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Endocrinology Vol. 138, No. 5 1893-1902
Copyright © 1997 by The Endocrine Society

Articles

Atrial Natriuretic Peptide (ANP) Inhibits Its Own Secretion via ANPA Receptors: Altered Effect in Experimental Hypertension1

Hanna Leskinen, Olli Vuolteenaho, Miklos Toth2 and Heikki Ruskoaho

Departments of Physiology (H.L., O.V.) and Pharmacology and Toxicology (M.T., H.R.) and Biocenter Oulu, University of Oulu, Oulu, Finland

Address all correspondence and requests for reprints to: Heikki Ruskoaho, M.D., Ph.D., Department of Pharmacology and Toxicology, University of Oulu, Kajaanintie 52 D, FIN-90220 Oulu, Finland. E-mail: heikki.ruskoaho{at}.oulu.fi


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Three atrial natriuretic peptide (ANP) receptors, ANPA, ANPB, and ANPC, have been identified in the heart, suggesting that natriuretic peptides may have direct effects on cardiac function. To characterize the possible role of atrial natriuretic peptide (ANP) in the regulation of its own secretion, we studied here the effects of ANP (greater affinity for ANPA than for ANPB receptors) and C-type natriuretic peptide (CNP), a potent activator of ANPB receptors, on the release of atrial peptides under basal conditions and during acute volume expansion in conscious normotensive Sprague-Dawley rats. The effects of HS-142–1, a nonpeptide ANPA and ANPB receptor antagonist, on volume load-induced atrial peptide release in 1-yr-old conscious normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were also studied. As an index of secretion of atrial peptides from the heart, plasma levels of N-terminal fragment of pro-ANP (NT-ANP) were measured. In Sprague-Dawley rats, iv infusion of ANP for 30 min in doses of 0.3 and 1.0 µg/kg·min blocked the plasma immunoreactive NT-ANP (IR-NT-ANP) response to volume load (P < 0.001), whereas CNP had no significant effect. Neither ANP nor CNP infusion had any effect on plasma IR-NT-ANP levels under basal conditions. Bolus administration of HS-142–1 increased baseline plasma IR-ANP concentrations in both WKY and SHR strains (WKY: 3 mg/kg, 46 ± 8 pmol/liter, P < 0.001; SHR: 1 mg/kg, 26 ± 9 pmol/liter, P < 0.01; SHR: 3 mg/kg, 40 ± 12 pmol/liter, P < 0.01). The corresponding increases in plasma IR-NT-ANP concentrations in the SHR in response to administration of HS-142–1 were 0.17 ± 0.06 nmol/liter (P < 0.01) and 0.40 ± 0.14 nmol/liter (P < 0.01). Moreover, HS-142–1 (3 mg/kg) augmented plasma IR-ANP and IR-NT-ANP responses to acute volume load in WKY rats. In contrast, HS-142–1 did not enhance the plasma IR-ANP response to acute volume load in SHR and resulted in a smaller increase in the plasma IR-NT-ANP concentration in SHR than in WKY rats. In conclusion, the findings that ANP, but not CNP, inhibited volume expansion-stimulated NT-ANP release and that HS-142–1, an antagonist of guanylate cyclase-linked natriuretic peptide receptors, increased plasma ANP and NT-ANP concentrations show that endogenous ANP directly modulates its own release via ANPA receptors in vivo. Furthermore, this modulation of acute volume expansion-induced atrial peptide release appears to be altered in experimental hypertension.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THERE ARE three members of the natriuretic peptide hormone family, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), that are involved in the regulation of blood pressure and fluid homeostasis. CNP is principally found in the central nervous system and vascular endothelial cells, whereas ANP and BNP are cardiac hormones (1, 2, 3). ANP and BNP cause natriuresis, diuresis, and vasorelaxation and inhibit the renin-angiotensin system and endothelin and vasopressin secretion (1, 3). CNP, in contrast, may be a local regulator of vessel tone (4) and the growth of vascular endothelial (5) and smooth muscle cells (6, 7). Most of the biological activities of the natriuretic peptides are mediated by intracellular accumulation of cGMP through the activation of particulate guanylyl cyclase. Molecular cloning studies have identified three different natriuretic peptides receptors (for review, see Refs. 8 and 9). Two of these, ANPA and ANPB receptors (also called GCA or NPR-A and GCB or NPR-B) contain a domain with guanylyl cyclase activity (10, 11, 12), whereas ANPC receptor is not coupled to guanylate cyclase. ANPA receptors mediate many of the physiological effects of ANP and BNP (8), whereas CNP is a potent and selective activator of ANPB receptors (13). The rank order of potency for cGMP production via the ANPA receptor is ANP >= BNP >> CNP, but that via the ANPB receptor is CNP > ANP >= BNP (14). ANP has also the highest affinity for the ANPC receptor, the rank order of binding affinity is ANP > CNP > BNP (14). ANPC receptor has been thought to act as clearance receptor, but it may also be involved in the modulation of adenylyl cyclase activity via a G protein (9, 15, 16) and alter phosphoinositide concentrations (17).

