This Article Abstract Full Text (PDF) All Versions of this Article: 148/7/3518    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dickey, D. M. Articles by Potter, L. R. Search for Related Content PubMed PubMed Citation Articles by Dickey, D. M. Articles by Potter, L. R.

Differential Regulation of Membrane Guanylyl Cyclases in Congestive Heart Failure: Natriuretic Peptide Receptor (NPR)-B, Not NPR-A, Is the Predominant Natriuretic Peptide Receptor in the Failing Heart

Departments of Biochemistry, Molecular Biology, and Biophysics (D.M.D., P.M.B., L.R.P.), Pharmacology (D.R.F., L.R.P.), and Medicine (X.X., Y.C.), Cardiology Division, University of Minnesota, Minneapolis, Minnesota 55455

Address all correspondence and requests for reprints to: Lincoln R. Potter, University of Minnesota, Department of Biochemistry, Molecular Biology, and Biophysics, 6-155 Jackson Hall, 321 Church Street Southeast, Minneapolis, Minnesota 55455. E-mail: potter{at}umn.edu.

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) bind natriuretic peptide receptor (NPR)-A and decrease blood pressure and cardiac hypertrophy by elevating cGMP concentrations. Physiological responses to ANP and BNP are diminished in congestive heart failure (CHF) by an unknown mechanism. C-type natriuretic peptide (CNP) binding to NPR-B decreases cardiac hypertrophy, but the effect of CHF on NPR-B is unknown. Here, we measured ANP/NPR-A-dependent and CNP/NPR-B-dependent guanylyl cyclase activities in membranes from failing and nonfailing hearts. Transaortic banding of mice resulted in marked CHF as indicated by increased heart/body weight ratios, increased left ventricular diameters, and decreased ejection fractions. In nonfailed hearts, saturating ANP concentrations increased particulate guanylyl cyclase activity almost 10-fold, whereas saturating CNP concentrations increased activity 6.9-fold, or to about 70% of the ANP response. In contrast, in failed heart preparations, CNP elicited twice as much activity as ANP due to dramatic reductions in NPR-A activity without changes in NPR-B activity. For the first time, these data indicate that NPR-B activity represents a significant and previously unappreciated portion of the natriuretic peptide-dependent guanylyl cyclase activity in the normal heart and that NPR-B accounts for the majority of the natriuretic peptide-dependent activity in the failed heart. Based on these findings, we suggest that drugs that target both NPRs may be more beneficial than drugs like nesiritide (Natrecor) that target NPR-A alone.

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

 
THREE GENETICALLY DISTINCT but highly similar natriuretic peptides exist in mammals: atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) (1). ANP and BNP elicit their effects by binding and activating the cell surface guanylyl cyclase natriuretic peptide receptor (NPR)-A, whereas CNP activates the homologous B-type NPR (NPR-B) (1, 2, 3). All three natriuretic peptides also bind the natriuretic peptide clearance receptor, which chiefly controls the local concentrations of these peptides through receptor-mediated internalization and degradation (4, 5). ANP and BNP are primarily released from the atria and ventricles of the heart, respectively, in response to cardiomyocyte stretch. The accepted production sites for CNP are endothelium, brain, and bone, but a role for CNP in the heart has been bolstered by studies showing increased CNP levels in patients with chronic heart failure in a manner that positively correlates with mean pulmonary capillary wedge pressure and degree of failure (6, 7).

Natriuretic peptides are endogenous diuretic and vasorelaxation factors. In healthy individuals, circulating ANP and BNP levels are low, but they rise dramatically in response to cardiovascular stress. In fact, recent studies indicate that increased BNP concentrations are a hallmark indicator of several cardiovascular diseases, including congestive heart failure (8, 9). In normal patients, elevated ANP and BNP levels activate NPR-A, which decreases blood pressure by stimulating natriuresis, diuresis, and vasorelaxation and generally antagonizing the renin-angiotensin-aldosterone system. In contrast, the renal and renin effects of ANP are attenuated in animal models and patients with congestive heart failure despite marked serum ANP and BNP concentrations (10, 11, 12, 13). Several possible explanations exist for the blunted natriuretic peptide response, including increased local natriuretic peptide degradation (14, 15), reduced bioactivity of ANP and BNP (16), increased degradation of cGMP (17, 18), and decreased NPR-A guanylyl cyclase activity (10, 19).

