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John C Burnett - One of the best experts on this subject based on the ideXlab platform.
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early activation of deleterious molecular pathways in the kidney in Experimental Heart Failure with atrial remodeling
2017Co-Authors: Tomoko Ichiki, Brenda K Huntley, Jeson S Sangaralingham, Gail J Harty, John C BurnettAbstract:Heart Failure (HF) is a major health problem with worsening outcomes when renal impairment is present. Therapeutics for early phase HF may be effective for cardiorenal protection, however the detailed characteristics of the kidney in early-stage HF (ES-HF), and therefore treatment for potential renal protection, are poorly defined. We sought to determine the gene and protein expression profiles of specific maladaptive pathways of ES-HF in the kidney and Heart. Experimental canine ES-HF, characterized by de-novo HF with atrial remodeling but not ventricular fibrosis, was induced by right ventricular pacing for 10 days. Kidney cortex (KC), medulla (KM), left ventricle (LV), and left atrial (LA) tissues from ES-HF versus normal canines (n = 4 of each) were analyzed using RT-PCR microarrays and protein assays to assess genes and proteins related to inflammation, renal injury, apoptosis, and fibrosis. ES-HF was characterized by increased circulating natriuretic peptides and components of the renin-angiotensin-aldosterone system and decreased sodium and water excretion with mild renal injury and up-regulation of CNP and renin genes in the kidney. Compared to normals, widespread genes, especially genes of the inflammatory pathways, were up-regulated in KC similar to increases seen in LA. Protein expressions related to inflammatory cytokines were also augmented in the KC. Gene and protein changes were less prominent in the LV and KM. The ES-HF displayed mild renal injury with widespread gene changes and increased inflammatory cytokines. These changes may provide important clues into the pathophysiology of ES-HF and for therapeutic molecular targets in the kidney of ES-HF.
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dietary sodium modulation of aldosterone activation and renal function during the progression of Experimental Heart Failure
2015Co-Authors: Wayne L Miller, Aaron J Grantham, Margaret M Redfield, Daniel D Borgeson, Andreas Luchner, John C BurnettAbstract:Aims Aldosterone activation is central to the sodium–fluid retention that marks the progression of Heart Failure (HF). The actions of dietary sodium restriction, a mainstay in HF management, on cardiorenal and neuroendocrine adaptations during the progression of HF are poorly understood. The study aim was to assess the role of dietary sodium during the progression of Experimental HF. Methods and results Experimental HF was produced in a canine model by rapid right ventricular pacing which evolves from early mild HF to overt, severe HF. Dogs were fed one of three diets: (i) high sodium [250 mEq (5.8 g) per day, n =6]; (ii) standard sodium [58 mEq (1.3 g) per day, n =6]; and (iii) sodium restriction [11 mEq (0.25 g) per day, n =6]. During the 38-day study, haemodynamics, renal function, plasma renin activity (PRA), and aldosterone were measured. Changes in haemodynamics at 38 days were similar in all three groups, as were changes in renal function. Aldosterone activation was demonstrated in all three groups; however, dietary sodium restriction, in contrast to high sodium, resulted in early (10 days) activation of PRA and aldosterone. High sodium demonstrated significant suppression of aldosterone activation over the course of HF progression. Conclusions Excessive dietary sodium restriction particularly in early stage HF results in early aldosterone activation, while normal and excess sodium intake are associated with delayed or suppressed activation. These findings warrant evaluation in humans to determine if dietary sodium manipulation, particularly during early stage HF, may have a significant impact on neuroendocrine disease progression.
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abstract 12651 atrium fibrosis and inflammation impaired atrial natriuretic peptide system in Experimental Heart Failure
2014Co-Authors: Tomoko Ichiki, Brenda K Huntley, Jeson S Sangaralingham, Gail J Harty, John C BurnettAbstract:Introduction: The cardiac atrium is an important endocrine organ which also releases natriuretic peptides (NPs). We reported that dysregulation of the proNP convertases, furin and corin, may disrupt NP progressing, causing atrial fibrosis in Experimental Heart Failure (HF). Atrial fibrosis results in atrial arrhythmias and impairs the prognosis of human HF, therefore understanding mechanisms of atrial fibrosis may help in designing treatment strategies for HF. We sought to extend our studies into the entire NP system and global gene profiles including fibrotic and inflammatory pathways in Experimental HF. Hypothesis: Components of the NP, pro-fibrotic and inflammatory system will be up-regulated in the atrium in HF. Methods: Experimental canine HF was induced by rapid right ventricular pacing at 240 bpm for 10 days. We examined hemodynamics, echo parameters, circulating neurohumoral factors, and global gene profiles using RT-PCR microarrays related to the NP system, fibrosis, growth factors, inflammation and cardiac hypertrophy in left atrium (LA) from normal and HF canines (n=4 of each). Results: Experimental HF was characterized by decreased % EF and LV radial strain, and increased circulating ANP, cGMP and aldosterone levels. HF LA weight significantly increased with fibrosis and interstitial edema compared to normals. Gene profile analyses showed increases in profibrotic cytokines and extracellular matrix related genes in LA. Increased ANP expression but also increased ANP degrading enzyme IDE and decreased proANP processing enzyme corin were also observed. Genes related to inflammatory cytokines such as TNF-alpha, members of the IL-6 family, MCP-1, and cell adhesion molecules were up-regulated in LA compared to normals. Conclusions: Experimental HF was characterized by on-going atrial fibrosis with increased circulating ANP levels. Although ANP gene expression increased in failing LA, impaired proANP processing and accelerated ANP degradation may impair any anti-fibrotic ANP effects. Further, atrium may be a source of inflammatory cytokines and pro-fibrotic growth factors which may advance organ damage in HF. Our studies suggest NP treatment, perhaps in a form less susceptible to IDE degradation, may be a novel therapeutic for HF.