Acutely, volume load has been shown to increase plasma ANP concentrations in vivo (18), and it is known that wall stretch and not pressure per se is a direct stimulator of ANP release from the atria (18, 19, 20). The predominant stimulus controlling the release of BNP from the atria and ventricles appears to be myocyte stretch (21, 22). ANP and BNP lower blood pressure and reduce intravascular volume. Therefore, decreased atrial pressure and atrial wall stretch secondary to these hemodynamic effects have been suggested to mediate the reduced release of natriuretic peptides from the heart, resulting in negative feedback (23). Natriuretic peptide receptors, however, are present in the heart (24, 25), indicating that natriuretic peptides may have direct effects on cardiac function. Indeed, natriuretic peptides have been reported to act as antigrowth factors in cardiac fibroblasts (26), and ANP has a direct negative intropic effect on heart (27, 28). The presence of ANPA, ANPB, and ANPC receptor messenger RNAs (mRNAs) in rat and human cardiac tissue has been confirmed by reverse transcriptase-PCR (24). Therefore, natriuretic peptides present in the heart or released into the peripheral circulation may act directly as feedback regulators of their own release.

To test this hypothesis, we studied the effects of ANP and CNP infusions on atrial peptide release during acute volume load in conscious normotensive rats. Furthermore, we examined the effects of HS-142–1 (29, 30, 31), a nonpeptide ANPA and ANPB receptor antagonist, on volume load-induced atrial peptide release in conscious spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. As an index of secretion of atrial peptides from the heart, we measured plasma levels of the N-terminal fragment of pro-ANP (NT-ANP), which is cosecreted with ANP in equimolar amounts, but is not subject to enzymatic degradation and receptor binding (32, 33). Our results show that ANP directly modulates its own release via ANPA receptors in vivo and that this modulation of ANP release is altered in experimental hypertension.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Male Sprague-Dawley (SD) rats (weighing 250–350 g), 1-yr-old SHR of the Okamoto-Aoki strain, and age-matched WKY rats from the colony of the Center of Experimental Animals and the Department of Pharmacology and Toxicology at the University of Oulu (Oulu, Finland) were used. The WKY and SHR strains were originally obtained from Mollegaards Avslaboratorium (Ejby, Skensved, Denmark). The rats were housed in plastic cages in a room with a controlled humidity of 40% and a temperature of 22 C. A 12-h light, 12-h dark environmental light cycle was maintained. The experimental design was approved by the animal experimentation committee of the University of Oulu.

Chronically instrumented rats
Under chloral hydrate (300–400 mg/kg, ip) anesthesia, a PE-60 catheter was placed into the abdominal aorta through the left femoral artery for the measurement of blood pressure and heart rate and for collection of blood samples, as previously described (34). PE-50 catheters were inserted into the right atrium through the jugular vein for measurement of right atrial pressure and into the femoral vein for administration of drugs. All catheters were exteriorized behind the neck, filled with a heparinized (500 IU/ml) saline solution, and plugged with a stainless pin. After operation, rats were housed individually in the experimental cages and had free access to food and water.

The day after the operation, the arterial and right atrial catheters were attached to pressure transducers (model MP-15, Micron Instruments, Los Angeles, CA) and a Grass polygraph (model 7E, Grass Instruments, Quincy, MA) for recording of mean arterial pressure, heart rate, and right atrial pressure. The venous catheter was connected to a syringe or an infusion pump (B. Braun Perfusor ED, Braun Melsungen, Melsungen, Germany) for administration of vehicle or drugs. The animals were left undisturbed for 30 min to become acclimatized to the laboratory before the recording of hemodynamic variables in the conscious, freely moving rats was begun. Mean arterial pressure, heart rate, and right atrial pressure were measured for 25 min before 1.0 ml blood was withdrawn from the arterial catheter for measurement of baseline plasma immunoreactive natriuretic peptide levels (B-5; Fig. 1Go). An equal volume of blood from a donor rat was then infused. Donor blood was obtained from conscious rats to which this volume was replaced by 0.9% NaCl. The baseline hemodynamic measurements were made 5 min later, when mean arterial pressure, heart rate, and right atrial pressure were stabilized near to the control values.



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  		Figure 1. Experimental design in chronically cannulated, conscious rats. Bx refers to blood samples (1.0 ml) that have been replaced by donor blood.

 
In the first series of experiments, SD rats were used to study the effects of ANP and CNP infusions on basal and volume load-induced NT-ANP release. ANP and CNP at concentrations of 0.3 and 1.0 µg/kg·min (1.2 ml/h) or vehicle (0.9% NaCl; 1.2 ml/h) were administered as an iv infusion for 30 min (protocol 1, Fig. 1Go). A second blood sample (B25) was obtained 25 min after the beginning of the infusion. Five minutes later (i.e. 30 min), right atrial pressure was acutely increased by infusing 4–6 ml physiological saline solution/rat over 1 min into vehicle- and drug-treated animals so that an identical degree of stretch (i.e. increase in right atrial pressure >3 mm Hg) was obtained. A blood sample for plasma natriuretic peptide measurements was taken 1 min (B32) after volume expansion, and a fourth sample was taken 5 min (B36) after volume expansion.

In the second series of experiments, SHR and their age-matched normotensive controls, WKY rats, were used to compare the effects of HS-142–1 (an ANPA and ANPB receptor antagonist) on basal and volume load-induced ANP and NT-ANP release in normotensive and hypertensive rats. HS-142–1 at concentrations of 1 and 3 mg/kg (injection volume, 0.1 ml/100 g BW) or vehicle (0.9% NaCl; 0.1 ml/100 g BW) was administered iv as a bolus injection (protocol 2, Fig. 1Go). These doses of HS-142–1 have been previously shown to inhibit the cardiovascular effects of ANP mediated by ANPA and ANPB receptors in rats (29, 30, 31). A second blood sample (B10) was obtained 10 min after the administration of vehicle or drugs. Five minutes later (i.e. 15 min), right atrial pressure was acutely increased by infusing 4–6 ml physiological saline solution/rat over 1 min into vehicle- and drug-treated animals. A third blood sample for plasma natriuretic peptide measurements was taken 1 min (B17) after volume expansion, and a fourth sample was taken 5 min (B21) after volume expansion. All samples were taken into precooled tubes containing 1.5 mg EDTA/1 ml blood on ice and immediately centrifuged (2000 x g, 10 min, 4 C). Plasma was stored at -20 C until assayed by RIA.