Mice lacking ANP (20) or NPR-A (21, 22) are hypertensive and display pressure-dependent and -independent cardiac hypertrophy (23, 24, 25). Mice lacking functional NPR-A display greater cardiac hypertrophy in response to pressure overload than wild-type animals (23), whereas the opposite is true for animals overexpressing a constitutively active form of NPR-A in the heart (26). In contrast, mice lacking CNP or NPR-B are normotensive but have a decreased life span due to defective bone growth (27). To overcome the complications of reduced lifespan, Langenickel et al. (28) used a transgenic dominant-negative approach to inhibit NPR-B but not NPR-A. They found that the transgenic rats displayed reduced NPR-B guanylyl cyclase activity, progressive blood pressure-independent cardiac hypertrophy, and increased heart rate. The transgenic animals also displayed marked hypertrophy in response to pressure overload, which is consistent with previous data showing that CNP inhibits cardiomyocyte hypertrophy in culture (29). Thus, recent data suggests that NPR-B may play a more important role in the regulation of cardiac hypertrophy than previously appreciated.

For the first time, we measured ANP/NPR-A-dependent and CNP/NPR-B-dependent guanylyl cyclase activities in the ventricle. We found that CNP-dependent activity is only slightly less than the ANP-dependent activity in the normal heart. However, in the failed heart, ANP-dependent activity is markedly reduced, whereas CNP-dependent activity is unchanged. Surprisingly, in the failed heart, CNP-dependent activity is twice as high as ANP-dependent activity. These data suggest that drugs designed to activate NPR-B alone or in combination with NPR-A may provide more effective cardiac therapy for congestive heart failure than the FDA-approved drug nesiritide, which activates only NPR-A.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results Discussion References

 
Reagents
Rat natriuretic peptides (ANP and CNP) were purchased from Sigma-Aldrich (St. Louis, MO). The cGMP RIA kit was purchased from Perkin-Elmer (Boston, MA).

All animal protocols were approved by the University of Minnesota Animal Care Committee.

Aortic banding of mice
Male C57 black mice were anesthetized with a mixture of 80 mg/kg ketamine and 30 mg/kg xylazine ip. The neck and upper chest were shaved, and a horizontal incision was made at the level of the suprasternal notch to allow direct visualization of the transverse aorta without entering the pleural space. Aortic constriction was performed by ligating the aorta between the right innominate artery and the left carotid arteries over a 26-gauge needle using 5-0 silk sutures and a dissecting microscope. The needle was then removed leaving the constriction in place, and the skin was closed. For control mice, sham surgeries were performed without constricting the aorta.

Echocardiographic measurement
Echocardiography was performed in mice anesthetized with 1.5% isoflurane by inhalation. Left ventricular (LV) wall thickness, LV end-diastolic dimension (LVEDD), LV end-systolic dimension (LVESD), LV end-systolic wall thickness, and end-diastolic wall thickness were measured using two-dimensional echocardiography. LV ejection fraction (LVEF) was calculated by the cubic method: LVEF = [(LVEDD)³ – (LVESD)³]/(LVEDD)³ x 100%. LV fractional shortening (FS) was calculated as: FS = (LVEDD – LVESD)/LVEDD x100%.

Collection of mouse tissues
The mice were euthanized with a mixture of 80 mg/kg ketamine and 30 mg/kg xylazine ip. Hearts were removed, trimmed of most of the atria, cleaned in sterile saline, weighed, and placed in ice-cold phosphatase inhibitor buffer (30).

