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1.
ChemMedChem ; 12(10): 728-737, 2017 05 22.
Article in English | MEDLINE | ID: mdl-28488817

ABSTRACT

Adenosine is known to be released under a variety of physiological and pathophysiological conditions to facilitate the protection and regeneration of injured ischemic tissues. The activation of myocardial adenosine A1 receptors (A1 Rs) has been shown to inhibit myocardial pathologies associated with ischemia and reperfusion injury, suggesting several options for new cardiovascular therapies. When full A1 R agonists are used, the desired protective and regenerative cardiovascular effects are usually overshadowed by unintended pharmacological effects such as induction of bradycardia, atrioventricular (AV) blocks, and sedation. These unwanted effects can be overcome by using partial A1 R agonists. Starting from previously reported capadenoson we evaluated options to tailor A1 R agonists to a specific partiality range, thereby optimizing the therapeutic window. This led to the identification of the potent and selective agonist neladenoson, which shows the desired partial response on the A1 R, resulting in cardioprotection without sedative effects or cardiac AV blocks. To circumvent solubility and formulation issues for neladenoson, a prodrug approach was pursued. The dipeptide ester neladenoson bialanate hydrochloride showed significantly improved solubility and exposure after oral administration. Neladenoson bialanate hydrochloride is currently being evaluated in clinical trials for the treatment of heart failure.


Subject(s)
Adenosine A1 Receptor Agonists/pharmacology , Dipeptides/pharmacology , Heart Diseases/drug therapy , Prodrugs/pharmacology , Pyridines/pharmacology , Receptor, Adenosine A1/metabolism , Adenosine A1 Receptor Agonists/administration & dosage , Adenosine A1 Receptor Agonists/chemistry , Administration, Oral , Animals , Chronic Disease , Dipeptides/administration & dosage , Dipeptides/chemistry , Disease Models, Animal , Dose-Response Relationship, Drug , Humans , Injections, Intravenous , Molecular Structure , Prodrugs/administration & dosage , Prodrugs/chemistry , Pyridines/administration & dosage , Pyridines/chemistry , Rats , Solubility , Structure-Activity Relationship
2.
Handb Exp Pharmacol ; 243: 177-203, 2017.
Article in English | MEDLINE | ID: mdl-27770217

ABSTRACT

Adenosine exerts a variety of physiological effects by binding to cell surface G-protein-coupled receptor subtypes, namely, A1, A2a, A2b, and A3. The central physiological role of adenosine is to preclude tissue injury and promote repair in response to stress. In the heart, adenosine acts as a cytoprotective modulator, linking cardiac function to metabolic demand predominantly via activation of adenosine A1 receptors (A1Rs), which leads to inhibition of adenylate cyclase activity, modulation of protein kinase C, and opening of ATP-sensitive potassium channels. Activation of myocardial adenosine A1Rs has been shown to modulate a variety of pathologies associated with ischemic cardiac injury, including arrhythmogenesis, coronary and ventricular dysfunction, apoptosis, mitochondrial dysfunction, and ventricular remodeling. Partial A1R agonists are agents that are likely to elicit favorable pharmacological responses in heart failure (HF) without giving rise to the undesirable cardiac and extra-cardiac effects observed with full A1R agonism. Preclinical data have shown that partial adenosine A1R agonists protect and improve cardiac function at doses that do not result in undesirable effects on heart rate, atrioventricular conduction, and blood pressure, suggesting that these compounds may constitute a valuable new therapy for chronic HF. Neladenoson bialanate (BAY1067197) is the first oral partial and highly selective A1R agonist that has entered clinical development for the treatment of HF. This review provides an overview of adenosine A1R-mediated signaling in the heart, summarizes the results from preclinical and clinical studies of partial A1R agonists in HF, and discusses the potential benefits of these drugs in the clinical setting.