Assay of immunoreactive NT-ANP (IR-NT-ANP) in plasma
IR-NT-ANP was determined directly from plasma samples by RIA, as previously described (35). Briefly, the plasma samples in duplicates of 25 µl were incubated with the rabbit antiserum (200 µl; final dilution, 1:40,000) and 125I-labeled human Tyr0-pro-ANP-(79–98) (200 µl; 10,000 cpm) overnight at 4 C. The bound and free fractions were separated with double antibody in the presence of polyethylene glycol. Synthetic human pro-ANP-(79–98) was used as standard. This as well as purified human and rat pro-ANP-(1–126) were recognized with similar avidity, whereas the antiserum did not recognize human or rat ANP-(99–126), rat BNP, or rat CNP (cross-reactivity, <0.01%). The sensitivity of the assay was 0.03 nmol/liter plasma, and the within- and between-assay coefficients of variation were less than 10% and less than 15%, respectively. The 50% displacement of the standard curve occurred at 0.4 nmol/liter.

Assay of IR-ANP and IR-CNP in plasma
IR-ANP and IR-CNP levels were determined by RIA from the extracted plasma samples, as previously described for ANP (36, 37). Briefly, the plasma samples (0.5 ml) were extracted by Sep-Pak C18 cartridges (37), and eluates were redissolved in 500 µl RIA buffer. The samples were incubated in duplicates of 100 µl with 100 µl of the specific rabbit ANP antiserum (final dilution, 1:200,000) (36) or rabbit CNP antiserum (final dilution, 1:100,000; Peninsula Laboratories Europe, St. Helens, UK) at 4 C. Synthetic rat ANP-(99–126) and rat CNP-(1–22) were used as standards. After incubation for 48 h, 125I-labeled rat ANP-(99–126) (100 µl; 10,000 cpm) or Tyr0-CNP-(1–22) (100 µl; 10,000 cpm) with normal rabbit serum (1 µl/tube) was added. After incubation for another 24 h at 4 C, the immunocomplexes were precipitated with double antibody in the presence of polyethylene glycol. The sensitivities of the ANP and CNP assays were 1.0 and 0.4 fmol/tube, and the within- and between-assay coefficients of variation were less than 10% and less than 15%, respectively. The 50% displacements of the standard curve occurred at 10 and 3 fmol/tube in the ANP and CNP assays, respectively. The ANP antiserum cross-reacts 100% with pro-ANP, but does not recognize NT-ANP, BNP, or CNP (cross-reactivity, <0.01%). The CNP antiserum does not cross-react with NT-ANP, ANP, or BNP (cross-reactivity, <0.01%).

Materials
Synthetic peptides were purchased from Peninsula Laboratories (St. Helens, UK). HS-142–1 was generously supplied by Dr. Yuzuru Matsuda from Kyowa Hakko Kogyo Co. (Tokyo Research Laboratories, Tokyo, Japan). For iv injections, ANP, CNP, and HS-142–1 were dissolved in 0.9% NaCl solution. Heparin was purchased from Leiras (Turku, Finland). Other chemicals were obtained from Sigma Chemical Co. (St. Louis, MO).

Statistical analysis
The results are expressed as the mean ± SEM. The data were analyzed by one- or two-way ANOVA. For the comparison of statistical significance between two groups, Student’s t test for paired and unpaired data was used. For multiple comparisons, one-way ANOVA followed by Bonferroni’s t test were used. The relationship between changes in plasma IR-ANP and IR-NT-ANP levels and hemodynamic variables was determined using linear regression analysis. Differences at the 95% level were considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Effects of ANP and CNP on hemodynamics and baseline plasma NT-ANP concentrations in normotensive rats
We first studied the effects of ANP and CNP infusions on basal hemodynamics and NT-ANP release in normotensive SD rats (protocol 1, Fig. 1Go). The basal mean arterial pressure, as measured directly in conscious chronically cannulated SD rats, was 117 ± 1 mm Hg, the heart rate was 390 ± 6 beats/min, and the right atrial pressure was 0.4 ± 0.1 mm Hg (n = 40). Intravenous administration of ANP in a dose of 1.0 µg/kg·min decreased mean arterial pressure by 14% (from 123 ± 2 to 106 ± 3 mm Hg; P < 0.001; Fig. 2Go and Table 1Go). Even though ANP in a dose of 1.0 µg/kg·min caused a significant decrease in mean arterial pressure, no reflex tachycardia was seen, and actually, there was a tendency for a decrease in heart rate, although this change was not statistically significant (Table 1Go). Further, ANP in a dose of 1.0 µg/kg·min decreased right atrial pressure from 0.1 ± 0.2 to -0.4 ± 0.2 mm Hg (P < 0.05). CNP did not have a statistically significant effect on mean arterial pressure or right atrial pressure (Table 1Go and Fig. 2Go), whereas heart rate was slightly higher (4–7%) at the end of CNP infusions than that in the vehicle group.