Preparation of membranes
Cardiac samples were homogenized in phosphatase inhibitor buffer containing 25 mM HEPES (pH 7.4), 50 mM NaCl, 20% glycerol, 50 mM NaF, 2 mM EDTA, 0.5 µM microcystin, and 1.3x Roche Complete protease inhibitors. The samples were then centrifuged at 10,000 x g for 10 min at 4 C. The supernatant was removed, and the pellet was washed three times in phosphatase inhibitor buffer by resuspension and centrifugation. After the final wash, the samples were resuspended in 1 ml phosphatase inhibitor buffer, and total protein concentrations were determined by the Bradford method. The protein concentrations of the membranes were normalized to 3.5 mg/ml and then used for cyclase determinations without freezing.

Measurement of guanylyl cyclase activity
Membrane fractions containing approximately 80 µg protein were assayed for guanylyl cyclase activity by addition of GTP/Mg²⁺ alone (for basal determination) or with GTP/Mg²⁺ plus 50 nM ANP, 1 µM ANP, 50 nM CNP, or 100 nM or 1 µM CNP. The receptor was stimulated by addition of 60 µl of cocktail containing 25 mM HEPES (pH 7.4), 50 mM NaCl, 0.1% BSA, 500 µM isobutylmethylxanthine, 1 mM GTP, 5 mM MgCl₂, 5 mM creatine phosphate, and 0.1 mg/ml creatine kinase. Membranes were assayed for 3 min. The reactions were stopped with 400 µl ice-cold 50 mM sodium acetate solution containing 5 mM EDTA. One fifth of the reaction was then removed and assayed for cGMP concentrations by RIA according to the manufacturer’s instructions as previously described (31).

Statistical analysis
GraphPad Prism software for the MacIntosh was used for the statistical analysis of the data. Unpaired t tests were conducted to determine the P values of the mean differences between sham (nonfailed) and banded (failed) mouse samples. Data are represented as mean ± SEM.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
Induction of congestive heart failure in mice
Transverse aortic constriction surgery was performed to induce heart failure in mice in two independent trials. The first trial was small and included five sham and five banded mice. The second trial was much larger and included 18 sham and 20 banded animals. The banded and sham animals were evaluated 8 wk after surgery in both trials. Echocardiography of anesthetized animals was performed to determine the degree of heart failure. All 10 of the animals in the first trial were analyzed. However, only eight controls and 10 banded animals were analyzed in the second trial. The parameters from both trials are summarized in Table 1. The banded animals displayed increased LV anterior and posterior wall thicknesses, 50% reductions in mean ejection fractions, and a 62% reduction in LV shortening compared with sham-operated animals. Similarly, the systolic aortic pressure, mean aortic pressure, and LV systolic pressure were measured in four control and six banded mice. The banding resulted in significantly increased systolic aortic pressure (94.8 ± 3.9 vs. 160 ± 17 mm Hg, P < 0.05), mean aortic pressure (82.4 ± 5.0 vs. 110 ± 10.5 mm Hg, P < 0.05), and LV systolic pressure (98.3 ± 3.7 vs. 163 ± 16 mm Hg, P < 0.05). Hence, the banded animals in both trials had clearly progressed to overt heart failure as a result of the increased pressure induced by transverse aortic constriction.