Subject(s)
Adenosine A1 Receptor Agonists/therapeutic use , Drug Partial Agonism , Heart Failure/drug therapy , Adenosine/analogs & derivatives , Adenosine/pharmacology , Adenosine/therapeutic use , Adenosine A1 Receptor Agonists/pharmacology , Aminopyridines/pharmacology , Aminopyridines/therapeutic use , Angina Pectoris/drug therapy , Animals , Anti-Arrhythmia Agents/pharmacology , Anti-Arrhythmia Agents/therapeutic use , Coronary Artery Disease , Diabetes Mellitus , Dipeptides/pharmacology , Dipeptides/therapeutic use , Furans/pharmacology , Furans/therapeutic use , Heart/drug effects , Heart Failure/physiopathology , Humans , Insulin Resistance , Ischemic Preconditioning, Myocardial , Lipolysis/drug effects , Mitochondria, Heart/drug effects , Mitochondria, Heart/metabolism , Myocardium/metabolism , Oxygen Consumption/drug effects , Pyridines/pharmacology , Pyridines/therapeutic use , Renal Insufficiency , Tachycardia, Supraventricular/drug therapy , Thiazoles/pharmacology , Thiazoles/therapeutic use
3.
Heart Fail Rev ; 21(1): 95-102, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26701329

ABSTRACT

Heart failure (HF) represents a global public health and economic problem associated with unacceptable rates of death, hospitalization, and healthcare expenditure. Despite available therapy, HF carries a prognosis comparable to many forms of cancer with a 5-year survival rate of ~50%. The current treatment paradigm for HF with reduced ejection fraction (EF) centers on blocking maladaptive neurohormonal activation and decreasing cardiac workload with therapies that concurrently lower blood pressure and heart rate. Continued development of hemodynamically active medications for stepwise addition to existing therapies carries the risk of limited tolerability and safety. Moreover, this treatment paradigm has thus far failed for HF with preserved EF. Accordingly, development of hemodynamically neutral HF therapies targeting primary cardiac pathologies must be considered. In this context, a partial adenosine A1 receptor (A1R) agonist holds promise as a potentially hemodynamically neutral therapy for HF that could simultaneous improve cardiomyocyte energetics, calcium homeostasis, cardiac structure and function, and long-term clinical outcomes when added to background therapies. In this review, we describe the physiology and pathophysiology of HF as it relates to adenosine agonism, examine the existing body of evidence and biologic rationale for modulation of adenosine A1R activity, and review the current state of drug development of a partial A1R agonist for the treatment of HF.


Subject(s)
Adenosine A1 Receptor Agonists/pharmacology , Heart Failure , Cardiovascular Agents/pharmacology , Drug Partial Agonism , Heart Failure/drug therapy , Heart Failure/metabolism , Heart Failure/physiopathology , Humans , Receptor, Adenosine A1/metabolism , Stroke Volume/physiology
4.
J Cardiovasc Pharmacol ; 64(1): 69-78, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24621652

ABSTRACT

Pharmacological blockade of the mineralocorticoid receptor (MR) ameliorates end-organ damage in chronic heart failure. However, the clinical use of available steroidal MR antagonists is restricted because of concomitant hyperkalemia especially in patients with diminished kidney function. We have recently identified a novel nonsteroidal MR antagonist, finerenone, which uniquely combines potency and selectivity toward MR. Here, we investigated the tissue distribution and chronic cardiorenal end-organ protection of finerenone in comparison to the steroidal MR antagonist, eplerenone, in 2 different preclinical rat disease models. Quantitative whole-body autoradiography revealed that [C]-labeled finerenone equally distributes into rat cardiac and renal tissues. Finerenone treatment prevented deoxycorticosterone acetate-/salt-challenged rats from functional as well as structural heart and kidney damage at dosages not reducing systemic blood pressure. Finerenone reduced cardiac hypertrophy, plasma prohormone of brain natriuretic peptide, and proteinuria more efficiently than eplerenone when comparing equinatriuretic doses. In rats that developed chronic heart failure after coronary artery ligation, finerenone (1 mg·kg·d), but not eplerenone (100 mg·kg·d) improved systolic and diastolic left ventricular function and reduced plasma prohormone of brain natriuretic peptide levels. We conclude that finerenone may offer end-organ protection with a reduced risk of electrolyte disturbances.


