Abstract P382: The Role of Atrial Natriuretic Peptide in Cardiac Damage During Salt Sensitive Hypertension

Abstract

Atrial natriuretic peptide (ANP), encoded by the Nppa gene, is an osmoregulatory hormone that promotes salt excretion. GWAS identified Nppa to be associated with hypertension; some studies suggest varying ANP levels as an indicator of salt-sensitivity. The aim of the current project was to assess the effects of ANP deficiency on cardiac damage and function using a knockout of Nppa in the Dahl Salt-Sensitive (SS) rat background (SS NPPA-/- ). A combination of in vivo techniques with ex vivo and biochemical methods were used to test the role of ANP in the development of SS hypertension in male and female rats. IHC analysis was employed to quantify tissue damage; echocardiography was used to test heart function. SS NPPA-/- rats demonstrated higher blood pressure compared to SS controls when fed a high salt (HS, 4% NaCl) diet: on day 21 of diet MAP was 185.8 ± 9 mmHg in SS NPPA-/- rats compared to 144.6 ± 4 mmHg in SS controls. Heart rate was found to be on average 40 bpm lower in SS NPPA-/- rats until day 8 of the HS challenge, when it rose up to the rate of wild type counterparts and continued to decline at the same pace. SS NPPA-/- rats showed exacerbated kidney damage, reduced diuresis and lower sodium excretion when fed a HS diet. SS NPPA-/- rats exhibited intensified cardiac damage compared to SS controls, as demonstrated by heart to body weight ratio after HS (3.9 ± 0.13 in wild type vs 5.5 ± 0.09 in KO rats), elevated cardiac fibrosis (up to 6% of fibrotic cardiac tissue area in SS NPPA-/- vs less than 3% in wild types), and a significantly increased cardiac vessel media thickness. Fibrosis and heart hypertrophy were attenuated in female rats. Echocardiography revealed that although SS NPPA-/- rats show heart remodeling, ejection fraction is preserved and they do not exhibit heart failure. Chronic i.v. infusion of ANP in SS rats (100 ng/kg/day) attenuated the HS-induced increase in blood pressure and renal damage, and resulted in less cardiac hypertrophy and fibrosis (1% fibrosis in ANP-infused animals vs 3% in vehicle-treated group). Therefore, ANP deficiency aggravates SS hypertension and cardiac damage; further work is needed to reveal if ANP deficiency causes heart failure of a HF/PEF phenotype, and what the interplay between heart and kidney is in this setting.