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differential expression of the pro natriuretic peptide convertases corin and furin in Experimental Heart Failure and atrial fibrosis
2013Co-Authors: Tomoko Ichiki, Brenda K Huntley, Jeson S Sangaralingham, Gail J Harty, Guido Boerrigter, Paul M Mckie, Gerald E Harders, John C BurnettAbstract:In Heart Failure (HF), the cardiac hormone natriuretic peptides (NPs) atrial (ANP), B-type (BNP), and C-type (CNP) play a key role to protect cardiac remodeling. The proprotein convertases corin and furin process their respective pro-NPs into active NPs. Here we define in a canine model of HF furin and corin gene and protein expression in normal and failing left atrium (LA) or ventricle (LV) testing the hypothesis that the NP proproteins convertases production is altered in Experimental HF. Experimental canine HF was produced by rapid right ventricular pacing for 10 days. NPs, furin, and corin mRNA expression were determined by quantitative RT-PCR. Protein concentration or expression was determined by immunostaining, radioimmunoassay, or Western blot. Furin and corin proteins were present in normal canine LA and LV myocardium and vasculature and in smooth muscle cells. In normal canines, expression of NPs was dominant in the atrium compared with the ventricle. In Experimental early stage HF characterized with marked atrial fibrosis, ANP, BNP, and CNP mRNA, and protein concentrations were higher in HF LA but not HF LV compared with normals. In LA, corin mRNA and protein expressions in HF were lower, whereas furin mRNA and protein expressions were higher than normals. NPs and furin expressions were augmented in the atrium in Experimental early stage HF and, conversely, corin mRNA and protein expressions were decreased with atrial remodeling. Selective changes of these NP convertases may have significance in the regulation of pro-NP processing and atrial remodeling in early stage HF.
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trv120027 a novel β arrestin biased ligand at the angiotensin ii type i receptor unloads the Heart and maintains renal function when added to furosemide in Experimental Heart Failure
2012Co-Authors: Guido Boerrigter, David G Soergel, Jonathan D Violin, Michael W Lark, John C BurnettAbstract:Background—TRV120027 is a novel β-arrestin biased ligand of the angiotensin II type 1 receptor; it antagonizes canonical G-protein–mediated coupling while, in contrast to classical angiotensin II type 1 receptor antagonists, it engages β-arrestin–mediated signaling. Consequently, TRV120027 inhibits angiotensin II–mediated vasoconstriction while, via β-arrestin coupling, it increases cardiomyocyte contractility. We hypothesized that TRV120027 would elicit beneficial cardiorenal actions when added to furosemide in Experimental Heart Failure. Methods and Results—Two groups of anesthetized dogs (n=6 each) with tachypacing-induced Heart Failure were studied. After a baseline clearance, 1 group (F+V) received furosemide (1 mg/kg per hour) plus saline for 90 minutes, whereas the other (F+T) received the same dose of furosemide plus TRV120027 (0.3 and 1.5 µg/kg per minute for 45 minutes each); 2 clearances were done during drug infusion. After a washout, a postinfusion clearance was done; *P<0.05 between groups. ...
Mark A Richards - One of the best experts on this subject based on the ideXlab platform.