Subject(s)
Heart Failure/prevention & control , Kidney Diseases/prevention & control , Mineralocorticoid Receptor Antagonists/pharmacology , Naphthyridines/pharmacology , Spironolactone/analogs & derivatives , Animals , Autoradiography , Cardiomegaly/prevention & control , Disease Models, Animal , Eplerenone , Male , Mineralocorticoid Receptor Antagonists/pharmacokinetics , Naphthyridines/pharmacokinetics , Natriuretic Peptide, Brain/blood , Peptide Fragments/blood , Rats , Rats, Sprague-Dawley , Rats, Wistar , Spironolactone/pharmacokinetics , Spironolactone/pharmacology , Tissue Distribution
5.
Naunyn Schmiedebergs Arch Pharmacol ; 387(4): 389-98, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24276219

ABSTRACT

Cardiac adenylyl cyclase (AC) activity was described to be differentially regulated in left and right ventricles (LVs and RVs) of rats with heart failure (HF) due to LV myocardial infarction (MI) (Sethi et al. Am J Physiol 272:H884-H893, 1997). AC activities in LVs and RVs were increased and decreased respectively in rats 8 and 16 weeks post MI under basal and stimulatory conditions including AC activation via ß-adrenergic receptors (ß-ARs), stimulatory G protein (Gs), and direct AC activation with forskolin (FS). The current study aimed to detect alterations in rat heart AC activities in a comparable model of HF 9 weeks post LV MI. Therefore, cardiac AC activities were measured under basal and ß-AR-, Gs-, or FS-stimulated conditions as well as under inhibition with various MANT [2'(3')-O-(N-methylanthraniloyl)]-nucleotide AC inhibitors and the P-site AC inhibitors NKY80 [2-amino-7-(2-furanyl)-7,8-dihydro-5(6H)-quinazolinone] and vidarabine (9-ß-D-arabinosyladenine, AraAde). Basal and stimulated AC activities along with AC inhibition experiments did not reveal evidence for changes in AC activity in LVs and RVs from MI group animals despite the presence of congestive HF. However, our study is indeterminate. Further studies are required to identify the factors responsible for previously described changes in cardiac AC activity in MI induced HF and to elucidate the role of altered AC regulation in the pathophysiology of HF. In order to detect small changes in AC regulation, larger group sizes than the ones used in our present study are required.


Subject(s)
Adenylyl Cyclases/metabolism , Heart Failure/metabolism , Heart Ventricles/metabolism , Myocardial Infarction/metabolism , Adenylyl Cyclase Inhibitors , Adenylyl Cyclases/physiology , Animals , Blood Pressure , Heart Failure/etiology , Heart Failure/physiopathology , Heart Rate , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Male , Myocardial Infarction/complications , Myocardial Infarction/physiopathology , Nucleotides/pharmacology , Rats , Rats, Wistar , Ventricular Function/physiology , Vidarabine/pharmacology
6.
Circ Heart Fail ; 6(3): 563-71, 2013 May.
Article in English | MEDLINE | ID: mdl-23564604

ABSTRACT

BACKGROUND: Adenosine elicits cardioprotection through A1-receptor activation. Therapy with adenosine A1-receptor agonists, however, is limited by undesirable actions of full agonism, such as bradycardia. This study examined the effects of capadenoson (CAP), a partial adenosine A1-receptor agonist, on left ventricular (LV) function and remodeling in dogs with heart failure. METHODS AND RESULTS: Twelve dogs with microembolization-induced heart failure were randomized to 12 weeks oral therapy with CAP (7.5 mg BID; n=6) or to no therapy (control; n=6). LV end-diastolic and end-systolic volumes, ejection fraction, plasma norepinephrine, and n-terminal pro-brain natriuretic peptide were measured before (pre) and 1 and 12 weeks after therapy (post). LV tissue obtained at post was used to assess volume fraction of interstitial fibrosis, sarcoplasmic reticulum calcium ATPase-2a activity, expression of mitochondria uncoupling proteins (UCP) and glucose transporters (GLUT). In controls, end-diastolic and end-systolic volumes increased and ejection fraction decreased significantly from pre to post (ejection fraction, 30±2 versus 27±1%; P<0.05). In CAP-treated dogs, end-diastolic volume was unchanged; ejection fraction increased significantly after 1 week (36±2 versus 27±2%; P<0.05) with a further increase at post (39±2%; P<0.05), whereas end-systolic volume decreased. CAP significantly decreased volume fraction of interstitial fibrosis, normalized sarcoplasmic reticulum calcium ATPase-2a activity and expression of UCP-2 and UCP-3, and GLUT-1 and GLUT-2 and significantly decreased plasma norepinephrine and n-terminal pro-brain natriuretic peptide. CONCLUSIONS: In heart failure dogs, CAP improves LV function and prevents progressive remodeling. Improvement of LV systolic function occurs early after initiating therapy. The results support development of partial adenosine A1-receptor agonists for the treatment of chronic heart failure.


