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Publication Record


Structure-Function Studies of Naphthalene, Phenanthrene, Biphenyl, and Their Derivatives in Interaction with and Oxidation by Cytochromes P450 2A13 and 2A6.
Shimada T, Takenaka S, Kakimoto K, Murayama N, Lim YR, Kim D, Foroozesh MK, Yamazaki H, Guengerich FP, Komori M
(2016) Chem Res Toxicol 29: 1029-40
MeSH Terms: Aryl Hydrocarbon Hydroxylases, Biphenyl Compounds, Cytochrome P-450 CYP2A6, Humans, Molecular Structure, Naphthalenes, Oxidation-Reduction, Phenanthrenes
Show Abstract · Added March 14, 2018
Naphthalene, phenanthrene, biphenyl, and their derivatives having different ethynyl, propynyl, butynyl, and propargyl ether substitutions were examined for their interaction with and oxidation by cytochromes P450 (P450) 2A13 and 2A6. Spectral interaction studies suggested that most of these chemicals interacted with P450 2A13 to induce Type I binding spectra more readily than with P450 2A6. Among the various substituted derivatives examined, 2-ethynylnaphthalene, 2-naphthalene propargyl ether, 3-ethynylphenanthrene, and 4-biphenyl propargyl ether had larger ΔAmax/Ks values in inducing Type I binding spectra with P450 2A13 than their parent compounds. P450 2A13 was found to oxidize naphthalene, phenanthrene, and biphenyl to 1-naphthol, 9-hydroxyphenanthrene, and 2- and/or 4-hydroxybiphenyl, respectively, at much higher rates than P450 2A6. Other human P450 enzymes including P450s 1A1, 1A2, 1B1, 2C9, and 3A4 had lower rates of oxidation of naphthalene, phenanthrene, and biphenyl than P450s 2A13 and 2A6. Those alkynylated derivatives that strongly induced Type I binding spectra with P450s 2A13 and 2A6 were extensively oxidized by these enzymes upon analysis with HPLC. Molecular docking studies supported the hypothesis that ligand-interaction energies (U values) obtained with reported crystal structures of P450 2A13 and 2A6 bound to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, indole, pilocarpine, nicotine, and coumarin are of use in understanding the basis of possible molecular interactions of these xenobiotic chemicals with the active sites of P450 2A13 and 2A6 enzymes. In fact, the ligand-interaction energies with P450 2A13 4EJG bound to these chemicals were found to relate to their induction of Type I binding spectra.
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8 MeSH Terms
Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition.
Hubers SA, Brown NJ
(2016) Circulation 133: 1115-24
MeSH Terms: Abnormalities, Drug-Induced, Aminobutyrates, Angioedema, Angiotensin Receptor Antagonists, Biphenyl Compounds, Bradykinin, Contraindications, Drug Combinations, Drug Costs, Drug Synergism, Enalapril, Enzyme Inhibitors, Female, Follow-Up Studies, Heart Failure, Humans, Hyperkalemia, Hypertension, Kidney, Multicenter Studies as Topic, Natriuretic Peptides, Neprilysin, Pregnancy, Prodrugs, Prospective Studies, Pyridines, Randomized Controlled Trials as Topic, Stroke Volume, Tetrazoles, Thiazepines, Valsartan
Show Abstract · Added April 6, 2017
Heart failure affects ≈5.7 million people in the United States alone. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, and aldosterone antagonists have improved mortality in patients with heart failure and reduced ejection fraction, but mortality remains high. In July 2015, the US Food and Drug Administration approved the first of a new class of drugs for the treatment of heart failure: Valsartan/sacubitril (formerly known as LCZ696 and currently marketed by Novartis as Entresto) combines the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril in a 1:1 ratio in a sodium supramolecular complex. Sacubitril is converted by esterases to LBQ657, which inhibits neprilysin, the enzyme responsible for the degradation of the natriuretic peptides and many other vasoactive peptides. Thus, this combined angiotensin receptor antagonist and neprilysin inhibitor addresses 2 of the pathophysiological mechanisms of heart failure: activation of the renin-angiotensin-aldosterone system and decreased sensitivity to natriuretic peptides. In the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, valsartan/sacubitril significantly reduced mortality and hospitalization for heart failure, as well as blood pressure, compared with enalapril in patients with heart failure, reduced ejection fraction, and an elevated circulating level of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide. Ongoing clinical trials are evaluating the role of valsartan/sacubitril in the treatment of heart failure with preserved ejection fraction and hypertension. We review here the mechanisms of action of valsartan/sacubitril, the pharmacological properties of the drug, and its efficacy and safety in the treatment of heart failure and hypertension.
