Biological Actions of a Novel Oral Human BNP in an Experimental Model of Acute Hypertension

Abstract

We previously reported the feasibility and prolonged actions of an orally delivered novel conjugated form of human BNP in normal animals. The objective of the current study was to further define actions of a more advanced oral conjugated hBNP (CONJ-hBNP054) in an experimental model of hypertension (HTN). Methods: We investigated in a randomized crossover-designed study the effects of oral CONJ-hBNP054 or vehicle in 6 dogs that received concomitant continuous intravenous infusion of angiotensin II (ANG II; 20 μg/kg/min, 1 ml/min for over 4 hrs) to induce acute hypertension. At baseline (BL), mean blood pressure (MAP) and blood collection for plasma hBNP, cGMP, and ANG II determination was obtained followed by continuous ANG II infusion. After 30 min of ANG II administration, all dogs received oral CONJ-hBNP054 (400 μg/kg) or vehicle in a random crossover fashion (one week of interval). Blood sampling and MAP measurements were repeated 30 min after ANG II administration, and 10, 30, 60, 120, 180 and 240 min after oral administration of CONJ-hBNP054 or vehicle. ∗p<0.05 vs ANG II. Results: hBNP was not present in canine plasma at BL and was not detected at any time in the vehicle group. In contrast, hBNP was detected throughout the duration of the study after oral CONJ-hBNP054 with a peak concentration at 30 min of 1060 ± 327 pg/ml. After ANG II, plasma cGMP was not increased with vehicle, while it significantly increased with oral CONJ-hBNP054 (from 14.4 ± 1 with ANG II to 30.7 ± 4∗ at 10 min, 43.1 ± 7∗ at 30 min and 41.3 ± 6∗ pmol/mL at 60 min; p<0.0001 between two groups). In the presence of sustained acute ANG-induced hypertension, no changes occurred in MAP after vehicle administration. Importantly, oral CONJ-hBNP054 significantly reduced MAP (from 138 ± 1 with ANG II to 142 ± 2∗ at 30 min, 124 ± 2∗ at 60 min, and 130 ± 2∗ mmHg at 120 min; p<0.0001 between two groups). No differences between vehicle and CONJ-hBNP were observed in ANG II concentrations throughout the study protocol. Conclusions: This study reports for the first time that a novel conjugated oral hBNP activates cGMP and significantly reduces MAP in a model of acute hypertension. These findings advance an innovative concept of orally administered BNP therapy for cardiovascular diseases.