Subject(s)
Adenosine A1 Receptor Agonists/pharmacology , Aminopyridines/pharmacology , Heart Failure/physiopathology , Thiazoles/pharmacology , Ventricular Function, Left/drug effects , Ventricular Remodeling/drug effects , Adenosine A1 Receptor Agonists/therapeutic use , Animals , Dogs , Echocardiography, Doppler , Heart Failure/diagnostic imaging , Heart Failure/drug therapy , Hemodynamics/drug effects , Stroke Volume/drug effects , Ventricular Function, Left/physiology , Ventricular Pressure/drug effects , Ventricular Pressure/physiology , Ventricular Remodeling/physiology
7.
J Am Coll Cardiol ; 59(4): 410-7, 2012 Jan 24.
Article in English | MEDLINE | ID: mdl-22261164

ABSTRACT

OBJECTIVES: This study investigated the effects of 17ß-estradiol (E2) on gene regulation in human cardiac tissues. We hypothesized that a candidate E2 effect is cardiomyocyte (CM)- and sex-specific, conserved between humans and mice, and that E2 impairs contractile function in male CMs only. BACKGROUND: Both men and women produce E2 locally from androgenic precursors. E2 regulates cardiovascular function, but specific mechanisms, protective or harmful, are not fully understood. METHODS: We performed genome-wide expression profiling of E2-treated cardiac tissues from men and women, and studied gene expression and function in CMs from hearts of male and female E2-treated mice. RESULTS: We found 36 E2-dependent genes regulated in a sex-specific manner. Of these, after E2 exposure, the myosin regulatory light chain interacting protein (MYLIP) gene was induced in tissues of men only. Focusing on Mylip and employing isolated mouse CMs, we confirmed our hypotheses that the E2 effect is CM- and sex-specific and conserved between humans and mice. The E2-treatment led to impaired contractile function in male CMs only, which was characterized by increased Mylip mRNA and protein levels, and decreased myosin regulatory light chain (Mrlc) protein. Our report is the first to our knowledge to show that cardiac Mrlc is an in vivo substrate for Mylip, leading to augmented Mrlc ubiquitination. Of relevance, we found that MYLIP expression levels rise with increasing age in hearts of men. CONCLUSIONS: E2 directly influences cardiac gene regulation, and E2 actions may be different between the sexes. Since E2 levels rise in older and/or obese men, pharmacological targeting of MYLIP in men with elevated E2 levels could possibly decrease their risk for the development or progression of cardiovascular disease.


Subject(s)
Estradiol/metabolism , Myocardial Contraction , Myocytes, Cardiac/metabolism , Sex Characteristics , Ubiquitin-Protein Ligases/metabolism , Adult , Aging/metabolism , Animals , Female , Gene Expression Regulation , Humans , Male , Mice , Mice, Inbred C57BL , Middle Aged , Myosin Light Chains/metabolism , Transcriptome , Ubiquitination
8.
Purinergic Signal ; 8(Suppl 1): 91-9, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22081230

