Therapeutic Insights for Heart Failure: In Vivo Comparison Between a Guanylyl Cyclase Receptor A and a Novel Guanylyl Cyclase Receptor B Activator

Abstract

The natriuretic peptide family consists of atrial and b-type natriuretic peptide (ANP, BNP) and C-type natriuretic peptide (CNP). ANP and BNP are mainly produced in the heart and possess potent blood pressure lowering as well as natriuretic and diuretic actions through guanylyl cyclase receptor A (GC-A) and cGMP activation. Meanwhile, CNP is an endothelium and renal derived hormone of which its mature biological active form, CNP22, has the most robust cardiorenal anti-remodeling properties via GC-B activation and generation of cGMP compared to GC-A. Recently we reported that heart failure (HF) patients have increased plasma and markedly elevated urinary levels of a larger CNP molecular form, CNP53, which also is biologically active and generates cGMP through the GC-B receptor. Notably, preliminary studies have demonstrated that CNP53 is more biologically active and has renal enhancing actions in vivo, compared to CNP22. However, it remains unclear if CNP53’s biological and renal actions differ from that of BNP in vivo. To define the cardiorenal and cGMP generating actions of CNP53, GC-B agonist, compared to BNP, a GC-A agonist, in vivo. We hypothesize that CNP53 has cardiorenal and cGMP actions in vivo, but will exhibit less hypotension than BNP. Vehicle (V), an equimolar dose of BNP or CNP53 (Phoenix Pharmaceuticals, CA) was infused intravenously into anesthetized normal rats. Mean arterial blood pressure (MAP), glomerular filtration rate (GFR) and urinary sodium (Na) excretion were assessed. Plasma and urinary cGMP was determined by radioimmunoassay. Data are presented as Mean±SE. *p<0.05 between all groups. During CNP53 and BNP infusion, plasma cGMP (V: 9±1, CNP53: 91±4, BNP: 190±37*, pmol/ml) and urinary cGMP excretion (V: 33±6, CNP53: 176±28, BNP: 509±124*, pmol/min) significantly increased compared to vehicle. Moreover, GFR (V: 4.8±0.3, CNP53: 5.7±0.2, BNP: 7.2±0.5*, ml/min/kg) and urinary Na excretion (V: 0.8±0.1, CNP53: 1.4±0.2, BNP: 2.4±0.1*,uEq/min) also significantly increased with CNP53 and BNP compared to vehicle. Notably, BNP had the greatest drop in MAP compared to vehicle and CNP53 (ΔMAP V: 2.0± 3.0, CNP53: -4.0±2.7, BNP: -11.3±3.8*, mmHg). We report CNP53 exerts favorable cardiorenal and cGMP actions without excessive hypotension as seen with BNP. These findings support an emerging concept that CNP53 may be an alternative therapeutic strategy for HF, especially in the setting of hypotension, and this warrants further investigation.