Cardiac NPR-A activity is reduced in heart-failed mice
To determine the responsiveness of NPR-A to hormonal stimulation, we measured the guanylyl cyclase activities of heart membranes derived from sham or banded mice in the presence of 0 (basal), 50 nM, or 1 µM ANP. Fifty nanomolar ANP was chosen as the representative low dose of ANP; previous preliminary experiments had determined that using doses lower than 50 nM did not yield reproducible changes in cGMP production compared with basal levels. One micromolar ANP was used to represent saturating concentrations as our previous experience indicates that this dose elicits maximal hormone-stimulated activity. In the first trial, conversion of GTP into cGMP under basal conditions (no ANP) was not different in cardiac membranes obtained from the two groups (2.58 pmol/mg/min for sham vs. 2.59 pmol/mg/min for banded) (Fig. 1A). However, cyclase activity in response to ANP was significantly reduced in the banded compared with the sham animals. ANP concentrations of 50 nM and 1 µM increased cyclase activity by 3.6- and 6.3-fold, respectively, in membranes from the sham animals. In contrast, the lower concentrations of ANP had no significant effect on cGMP production in membranes from banded animals, whereas the higher concentrations increased activity only 1.8-fold. The reduction in activity was statistically significant when analyzed using unpaired t tests with P values of 0.01 and 0.015 at 50 nM and 1 µM ANP concentrations, respectively.

View larger version (20K): [in this window] [in a new window]   FIG. 1. Changes in ANP- and CNP-dependent guanylyl cyclase activities in failed mouse hearts. Crude membranes were prepared from fresh heart ventricles from sham or banded animals. The membranes were assayed for guanylyl cyclase activity under basal conditions (no natriuretic peptide) or with the indicated concentrations of ANP or CNP. The 1 µM dose represents the maximal hormone-stimulated response. A, Results of the first trial; B, results of the second larger trial. **, Statistical significance from nonfailed samples where P 0.01; ***, statistical significance from nonfailed samples where P 0.0001.

NPR-B, not NPR-A, is the most active NPR in the failed heart
Because NPR-B was recently shown to inhibit cardiac hypertrophy in rats (28), we investigated the contribution of NPR-B to the natriuretic peptide-dependent guanylyl cyclase response in hearts from the sham and banded mice. We found that 100 nM and 1 µM concentrations of CNP increased guanylyl cyclase activities 2.6 and 4.7-fold in membranes from sham animals, and the maximal concentration of CNP elevated cGMP levels to 74% of the levels elicited by the maximal ANP concentration (Fig. 1A). However, in contrast to the ANP scenario, the CNP-dependent responses were not decreased in preparations from heart-failed animals. In fact, the CNP-dependent responses were increased to 2.9- and 5.7-fold, respectively, in membranes from the banded hearts, although the differences were not statistically significant. Importantly, the fact that the CNP responses are increased or unchanged when the ANP responses are decreased clearly indicates that the CNP-dependent activity is not due to cross-activation of NPR-A.

When we repeated this experiment with more animals, we observed similar CNP-dependent increases in particulate guanylyl cyclase activities at the two different concentrations in cardiac membranes from sham animals (Fig. 1B). Maximum CNP-dependent activity accounted for 67% of maximum ANP response. Again, guanylyl cyclase activities measured under identical conditions in membranes from the banded animals were slightly, but not significantly, increased (P = 0.13 for 50 nM and 0.34 for 1 µM CNP). Maximal CNP-dependent activity was about twice that of maximal ANP-dependent activity in the failed heart. Hence, although NPR-A and NPR-B account for similar amounts of natriuretic peptide-dependent particulate guanylyl cyclase activity in the normal mouse heart, NPR-B, not NPR-A, accounts for the majority of natriuretic peptide-dependent activity in the failed mouse heart.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
Increased ANP and BNP levels are hallmark indicators of heart failure (8, 9). Despite these elevations, the body’s response to these peptides is diminished in heart failure (11). Here, we show that NPR-A activity is reduced, whereas NPR-B activity is increased or unchanged in the failed heart. Significantly, NPR-B accounts for almost as much natriuretic peptide-dependent guanylyl cyclase activity as NPR-A in normal hearts and about twice as much activity as NPR-A in failed hearts.

NPR-A guanylyl cyclase activity is elicited by binding ANP or BNP, whereas NPR-B is activated by CNP (1, 2, 3); however, at high peptide concentrations, cross-reactivity does occur (32, 33). Whether ANP and BNP cross-activate NPR-B in the heart is unknown but remains an intriguing possibility. In our results, only a small increase in activity is seen in membranes from banded animals when maximal vs. low doses of ANP are included in the cyclase assay. Unfortunately, because there are no specific antagonists to these receptors, whether some of the ANP-dependent activity is due to cross-activation of NPR-B cannot be determined.

