Subcutaneous administration of the cardiac hormone BNP in symptomatic human heart failure

Background: Brain natriuretic peptide (BNP) is a cardiac hormone with vasodilating, natriuretic, renin-angiotensin-aldosterone-inhibiting and lusitropic properties. We have demonstrated that acute subcutaneous (SQ) administration of BNP in experimental congestive heart failure results in elevation of plasma BNP and its second messenger 3',5'-cyclic guanosine monophosphate (cGMP) with natriuresis and reduction in cardiac filling pressures. Furthermore, chronic subcutaneous BNP in experimental congestive heart failure also resulted in increases in cardiac output and decreases in pulmonary capillary wedge pressure and systemic vascular resistance. Methods: The objective of the current study was to assess the safety and efficacy of repeated doses of subcutaneous human BNP, nesiritide, a recombinant form of human BNP (Scios Inc, Fremont, CA) in human subjects with New York Heart Association class II-III congestive heart failure. We defined the cardiorenal and Immoral responses to subcutaneous BNP (nesiritide) administered every 12 hours with a total of 5 doses over 72 hours in a single-blind placebo-controlled design (n = 8). The mean dose of nesiritide was 10 mug/kg every 12 hours. Results: Initial saline placebo resulted in no change in any measured parameters (P < .05 versus baseline). With the first dose of BNP (nesiritide), cardiac output increased (4.8 +/- 0.4 to 6.4 +/- 0.5 L/min) and systolic blood pressure decreased (125 +/- 5 to 104 +/- 3 mm Hg) without a change in heart rate. Plasma BNP (167 +/- 115 to 830 +/- 470 pg/mL), cGMP (4 +/- 2 to 14 +/- 4 pmol/mL), and urinary cGMP excretion (3900 +/- 930 to 10,600 +/- 5000 pmol/min) increased with natriuresis and diuresis. Both plasma renin activity and plasma aldosterone decreased. These favorable biologic responses were observed with the fifth dose 72 hours after the initial dose. All the subjects tolerated the study well without any adverse events except for 1 subject who had a vasovagal episode during micturition after receiving the fifth dose on day 3. Conclusion: We conclude that subcutaneous administration of BNP (nesiritide) represents a novel and efficacious therapeutic strategy in human congestive heart failure to deliver BNP, a cardiac hormone which possesses unique cardiorenal and neurohumoral properties.