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  		Figure 2. Bar graphs showing the percent change in mean arterial pressure (MAP) during infusion of ANP at concentrations of 0.3 and 1.0 µg/kg·min and CNP at concentrations of 0.3 and 1.0 µg/kg·min in conscious SD rats. Mean arterial pressure after 25-min ANP or CNP infusion was compared to the corresponding value before the beginning of infusion ({Delta} MAP). For other details, see Fig. 1Go. *, P < 0.05; ***, P < 0.001 (vs. vehicle-treated group, by Student’s t test for unpaired data).

 

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  		Table 1. Effects of ANP and CNP infusions on basal hemodynamics and plasma IR-NT-ANP concentrations in conscious rats

 
The baseline plasma concentration of IR-NT-ANP in SD rats was 1.00 ± 0.06 nmol/liter (n = 40). Plasma IR-NT-ANP levels had a tendency to decrease in all experimental groups during the 25-min infusion period (Table 1Go), but neither ANP nor CNP infusion had any significant effect on the plasma IR-NT-ANP concentration. ANP infusion at a concentration of 0.3 µg/kg·min increased the plasma IR-ANP concentration 5-fold (from 54 ± 7 to 289 ± 29 pmol/liter; n = 8) and at a concentration of 1.0 µg/kg·min increased plasma IR-ANP 34-fold (from 43 ± 4 to 1469 ± 89 pmol/liter; n = 8). The maximal increase in plasma IR-ANP levels in response to exogenous ANP infusion at a concentration of 0.3 µg/kg·min was comparable to that produced by acute volume expansion with saline in WKY and SHR strains (see below). CNP infusion at a concentration of 0.3 µg/kg·min increased the plasma IR-CNP concentration from undetectable (<4 pmol/liter) to 234 ± 27 pmol/liter (n = 8); at a concentration of 1.0 µg/kg·min, it increased plasma IR-CNP to 945 ± 260 pmol/liter (n = 8).

Effects of ANP and CNP on the volume expansion-stimulated increase in NT-ANP release in normotensive rats
Next, we studied the effects of ANP and CNP infusions on volume load-induced NT-ANP release in conscious normotensive SD rats (protocol 1, Fig. 1Go). Acute volume expansion with 0.9% saline increased right atrial pressure by 4.2 ± 0.1 mm Hg (P < 0.001) and slightly decreased heart rate (-31 ± 5 beats/min; P < 0.05) in the vehicle-treated group. In the CNP-infused animals, hemodynamic changes in response to volume load similar to those seen in the control group were observed, whereas in the ANP-infused rats, mean arterial pressure and heart rate increased (Table 2Go), probably because the infusion of ANP was finished just before volume loading. In conscious animals with indwelling catheters, volume expansion interposed 30 min after vehicle infusion resulted in a 1.6-fold increase in the plasma IR-NT-ANP concentration (from 0.70 ± 0.08 to 1.09 ± 0.11 nmol/liter; P < 0.05; Fig. 3Go). In contrast, IR-NT-ANP levels did not increase in response to volume expansion after ANP infusion (0.3 µg/kg·min, 0.96 ± 0.11 vs. 0.80 ± 0.08 nmol/liter; 1.0 µg/kg·min, 0.96 ± 0.14 vs. 0.69 ± 0.09 nmol/liter). Both of these responses were significantly different from those in the vehicle-treated animals (P < 0.001). Volume load caused a small, but not significant, increase in plasma IR-NT-ANP in the presence of 0.3 µg/kg·min CNP (from 0.55 ± 0.07 to 0.78 ± 0.12 pmol/liter; F = 1.99; P = NS, CNP vs. vehicle). After pretreatment with 1.0 µg/kg·min CNP, volume load resulted in a 1.6-fold increase (from 0.54 ± 0.04 to 0.85 ± 0.09 pmol/liter; P < 0.01) in the plasma IR-NT-ANP concentration similar to that observed in the control group (F = 0.55; P = NS, CNP vs. vehicle; Fig. 3Go).


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  		Table 2. Effects of volume load and ANP and CNP infusions on hemodynamic variables in conscious rats

 


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  		Figure 3. Bar graphs showing the effects of ANP and CNP on volume expansion-induced changes in plasma IR-NT-ANP concentrations in conscious SD rats. Open bars, Plasma IR-NT-ANP concentrations before volume load (B25); hatched bars, 1 min after volume load (B32); solid bars, 5 min after volume load (B36). For details, see Fig. 1Go. Results are expressed as the mean ± SEM. *, P < 0.05; **, P < 0.01 (vs. before volume expansion, by one-way ANOVA followed by Bonferroni’s t test).

 
To further analyze the effects of ANP and CNP infusions on the plasma IR-NT-ANP concentration, the increase in plasma IR-NT-ANP levels (absolute values, nanomoles per liter) in response to volume load was correlated with changes in right atrial pressure (i.e. the degree of atrial stretch; Fig. 4Go). The major stimulus in the regulation of ANP release is known to be myocyte stretch (3), and in vivo, the increase in plasma ANP and NT-ANP concentrations in response to acute volume load correlates closely with the increase in right atrial pressure. Thus, it is important to normalize all changes in plasma NT-ANP to changes in right atrial pressure, i.e. to analyze increases at an identical degree of right atrial pressure. The maximal increase in plasma IR-NT-ANP levels was noted 5 min after volume load; therefore, this value was used to plot the data as a function of change in right atrial pressure. In the vehicle-infused SD rats, the increase in plasma IR-NT-ANP concentrations in response to acute volume expansion corresponding to a 3-mm Hg increase in right atrial pressure was 0.28 nmol/liter. ANP infusion abolished this response to volume load in both doses, whereas CNP did not statistically significantly modulate the NT-ANP response (Fig. 4Go).