There are a number of reasons why this work is particularly timely and why the role of the cardiac CNP/NPR-B system should be considered more seriously than it has in the past. First, CNP is increased in the human heart in a manner that correlates with increased pulmonary wedge pressures and degree of failure (6, 7). Second, inhibition of NPR-B in the rat results in cardiac hypertrophy that is exacerbated by congestive heart failure (28). Third, CNP prevents cardiac remodeling after myocardial infarction in rats (34). Finally, our work indicates that NPR-B accounts for about 70% of the activity attributable to NPR-A in the nonfailing heart and, more importantly, that NPR-B is responsible for the majority of particulate guanylyl cyclase activity in the failing heart. Together, these independent observations suggest that NPR-B is playing a very important role in regulating cardiac hypertrophy and remodeling. The implications of these combined findings are that NPR-B may be an equally important drug target for the treatment of heart failure as is NPR-A, the receptor for the FDA-approved drug nesiritide.

Changes in natriuretic peptide activity in the heart were previously reported in a monocrotaline model for right ventricular hypertrophy (35). Using membranes prepared from endocardial cells of the right ventricle, Kim and colleagues (35) found that the cyclase activities of both NPR-A and NPR-B were reduced in membranes from the monocrotaline-treated animals. Interestingly, they found that NPR-B-dependent guanylyl cyclase activity was greater than NPR-A-dependent guanylyl cyclase activity in membranes from the sham animals. It will be interesting to determine whether the differences in NPR-B activity in heart failure reported by our group and Kim’s are due to the experimental models (monocrotaline vs. banding), heart regions (right ventricular vs. total ventricle), or the membranes assayed (from endocardial cells in the right ventricle vs. all cell types in both ventricles).

Singh et al. (36) recently reported interesting data suggesting that NPR-A levels are decreased in heart failure. This conclusion was based on the binding of a radiolabeled snake venom ligand, Dendroaspis natriuretic peptide ([¹²⁵I]DNP), which binds to NPR-A but not NPR-B. However, the initial characterization of DNP indicated that DNP also binds to the natriuretic peptide clearance receptor (37). That DNP binding is not specific for NPR-A is also supported by the data of Singh and colleagues (36) because CNP was able to displace the majority of the [¹²⁵I]DNP binding to LV sections. If binding was specific for NPR-A, then CNP should have been a much less potent competitor than ANP and BNP, but it was not. Furthermore, it has been reported many times that the clearance receptor is the most abundant natriuretic peptide receptor in most tissues (4). Unfortunately, no guanylyl cyclase activity measurements were performed to verify that ANP-dependent activity was reduced in the failed hearts. Therefore, although the data support our findings, further investigation is required to determine the cause for the decrease in NPR-A activity in the failed heart. Specifically, experiments measuring changes in phosphorylation levels vs. total protein levels need to be conducted.

In conclusion, our study demonstrates for the first time that NPR-B is responsible for a significant and previously unappreciated amount of natriuretic peptide-dependent guanylyl cyclase activity in the nonfailed heart and the majority of activity in the failed heart. Thus, NPR-B represents an exciting new potential drug target for the treatment of congestive heart failure.

	Footnotes

 
This work was supported by National Institutes of Health Grants R01HL66397 to L.R.P., R01HL071790 to Y.C., and Training Grant 5T32-DK007203-28 to D.M.D.

Author Disclosure Statement: D.M.D., D.R.F., P.M.B., X.X., and Y.C. have nothing to declare. L.R.P. consulted for Scios and received lecture fees from Hospira, Inc.