ABSTRACT

Adenosine, a purine nucleoside, is present in all cells in tightly regulated concentrations. It has many different physiological effects in the whole body and in the heart. Adenosine activates four G protein-coupled receptors A1, A2a, A2b, and A3. Activation of myocardial A1 receptors has been shown to inhibit a variety of myocardial pathologies associated with ischemia and reperfusion injury, including stunning, arrhythmogenesis, coronary and ventricular dysfunction, acute myocardial infarction, apoptosis, and chronic heart failure, implying several options for new cardiovascular therapies for diseases, like angina pectoris, control of cardiac rhythm, ischemic injury during an acute coronary syndrome, or heart failure. However, the main issue of using full A1 receptor agonists in such indications is the broad physiologic spectrum of cardiac and extracardiac effects. Desired A1 receptor-mediated protective and regenerative cardiovascular effects might be counter-regulated by unintended side effects when considering full A1 receptor agonists. These effects can be overcome by partial A1 agonists. Partial A1 agonists can be used to trigger only some of the physiological responses of receptor activation depending on endogenous adenosine levels and on receptor reserve in different tissues. CV-Therapeutics reported the identification of a partial A1 receptor agonist CVT-3619, and recently, another partial A1 receptor agonist VCP28 was published. Both compounds are adenosine derivatives. Adenosine-like A1 receptor agonists often have the drawback of a short half-life and low bioavailability, making them not suitable for chronic oral therapy. We identified the first non-adenosine-like partial A1 receptor agonist(s) with pharmacokinetics optimal for oral once daily treatment and characterized the qualities of the partial character of the A1 receptor agonist(s) in preclinical and clinical studies.

9.
Kidney Int ; 80(11): 1182-97, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21814170

ABSTRACT

Recent studies have shown renoprotective effects of the peroxisome proliferator-activated receptor-α (PPAR-α), but its role in kidney fibrosis is unknown. In order to gain insight into this, we examined the effect of a novel PPAR-α agonist, BAY PP1, in two rat models of renal fibrosis: unilateral ureteral obstruction and the 5/6 nephrectomy. In healthy animals, PPAR-α was expressed in tubular but not in interstitial cells. Upon induction of fibrosis, PPAR-α was significantly downregulated, and treatment with BAY PP1 significantly restored its expression. During ureteral obstruction, treatment with BAY PP1 significantly reduced tubulointerstitial fibrosis, proliferation of interstitial fibroblasts, and TGF-ß(1) expression. Treatment with a less potent PPAR-α agonist, fenofibrate, had no effects. Treatment with BAY PP1, initiated in established disease in the 5/6 nephrectomy, halted the decline of renal function and significantly ameliorated renal fibrosis. In vitro, BAY PP1 had no direct effect on renal fibroblasts but reduced collagen, fibronectin, and TGF-ß(1) expression in tubular cells. Conditioned media of BAY PP1-treated tubular cells reduced fibroblast proliferation. Thus, renal fibrosis is characterized by a reduction of PPAR-α expression, and treatment with BAY PP1 restores PPAR-α expression and ameliorates renal fibrosis by modulating the cross-talk between tubular cells and fibroblasts. Hence, potent PPAR-α agonists might be useful in the treatment of renal fibrosis.


Subject(s)
3-Mercaptopropionic Acid/analogs & derivatives , Fibrosis/prevention & control , Kidney Diseases/drug therapy , Peroxisome Proliferator-Activated Receptors/agonists , Pyrimidines/therapeutic use , 3-Mercaptopropionic Acid/pharmacology , 3-Mercaptopropionic Acid/therapeutic use , Animals , Cell Proliferation/drug effects , Fibrosis/drug therapy , Kidney Diseases/pathology , Kidney Tubules/pathology , Nephrectomy , Protective Agents , Pyrimidines/pharmacology , Rats , Treatment Outcome , Ureteral Obstruction/drug therapy
10.
J Hypertens ; 29(5): 961-70, 2011 May.
Article in English | MEDLINE | ID: mdl-21451422