© 2016 American Heart Association, Inc.
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31 MeSH Terms
PIM kinase inhibitor AZD1208 for treatment of MYC-driven prostate cancer.
Kirschner AN, Wang J, van der Meer R, Anderson PD, Franco-Coronel OE, Kushner MH, Everett JH, Hameed O, Keeton EK, Ahdesmaki M, Grosskurth SE, Huszar D, Abdulkadir SA
(2015) J Natl Cancer Inst 107:
MeSH Terms: Administration, Oral, Allografts, Animals, Antineoplastic Agents, Apoptosis, Biphenyl Compounds, Cell Hypoxia, Cell Proliferation, Down-Regulation, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Genes, myc, Humans, Male, Mice, Prostatic Neoplasms, Prostatic Neoplasms, Castration-Resistant, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-pim-1, Thiazolidines, Tumor Suppressor Protein p53, Xenograft Model Antitumor Assays
Show Abstract · Added January 21, 2015
BACKGROUND - PIM1 kinase is coexpressed with c-MYC in human prostate cancers (PCs) and dramatically enhances c-MYC-induced tumorigenicity. Here we examine the effects of a novel oral PIM inhibitor, AZD1208, on prostate tumorigenesis and recurrence.
METHODS - A mouse c-MYC/Pim1-transduced tissue recombination PC model, Myc-CaP allografts, and human PC xenografts were treated with AZD1208 (n = 5-11 per group). Androgen-sensitive and castrate-resistant prostate cancer (CRPC) models were studied as well as the effects of hypoxia and radiation. RNA sequencing was used to analyze drug-induced gene expression changes. Results were analyzed with χ(2) test. Student's t test and nonparametric Mann-Whitney rank sum U Test. All statistical tests were two-sided.
RESULTS - AZD1208 inhibited tumorigenesis in tissue recombinants, Myc-CaP, and human PC xenograft models. PIM inhibition decreased c-MYC/Pim1 graft growth by 54.3 ± 39% (P < .001), decreased cellular proliferation by 46 ± 14% (P = .016), and increased apoptosis by 326 ± 170% (P = .039). AZD1208 suppressed multiple protumorigenic pathways, including the MYC gene program. However, it also downregulated the p53 pathway. Hypoxia and radiation induced PIM1 in prostate cancer cells, and AZD1208 functioned as a radiation sensitizer. Recurrent tumors postcastration responded transiently to either AZD1208 or radiation treatment, and combination treatment resulted in more sustained inhibition of tumor growth. Cell lines established from recurrent, AZD1208-resistant tumors again revealed downregulation of the p53 pathway. Irradiated AZD1208-treated tumors robustly upregulated p53, providing a possible mechanistic explanation for the effectiveness of combination therapy. Finally, an AZD1208-resistant gene signature was found to be associated with biochemical recurrence in PC patients.
CONCLUSIONS - PIM inhibition is a potential treatment for MYC-driven prostate cancers including CRPC, and its effectiveness may be enhanced by activators of the p53 pathway, such as radiation.
© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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22 MeSH Terms
Visit-to-visit variability in blood pressure and kidney and cardiovascular outcomes in patients with type 2 diabetes and nephropathy: a post hoc analysis from the RENAAL study and the Irbesartan Diabetic Nephropathy Trial.