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natriuretic peptide analogues with distinct vasodilatory or renal activity integrated effects in health and Experimental Heart Failure
2021Co-Authors: Miriam T Rademaker, Mark A Richards, Nicola J A Scott, Cho Yeow Koh, Manjunatha R KiniAbstract:AIMS Management of acute decompensated Heart Failure (ADHF) requires disparate treatments depending on the state of systemic/peripheral perfusion and the presence/absence of expanded body-fluid volumes. There is an unmet need for therapeutics that differentially treat each aspect. Atrial natriuretic peptide (ANP) plays an important role in blood pressure and volume regulation. We investigate for the first time the integrated haemodynamic, endocrine and renal effects of human ANP analogues, modified for exclusive vasodilatory (ANP-DRD) or diuretic (ANP-DGD) activities, in normal health and Experimental ADHF. METHODS AND RESULTS We compared the effects of incremental infusions of ANP analogues ANP-DRD and ANP-DGD with native ANP, in normal (n = 8) and ADHF (n = 8) sheep. ANP-DRD administration increased plasma cyclic guanosine monophosphate (cGMP) in association with dose-dependent reductions in arterial pressure in normal and Heart Failure (HF) sheep similarly to ANP responses. In contrast to ANP, which in HF produced a diuresis/natriuresis, this analogue was without significant renal effect. Conversely, ANP-DGD induced marked stepwise increases in urinary cGMP, urine volume, and sodium excretion in HF comparable to ANP, but without accompanying vasodilatory effects. All peptides increased packed cell volume relative to control in both states, and in HF, decreased left atrial pressure. In response to ANP-DRD-induced blood pressure reductions, plasma renin activity rose compared to control only during the high dose in normals, and not at all in HF-suggesting relative renin inhibition, with no increase in aldosterone in either state, whereas renin and aldosterone were both significantly reduced by ANP-DGD in HF. CONCLUSION These ANP analogues exhibit distinct vasodilatory (ANP-DRD) and diuretic/natriuretic (ANP-DGD) activities, and therefore have the potential to provide precision therapy for ADHF patients with differing pathophysiological derangement of pressure-volume homeostasis.
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hemodynamic hormonal and renal actions of phosphodiesterase 9 inhibition in Experimental Heart Failure
2019Co-Authors: Nicola J A Scott, Miriam T Rademaker, Christopher J Charles, E A Espiner, Mark A RichardsAbstract:Abstract Background Phosphodiesterase-9 (PDE9) reduces natriuretic peptide (NP) signaling and may be involved in the pathophysiology of Heart Failure (HF). Objectives This study investigated for the first time the integrated hemodynamic, endocrine, and renal effects of phosphodiesterase-9 inhibition (PDE9-I). Methods A total of 8 normal sheep and 8 sheep with pacing-induced HF received incremental intravenous boluses of PDE9-I (30, 100, and 300 mg PF-04749982 at 1-h intervals). Results PDE9-I dose-dependently increased plasma cyclic guanosine monophosphate (cGMP) in normal sheep (p Conclusions PDE9-I improves NP efficacy in conjunction with beneficial hemodynamic and renal effects in Experimental HF. These results support a role for PDE9 in HF pathophysiology and suggest its inhibition may constitute a novel therapeutic approach to this disease.
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hemodynamic hormonal and renal effects of pro renin receptor blockade in Experimental Heart Failure
2012Co-Authors: Miriam T Rademaker, Christopher J Charles, Gary M Nicholls, Leigh J Ellmers, Timothy G Yandle, Mark A RichardsAbstract:Background—The (pro)renin receptor (P)RR is implicated in blood pressure regulation and the pathophysiology of Heart Failure (HF). The effects of (P)RR blockade in HF have not been previously investigated. Methods and Results—Eight sheep received on 2 separate days a vehicle control and incremental intravenous boluses of a (P)RR antagonist, ovine handle region peptide (HRP) (1, 5, and 25 mg at 90-minute intervals), both before (normal) and after induction of HF by rapid left ventricular pacing. In normal sheep, HRP reduced Heart rate (P<0.001) and hematocrit (P=0.019) compared with time-matched control data, without significantly affecting any other hemodynamic, hormonal, or renal variables. In sheep with HF, HRP treatment induced progressive falls in mean arterial pressure (P<0.001) in association with decreases in left atrial pressure (P<0.001), peripheral resistance (P=0.014), and hematocrit (P<0.001). Cardiac contractility tended to decline (P=0.096), whereas cardiac output was unaltered. HRP administ...
