100 minutes total). Urine sodium and potassium concentrations were measured by flame photometry (Model 943, Instrumentation Laboratories, Lexington, MA).

The molecular species of the immunoreactive ANP and proANP peptides in atrial extracts were determined by high performance gel permeation chromatography [HP-GPC; (29)(30)]. HP-GPC was performed on a TSK-Gel G2000SW column equipped with a guard column (TososHaas, Montgomeryville, PA). An aliquot (0.5 ml) of each extract was used for gel filtration. The column was calibrated with blue dextran (Vo), myoglobin (16.9 kD), cytochrome C (12.4 kD), vasoactive intestinal peptide (3.3 kD), (Tyr)-somatostatin (1.7 kD), synthetic rat ANP, and synthetic human proANP1-30 (29). Each curve presented (Fig. 4) represents the average of three extracted atria from either young or aged rats.



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  		Figure 4. Gel filtration profiles of ANP and proANP 1-30 immunoreactivity in extracts of atrial tissue from aged versus young rats. Arrows indicate the elution positions of protein molecular weight calibrators. Vo indicates void volume, and Vt indicates total volume. Each curve represents the average of three extracted atria from either young or aged rats.

 
Statistics.
The data obtained in this investigation were illustrated as mean ± SEM. Data were evaluated by a two-way analysis of variance (ANOVA) with repeated measures on one factor (group as one factor and time as the other). Post-hoc tests were assessed using the Student-Newman-Keuls test. Differences between groups at specific time points were also assessed with Student's t test. In all cases p < .05 was considered the criterion for statistical significance.


   Results
Top
 Abstract
 Materials and Methods
 Results
Discussion
 References
 
The results for mean arterial pressure (MAP) of bioassay rats with atrial extract infusion from either aged or young rats are shown in Fig. 1. It illustrates that atrial extract from aged rats caused a significant decrease in MAP ( p < .05, ANOVA), which remained at a reduced level until the end of the experiment. The MAP decreased in the aged extract group from 108 ± 3.0 mm Hg at 30 minutes to 97 ± 2.9 mm Hg at 50 minutes, 99 ± 2.2 mm Hg at 70 minutes, and 103 ± 1.8 mm Hg at 90 minutes. However, the MAP did not change significantly in the group infused with atrial extract from young rats (from 112 ± 2.8 mm Hg at 30 minutes to 110 ± 2.3 mm Hg at 50 minutes, p > .05). When the two groups were compared, MAP in the bioassay rats infused with atrial extract from aged rats was significantly lower than that in animals infused with extract obtained from young rats (50 minutes, 70 minutes, and 90 minutes, p < .05).



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  		Figure 1. Effect of infusion of atrial extract from aged and young rats on mean arterial pressure (MAP). Values are expressed as means ± SEM. in each group. * indicates p < .05 between the two groups (Student's t test). Two-way analysis of variance showed a significant decrease in arterial pressure in the aged extract group ( p < .05, time effect) but not in the young extract group and a significant difference between the groups (Age x Group interaction, p < .05).

 
Urine output and sodium and potassium excretion were all significantly increased by infusion of atrial extract from both aged and young rats (Fig. 2). There were no significant differences between the two groups.



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  		Figure 2. Effect of infusion of atrial extract from aged and young rats on urine output (µl/min) and sodium and potassium excretion (µEq/min). Values are means ± SEM. in each group. Two-way analysis of variance showed a significant increase in the urine flow and sodium and potassium excretion in the young and aged extracts groups ( p < .05, time effect). There was no significant difference between the groups (two-way ANOVA, age effect, p > .05).