McMullan CJ, Lambers Heerspink HJ, Parving HH, Dwyer JP, Forman JP, de Zeeuw D
(2014) Am J Kidney Dis 64: 714-22
MeSH Terms: Aged, Angiotensin II Type 1 Receptor Blockers, Biphenyl Compounds, Blood Pressure, Cardiovascular Diseases, Cohort Studies, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Double-Blind Method, Female, Follow-Up Studies, Humans, Irbesartan, Kidney, Male, Middle Aged, Office Visits, Prospective Studies, Tetrazoles, Treatment Outcome
Show Abstract · Added October 28, 2014
BACKGROUND - Increased systolic blood pressure variability between outpatient visits is associated with increased incidence of cardiovascular end points. However, few studies have examined the association of visit-to-visit variability in systolic blood pressure with clinically relevant kidney disease outcomes. We analyzed the association of systolic blood pressure visit-to-visit variability with renal and cardiovascular morbidity and mortality among individuals with diabetes and nephropathy.
STUDY DESIGN - Observational analysis of IDNT (Irbesartan Diabetic Nephropathy Trial) and the RENAAL (Reduction of End Points in Non-Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan) Study.
SETTING & PARTICIPANTS - 2,739 participants with type 2 diabetes and nephropathy with at least 1 year of blood pressure measurements available.
PREDICTORS - Systolic blood pressure visit-to-visit variability was calculated from the SD of the systolic blood pressure from 4 visits occurring 3-12 months postrandomization.
OUTCOMES - The kidney disease outcome was defined as time to confirmed doubling of serum creatinine level, end-stage renal disease, or death; the cardiovascular outcome was defined as time to cardiovascular death, myocardial infarction, stroke, hospitalization for heart failure, or revascularization.
RESULTS - Mean visit-to-visit variability in systolic blood pressure from 3 to 12 months postrandomization was 12.0±6.8(SD)mmHg. Following this ascertainment period, there were 954 kidney disease and 542 cardiovascular events. Greater systolic blood pressure visit-to-visit variability was associated independently with increased risk of the composite kidney disease end point (HR per 1-SD increment, 1.08 [95%CI, 1.01-1.16]; P=0.02) and end-stage renal disease, but not with the cardiovascular outcome.
LIMITATIONS - Observational study with the potential for confounding.
CONCLUSIONS - In diabetic individuals with nephropathy, systolic blood pressure visit-to-visit variability is associated independently with hard kidney disease outcomes.
Copyright © 2014 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.
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20 MeSH Terms
Estimated GFR decline as a surrogate end point for kidney failure: a post hoc analysis from the Reduction of End Points in Non-Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan (RENAAL) study and Irbesartan Diabetic Nephropathy Trial (IDNT).
Lambers Heerspink HJ, Weldegiorgis M, Inker LA, Gansevoort R, Parving HH, Dwyer JP, Mondal H, Coresh J, Greene T, Levey AS, de Zeeuw D
(2014) Am J Kidney Dis 63: 244-50
MeSH Terms: Aged, Angiotensin II Type 1 Receptor Blockers, Biomarkers, Biphenyl Compounds, Diabetes Mellitus, Type 2, Double-Blind Method, Female, Glomerular Filtration Rate, Humans, Irbesartan, Kidney Failure, Chronic, Losartan, Male, Middle Aged, Tetrazoles
Show Abstract · Added October 28, 2014
BACKGROUND - A doubling of serum creatinine value, corresponding to a 57% decline in estimated glomerular filtration rate (eGFR), is used frequently as a component of a composite kidney end point in clinical trials in type 2 diabetes. The aim of this study was to determine whether alternative end points defined by smaller declines in eGFR would improve the statistical power of these clinical trials.
STUDY DESIGN - Post hoc analyses of 2 multinational randomized controlled trials (Reduction of End Points in Non-Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan [RENAAL] and Irbesartan Diabetic Nephropathy Trial [IDNT]) that assessed the treatment effect of the angiotensin receptor blockers (ARBs) losartan and irbesartan.
SETTING & PARTICIPANTS - 1,513 (RENAAL) and 1,715 (IDNT) adult patients with type 2 diabetes and nephropathy.
PREDICTOR - Established versus alternative end points defined as a confirmed doubling of serum creatinine level versus confirmed eGFR decline of 57%, 40%, 30%, or 20% as a component of a composite end point of end-stage renal disease or eGFR < 15mL/min/1.73m(2).
OUTCOMES - Numbers of patients reaching end points, precision (standard error), and significance (z score) of ARB treatment effect (HR) during follow-up.