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prolonged urocortin 2 administration in Experimental Heart Failure sustained hemodynamic endocrine and renal effects
2011Co-Authors: Miriam T Rademaker, Christopher J Charles, Gary M Nicholls, Leigh J Ellmers, Lynley K Lewis, Mark A RichardsAbstract:Although acute administration of urocortin 2 has beneficial actions in Heart Failure, the integrated hemodynamic, hormonal, and renal effects of sustained urocortin 2 treatment in this disease have not been investigated. In the current study, we administered a 4-day infusion of a vehicle control (0.9% saline; n=6) or urocortin 2 (0.75 μg/kg per hour; n=6) to sheep with pacing-induced Heart Failure. Compared with time-matched controls, infusion of urocortin 2 produced rapid (30-minute) and persistent (4-day) improvements in cardiac contractility (day 4: control 905±73 versus urocortin 2 1424±158 mm Hg/s; P P P P P P P P P P P P P P P P
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urocortin 3 haemodynamic hormonal and renal effects in Experimental Heart Failure
2006Co-Authors: Miriam T Rademaker, Christopher J Charles, Vicky A Cameron, Mark A RichardsAbstract:Aims To investigate the haemodynamic, hormonal, and renal effects of peripheral urocortin 3 (Ucn3) administration for the first time in either normal health or Heart Failure (HF). Methods and results Eight sheep received incremental intravenous boli of Ucn3 (10, 50, and 100 m ga t 2-h intervals) before (normal) and during pacing-induced HF. Compared with controls, Ucn3 induced immediate, dose-dependent increases in cardiac output (normal 4.21+ 0.23 vs. 5.65+ 0.32 L/min, P , 0.001; HF 2.20+ 0.14 vs. 4.43+ 0.31 L/min, P , 0.001) and decreases in peripheral resistance (normal 20.8+ 1.0 vs. 16.2+ 0.8 mmHg/L/min, P , 0.01; HF 34.4+ 1.7 vs. 16.2+ 0.5 mmHg/L/min, P , 0.001) and left atrial pressure (normal 4.5+ 0.3 vs. 0.6+ 0.2 mmHg, P , 0.001; HF 23.0+ 0.6 vs. 5.8+ 1.9 mmHg/L/min, P , 0.001). Arterial pressure was minimally elevated in normals (P , 0.001) and reduced in HF (P , 0.05). In HF only, Ucn3 decreased plasma vasopressin (3.33+ 0.36 vs. 1.73+ 0.21 pmol/L, P , 0.05), endothelin-1 (3.56+ 0.28 vs. 2.64+ 0.24 pmol/L, P , 0.001), renin (2.74+ 1.17 vs. 1.04+ 0.22 nmol/L/h, P , 0.001), aldosterone (1494+ 400 vs. 726+ 168 pmol/L, P , 0.05), and epinephrine (1608+ 278 vs. 1039+ 75 pmol/L, P , 0.05), and increased urine output (P , 0.05), sodium excretion (P , 0.01), and creatinine clearance (P , 0.05). Conclusion Ucn3 has significant cardiovascular effects in normal and HF sheep, supporting a role for this peptide in circulatory regulation. In HF, more prominent haemodynamic changes were associated with beneficial endocrine and renal effects, suggesting Ucn3 has therapeutic potential in this disease.
Horng H Chen - One of the best experts on this subject based on the ideXlab platform.
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local renal delivery of a natriuretic peptide a renal enhancing strategy for b type natriuretic peptide in overt Experimental Heart Failure
2009Co-Authors: Horng H Chen, Alessandro Cataliotti, John A Schirger, Fernando L Martin, Lynn K Harstad, John C BurnettAbstract:Objectives The purpose of this study was to test the hypothesis that local renal delivery of B-type natriuretic peptide (BNP) will overcome renal resistance to BNP without systemic hypotension. Background BNP has vasodilating, natriuretic, and renin-inhibiting properties. In overt Heart Failure (HF), there is development of renal resistance to BNP. Methods We defined the cardiorenal and humoral effects of systemic (n = 6) or local renal (n = 7) administration of canine BNP (0.01 μg/kg/min) in 2 separate groups of dogs with pacing-induced subacute overt HF complicated by renal dysfunction. We used a commercially available small (3.1-F) bifurcated renal catheter (FlowMedica Inc., Fremont, California) for direct bilateral infusion of BNP into both renal arteries. Results With systemic BNP at this clinically used dose (without the bolus), urine flow increased, but there was only a trend for an increase in urinary sodium excretion and glomerular filtration rate (GFR). In contrast, local renal delivery of BNP resulted in significant diuresis and natriuresis and an increase in GFR. These diuretic and natriuretic responses were greater with local renal BNP compared with systemic BNP, and were associated with increased delivery of BNP to the renal tubules as evident by a greater urinary BNP excretion resulting in a decrease in distal reabsorption of sodium. Importantly, local renal BNP did not result in a significant decrease in mean arterial pressure that was observed with systemic BNP. Conclusions We conclude that local renal BNP delivery is a novel strategy that may overcome renal assistance to BNP in overt HF by increasing local delivery of BNP to the renal tubules.
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equimolar doses of atrial and brain natriuretic peptides and urodilatin have differential renal actions in overt Experimental Heart Failure
2005Co-Authors: Horng H Chen, Alessandro Cataliotti, John A Schirger, Fernando L Martin, John C BurnettAbstract:A hallmark of overt congestive Heart Failure (CHF) is attenuated cGMP production by endogenous atrial natriuretic peptide (ANP) with renal resistance to ANP. ANP and brain natriuretic peptides (BNP...