First Published Online April 5, 2007

Abbreviations: ANP, Atrial natriuretic peptide; BNP, B-type natriuretic peptide; CNP, C-type natriuretic peptide; DNP, Dendroaspis natriuretic peptide; LV, left ventricular; LVEDD, LV end-diastolic dimension; LVESD, LV end-systolic dimension; NPR, natriuretic peptide receptor.

Received January 19, 2007.

Accepted for publication March 28, 2007.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 

1. Potter LR, Abbey-Hosch S, Dickey DM 2006 Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions. Endocr Rev 27:47–72[Abstract/Free Full Text]
2. Kuhn M 2003 Structure, regulation, and function of mammalian membrane guanylyl cyclase receptors, with a focus on guanylyl cyclase-A. Circ Res 93:700–709[Abstract/Free Full Text]
3. Garbers DL, Chrisman TD, Wiegn P, Katafuchi T, Albanesi JP, Bielinski V, Barylko B, Redfield MM, Burnett Jr JC 2006 Membrane guanylyl cyclase receptors: an update. Trends Endocrinol Metab 17:251–258[CrossRef][Medline]
4. Maack T 1992 Receptors of atrial natriuretic factor. Annu Rev Physiol 54:11–27[CrossRef][Medline]
5. Matsukawa N, Grzesik WJ, Takahashi N, Pandey KN, Pang S, Yamauchi M, Smithies O 1999 The natriuretic peptide clearance receptor locally modulates the physiological effects of the natriuretic peptide system. Proc Natl Acad Sci USA 96:7403–7408[Abstract/Free Full Text]
6. Del Ry S, Passino C, Maltinti M, Emdin M, Giannessi D 2005 C-type natriuretic peptide plasma levels increase in patients with chronic heart failure as a function of clinical severity. Eur J Heart Fail 7:1145–1148[CrossRef][Medline]
7. Kalra PR, Clague JR, Bolger AP, Anker SD, Poole-Wilson PA, Struthers AD, Coats AJ 2003 Myocardial production of C-type natriuretic peptide in chronic heart failure. Circulation 107:571–573[Abstract/Free Full Text]
8. Ruskoaho H 2003 Cardiac hormones as diagnostic tools in heart failure. Endocr Rev 24:341–356[Abstract/Free Full Text]
9. Gardner DG 2003 Natriuretic peptides: markers or modulators of cardiac hypertrophy? Trends Endocrinol Metab 14:411–416[CrossRef][Medline]
10. Tsutamoto T, Kanamori T, Morigami N, Sugimoto Y, Yamaoka O, Kinoshita M 1993 Possibility of downregulation of atrial natriuretic peptide receptor coupled to guanylate cyclase in peripheral vascular beds of patients with chronic severe heart failure. Circulation 87:70–75[Abstract/Free Full Text]
11. Cody RJ, Atlas SA, Laragh JH, Kubo SH, Covit AB, Ryman KS, Shaknovich A, Pondolfino K, Clark M, Camargo MJ, Scarborough RM, Lewicki JA 1986 Atrial natriuretic factor in normal subjects and heart failure patients. Plasma levels and renal, hormonal, and hemodynamic responses to peptide infusion. J Clin Invest 78:1362–1374[Medline]
12. Supaporn T, Sandberg SM, Borgeson DD, Heublein DM, Luchner A, Wei CM, Dousa TP, Burnett Jr JC 1996 Blunted cGMP response to agonists and enhanced glomerular cyclic 3',5'-nucleotide phosphodiesterase activities in experimental congestive heart failure. Kidney Int 50:1718–1725[Medline]
13. Garcia R, Bonhomme MC, Schiffrin EL 1992 Divergent regulation of atrial natriuretic factor receptors in high-output heart failure. Am J Physiol 263:H1790–H1797
14. Iervasi G, Clerico A, Berti S, Pilo A, Biagini A, Bianchi R, Donato L 1995 Altered tissue degradation and distribution of atrial natriuretic peptide in patients with idiopathic dilated cardiomyopathy and its relationship with clinical severity of the disease and sodium handling. Circulation 91:2018–2027[Abstract/Free Full Text]
