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  • 2018  (4)
  • Truebel, Hubert  (4)
  • 1
    In: Circulation, 2018, Vol.138(Suppl_1 Suppl 1), pp.A15975-A15975
    Description: Introduction: Hypertension (HtN) is one of the major cardiovascular risk factors. Studies have shown that therapy resistant hypertension (rHtN), i.e. elevated blood pressure despite the concurrent use of three antihypertensive agents of different classes including a diuretic is an emerging phenomenon. Preclinical and clinical data suggest that stimulators of the soluble guanylate cyclase (sGC) could be a therapeutic alternative for those patients poorly or not responding to antihypertensive standard of care (SoC).Hypothesis: The sGC stimulator BAY412272 might be a new therapeutic option for patients with rHtN by efficacious blood pressure lowering on top of SoC.Methods: A novel canine animal model of rHtN was established. Therefore 6 beagle dogs were treated with one-sided renal wrapping followed by renal artery occlusion. Innovative telemetry systems were implanted to cover relevant physiologic parameters, including blood pressure (BP) in conscious animals. Following HtN progression period, used standard antihypertensive medications and the sGC stimulator BAY412272 were administered orally and the acute effect on blood pressure was assessed.Results: Following both procedures the animals developed a phenotype of low renin HtN according to standard classification. Mean blood pressure (MBP) was increased from 93.1 +/- 3.6 mmHg from baseline to 123.4 +/- 10.0 mmHg in maximum. Serum creatinine increased from baseline 74.8 +/- 2.4 μmol/l to 148.8 +/-23.2 μmol/l in maximum. The standard medications showed varying results. The sGC stimulator BAY412272 administered as monotherapy as well as in combinational therapy restored HtN (- 12.4 +/- 5.0 mmHg), only amlodipine (-19.6 +/- 12.4 mmHg) showed a similar effect. BP effects were strictly dose dependent.Conclusions: We established a new low renin canine animal model for HtN, which also reflects important features of rHTN. This model will improve preclinical drug discovery & development especially for HtN not responding to SoC. Furthermore we demonstrated that sGC stimulation by BAY412272 is an efficacious antihypertensive approach when administered alone or in combination with SoC. Therefore, the sGC stimulator BAY412272 might represent an efficacious treatment alternative for rHtN patients.
    ISSN: 0009-7322
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  • 2
    Language: English
    In: European Journal of Applied Physiology, 2018, Vol.118(1), pp.195-203
    Description: Purpose Testing of investigational drugs in animal models is a critical step in drug development. Current models of pulmonary hypertension (PH) have limitations. The most relevant outcome parameters such as pulmonary artery pressure (PAP) are measured invasively which requires anesthesia of the animal. We developed a new canine PH model in which pulmonary vasodilators can be characterized in conscious dogs and lung selectivity can be assessed non-invasively. Methods Telemetry devices were implanted to measure relevant hemodynamic parameters in conscious dogs. A hypoxic chamber was constructed in which the animals were placed in a conscious state. By reducing the inspired oxygen fraction (FiO2) to 10%, a hypoxic pulmonary vasoconstriction was induced leading to PH. The PDE-5 inhibitor sildenafil, the current standard of care was compared to atrial natriuretic peptide (ANP). Results The new hypoxic chamber provided a stable hypoxic atmosphere during all experiments. The mean PAP under normoxic conditions was 15.8 ± 1.8 mmHg. Hypoxia caused a reliable increase in mean PAP (+ 12.2 ± 3.2 mmHg, p 〈 0.0001). Both, sildenafil (− 6.8 ± 4.4 mmHg) and ANP (− 6.4 ± 3.8 mmHg) significantly (p 〈 0.05) decreased PAP. Furthermore sildenafil and ANP showed similar effects on systemic hemodynamics. In subsequent studies, the in vitro effects and gene expression pattern of the two pathways were exemplified. Conclusions By combining the hypoxic environment with the telemetric approach, we could successfully establish a new acute PH model. Sildenafil and ANP demonstrated equal effects regarding pulmonary selectivity. This non-invasive model could help to rapidly screen pulmonary vasodilators with decreased animal burden.