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brain natriuretic peptide enhances renal actions of furosemide and suppresses furosemide induced aldosterone activation in Experimental Heart Failure
2004Co-Authors: Alessandro Cataliotti, Horng H Chen, John A Schirger, Guido Boerrigter, Lisa C Costelloboerrigter, Toshihiro Tsuruda, Denise M Heublein, Lorenzo Malatino, John C BurnettAbstract:Background— The renal actions of brain natriuretic peptide (BNP) in congestive Heart Failure (CHF) are associated with increased diuresis and natriuresis, preserved glomerular filtration rate (GFR), and lack of activation of the renin-angiotensin-aldosterone system (RAAS). In contrast, diuretic-induced natriuresis may be associated with reduced GFR and RAAS activation. The objective of this study was to test the hypothesis that exogenous BNP enhances the renal diuretic and natriuretic actions of furosemide (Fs) and retards the activation of aldosterone in a model of CHF. Methods and Results— CHF was produced in 2 groups of dogs by ventricular pacing. One group received continuous (90-minute) intravenous Fs (1 mg · kg−1 · h−1). A second group (Fs+BNP) received 45-minute intravenous coinfusion of Fs (1 mg · kg−1 · h−1) and low-dose (2 pmol · kg−1 · min−1) BNP followed by 45-minute coinfusion of Fs (1 mg · kg−1 · h−1) and high-dose (10 pmol · kg−1 · min−1) BNP. Fs increased urinary flow, but the effect of Fs...
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cardiotrophin 1 stimulation of cardiac fibroblast growth roles for glycoprotein 130 leukemia inhibitory factor receptor and the endothelin type a receptor
2002Co-Authors: Toshihiro Tsuruda, Alessandro Cataliotti, Horng H Chen, Michihisa Jougasaki, Brenda K Huntley, Guido Boerrigter, Antonino B Dassoro, Shang C Lee, Amy M Larsen, John C BurnettAbstract:Cardiotrophin-1 (CT-1), a member of the interleukin-6 superfamily, and endothelin-1 (ET-1) are potent hypertrophic factors in cardiomyocytes. Although CT-1 and ET-1 gene expression in the Heart is upregulated in Experimental Heart Failure, their role in the activation of the cardiac fibroblast is unknown. This study was designed to identify the presence and action of CT-1 and its receptor complex, glycoprotein130 (gp130) and leukemia inhibitory factor (LIF) receptor, on cardiac fibroblast growth in cultured adult canine cardiac fibroblasts. In addition, we investigated the interaction between CT-1/gp130/LIF receptor and ET-1/endothelin type A (ETA) receptor axis. Immunohistochemistry was performed using the indirect immunoperoxidase method, while we assessed the cell cycle of cardiac fibroblasts by flow cytometry, DNA synthesis by [3H]thymidine incorporation, and collagen synthesis by [3H]proline incorporation, respectively. CT-1 and gp130/LIF receptor were widely present in the cytoplasm of the cardiac f...
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role of the natriuretic peptides in the cardiorenal and humoral actions of omapatrilat insights from Experimental Heart Failure
2001Co-Authors: Horng H Chen, Alessandro Cataliotti, John C BurnettAbstract:Vasopeptidase (VP) inhibitors are novel molecules that coinhibit neutral endopeptidase 24.11 (NEP), which degrades natriuretic peptides and angiotensin-converting enzyme (ACE). We review the biology of the natriuretic peptide system and a recent study of the role for the natriuretic peptide system in the mechanism of action of omapatrilat (the most clinically advanced VP inhibitor). This study compared the cardiorenal and humoral actions of omapatrilat with those of ACE inhibition. The actions of omapatrilat were further defined in the presence and absence of a natriuretic peptide receptor antagonist. This investigation provided insight into a unique new pharmacologic agent that has beneficial renal actions in Experimental mild Heart Failure that exceed those seen with ACE inhibition alone and that are linked to the natriuretic peptide system.
Alessandro Cataliotti - One of the best experts on this subject based on the ideXlab platform.
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renal and anti aldosterone actions of vasopressin 2 receptor antagonism and b type natriuretic peptide in Experimental Heart Failure
2010Co-Authors: Lisa C Costelloboerrigter, Alessandro Cataliotti, Gail J Harty, Guido Boerrigter, John C BurnettAbstract:Background— Hemodynamic and neurohumoral function can affect the efficacy of diuretic therapy in congestive Heart Failure. Arginine vasopressin increases water reabsorption through the V2 receptor in the collecting duct, whereas B-type natriuretic peptide (BNP) decreases sodium reabsorption in the collecting duct. We hypothesized that combining BNP to the V2-receptor antagonist tolvaptan (TLV) would enhance renal excretory function by augmenting sodium excretion together with aquaresis without adversely affecting renal hemodynamics in Experimental congestive Heart Failure. Methods and Results— Congestive Heart Failure was induced in 3 groups (n=6 per group) of dogs by tachypacing. A acute experiment was done after 10 days. After baseline measurements, study groups received a 0.1 mg/kg IV bolus of TLV alone (TLV), TLV in combination with BNP (TLV+BNP; 50 ng/[kg · min]), or BNP alone (BNP). Mean arterial pressure increased with TLV, remained unchanged with TLV+BNP, and decreased with BNP (+5±1mm Hg versus −1±1 mm Hg versus −15±1 mm Hg; P <0.05). Renal blood flow and glomerular filtration rate were preserved with all regimens. Urine flow increased in all 3 groups but significantly more so with TLV+BNP (TLV: +0.4±0.1 mL/min versus TLV+BNP: +2.4±0.5 mL/min versus BNP: +0.8±0.3 mL/min; P <0.05). Only TLV+BNP and BNP were natriuretic ( P <0.05), whereas only TLV and TLV+BNP increased electrolyte-free water excretion ( P <0.05). Compared with TLV alone, TLV+BNP prevented an increase in aldosterone ( P <0.05). Conclusions— Coadministration of TLV and BNP in Experimental HF resulted in a beneficial profile of renal, neurohumoral, and hemodynamic actions, specifically potent diuresis with natriuresis, neutral effect on mean arterial pressure, and lack of aldosterone activation.