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  		Figure 4. The change in plasma IR-NT-ANP concentrations and right atrial pressure (RAP) in response to volume load in conscious SD rats. {Delta} NT-ANP, Change in plasma NT-ANP concentration (nanomoles per liter) in response to volume load (B36 plasma NT-ANP concentration 5 min after volume load vs. B25 before volume load). ANP: Solid circle, vehicle (n = 8); solid triangle, 0.3 µg/kg·min (n = 8); solid square, 1.0 µg/kg·min (n = 8). CNP: Solid circle, vehicle (n = 8); solid triangle, 0.3 µg/kg·min (n = 8); solid square, 1.0 µg/kg·min (n = 8). ***, P < 0.001 vs. vehicle-treated group (by Student’s t test for unpaired data).

 
Effects of HS-142–1 on hemodynamics and baseline plasma NT-ANP and ANP concentrations in normotensive and hypertensive rats
As administration of ANP inhibited volume expansion-stimulated atrial peptide release from the heart, we hypothesized that ANP receptor antagonists could have the opposite effect. Therefore, we examined the effects of HS-142–1, a nonpeptide ANPA and ANPB receptor antagonist, on hemodynamics and atrial peptide release in SHR and WKY rats (protocol 2, Fig. 1Go). The basal mean arterial pressure, which was measured directly in conscious, chronically cannulated rats, was significantly higher in SHR than in WKY rats [183 ± 3 mm Hg (n = 22) vs. 137 ± 2 mm Hg (n = 16); P < 0.001]. The heart rate of WKY rats was 354 ± 10 beats/min, and the right atrial pressure was 0.3 ± 0.1 mm Hg (n = 16); these values in the SHR strain were 371 ± 8 beats/min and 0.4 ± 0.2 mm Hg (n = 22), respectively. In SHR rats, a bolus injection of HS-142–1 in a dose of 1 mg/kg decreased mean arterial pressure by 3% (from 179 ± 6 to 174 ± 7; P < 0.05); in a dose of 3 mg/kg, it decreased mean arterial pressure by 7% (from 193 ± 2 to 180 ± 2; P < 0.001), whereas heart rate and right atrial pressure remained unchanged (Table 3Go). HS-142–1 (3 mg/kg) did not have any significant effect on hemodynamic variables in the WKY rats (Table 3Go).


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  		Table 3. Effects of HS-142-1 on basal hemodynamics in conscious WKY and SHR rats

 
The resting plasma IR-ANP concentration was 1.9-fold higher in SHR rats compared with that in WKY rats (131 ± 10 vs. 71 ± 7 pmol/liter; n = 16; P < 0.01), which agrees with our previous findings in 1-yr-old SHR (34). The plasma IR-NT-ANP concentration in SHR rats (1.20 ± 0.08 nmol/liter) was not statistically significantly different from that in WKY rats (1.09 ± 0.15 nmol/liter). Bolus administration of HS-142–1 (3 mg/kg) in WKY rats increased the plasma IR-ANP concentration by 46 ± 8 pmol/liter (from 74 ± 13 to 120 ± 18 pmol/liter; P < 0.001; Fig. 5Go, upper left panel), whereas no statistically significant change in the plasma IR-NT-ANP concentration was seen compared to values in the vehicle-infused group (Fig. 5Go, lower left panel). In the SHR strain, HS-142–1 increased basal plasma IR-ANP and IR-NT-ANP concentrations dose dependently (Fig. 5Go, right panel). HS-142–1 in a dose of 1 mg/kg increased the plasma IR-ANP concentration by 26 ± 9 pmol/liter (P < 0.01), and in a dose of 3 mg/kg, it increased plasma IR-ANP by 40 ± 12 pmol/liter (P < 0.01; Fig. 5Go, upper left panel). The corresponding changes in IR-NT-ANP in the SHR strain in response to bolus administration of HS-142–1 in doses of 1 and 3 mg/kg were 0.17 ± 0.06 nmol/liter (P < 0.01) and 0.40 ± 0.14 nmol/liter (P < 0.01), respectively.



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  		Figure 5. Bar graphs showing the effects of HS-142–1 on basal plasma IR-ANP and IR-NT-ANP concentrations in conscious normotensive WKY and SHR rats. {Delta} ANP, Change in plasma ANP concentration (picomoles per liter; B-5 plasma ANP concentration before HS-142–1 administration vs. B10 after HS-142–1 administration); {Delta} NT-ANP, change in plasma NT-ANP concentration (nanomoles per liter; B-5: plasma NT-ANP concentration before HS-142–1 administration vs. B10: after HS-142–1 administration). Results are expressed as the mean ± SEM. **, P < 0.01; ***, P < 0.001 (vs. vehicle-treated group; by Student’s t test for unpaired data).

 
In agreement with the finding that blood pressure decreased after HS-142–1 administration, a significant correlation was found in the SHR strain between the increase in plasma IR-NT-ANP levels and the decrease in mean arterial pressure in response to HS-142–1 (r = -0.47; P = 0.03). On the other hand, the correlation between the increase in plasma IR-ANP concentrations and the decrease in mean arterial pressure in response to HS-142–1 in SHR was not significant (r = -0.34; P = 0.12). As blood pressure remained unchanged after HS-142–1 administration in WKY rats (Table 3Go), no correlations between changes in plasma IR-ANP and IR-NT-ANP concentrations and mean arterial pressure were found.