    Keywords: Pulmonary hypertension ; Atrial natriuretic peptide ; Drug development ; Sildenafil ; Dog ; Animal model
    ISSN: 1439-6319
    E-ISSN: 1439-6327
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  • 3
    Language: English
    In: Journal of Pharmacological and Toxicological Methods, March 2018, Vol.90, pp.7-12
    Description: Quantitative assessment of renal function by measurement of glomerular filtration rate (GFR) is an important part of safety and efficacy evaluation in preclinical drug development. Existing methods are often time consuming, imprecise and associated with animal burden. Here we describe the comparison between GFR determinations with sinistrin (PS-GFR) and fluorescence-labelled sinistrin-application and its transcutaneous detection (TD-GFR) in a large animal model of chronic kidney disease (CKD). TD-GFR measurements compared to a standard method using i.v. sinistrin were performed in a canine model. Animals were treated with one-sided renal wrapping (RW) followed by renal artery occlusion (RO). Biomarker and remote hemodynamic measurements were performed. Plasma sinistrin in comparison to transcutaneous derived GFR data were determined during healthy conditions, after RW and RW + RO. RW alone did not led to any significant changes in renal function, neither with PS-GFR nor TD-GFR. Additional RO showed a rise in blood pressure (+ 68.0 mm Hg), plasma urea (+ 28.8 mmol/l), creatinine (+ 224,4 μmol/l) and symmetric dimethylarginine (SDMA™; + 12.6 μg/dl). Plasma sinistrin derived data confirmed the expected drop (− 44.7%, p 〈 0.0001) in GFR. The calculated transcutaneous determined Fluorescein Isothiocyanate (FITC)-sinistrin GFR showed no differences to plasma sinistrin GFR at all times. Both methods were equaly sensitive to diagnose renal dysfunction in the affected animals. Renal function assessment using TD-GFR is a valid method to improve preclinical drug discovery and development. Furthermore, TD-GFR method offers advantages in terms of reduced need for blood sampling and thus decreasing animal burden compared to standard procedures.
    Keywords: Animal Model ; Drug Development ; Glomerular Filtration Rate ; Kidney Disease ; Methods ; Pharmacy, Therapeutics, & Pharmacology ; Chemistry
    ISSN: 1056-8719
    E-ISSN: 1873-488X
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  • 4
    In: Circulation: Cardiovascular Interventions, 2018, Vol.11(5), pp.e006258-e006258
    Description: BACKGROUND—: Heart failure (HF) remains the most common reason for hospital admission in patients aged 〉65 years. Despite modern drug therapy, mortality and readmission rates for patients hospitalized with HF remain high. This necessitates further research to identify early patients at risk for readmission to limit hospitalization by timely adjustment of medical therapy. Implantable devices can monitor left ventricular (LV) hemodynamics and remotely and continuously detect the early signs of decompensation to trigger interventions and reduce the risk of hospitalization for HF. Here, we report the first preclinical study validating a new batteryless and easy to implant LV-microelectromechanical system to assess LV performance. METHODS AND RESULTS—: A miniaturized implantable wireless pressure sensor was adapted for implantation in the LV apex. The LV-microelectromechanical system sensor was tested in a canine model of HF. The wireless pressure sensor measurements were compared with invasive left heart catheter-derived measurements at several time points. During different pharmacological challenge studies with dobutamine or vasopressin, the device was equally sensitive compared with invasive standard procedures. No adverse events or any observable reaction related to the implantation and application of the device for a period of 35 days was observed. CONCLUSIONS—: Our miniaturized wireless pressure sensor placed in the LV (LV-microelectromechanical system) has the potential to become a new telemetric tool to earlier identify patients at risk for HF decompensation and to guide the treatment of patients with HF.
    Keywords: Heart Failure -- Care And Treatment ; Heart Failure -- Drug Therapy ; Heart Failure -- Risk Factors ; Elderly Patients -- Health Aspects ; Microelectromechanical Systems -- Usage ; Left Ventricular Function -- Analysis;
    ISSN: 1941-7640
    E-ISSN: 19417632
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