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local renal delivery of a natriuretic peptide a renal enhancing strategy for b type natriuretic peptide in overt Experimental Heart Failure
2009Co-Authors: Horng H Chen, Alessandro Cataliotti, John A Schirger, Fernando L Martin, Lynn K Harstad, John C BurnettAbstract:Objectives The purpose of this study was to test the hypothesis that local renal delivery of B-type natriuretic peptide (BNP) will overcome renal resistance to BNP without systemic hypotension. Background BNP has vasodilating, natriuretic, and renin-inhibiting properties. In overt Heart Failure (HF), there is development of renal resistance to BNP. Methods We defined the cardiorenal and humoral effects of systemic (n = 6) or local renal (n = 7) administration of canine BNP (0.01 μg/kg/min) in 2 separate groups of dogs with pacing-induced subacute overt HF complicated by renal dysfunction. We used a commercially available small (3.1-F) bifurcated renal catheter (FlowMedica Inc., Fremont, California) for direct bilateral infusion of BNP into both renal arteries. Results With systemic BNP at this clinically used dose (without the bolus), urine flow increased, but there was only a trend for an increase in urinary sodium excretion and glomerular filtration rate (GFR). In contrast, local renal delivery of BNP resulted in significant diuresis and natriuresis and an increase in GFR. These diuretic and natriuretic responses were greater with local renal BNP compared with systemic BNP, and were associated with increased delivery of BNP to the renal tubules as evident by a greater urinary BNP excretion resulting in a decrease in distal reabsorption of sodium. Importantly, local renal BNP did not result in a significant decrease in mean arterial pressure that was observed with systemic BNP. Conclusions We conclude that local renal BNP delivery is a novel strategy that may overcome renal assistance to BNP in overt HF by increasing local delivery of BNP to the renal tubules.
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targeting heme oxidized soluble guanylate cyclase in Experimental Heart Failure
2007Co-Authors: Guido Boerrigter, Alessandro Cataliotti, Lisa C Costelloboerrigter, Harald Lapp, Johannespeter Stasch, John C BurnettAbstract:Soluble guanylate cyclase is a heterodimeric enzyme with a prosthetic heme group that, on binding of its main ligand, NO, generates the second messenger cGMP. Unlike conventional nitrovasodilators, the novel direct NO- and heme-independent soluble guanylate cyclase activator BAY 58-2667 is devoid of non-cGMP actions, lacks tolerance development, and preferentially activates NO-insensitive heme-free or oxidized soluble guanylate cyclase. BAY 58-2667, therefore, represents a novel therapeutic advance in mediating vasodilation. To date, its cardiorenal actions in congestive Heart Failure (CHF) are undefined. We, therefore, hypothesized that BAY 58-2667 would have beneficial preload- and afterload-reducing actions in Experimental severe CHF together with renal vasodilating properties. We assessed the cardiorenal actions of intravenous administration of 2 doses of BAY 58-2667 (0.1 and 0.3 μg/kg per minute, respectively) in a model of tachypacing-induced severe CHF. In CHF, BAY 58-2667 dose-dependently reduced mean arterial, right atrial, pulmonary artery, and pulmonary capillary wedge pressure (from baseline 19±1 to 12±2 mm Hg). Cardiac output (2.4±0.3 to 3.2±0.4 L/min) and renal blood flow increased. Glomerular filtration rate and sodium and water excretion were maintained. Consistent with cardiac unloading, atrial and B-type natriuretic peptide decreased. Plasma renin activity ( P =0.31) and aldosterone remained unchanged ( P =0.19). In summary, BAY 58-2667 in Experimental CHF potently unloaded the Heart, increased cardiac output and renal blood flow, and preserved glomerular filtration rate and sodium and water excretion without further neurohumoral activation. These beneficial properties make direct soluble guanylate cyclase stimulation with BAY 58-2667 a promising new therapeutic strategy for cardiovascular diseases, such as Heart Failure.