15. Knecht M, Pagel I, Langenickel T, Philipp S, Scheuermann-Freestone M, Willnow T, Bruemmer D, Graf K, Dietz R, Willenbrock R 2002 Increased expression of renal neutral endopeptidase in severe heart failure. Life Sci 71:2701–2712[CrossRef][Medline]
16. Hawkridge AM, Heublein DM, Bergen 3rd HR, Cataliotti A, Burnett Jr JC, Muddiman DC 2005 Quantitative mass spectral evidence for the absence of circulating brain natriuretic peptide (BNP-32) in severe human heart failure. Proc Natl Acad Sci USA 102:17442–17447[Abstract/Free Full Text]
17. Margulies KB, Burnett Jr JC 1994 Inhibition of cyclic GMP phosphodiesterases augments renal responses to atrial natriuretic factor in congestive heart failure. J Card Fail 1:71–80[Medline]
18. Valentin JP, Qiu C, Muldowney WP, Ying WZ, Gardner DG, Humphreys MH 1992 Cellular basis for blunted volume expansion natriuresis in experimental nephrotic syndrome. J Clin Invest 90:1302–1312[Medline]
19. Tsutamoto T, Wada A, Maeda K, Hisanaga T, Maeda Y, Fukai D, Ohnishi M, Sugimoto Y, Kinoshita M 1997 Attenuation of compensation of endogenous cardiac natriuretic peptide system in chronic heart failure: prognostic role of plasma brain natriuretic peptide concentration in patients with chronic symptomatic left ventricular dysfunction. Circulation 96:509–516[Abstract/Free Full Text]
20. John SW, Krege JH, Oliver PM, Hagaman JR, Hodgin JB, Pang SC, Flynn TG, Smithies O 1995 Genetic decreases in atrial natriuretic peptide and salt-sensitive hypertension. Science [Erratum (1995) 267:1753] 267:679–681
21. Lopez MJ, Wong SK, Kishimoto I, Dubois S, Mach V, Friesen J, Garbers DL, Beuve A 1995 Salt-resistant hypertension in mice lacking the guanylyl cyclase-A receptor for atrial natriuretic peptide. Nature 378:65–68[CrossRef][Medline]
22. Oliver PM, Fox JE, Kim R, Rockman HA, Kim HS, Reddick RL, Pandey KN, Milgram SL, Smithies O, Maeda N 1997 Hypertension, cardiac hypertrophy, and sudden death in mice lacking natriuretic peptide receptor A. Proc Natl Acad Sci USA 94:14730–14735[Abstract/Free Full Text]
23. Knowles JW, Esposito G, Mao L, Hagaman JR, Fox JE, Smithies O, Rockman HA, Maeda N 2001 Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A-deficient mice. J Clin Invest 107:975–984[Medline]
24. Kishimoto I, Rossi K, Garbers DL 2001 A genetic model provides evidence that the receptor for atrial natriuretic peptide (guanylyl cyclase-A) inhibits cardiac ventricular myocyte hypertrophy. Proc Natl Acad Sci USA 98:2703–2706[Abstract/Free Full Text]
25. Holtwick R, Van Eickels M, Skryabin BV, Baba HA, Bubikat A, Begrow F, Schneider MD, Garbers DL, Kuhn M 2003 Pressure-independent cardiac hypertrophy in mice with cardiomyocyte-restricted inactivation of the atrial natriuretic peptide receptor guanylyl cyclase-A. J Clin Invest 111:1399–1407[CrossRef][Medline]
26. Zahabi A, Picard S, Fortin N, Reudelhuber TL, Deschepper CF 2003 Expression of constitutively active guanylate cyclase in cardiomyocytes inhibits the hypertrophic effects of isoproterenol and aortic constriction on mouse hearts. J Biol Chem 278:47694–47699[Abstract/Free Full Text]