Effects of HS-142–1 on the volume expansion-stimulated increase in plasma NT-ANP and ANP release in normotensive and hypertensive rats
Finally, we studied the effects of HS-142–1 on volume load-induced atrial peptide release in normotensive and hypertensive rats (protocol 2, Fig. 1Go). In WKY rats, acute volume expansion with 0.9% saline increased right atrial pressure by 3.9 ± 0.1 mm Hg (P < 0.001). In response to acute volume expansion, mean arterial pressure also increased significantly, whereas heart rate remained unchanged (Table 4Go). After a bolus injection of HS-142–1 (3 mg/kg) in WKY rats, there were changes in hemodynamic variables similar to those in the control group (Table 4Go). Volume expansion interposed 30 min after the vehicle infusion caused a 2.9-fold increase in plasma IR-ANP in the WKY rats (from 71 ± 9 to 202 ± 22 pmol/liter; P < 0.001; Fig. 6Go, left panel), whereas it increased 3.4-fold in response to volume load after the injection of 3 mg/kg HS-142–1 (from 120 ± 18 to 404 ± 41 pmol/liter). The IR-ANP response to volume expansion was significantly augmented compared to that in the vehicle-treated WKY rats (F = 7.8; P < 0.01). Accordingly, volume load resulted in a 1.6-fold increase in the plasma IR-NT-ANP concentrations in the vehicle-infused WKY rats (from 1.13 ± 0.16 to 1.85 ± 0.12 nmol/liter; P < 0.01) and a 1.8-fold increase in HS-142–1-treated WKY rats (from 1.41 ± 0.15 to 2.85 ± 0.21 nmol/liter; Fig. 6Go, left panel). Also, this NT-ANP response to volume expansion was significantly greater in the HS-142–1-infused WKY rats than in the vehicle-infused WKY rats (F = 5.3; P < 0.05). To further analyze the effects of HS-142–1 on plasma IR-ANP and IR-NT-ANP concentrations, the increases in plasma IR-ANP and IR-NT-ANP levels (absolute changes) in response to volume load were correlated with changes in right atrial pressure (i.e. the degree of atrial stretch; Fig. 7Go). For the plasma IR-ANP concentration, a 1-min value was selected to plot the data as a function of change in right atrial pressure, because the maximal response in plasma ANP was seen in the blood sample taken 1 min after acute volume expansion. The maximal increase in plasma NT-ANP levels was noted 5 min after volume load; therefore, this value was used to plot the data as a function of change in right atrial pressure. Volume expansion in WKY rats pretreated with HS-142–1 resulted in significantly greater increases in plasma IR-ANP (238 vs. 102 pmol/liter) and IR-NT-ANP (1.2 vs. 0.6 nmol/liter) levels than in vehicle-infused animals (Fig. 7Go).


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  		Table 4. Effect of volume load and HS-142-1 on hemodynamic variables in conscious WKY and SHR rats

 


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  		Figure 6. Bar graphs showing the effects of HS-142–1 on volume expansion-induced changes in plasma IR-ANP and IR-NT-ANP concentrations in conscious normotensive WKY and SHR rats. Open bars, Plasma IR-ANP and IR-NT-ANP concentrations before volume load (B10); hatched bars, 1 min after volume load (B17); solid bars, 5 min after volume load (B21). For details, see Fig. 1Go. Results are expressed as the mean ± SEM. *, P < 0.05; **, P < 0.01; ***, P < 0.001 (vs. before volume expansion; by one-way ANOVA, followed by the Bonferroni’s ttest).

 


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  		Figure 7. The relation between the change in plasma IR-ANP and IR-NT-ANP concentrations and right atrial pressure (RAP) in response to volume load and HS-142–1 treatment in conscious normotensive WKY and SHR rats. {Delta} ANP, Change in plasma ANP concentration (picomoles per liter) in response to volume load (B17, plasma ANP concentration 1 min after volume load vs. B10, before volume load); {Delta} NT-ANP, change in plasma NT-ANP concentration (nanomoles per liter) in response to volume load (B21, plasma NT-ANP concentration 5 min after volume load vs. B10, before volume load). WKY: Solid circle, vehicle (n = 8); solid square, 3 mg/kg (n = 8). SHR: Solid circle, vehicle (n = 8); solid triangle, 1 mg/kg (n = 8); solid square, 3 mg/kg (n = 8). *, P < 0.05; **, P < 0.01 (vs. vehicle-treated group; by Student’s t test for unpaired data).