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equimolar doses of atrial and brain natriuretic peptides and urodilatin have differential renal actions in overt Experimental Heart Failure
2005Co-Authors: Horng H Chen, Alessandro Cataliotti, John A Schirger, Fernando L Martin, John C BurnettAbstract:A hallmark of overt congestive Heart Failure (CHF) is attenuated cGMP production by endogenous atrial natriuretic peptide (ANP) with renal resistance to ANP. ANP and brain natriuretic peptides (BNP...
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brain natriuretic peptide enhances renal actions of furosemide and suppresses furosemide induced aldosterone activation in Experimental Heart Failure
2004Co-Authors: Alessandro Cataliotti, Horng H Chen, John A Schirger, Guido Boerrigter, Lisa C Costelloboerrigter, Toshihiro Tsuruda, Denise M Heublein, Lorenzo Malatino, John C BurnettAbstract:Background— The renal actions of brain natriuretic peptide (BNP) in congestive Heart Failure (CHF) are associated with increased diuresis and natriuresis, preserved glomerular filtration rate (GFR), and lack of activation of the renin-angiotensin-aldosterone system (RAAS). In contrast, diuretic-induced natriuresis may be associated with reduced GFR and RAAS activation. The objective of this study was to test the hypothesis that exogenous BNP enhances the renal diuretic and natriuretic actions of furosemide (Fs) and retards the activation of aldosterone in a model of CHF. Methods and Results— CHF was produced in 2 groups of dogs by ventricular pacing. One group received continuous (90-minute) intravenous Fs (1 mg · kg−1 · h−1). A second group (Fs+BNP) received 45-minute intravenous coinfusion of Fs (1 mg · kg−1 · h−1) and low-dose (2 pmol · kg−1 · min−1) BNP followed by 45-minute coinfusion of Fs (1 mg · kg−1 · h−1) and high-dose (10 pmol · kg−1 · min−1) BNP. Fs increased urinary flow, but the effect of Fs...
Miriam T Rademaker - One of the best experts on this subject based on the ideXlab platform.
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natriuretic peptide analogues with distinct vasodilatory or renal activity integrated effects in health and Experimental Heart Failure
2021Co-Authors: Miriam T Rademaker, Mark A Richards, Nicola J A Scott, Cho Yeow Koh, Manjunatha R KiniAbstract:AIMS Management of acute decompensated Heart Failure (ADHF) requires disparate treatments depending on the state of systemic/peripheral perfusion and the presence/absence of expanded body-fluid volumes. There is an unmet need for therapeutics that differentially treat each aspect. Atrial natriuretic peptide (ANP) plays an important role in blood pressure and volume regulation. We investigate for the first time the integrated haemodynamic, endocrine and renal effects of human ANP analogues, modified for exclusive vasodilatory (ANP-DRD) or diuretic (ANP-DGD) activities, in normal health and Experimental ADHF. METHODS AND RESULTS We compared the effects of incremental infusions of ANP analogues ANP-DRD and ANP-DGD with native ANP, in normal (n = 8) and ADHF (n = 8) sheep. ANP-DRD administration increased plasma cyclic guanosine monophosphate (cGMP) in association with dose-dependent reductions in arterial pressure in normal and Heart Failure (HF) sheep similarly to ANP responses. In contrast to ANP, which in HF produced a diuresis/natriuresis, this analogue was without significant renal effect. Conversely, ANP-DGD induced marked stepwise increases in urinary cGMP, urine volume, and sodium excretion in HF comparable to ANP, but without accompanying vasodilatory effects. All peptides increased packed cell volume relative to control in both states, and in HF, decreased left atrial pressure. In response to ANP-DRD-induced blood pressure reductions, plasma renin activity rose compared to control only during the high dose in normals, and not at all in HF-suggesting relative renin inhibition, with no increase in aldosterone in either state, whereas renin and aldosterone were both significantly reduced by ANP-DGD in HF. CONCLUSION These ANP analogues exhibit distinct vasodilatory (ANP-DRD) and diuretic/natriuretic (ANP-DGD) activities, and therefore have the potential to provide precision therapy for ADHF patients with differing pathophysiological derangement of pressure-volume homeostasis.
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hemodynamic hormonal and renal actions of phosphodiesterase 9 inhibition in Experimental Heart Failure
2019Co-Authors: Nicola J A Scott, Miriam T Rademaker, Christopher J Charles, E A Espiner, Mark A RichardsAbstract:Abstract Background Phosphodiesterase-9 (PDE9) reduces natriuretic peptide (NP) signaling and may be involved in the pathophysiology of Heart Failure (HF). Objectives This study investigated for the first time the integrated hemodynamic, endocrine, and renal effects of phosphodiesterase-9 inhibition (PDE9-I). Methods A total of 8 normal sheep and 8 sheep with pacing-induced HF received incremental intravenous boluses of PDE9-I (30, 100, and 300 mg PF-04749982 at 1-h intervals). Results PDE9-I dose-dependently increased plasma cyclic guanosine monophosphate (cGMP) in normal sheep (p Conclusions PDE9-I improves NP efficacy in conjunction with beneficial hemodynamic and renal effects in Experimental HF. These results support a role for PDE9 in HF pathophysiology and suggest its inhibition may constitute a novel therapeutic approach to this disease.