27. Tamura N, Doolittle LK, Hammer RE, Shelton JM, Richardson JA, Garbers DL 2004 Critical roles of the guanylyl cyclase B receptor in endochondral ossification and development of female reproductive organs. Proc Natl Acad Sci USA 101:17300–17305[Abstract/Free Full Text]
28. Langenickel TH, Buttgereit J, Pagel-Langenickel I, Lindner M, Monti J, Beuerlein K, Al-Saadi N, Plehm R, Popova E, Tank J, Dietz R, Willenbrock R, Bader M 2006 Cardiac hypertrophy in transgenic rats expressing a dominant-negative mutant of the natriuretic peptide receptor B. Proc Natl Acad Sci USA 103:4735–4740[Abstract/Free Full Text]
29. Tokudome T, Horio T, Soeki T, Mori K, Kishimoto I, Suga SI, Yoshihara F, Kawano Y, Kohno M, Kangawa K 2004 Inhibitory effect of C-type natriuretic peptide (CNP) on cultured cardiac myocyte hypertrophy: interference between CNP and endothelin-1 signaling pathways. Endocrinology 145:2131–2140[Abstract/Free Full Text]
30. Bryan PM, Smirnov D, Smolenski A, Feil S, Feil R, Hofmann F, Lohmann S, Potter LR 2006 A sensitive method for determining the phosphorylation status of natriuretic peptide receptors: cGK-I does not regulate NPR-A. Biochemistry 45:1295–1303[CrossRef][Medline]
31. Bryan PM, Potter LR 2002 The atrial natriuretic peptide receptor (NPR-A/GC-A) is dephosphorylated by distinct microcystin-sensitive and magnesium-dependent protein phosphatases. J Biol Chem 277:16041–16047[Abstract/Free Full Text]
32. Koller KJ, Lowe DG, Bennett GL, Minamino N, Kangawa K, Matsuo H, Goeddel DV 1991 Selective activation of the B natriuretic peptide receptor by C-type natriuretic peptide (CNP). Science 252:120–123[Abstract/Free Full Text]
33. Suga S, Nakao K, Hosoda K, Mukoyama M, Ogawa Y, Shirakami G, Arai H, Saito Y, Kambayashi Y, Inouye K, Imura H 1992 Receptor selectivity of natriuretic peptide family, atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide. Endocrinology 130:229–239[Abstract]
34. Soeki T, Kishimoto I, Okumura H, Tokudome T, Horio T, Mori K, Kangawa K 2005 C-type natriuretic peptide, a novel antifibrotic and antihypertrophic agent, prevents cardiac remodeling after myocardial infarction. J Am Coll Cardiol 45:608–616[Abstract/Free Full Text]
35. Kim SZ, Cho KW, Kim SH 1999 Modulation of endocardial natriuretic peptide receptors in right ventricular hypertrophy. Am J Physiol 277:H2280–H2289
36. Singh G, Kuc RE, Maguire JJ, Fidock M, Davenport AP 2006 Novel snake venom ligand dendroaspis natriuretic peptide is selective for natriuretic peptide receptor-A in human heart: downregulation of natriuretic peptide receptor-A in heart failure. Circ Res 99:183–190[Abstract/Free Full Text]
37. Schweitz H, Vigne P, Moinier D, Frelin C, Lazdunski M 1992 A new member of the natriuretic peptide family is present in the venom of the green mamba (Dendroaspis angusticeps). J Biol Chem 267:13928–13932[Abstract/Free Full Text]

This article has been cited by other articles:

				O. Lisy, B. K. Huntley, D. J. McCormick, P. A. Kurlansky, and J. C. Burnett Jr Design, Synthesis, and Actions of a Novel Chimeric Natriuretic Peptide: CD-NP. J. Am. Coll. Cardiol., July 1, 2008; 52(1): 60 - 68. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 148/7/3518    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dickey, D. M. Articles by Potter, L. R. Search for Related Content PubMed PubMed Citation Articles by Dickey, D. M. Articles by Potter, L. R.