RESULTS - Lesser eGFR declines resulted in a greater number of patients reaching end points in both treatment groups and lower standard error of the HR, but the effect on z score was counterbalanced by attenuation of the HR. When calculating the eGFR decline from month 3, attenuation of the HR was less pronounced.
LIMITATIONS - Post hoc analysis.
CONCLUSIONS - Despite increases in precision of the treatment effect, eGFR declines less than a doubling of serum creatinine value did not consistently improve statistical power of the clinical trials due to attenuation of the treatment effect. Attenuation of the treatment effect appears to be due in part to acute effects of ARBs on eGFR. These findings should be taken into account when using lesser eGFR declines as alternative end points for clinical trials.
Copyright © 2014 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.
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15 MeSH Terms
The stress protein BAG3 stabilizes Mcl-1 protein and promotes survival of cancer cells and resistance to antagonist ABT-737.
Boiani M, Daniel C, Liu X, Hogarty MD, Marnett LJ
(2013) J Biol Chem 288: 6980-90
MeSH Terms: Adaptor Proteins, Signal Transducing, Antineoplastic Agents, Apoptosis, Apoptosis Regulatory Proteins, Biphenyl Compounds, Cell Line, Tumor, Cell Survival, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, Immunoblotting, Myeloid Cell Leukemia Sequence 1 Protein, Neoplasms, Nitrophenols, Piperazines, Proteasome Endopeptidase Complex, Protein Binding, Protein Stability, Proteolysis, Proto-Oncogene Proteins c-bcl-2, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, Sulfonamides, Ubiquitination
Show Abstract · Added March 7, 2014
Members of the Bcl-2 family of proteins are important inhibitors of apoptosis in human cancer and are targets for novel anticancer agents such as the Bcl-2 antagonists, ABT-263 (Navitoclax), and its analog ABT-737. Unlike Bcl-2, Mcl-1 is not antagonized by ABT-263 or ABT-737 and is considered to be a major factor in resistance. Also, Mcl-1 exhibits differential regulation when compared with other Bcl-2 family members and is a target for anticancer drug discovery. Here, we demonstrate that BAG3, an Hsp70 co-chaperone, protects Mcl-1 from proteasomal degradation, thereby promoting its antiapoptotic activity. Using neuroblastoma cell lines, with a defined Bcl-2 family dependence, we found that BAG3 expression correlated with Mcl-1 dependence and ABT-737 resistance. RNA silencing of BAG3 led to a marked reduction in Mcl-1 protein levels and overcame ABT-737 resistance in Mcl-1-dependent cells. In ABT-737-resistant cells, Mcl-1 co-immunoprecipitated with BAG3, and loss of Mcl-1 after BAG3 silencing was prevented by proteasome inhibition. BAG3 and Mcl-1 were co-expressed in a panel of diverse cancer cell lines resistant to ABT-737. Silencing BAG3 reduced Mcl-1 protein levels and overcame ABT-737 resistance in several of the cell lines, including triple-negative breast cancer (MDA-MB231) and androgen receptor-negative prostate cancer (PC3) cells. These studies identify BAG3-mediated Mcl-1 stabilization as a potential target for cancer drug discovery.
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25 MeSH Terms
Chemical modification of the M(1) agonist VU0364572 reveals molecular switches in pharmacology and a bitopic binding mode.
