PRECLINICAL RESEARCH: EDITORIAL COMMENT
From B-Type Natriuretic Peptide to Green MambasThe Process of Discovery*
Gary S. Francis, MD, FACC*
Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio.
* Reprint requests and correspondence: Dr. Gary S. Francis, Heart and Vascular Institute, Cleveland Clinic, Desk F15, 9500 Euclid Avenue, Cleveland, Ohio 44195. (Email: francig{at}ccf.org).
Key Words: B-type natriuretic peptide • C-type natriuretic peptide • Dendraspis natriuretic peptide • heart failure
The study by Lisy et al. (1) in this issue of the Journal reports on the design, synthesis, and properties of a new chimeric natriuretic peptide (1). The work represents an ongoing interest by the Mayo Clinic Burnett Laboratory in the development of therapy that will increase natriuresis and diuresis without attendant hypotension. B-type natriuretic peptide (BNP) is a counter-regulatory endogenous neurohormone that is synthesized by the heart and released in response to increased myocardial wall stress in conditions such as heart failure. However, the amount of BNP released, though often substantial, can be of insufficient quantity to offset the excessive vasoconstrictor and sodium-water retentive state characteristic of advanced heart failure. This is, in part, because only a small amount of BNP is actually stored in the heart (relative to atrial natriuretic peptide), and its release is in large measure regulated by myocardial BNP synthesis rather than by storage capacity. To synthesize new BNP is presumably a more time-consuming process than release of BNP from storage vesicles.
With this problem in mind, synthetic exogenous BNP (nesiritide) was developed by Scios (Mountain View, California) using a recombinant deoxyribonucleic acid technique to produce essentially pure BNP. Although initial sales of nesiritide were robust, clinicians eventually recognized that nesiritide often had only a modest effect on natriuresis, diuresis, and renal function in patients with acute decompensated heart failure (2). Some problems with nesiritide arose (3), but have now been more or less laid to rest by the safety record of the FUSION-2 (Follow-Up Serial Infusion of Nesiritide in Advanced Heart Failure) study. The large ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) mortality trial has now been launched. Some loss of confidence in nesiritide has occurred despite very careful and tightly controlled studies by the Burnett Laboratory. The Mayo Clinic investigations had consisted primarily of inducement of experimental heart failure by rapid pacing in animals and subsequent demonstration of significant diuretic and natriuretic effects of nesiritide in this model. One might ask, how did this disparity occur?
Looking back on our experience, the strategy of giving a fixed bolus of nesiritide followed by an infusion was probably not a prudent strategy. Very often patients receiving nesiritide had been aggressively pre-treated with intravenous loop diuretics. They may have been in a state of intense vasoconstriction due to activation of the neurohumoral systems (4), might have had marginal blood pressure after intravenous loop diuretics, and in some cases were likely made more hypotensive by a bolus and infusion of nesiritide. Perhaps a more rational strategy would have been to temporarily stop the diuretics, forego the bolus of nesiritide, and give only one-half the recommended maintenance infusion dose slowly over several days so as to not further lower blood pressure to signal the kidney to retain salt and water. Loop diuretics could be added back as needed. Giving a smaller maintenance dose of nesiritide (0.005 µg/kg/min) over a longer period of time without additional large boluses of intravenous loop diuretics might lead to better outcomes with nesiritide use (5), but we simply do not have the data. Renal blood flow probably has to be well maintained for any natriuretic peptide to work properly.
That being said, the Burnett group has now developed an entirely new strategy. They have designed, synthesized, and studied a novel chimeric natriuretic peptide. It is a hybrid molecule that includes the C-terminus tail of exogenous Dendraspis natriuretic peptide (DNP) and the 22-amino acid endogenous peptide C-type natriuretic peptide (CNP) to create CD-NP. The new chimeric molecule includes the whole CNP molecule, a vasodilator peptide with essentially no renal actions, and the natriuretic and diuretic properties of the C-terminus of DNP. The ring structure of DNP is not included for good reasons, as it causes marked hypotension, and essentially serves as a lethal defense mechanism for the green mamba snake (Denarbaspis angusticeps). The long C-terminus of the DNP peptide probably allows for less degradation by endopeptidases per unit time, thus prolonging the action of CD-NP. When injected into normal anesthetized dogs, CD-NP increased urinary sodium excretion, urine flow, and glomerular filtration rate despite a slight decrease in mean arterial pressure during infusion of the high dose. Renal blood flow was not measured. CD-NP also suppressed cell proliferation in cultured human fibroblasts using cardiotropin-1 stimulation, an antiremodeling effect previously observed with atrial natriuretic peptide (6).
