Engineered Mutation of Human B-Type Natriuretic Peptide To Preserve Renal Perfusion Pressure

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Background: Human atrial natriuretic peptide (hANP) and B-type NP (hBNP) exert natriuretic, diuretic, cardiac-unloading, and renin-inhibiting actions via NP receptor (NPR)-A and the second messenger cGMP. Increasing data demonstrate that ANP and BNP confer cardiorenal protection during ischemia-reperfusion and in perioperative settings especially if given at doses which limit hypotension. Previous studies have underscored the role of the C-terminus of BNP in NPR-A activation and vasodilation and the importance of the N-terminus of BNP as a target for enzymatic degradation. We hypothesized that a designer peptide which retains the ring of hBNP together with N- and C-termini of hANP would activate cGMP, possess an improved profile in preserving renal perfusion pressure (RPP), be natriuetic, diuretic, cardiac unloading and suppress the renin-angiotensin (RA) system. Methods: This novel peptide, named BAA-NP, was synthesized (MW 3158.60, SLRRSSCFGRKMDRISSSSGLGCNSFRY). BAA-NP (n=6) or hBNP (n=7) 14 pmol/kg/min was infused i.v. into normal anesthetized dogs. Clearances were performed at pre-infusion (pre-I) and during I. Data are reported for 30 and 60min I vs pre-I (P<0.05*, <0.01^†, <0.001^‡). Results: BAA-NP increased plasma cGMP (11.2±1.5 to 45.4±2.6^† to 44.6±3.9^† pmol/mL), urinary cGMP excretion (1123±308 to 6379±627^† to 8425±1046^† pmol/min), and net renal generation of cGMP (716±232 to 4175±633* to 6160±1148^† pmol/min). BAA-NP increased urine flow (0.17±.06 to 1.5 ± .3^† to 1.9 ± .2^†mL/min), urinary Na⁺ excretion (8±4 to 214±44^† to 303±33^†μEq/min) and renal blood flow (205±35 to 253±37^† to 286±34^†mL/min). PCWP (5 ± .7 to 2 ± .7^† to 1 ± .6^† mmHg) and RAP (3 ± .7 to 2 ± .4 to 1±.4^† mmHg) were reduced with minimal hypotension (117±7 to 113±7* 112±6^† mmHg). Plasma renin activity (13±3 to 3±1^† to 2 ± .3^† ng/mL/hr) and angiotensin II (12±2 to 4±1^† to 3 ± .1^†pg/mL) were suppressed. Compared to hBNP, BAA-NP possessed similar natriuretic, cardiac-unloading, and RA-suppressing properties but preserved RPP (mmHg) (116±7 pre-I to 111±7 at 60-min I) in contrast to hBNP (122±5 to 106±5^‡). Conclusion: The novel designer NP, BAA-NP, activates cGMP and exerts natriuretic, diuretic, cardiac-unloading, and RA-inhibiting actions in vivo, which are similar to hBNP. The unique modifications of hBNP with the C- and N-termini of hANP at doses used has an enhanced RPP-preserving property vs hBNP which may be an advance in BNP structure and function.