 
In the SHR strain, acute volume expansion with 0.9% saline increased right atrial pressure by 3.4 ± 0.2 mm Hg (P < 0.001). After the infusion of HS-142–1 in doses of 1 and 3 mg/kg, a similar change in right atrial pressure in response to volume load was observed (Table 4Go). Acute volume expansion in the vehicle-infused group increased mean arterial pressure, whereas heart rate did not change significantly. After the infusion of HS-142–1 in a dose of 1 mg/kg, significant increases in mean arterial pressure and heart rate were noted (Table 4Go). Volume expansion interposed 30 min after the vehicle infusion resulted in a 2.4-fold increase in plasma IR-ANP in the vehicle-infused SHR (from 132 ± 15 to 322 ± 22 nmol/liter; P < 0.001; Fig. 6Go, right panel). After pretreatment with 1 and 3 mg/kg HS-142–1, the plasma IR-ANP concentration increased in response to volume load 2.4-fold (from 148 ± 18 to 353 ± 50 nmol/liter; P < 0.001) and 2.1-fold (from 170 ± 16 to 364 ± 36 nmol/liter; P < 0.001), respectively. These responses did not differ significantly from that seen in the vehicle-infused SHR. Furthermore, when the relation of changes in plasma IR-ANP levels and right atrial pressure in SHR was calculated, the increases in the plasma IR-ANP concentration corresponding a 3-mm Hg increase in right atrial pressure were similar in vehicle (157 pmol/liter), 1 mg/kg HS-142–1-treated (175 pmol/liter), and 3 mg/kg HS 142–1-treated (171 pmol/liter) groups (Fig. 7Go). Furthermore, HS-142–1 in doses of 1 and 3 mg/kg did not significantly augment the IR-NT-ANP response to volume load (Fig. 6Go, right panel). The increases in plasma IR-NT-ANP concentration corresponding to a 3-mm Hg increase in right atrial pressure were 0.2, 0.1, and 0.6 nmol/liter (P < 0.05) in vehicle-, 1 mg/kg HS-142–1-, and 3 mg/kg HS 142–1-infused SHR (Fig. 7Go). Thus, HS-142–1 at a dose of 3 mg/kg resulted in a smaller increase in the plasma IR-NT-ANP concentration in SHR rats (0.6 nmol/liter) than in WKY rats (1.2 pmol/liter).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Previous studies suggest that elevated plasma ANP levels participate in the regulation of its own secretion by decreasing wall stretch through actions in the target tissues. Yet, natriuretic peptide receptors are present in the heart (24, 25), suggesting that natriuretic peptides may have direct effects on cardiac function. In the present study we found, firstly, that ANP infusion markedly inhibited the plasma IR-NT-ANP response to acute volume expansion in conscious normotensive rats, whereas CNP infusion had no significant effect on this response, showing that ANPA receptors directly modulate ANP release in vivo. Secondly, HS-142–1, an antagonist of guanylate cyclase-linked receptors, increased both baseline and volume expansion-stimulated increases in plasma ANP concentrations in conscious normotensive rats. This shows that a normal physiological concentration of ANP inhibits its own release from the heart, which can be revealed by blockade of ANPA and ANPB receptors. Thirdly, although HS-142–1 enhanced plasma ANP and NT-ANP responses to volume expansion in normotensive WKY rats, no augmentation in response to HS-142–1 was observed in the SHR strain, suggesting an altered regulation of ANP release during acute volume loading in experimental hypertension.

In vivo, ANP infusion has been shown to cause hypotension consistently in humans and experimental animals, including both anesthetized (38) and conscious (39) rats, whereas there are contradictory findings concerning the hypotensive effects of CNP. CNP infusion at concentrations of 10 and 100 ng/kg·min decreases mean arterial pressure in anesthetized dogs (40, 41), and in these studies CNP caused a greater decrease in blood pressure than did ANP at similar concentrations (41). In anesthetized rats, a bolus injection of CNP-22 or CNP-53 at a concentration of 100 nmol/kg (~220 µg/kg) decreased blood pressure by 10%, whereas a comparable hypotensive effect with ANP was seen at a concentration of 1 nmol/kg (~2 µg/kg) (42, 43). On the other hand, infusion of CNP at a concentration of 10 pmol/kg·min (~20 ng/kg·min) had no significant hemodynamic effect in men (44). Similarly, in conscious sheep, CNP-22 in doses of 1 and 10 pmol/kg·min (~2 and 20 ng/kg·min) had no hypotensive effect despite a significant natriuretic response (45). In our study, ANP infusion in conscious normotensive rats caused a decrease in mean arterial pressure, as previously described. In contrast, CNP infusion at equal concentrations (0.3 and 1 µg/kg·min) had no significant effect on blood pressure, even though plasma immunoreactive CNP and ANP concentrations during infusions were approximately similar. Thus, our findings suggest that in conscious rats, the hypotensive effect of ANP is clearly greater than that of CNP, which agrees with previous studies of anesthetized rats (42, 43).

Volume load has been shown to increase plasma ANP concentrations in vivo (18), and it is known that wall stretch and not pressure per se is a direct stimulator of ANP release (18, 19, 20). However, it is not known whether ANP release is due to direct effects on atrial myocytes or to the liberation of autocrine/paracrine factors, which could then influence hormone release from atrial secretory granules. We have previously shown that nitric oxide (46) and endothelin (47) are involved in the regulation of volume load-induced ANP release in vivo. In the present study, we tested the hypothesis that ANP present in the heart or ANP released into the circulation may also act as a regulator of its own release by stimulating cardiac natriuretic peptide receptors. ANP infusion did not have any significant effect on baseline plasma IR-NT-ANP concentrations, but it completely blocked acute volume expansion-stimulated NT-ANP release (Fig. 4Go). Therefore, ANP seems to inhibit its own release in response to cardiac overload. This inhibitory effect was not seen after CNP infusion. This, in turn, suggests that ANPA receptors, but not ANPB receptors, mediate the negative feedback regulation of ANP release.

