The Tumultuous Journey of Nesiritide

Abstract

Almost 3 decades ago, we witnessed the discovery of the natriuretic peptides and the role of the heart as an endocrine organ in which peptides of cardiovascular origin emerged as a humoral link between the heart and the kidney in cardiorenal homeostasis. In the United States, one such natriuretic peptide, B-type natriuretic peptide (BNP), was approved by the US Food and Drug Administration in 2001 as a drug (nesiritide) for the treatment of acute decompensated heart failure (ADHF). The rationale for the use of BNP as a cardiovascular therapy was in response to laboratory-based research and a series of clinical trials. What emerged was a theme that BNP was an endogenous ligand for the natriuretic peptide-A receptor that is linked to particulate guanylyl cyclase and the second messenger 3′,5′-cyclic guanosine monophosphate (cGMP).1 After receptor activation, the biological actions of BNP include vasodilatation, diuresis and natriuresis, positive lusitropism, inhibition of the renin-angiotensin-aldosterone system, suppression of the myocardial hypertrophy response to pressure overload, and attenuation of myocardial fibrosis. Article p 9 Although a hallmark of acute and chronic congestive heart failure (CHF) is an increased plasma level of BNP, there are functional derangements in the BNP/cGMP signaling pathway that provide additional rationale for the exogenous administration of BNP or nesiritide to treat CHF. The 2 most compelling abnormalities include increased production of less biologically active BNP forms and increased renal resistance to BNP in severe experimental CHF.2–5 Since the initial report in 1991 by Yoshimura et al6 and after several clinical trials over the past decade,7–10 the consensus has been that human recombinant BNP (nesiritide) in patients with ADHF improved cardiovascular hemodynamics and/or renal function in association with improved symptoms of HF. Moreover, some investigators reported that nesiritide therapy was safer than the use of positive inotropic drugs …