Abstract 1481: Renal Targeted Protein Therapeutics in Experimental Overt Heart Failure With Renal Dysfunction
BACKGROUND: C-type natriuretic peptide (CNP) is a 22-amino-acid peptide produced mainly in the endothelium and is a ligand for a guanylyl cyclase-coupled receptor, the NPR-B receptor. Recent studies have revealed that in overt heart failure (HF), the predominant natriuretic peptide (NP) receptor in the kidney is the NPR-B receptor. CNP has a potent cardiac unloading action with modest hypotensive actions but with minimal renal actions. Based on our previous knowledge, we mutated 3 amino acid (aa) sequence in the ring structure of CNP (GSM 15–17 to REA15–17) and fused a novel 5 aa sequence from ANP to the N-terminus together with the 6 aa C-terminus of BNP to the C-terminus of CNP. We hypothesized that this novel hybrid peptide ABC-NP would maintain CNP’s inherent cardiac unloading characteristics plus gaining renal enhancing properties without hypotension effects.
METHODS: We determined the cardiorenal and humoral actions of intravenous infusion of ABC-NP at 2 pmol/Kg/min, 10 pmol/Kg/min and 100 pmol/Kg /min in 7 dogs with rapid ventricular pacing induced overt HF with cardiorenal dysfunction (240 bpm for 10 days). * p<0.05
RESULTS: ABC-NP enhanced glomerular filtration rate (GFR), from 31±5 to 45±7, 51±6 and 60±7 ml/min*, induced natriuresis (from 3±2 to 12±8, 17±13 and 29±19 μEq/min*) and diuresis (from 0.13±0.03 to 0.4±0.1, 0.6±0.2 and 0.8±0.3 ml/min*) with a modest reduction in pulmonary capillary wedge pressure (PCWP) (from 21±1 to 19±1, 20±1 and 21±1 mmHg*). Importantly, mean arterial blood pressure was maintained. These actions were associated with suppression of plasma renin* and increases in urinary cGMP* and cAMP* excretion.
CONCLUSION: We report for the first time that this novel peptide ABC-NP has potent natriuretic and GFR enhancing actions without hypotensive properties in an experimental model of overt CHF. The increase of urinary cAMP excretion in addition to cGMP excretion suggests that this novel peptide may have biological effects beyond the known natriuretic peptide receptors which are linked to cGMP. This renal specific peptide may have potential therapeutic benefit in states of renal dysfunction with volume overload to enhance GFR and sodium excretion without the detrimental side effect of hypotension.