The authors should be congratulated for engineering a novel chimeric protein that has real therapeutic possibilities. The protein chemistry was probably not easy. Further studies will, of course, be necessary, and should include measures of renal blood flow and renal function in animals with heart failure, where the proclivity to retain salt and water may possibly offset the natriuretic and diuretic responses to CD-NP. Understanding how to dose the new molecule will be critical, as in retrospect, an imprudent front-loaded dosing schedule for nesiritide may have hampered our understanding of how to best use this exogenous natriuretic peptide.
Beyond the elegant biochemistry involved in the development of CD-NP, the authors are to be also congratulated for their pure reasoning powers in the design of this novel chimeric molecule. Linking molecular structure to function requires imagination and creativity, two of the most important hallmarks of good science. Clinicians are at times too quick to latch on to a "new drug" without thinking or caring about what part of the molecule is responsible for a specific activity. Perhaps just seeing that long C-terminus tail of DNP was enough to awaken the Mayo Clinic investigators to interesting new possibilities about how to create a better natriuretic peptide molecule. This work represents a classic example of how to take advantage of a prepared mind. To the noncognoscente, the DNP amino-acid sequence probably meant little beyond just another peptide sequence in snake venom from a different species. To the Burnett laboratory, the C-terminus perhaps immediately suggested a most interesting hypothesis to test. They then proceeded to develop a chimeric molecule that incorporated the best features of CNP and DNP. It represents an example whereby investigators can "move a field" through the powers of careful observation and reason. We look forward to additional studies with this interesting new chimeric molecule.
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Footnotes
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Dr. Francis received financial support from the NHLBI: SCCOR 1-P50-HL 077107-01 and SCCOR 1-P50-HL 081011-01. Dr. Francis has served on advisory boards for Scios and Biosite.
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Lisy O, Huntley BK, McCormick DJ, Kurlansky PA, Burnett Jr JC. Design, synthesis, and actions of a novel chimeric natriuretic peptide: CD-NP J Am Coll Cardiol 2008;52:60-68.[Abstract/Free Full Text]2. Witteles RM, Kao D, Christopherson D, et al. Impact of nesiritide on renal function in patients with acute decompensated heart failure and pre-existing renal dysfunction J Am Coll Cardiol 2007;50:1835-1840.[Abstract/Free Full Text] 3. Hauptman PJ, Schnitzler MA, Swindle J, Burroughs TE. Use of nesiritide before and after publications suggesting drug-related risks in patients with acute decompensated heart failure JAMA 2006;296:1877-1884.[Abstract/Free Full Text] 4. Francis GS, Siegel R, Goldsmith SR, Olivari MT, Levine TB, Cohn JN. The acute vasoconstrictor response of intravenous furosemide in patients with chronic congestive heart failure Ann Intern Med 1985;103:1-6.[Abstract/Free Full Text] 5. Chen HH, Sundt TM, Cook DJ, Heublein DM, Burnett JC. Low dose nesiritide and the preservation of renal function in patients with renal dysfunction undergoing cardiopulmonary-bypass surgery. A double-blind placebo-controlled pilot study. Circulation 2007;116(Suppl I):I134-I138.[Web of Science][Medline] 6. Hayashi M, Tsutamoto T, Wada A, et al. Intravenous atrial natriuretic peptide prevents left ventricular remodeling in patients with first anterior acute myocardial infarction J Am Coll Cardiol 2001;37:1820-1826.[Abstract/Free Full Text]
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