Intact acute cardiorenal and humoral responsiveness following chronic subcutaneous administration of the cardiac peptide BNP in experimental heart failure

Background: BNP is a cardiac peptide with vasodilating, lusitropic and natriuretic properties mediated by the second messenger cGMP. We have previously shown that chronic subcutaneous (SQ) administration of BNP in experimental CHF resulted in improved haemodynamics and unloading of the heart. However, it is unknown if this will lead to the development of tolerance to exogenous BNP. Methods: The current study extends our previous study and compares the cardiorenal effects of acute administration of SQ BNP (5 μg/kg) in a group of dogs (n = 5) with rapid ventricular pacing induced CHF (180 bpm for 10 days) to a separate group of CHF dogs (n = 6), who received chronic SQ BNP (5 μg/kg) three times a day for 10 days. Results: Acute administration of SQ BNP resulted in similar increases in both plasma cGMP (35 ± 5 vs. 29 ± 2 pmol/ml) and urinary cGMP excretion (UcGMPV) (6000 ± 1000 vs. 4000 ± 600 pmol/min) in both the Chronic SQ BNP treated and the Untreated CHF groups (P > 0.05). These were associated with decreased cardiac filling pressures and increased urine flow, which were also similar in both groups. Conclusion: In experimental CHF, chronic SQ BNP administration did not result in the development of tolerance as demonstrated by increases in both plasma cGMP and UcGMPV following acute administration of SQ BNP. This may have important clinical implications, suggesting that chronic BNP administration does not lead to the development of tolerance to acute BNP administration.