ABSTRACT

BACKGROUND: The cardiac nitric oxide and endothelin-1 (ET-1) systems are closely linked and play a critical role in cardiac physiology. The balance between both systems is often disturbed in cardiovascular diseases. To define the cardiac effect of excessive ET-1 in a status of nitric oxide deficiency, we compared left ventricular function and morphology in wild-type mice, ET-1 transgenic (ET(+/+)) mice, endothelial nitric oxide synthase knockout (eNOS(-/-)) mice, and ET(+/+)eNOS(-/-) mice. METHODS AND RESULTS: eNOS(-/-) and ET(+/+)eNOS(-/-) mice developed high blood pressure compared with wild-type and ET(+/+) mice. Left ventricular catheterization showed that eNOS(-/-) mice, but not ET(+/+)eNOS(-/-) , developed diastolic dysfunction characterized by increased end-diastolic pressure and relaxation constant tau. To elucidate the causal molecular mechanisms driving the rescue of diastolic function in ET(+/+)eNOS(-/-) mice, the cardiac proteome was analyzed. Two-dimensional gel electrophoresis coupled to mass spectrometry offers an appropriate hypothesis-free approach. ET-1 overexpression on an eNOS(-/-) background led to an elevated abundance and change in posttranslational state of antioxidant enzymes (e.g., peroxiredoxin-6, glutathione S-transferase mu 2, and heat shock protein beta 7). In contrast to ET(+/+)eNOS(-/-) mice, eNOS(-/-) mice showed an elevated abundance of proteins responsible for sarcomere disassembly (e.g., cofilin-1 and cofilin-2). In ET(+/+)eNOS(-/-) mice, glycolysis was favored at the expense of fatty acid oxidation. CONCLUSION: eNOS(-/-) mice developed diastolic dysfunction; this was rescued by ET-1 transgenic overexpression. This study furthermore suggests that cardiac ET-1 overexpression in case of eNOS deficiency causes specifically the regulation of proteins playing a role in oxidative stress, myocytes contractility, and energy metabolism.


Subject(s)
Diastole , Endothelin-1/physiology , Nitric Oxide Synthase Type III/physiology , Animals , Blood Pressure , Blotting, Western , Body Weight , Endothelin-1/genetics , Female , Immunohistochemistry , Male , Mice , Mice, Knockout , Mice, Transgenic , Natriuretic Peptide, Brain/metabolism , Nitric Oxide Synthase Type III/genetics , Organ Size , Spectrometry, Mass, Electrospray Ionization , Tandem Mass Spectrometry
11.
PLoS One ; 6(3): e18048, 2011 Mar 28.
Article in English | MEDLINE | ID: mdl-21464936

ABSTRACT

The release of the neurotransmitter norepinephrine (NE) is modulated by presynaptic adenosine receptors. In the present study we investigated the effect of a partial activation of this feedback mechanism. We hypothesized that partial agonism would have differential effects on NE release in isolated hearts as well as on heart rate in vivo depending on the genetic background and baseline sympathetic activity. In isolated perfused hearts of Wistar and Spontaneously Hypertensive Rats (SHR), NE release was induced by electrical stimulation under control conditions (S1), and with capadenoson 6 · 10(-8) M (30 µg/l), 6 · 10(-7) M (300 µg/l) or 2-chloro-N(6)-cyclopentyladenosine (CCPA) 10(-6) M (S2). Under control conditions (S1), NE release was significantly higher in SHR hearts compared to Wistar (766+/-87 pmol/g vs. 173+/-18 pmol/g, p<0.01). Capadenoson led to a concentration-dependent decrease of the stimulation-induced NE release in SHR (S2/S1  =  0.90 ± 0.08 with capadenoson 6 · 10(-8) M, 0.54 ± 0.02 with 6 · 10(-7) M), but not in Wistar hearts (S2/S1  =  1.05 ± 0.12 with 6 · 10(-8) M, 1.03 ± 0.09 with 6 · 10(-7) M). CCPA reduced NE release to a similar degree in hearts from both strains. In vivo capadenoson did not alter resting heart rate in Wistar rats or SHR. Restraint stress induced a significantly greater increase of heart rate in SHR than in Wistar rats. Capadenoson blunted this stress-induced tachycardia by 45% in SHR, but not in Wistar rats. Using a [(35)S]GTPγS assay we demonstrated that capadenoson is a partial agonist compared to the full agonist CCPA (74+/-2% A(1)-receptor stimulation). These results suggest that partial adenosine A(1)-agonism dampens stress-induced tachycardia selectively in rats susceptible to strong increases in sympathetic activity, most likely due to a presynaptic attenuation of NE release.


Subject(s)
Adenosine A1 Receptor Agonists/pharmacology , Heart Rate/drug effects , Norepinephrine/metabolism , Receptor, Adenosine A1/metabolism , Stress, Physiological/drug effects , Animals , Blood Pressure/drug effects , Female , In Vitro Techniques , Rats , Rats, Inbred SHR , Rats, Wistar , Restraint, Physical
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