 
Fig. 3 illustrates plasma ANP and proANP 1-30 concentrations with atrial extract infusion. Infusion of atrial extract from either aged or young rats led to a significant increase in ANP concentration. At the end of the experiments (100 minutes), plasma ANP concentrations in both groups tended to return toward their baseline levels. However, they were still significantly increased compared to their pre-infusion levels ( p < .05). Although extract infusion from aged rats appeared to cause a greater change of plasma ANP concentration in bioassay rats than that from young rats, there was no statistically significant difference in plasma ANP level between the two groups ( p > .05). Atrial extracts from either aged or young rats caused significant increases in plasma proANP 1-30 levels ( p < .05 in both groups, ANOVA). Although the plasma proANP 1-30 concentration tended to return toward the baseline at the end of the experiment (100 minutes), it was still significantly increased compared to the baseline level ( p < .05). The infusion of the extract from aged rats led to a significantly greater plasma proANP 1-30 level than the extract from young rats ( p < .05). It should be noted that in our RIA analysis, antibody against proANP 1-30 crossreacts with proANP 1-98 (30); therefore, the proportion of proANP 1-30 to proANP 1-98 could not be determined at the present time. However, our previous work showed that in rat, the primary N-terminal peptide secreted by the isolated atria is proANP 1-30, as opposed to proANP 1-98 (31).



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  		Figure 3. Effect of infusion of atrial extract from aged and young rats on plasma ANP and proANP 1-30 (pg/ml). Values are expressed as means ± SEM. for each group. * indicates p < .05 between the two groups (Student's t test). Two-way analysis of variance showed a significant increase in the plasma levels of both hormones in both the young and aged extract groups (time effect, p < .05).

 
Extracts of atrial tissue showed major peaks of ANP and proANP 1-30 immunoreactivities when run on HP-GPC (Fig. 4). This observation, together with the fact that the peaks co-elute at a molecular weight of approximately 12,000 Daltons, suggests that these peaks represent the intact prohormone, proANP 1-126. The extract from aged rats had relatively higher proANP content than the extract from young rats. The smaller peak in this figure represents a peptide that can be recognized by ANP antibody but not proANP 1-30 antibody, suggesting that this is a C-terminal peptide. The apparent molecular weight of this C-terminal peptide is approximately twice that of ANP. The data suggest that the atrial extract from aged rats contains more of this C-terminal peptide than the extract from young rats (Fig. 4).


   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
These results clearly show that atrial extracts from aged rats have a significantly greater hypotensive action than atrial extracts from young rats when injected into anesthetized bioassay animals (see Fig. 1). In our present experiments, urine output as well as sodium and potassium excretion increased significantly after extract infusion in both groups, but there were no significant differences between the two groups (Fig. 2). However, it can be argued that the response of the kidney to atrial extract from aged rats was relatively greater considering the significant decrease in MAP (approximately 11 mm Hg) after extract infusion in that group. It is well known that decreased arterial pressure limits the response of the kidney to natriuretic factors (32). The change in arterial pressure that we observed was clearly in the autoregulatory range for the rat where glomerular filtration rate (GFR) and renal blood flow should remain nearly constant. However, studies (33) have clearly shown that renal excretion does not show a high degree of autoregulation over this range of perfusion pressures. In fact, changes in urine flow and sodium excretion over this range of arterial pressures are almost linear (33). Thus, if we had kept hemodynamics constant, we would predict a significantly greater increase in the rates of sodium and potassium excretion with infusion of atrial extract from aged rats.

These results could be attributed to two possible causes. Either the structure and/or processing of proANP is different in the atria of aged rats, resulting in a greater bioavailability of ANP or the N-terminal atrial natriuretic peptides. Second, the concentration of some other atrial hypotensive and natriuretic factors could be elevated in aging. Our previous studies have shown that the primary storage form of ANP in the atria is proANP 1-126 (24). The prohormone appears to be processed in the heart (24) to several biologically active peptides, primarily proANP 1-30, proANP 31-67, proANP 79-98, and ANP. These peptides have been shown to have vasodilator, natriuretic, and/or kaliuretic properties (26)(27)(28). In the present study, HP-GPC analysis of the extracts showed that the atria from aged or young rats contain primarily proANP 1-126 (Fig. 4). The atria also contain a C-terminal peptide of proANP whose molecular weight is about twice that of ANP (99-126), which we speculate may be an ANP dimer (Fig. 4). Whether differences in the concentration of this C-terminal peptide contribute to the increased hypotensive and natriuretic effects of the extracts from aged rats remains to be determined. However, this appears to be an unlikely possibility, because the injections of atrial extracts from aged rats did not result in a greater increase in plasma ANP, measured with the C-terminal assay (Fig. 3, upper panel).