To further characterize the physiological role of ANP in the regulation of its own release, we used HS-142–1, a selective inhibitor of guanylyl cyclase-coupled ANPA and ANPB receptors (29, 30, 31). HS-142–1 is a polysaccharide isolated from the culture broth of Aureobasidium sp. (29). In bovine adrenal cortex membranes, HS-142–1 inhibited the binding of [125I]ANP to ANPA and ANPB receptors without affecting ANPC receptors and also inhibited the activation of particulate guanylyl cyclase (29). In vitro, HS-142–1 has been shown to inhibit the relaxation of isolated rabbit aorta and cGMP accumulation in response to natriuretic peptides (30). In anesthetized rats, HS-142–1 in doses of 0.3 and 1.0 mg/kg caused a significant and dose-dependent inhibition of the increase in urine flow and urinary excretion of sodium produced by iv administered ANP and BNP, but did not have any effect on furosemide-induced renal responses (31). The reduction of blood pressure induced by ANP was also partially, but not completely, reversed by HS-142–1 at doses similar to those used in this study (31). A major finding of this study was that HS-142–1 increased both baseline and volume expansion-stimulated increases in plasma ANP concentrations in conscious normotensive rats. This shows that normal physiological concentrations of ANP inhibit its own release from the heart, which can be revealed by blockade of ANPA and ANPB receptors.

Finally, we compared the effects of receptor antagonist on baseline and acute volume load-induced increases in atrial peptide secretion in SHR and WKY rats. As reported previously, baseline plasma ANP concentrations in SHR rats were higher than those in age-matched WKY rats (48, 49, 50). Administration of HS-142–1 increased plasma natriuretic peptide levels under basal conditions similarly in both normotensive and hypertensive animals. However, no augmentation of the ANP response to acute volume expansion was observed in the SHR strain after HS-142–1 pretreatment, whereas it significantly enhanced both plasma ANP and NT-ANP responses to volume expansion in normotensive WKY rats. This suggests that in hypertensive animals, the modulation of ANP release is changed, for example by altered natriuretic receptor number or postreceptor events. Indeed, the general pattern observed in hypertensive animals is a decrease in ANP binding to receptors in most organs (for review, see Ref.9). However, it has been also reported that progressive cardiac hypertrophy is accompanied by increased mRNA levels for ANPA and ANPB receptors, whereas mRNA levels for ANPC receptors are gradually decreased (25). Another possible mechanism for the difference between SHR and WKY rats in the response of ANP to volume load after treatment with HS-142–1 may be diminished atrial ANP stores in hypertensive rats. There are, however, contradictory results about the effects of hypertension on the atrial ANP content. Some studies have reported reduced atrial ANP concentrations in SHR rats (48, 49, 51), whereas others have found no significant difference between SHR and WKY rats (50, 52). In the SHR strain used in the present study, atrial ANP concentrations are decreased by 35% with increasing age compared to those in normotensive WKY rats (53). Thus, the reduction in atrial ANP stores may contribute to the altered regulation of ANP release in this experimental model of hypertension.

An unexpected finding in our study was that iv administration of HS-142–1 decreased basal mean arterial pressure dose dependently in hypertensive rats. This may be due to increased plasma ANP concentrations caused by HS-142–1 in the SHR strain. As HS-142–1 selectively blocks guanylate cyclase-linked ANP receptors, the hypotensive effect of ANP could, in turn, be mediated by guanylyl cyclase-independent mechanisms. Indeed, ANP can enhance or suppress phospholipase C activity, activate sodium-hydrogen exchange, facilitate sodium-potassium-chloride cotransport and calcium efflux by both sodium-calcium exchange and calcium extrusion via a calcium pump, inhibit adenylyl cyclase activity, and promote the sequestration of intracellular calcium (9). In addition, ANPC receptor has been thought to be involved in the modulation of adenylyl cyclase activity via a G protein (15, 16) and to alter phosphoinositide concentrations (17). Therefore, HS-142–1, by blocking ANPA and ANPB receptors, could enhance the possible hypotensive actions of ANP mediated by ANPC receptors. As the hypotensive effect of HS-142–1 was only seen in hypertensive rats, not in normotensive age-matched control animals, vasodilatory mechanisms activated by HS-142–1 appear to be facilitated in this experimental model of hypertension. This is in accordance with previous studies showing that the cardiovascular responses to ANP are enhanced in SHR (54). Taken together, our observation of the hypotensive effect of HS-142–1 in SHR rats could be explained by guanylyl cyclase-independent vasodilatory mechanisms produced by the HS-142–1-induced increase in plasma ANP.

In conclusion, endocrine systems are commonly activated by a stimulus or stimuli to release a hormone that acts on a distal target to elicit responses. These responses induce negative feedback, diminishing the stimulus and thereby additional hormone release. The actions of ANP, mediated mainly by ANPA receptors, on vasculature, kidneys, adrenals, and other organs serve both acutely and chronically to reduce systemic blood pressure as well as intravascular volume, thereby reducing local wall stretch, the predominant stimulus for ANP release from the atria. Our present results showed that ANP also directly modulates its own release by ANPA receptors in vivo, whereas CNP, whose effects are mainly mediated by ANPB receptors, did not inhibit atrial peptide release. Another novel finding of the present study was that HS-142–1, a nonpeptide ANPA and ANPB receptor antagonist, increased baseline and volume expansion stimulated plasma ANP and NT-ANP concentrations in normotensive conscious rats. Finally, the difference in the effects of HS-142–1 on plasma ANP and NT-ANP responses to volume load between SHR and WKY rats suggest that regulation of atrial peptide release during increased cardiac overload is altered in experimental hypertension.


   Acknowledgments
 
We thank Ms. Tuula Lumijärvi and Mrs. Sirpa Rutanen for expert technical assistance.


   Footnotes
 
1 This work was supported by the Medical Research Council of the Academy of Finland, the Sigrid Juselius Foundation, the Emil Aaltonen Foundation, and the Finnish Cultural Society. Back

2 Present address: Cardiovascular Surgical Clinic, Semmelweis University Medical School, Budapest, Hungary. Back

Received October 15, 1996.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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