Congestive heart failure is a long-term condition when the heart cannot pump blood well enough to provide a normal supply to the body. This chronic illness can get worse quickly leading to Acute Decompensated Heart Failure (ADHF). In this life-threatening condition, patients show abrupt deterioration of hemodynamic stability, pulmonary edema and decline in renal function. Based on the evidence for congestion and low cardiac output, ADHF patients are classified as “Warm and wet”, “Cold and wet”, “Warm and dry”, and “Cold and dry” presentations. As expected, each sub-type of presentation needs specific treatment. The unmet need is for a menu of agents allowing controlled vasodilation without excess diuresis at one end of the spectrum and effective diuresis without excess lowering of blood pressure on the other. Here, I describe the design of two human ANP analogues that are suitable for the treatment of ADHF patients: DGD-ANP retains full renal activities and shows diuretic effects without vasodilatory effects, while DRD-ANP is entirely renal neutral and shows vasodilatory effects without diuresis. These ANP analogues show excellent efficacy in anesthetized rats and in conscious normal and heart failure sheep models. We have shown that one residue difference between these two analogues results in (a) two opposite ends of spectrum of pharmacology; (b) altered kinetics of cGMP production by NPR-A; (c) structural changes in the ligands; and (d) induces distinct conformational changes in the receptor NPR-A. Fine-tuning of cGMP production appears to be responsible for differential renal function of the ANP analogues.
1. Sridharan, S., Kini, R.M. Biochem. J. 475, 399-413, 2018.
2. Rademaker, M.T., Scott, N.J.A., Koh, C.Y., Kini, R.M., Richards, A.M. Cardiovasc. Res., 117, 508-519, 2021.
3. Sridharan, S., Kini, R.M., Richards, A.M. Pharmacol. Res. 155, 104687, 2020.
4. Ang, W.F., Koh, C.Y., Kini, R.M. Pharmaceuticals, 15, 1153, 2022.