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hemodynamic hormonal and renal effects of pro renin receptor blockade in Experimental Heart Failure
2012Co-Authors: Miriam T Rademaker, Christopher J Charles, Gary M Nicholls, Leigh J Ellmers, Timothy G Yandle, Mark A RichardsAbstract:Background—The (pro)renin receptor (P)RR is implicated in blood pressure regulation and the pathophysiology of Heart Failure (HF). The effects of (P)RR blockade in HF have not been previously investigated. Methods and Results—Eight sheep received on 2 separate days a vehicle control and incremental intravenous boluses of a (P)RR antagonist, ovine handle region peptide (HRP) (1, 5, and 25 mg at 90-minute intervals), both before (normal) and after induction of HF by rapid left ventricular pacing. In normal sheep, HRP reduced Heart rate (P<0.001) and hematocrit (P=0.019) compared with time-matched control data, without significantly affecting any other hemodynamic, hormonal, or renal variables. In sheep with HF, HRP treatment induced progressive falls in mean arterial pressure (P<0.001) in association with decreases in left atrial pressure (P<0.001), peripheral resistance (P=0.014), and hematocrit (P<0.001). Cardiac contractility tended to decline (P=0.096), whereas cardiac output was unaltered. HRP administ...
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prolonged urocortin 2 administration in Experimental Heart Failure sustained hemodynamic endocrine and renal effects
2011Co-Authors: Miriam T Rademaker, Christopher J Charles, Gary M Nicholls, Leigh J Ellmers, Lynley K Lewis, Mark A RichardsAbstract:Although acute administration of urocortin 2 has beneficial actions in Heart Failure, the integrated hemodynamic, hormonal, and renal effects of sustained urocortin 2 treatment in this disease have not been investigated. In the current study, we administered a 4-day infusion of a vehicle control (0.9% saline; n=6) or urocortin 2 (0.75 μg/kg per hour; n=6) to sheep with pacing-induced Heart Failure. Compared with time-matched controls, infusion of urocortin 2 produced rapid (30-minute) and persistent (4-day) improvements in cardiac contractility (day 4: control 905±73 versus urocortin 2 1424±158 mm Hg/s; P P P P P P P P P P P P P P P P
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urocortin 3 haemodynamic hormonal and renal effects in Experimental Heart Failure
2006Co-Authors: Miriam T Rademaker, Christopher J Charles, Vicky A Cameron, Mark A RichardsAbstract:Aims To investigate the haemodynamic, hormonal, and renal effects of peripheral urocortin 3 (Ucn3) administration for the first time in either normal health or Heart Failure (HF). Methods and results Eight sheep received incremental intravenous boli of Ucn3 (10, 50, and 100 m ga t 2-h intervals) before (normal) and during pacing-induced HF. Compared with controls, Ucn3 induced immediate, dose-dependent increases in cardiac output (normal 4.21+ 0.23 vs. 5.65+ 0.32 L/min, P , 0.001; HF 2.20+ 0.14 vs. 4.43+ 0.31 L/min, P , 0.001) and decreases in peripheral resistance (normal 20.8+ 1.0 vs. 16.2+ 0.8 mmHg/L/min, P , 0.01; HF 34.4+ 1.7 vs. 16.2+ 0.5 mmHg/L/min, P , 0.001) and left atrial pressure (normal 4.5+ 0.3 vs. 0.6+ 0.2 mmHg, P , 0.001; HF 23.0+ 0.6 vs. 5.8+ 1.9 mmHg/L/min, P , 0.001). Arterial pressure was minimally elevated in normals (P , 0.001) and reduced in HF (P , 0.05). In HF only, Ucn3 decreased plasma vasopressin (3.33+ 0.36 vs. 1.73+ 0.21 pmol/L, P , 0.05), endothelin-1 (3.56+ 0.28 vs. 2.64+ 0.24 pmol/L, P , 0.001), renin (2.74+ 1.17 vs. 1.04+ 0.22 nmol/L/h, P , 0.001), aldosterone (1494+ 400 vs. 726+ 168 pmol/L, P , 0.05), and epinephrine (1608+ 278 vs. 1039+ 75 pmol/L, P , 0.05), and increased urine output (P , 0.05), sodium excretion (P , 0.01), and creatinine clearance (P , 0.05). Conclusion Ucn3 has significant cardiovascular effects in normal and HF sheep, supporting a role for this peptide in circulatory regulation. In HF, more prominent haemodynamic changes were associated with beneficial endocrine and renal effects, suggesting Ucn3 has therapeutic potential in this disease.