We found that proANP 1-126 content was greater in atria from aged rats (Fig. 4). This is consistent with our previous data (18) showing that the concentration of proANP 1-126 is decreased in atria of aged rats, but total proANP atrial content of aged rats was increased due to the tremendously increased atrial size (18). For this reason, we diluted the atrial extracts from aged rats in order to infuse extracts with the same concentration of proANP into two groups of bioassay rats. This produced a similar plasma concentration of ANP in both groups (Fig. 3), which suggests that the processing of proANP into ANP is not altered in the aged rats. However, the peak plasma proANP 1-30 concentration was significantly greater in the group receiving extracts from the aged rats (Fig. 3, lower panel). This suggests that an alteration in the processing of the N-terminal portion of the proANP molecule could contribute to the different responses between the two groups. Previous work has shown that proANP 1-30 has hypotensive and natriuretic actions in both rats (26) and humans (28). If this hypothesis is correct, then there may be structural differences in the proANP produced in the atria of the aged rats because there is no reason to believe that the two groups of bioassay rats differ in their ability to process proANP.

Another distinct explanation for the increased hypotensive and natriuretic actions of atrial extracts from aged rats is the possibility that atrial factors, other than proANP, are increased in aging. Sakata and associates (22) observed that acute volume expansion resulted in a diuresis and natriuresis without a change in plasma ANP levels. Villarreal and colleagues (23) showed that the natriuretic response to volume expansion is clearly attenuated in atrial appendectomized rats. These experiments suggest that the atria may release natriuretic and hypotensive factor(s) other than immunoreactive ANP. However, none of these earlier studies measured proANP 1-30, which we have shown is increased by volume expansion (24).

Another peptide hormone, adrenomedullin, has been found in atria in a variety of species including rats (34). It has been demonstrated that, similar to ANP, this hormone has hypotensive, diuretic, natriuretic, and kaliuretic effects (35). However, the relationship of adrenomedullin with aging has not been investigated. Other factors such as brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) can also not be excluded because both of these ANP-related peptides show hypotensive and natriuretic properties in a variety of species (36)(37). The primary source of plasma BNP is not known, and although CNP may be synthesized in the heart, there is no clear evidence for secretion of physiologically significant amounts of this peptide. Experiments have shown that plasma levels of BNP correlate with age (38), but it is not clear whether circulating BNP comes from the heart or other tissues. The relationship between CNP and aging is also not clear.

Summary.
It has been demonstrated that the natriuretic response to exogenous ANP (18)(19) and the hypotensive action of ANP (20) are both attenuated with aging, which could contribute to increased blood pressure in aging. Our present findings, which clearly show an increased hypotensive response to atrial extract from aged rats, indicate an important compensatory response that prevents a further rise in arterial pressure in elderly subjects. The data also suggest possible increased diuretic, natriuretic, and kaliuretic responses. Thus, an upregulation of the cardiac endocrine system with a concomitant release of more proANP 1-30 may help to offset the changes in renal excretory function and blood vessel reactivity observed in aging.


   Acknowledgments
 
This study was supported by a grant from the American Heart Association, Florida Affiliate. Ping Lai was supported by a Graduate Student Research Fellowship from the American Heart Association, Florida Affiliate. The authors wish to acknowledge the expert technical assistance of Dionne Scott.

Received July 8, 1999

Accepted January 14, 2000


   References
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 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

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