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Based on the cardiac hormone atrial natriuretic peptide (ANP) and its seminal role in blood pressure (BP) homeostasis, we investigated the chronic BP lowering actions of a novel ANP analog currently entering clinical trials for hypertension. Previous reports demonstrate that this analog MANP activates the guanylyl cyclase A receptor (GC-A) and results in more potent biological actions compared with ANP; thus, it may represent a new therapeutic drug for hypertension. A major goal of this study was to establish that chronic subcutaneous delivery of MANP is feasible and hypotensive together with cGMP effects. We investigated the BP-lowering and cGMP-activating actions of acute and chronic subcutaneous delivery in normal and hypertensive rats. Furthermore, we explored vascular mechanisms of MANP in human aortic smooth muscle cells (HASMC) and ex vivo in isolated arteries. In normal rats with a single subcutaneous injection, MANP promoted robust dose-dependent BP-lowering actions and natriuresis, together with cGMP activation. Most importantly in hypertensive rats, once-a-day subcutaneous injection of MANP for 7 days induced cGMP elevation and long-term BP reduction compared with vehicle. Mechanistically, in HASMC, MANP activated cGMP and attenuated angiotensin II-mediated increases in intracellular Ca2+ levels while directly vasorelaxing arterial rings. Our study demonstrates for the first time the effectiveness of subcutaneous administration of MANP for 7 days and provides innovative, vascular mechanisms of BP regulation supporting its continued development as a novel therapeutic for hypertension.

AimsThe effect of extravascular lung water (EVLW) and relationship to functional status as a result of acute decompensated heart failure (ADHF) are not well understood. We sought to quantify changes in clinical variables, EVLW, airway anatomy, spirometry, and diffusing capacity for carbon monoxide before and after treatment for ADHF.Methods and resultsFifteen patients were recruited within 24 h of hospital admission. Spirometry, diffusing capacity for carbon monoxide, and surrogates of EVLW by computed tomography were measured and were then repeated within 24 h of discharge. From the computed tomography (CT) scan, surrogates of EVLW were calculated from the distribution of CT attenuation of the lung tissue. Airways were segmented using the vida apollo software. Patients were hospitalized for 4.6 ± 2.1 days, had 10 ± 4.8 L of fluid removed (7.0 ± 4.2 L between study visits), and lost 7.1 ± 4.9 kg. Patients had significant clearance of fluid from the lungs (per cent change: mean, 4.2 ± 6.1%; skew, 17.5 ± 27.0%; kurtosis, 37.6 ± 56.7%; full‐width half‐maximum, 10.2 ± 13.5%). Static lung volumes and maximal flows improved significantly (per cent change: forced vital capacity, 14.5 ± 13.6%; forced expiratory volume in 1 s, 15.9 ± 14.0%; forced expiratory flow at 25–75% of forced vital capacity, 27.2 ± 42.9%). The ratio of membrane conductance to capillary blood volume improved significantly (per cent change: alveolar–capillary membrane conductance/capillary blood volume, 23.4 ± 22.8%). Weight loss during hospitalization was significantly correlated with improved spirometry and diffusing capacity.ConclusionsExtravascular lung water contributes to the pulmonary congestive syndrome in ADHF patients, and its clearance is an important component of the improvement in pulmonary function as a result of inpatient treatment.

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HeartMate II left ventricular assist device controllers provide data including pulsatility index, reflecting the relationship between pump function and hemodynamics. We propose that a higher pulsatility index at hospital discharge following implant may be associated with less vascular congestion and improved clinical outcomes. A retrospective analysis of 40 patients (age 59.2 ± 10.3 years) supported with the HeartMate II devices was conducted. Data revealed moderate Pearson correlations between pulsatility index at discharge and right atrial pressure, pulmonary artery systolic pressure, pulmonary artery diastolic pressure, mean pulmonary arterial pressure, and pulmonary capillary wedge pressure, respectively, post-surgery (median of 377 days), demonstrating a stronger relationship when analyzed for the EPC controller (n = 28) only (r = −.57, p < .01; r = −.38, p < .05; r = −.59, p < .01; r = −.47, p = .01 and r = −.53, p < .01, respectively). The pulsatility index derived from the EPC controller was associated with the significant risk of re-hospitalization within 1 and 2 years after the implantation of left ventricular assist device; hazard ratio = 0.557 with 95% confidence interval (0.315–0.983), p = .04 and hazard ratio = .579 (0.341–0.984), p = .04. A higher pulsatility index at discharge was associated with greater volume unloading, lower pulmonary pressures, and lower risk of all-cause re-hospitalizations within 1 and 2 years post-surgery. As such, pump-derived data may provide additional value in predicting left ventricular assist device hemodynamics.