Digby GJ, Utley TJ, Lamsal A, Sevel C, Sheffler DJ, Lebois EP, Bridges TM, Wood MR, Niswender CM, Lindsley CW, Conn PJ
(2012) ACS Chem Neurosci 3: 1025-36
MeSH Terms: Allosteric Regulation, Allosteric Site, Animals, Benzamides, Biphenyl Compounds, CHO Cells, Cricetinae, Ligands, Muscarinic Agonists, Rats, Receptor, Muscarinic M1
Show Abstract · Added March 7, 2014
We previously reported the discovery of VU0364572 and VU0357017 as M(1)-selective agonists that appear to activate M(1) through actions at an allosteric site. Previous studies have revealed that chemical scaffolds for many allosteric modulators contain molecular switches that allow discovery of allosteric antagonists and allosteric agonists or positive allosteric modulators (PAMs) based on a single chemical scaffold. Based on this, we initiated a series of studies to develop selective M(1) allosteric antagonists based on the VU0364572 scaffold. Interestingly, two lead antagonists identified in this series, VU0409774 and VU0409775, inhibited ACh-induced Ca(2+) responses at rat M(1-5) receptor subtypes, suggesting they are nonselective muscarinic antagonists. VU0409774 and VU0409775 also completely displaced binding of the nonselective radioligand [(3)H]-NMS at M(1) and M(3) mAChRs with affinities similar to their functional IC(50) values. Finally, Schild analysis revealed that these compounds inhibit M(1) responses through a fully competitive interaction at the orthosteric binding site. This surprising finding prompted further studies to determine whether agonist activity of VU0364572 and VU0357017 may also engage in previously unappreciated actions at the orthosteric site on M(1). Surprisingly, both VU0364572 and VU0357017 completely displaced [(3)H]-NMS binding to the orthosteric site of M(1)-M(5) receptors at high concentrations. Furthermore, evaluation of agonist activity in systems with varying levels of receptor reserve and Furchgott analysis using a cell line expressing M(1) under control of an inducible promotor was consistent with an action of these compounds as weak orthosteric partial agonists of M(1). However, consistent with previous studies suggesting actions at a site that is distinct from the orthosteric binding site, VU0364572 or VU0357017 slowed the rate of [(3)H]-NMS dissociation from CHO-rM(1) membranes. Together, these results suggest that VU0364572 and VU0357017 act as bitopic ligands and that novel antagonists in this series act as competitive orthosteric site antagonists.
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11 MeSH Terms
A comprehensive strategy to discover inhibitors of the translesion synthesis DNA polymerase κ.
Yamanaka K, Dorjsuren D, Eoff RL, Egli M, Maloney DJ, Jadhav A, Simeonov A, Lloyd RS
(2012) PLoS One 7: e45032
MeSH Terms: Acrolein, Benzimidazoles, Biphenyl Compounds, Cell Line, Transformed, Cell Survival, DNA, DNA Adducts, DNA Damage, DNA Repair, DNA-Directed DNA Polymerase, Deoxyguanosine, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Enzyme Inhibitors, Humans, Indoles, Nucleic Acid Synthesis Inhibitors, Small Molecule Libraries, Terpenes, Tetrazoles, Ultraviolet Rays
Show Abstract · Added May 27, 2014
Human DNA polymerase kappa (pol κ) is a translesion synthesis (TLS) polymerase that catalyzes TLS past various minor groove lesions including N(2)-dG linked acrolein- and polycyclic aromatic hydrocarbon-derived adducts, as well as N(2)-dG DNA-DNA interstrand cross-links introduced by the chemotherapeutic agent mitomycin C. It also processes ultraviolet light-induced DNA lesions. Since pol κ TLS activity can reduce the cellular toxicity of chemotherapeutic agents and since gliomas overexpress pol κ, small molecule library screens targeting pol κ were conducted to initiate the first step in the development of new adjunct cancer therapeutics. A high-throughput, fluorescence-based DNA strand displacement assay was utilized to screen ∼16,000 bioactive compounds, and the 60 top hits were validated by primer extension assays using non-damaged DNAs. Candesartan cilexetil, manoalide, and MK-886 were selected as proof-of-principle compounds and further characterized for their specificity toward pol κ by primer extension assays using DNAs containing a site-specific acrolein-derived, ring-opened reduced form of γ-HOPdG. Furthermore, candesartan cilexetil could enhance ultraviolet light-induced cytotoxicity in xeroderma pigmentosum variant cells, suggesting its inhibitory effect against intracellular pol κ. In summary, this investigation represents the first high-throughput screening designed to identify inhibitors of pol κ, with the characterization of biochemical and biologically relevant endpoints as a consequence of pol κ inhibition. These approaches lay the foundation for the future discovery of compounds that can be applied to combination chemotherapy.
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21 MeSH Terms
Novel allosteric agonists of M1 muscarinic acetylcholine receptors induce brain region-specific responses that correspond with behavioral effects in animal models.
Digby GJ, Noetzel MJ, Bubser M, Utley TJ, Walker AG, Byun NE, Lebois EP, Xiang Z, Sheffler DJ, Cho HP, Davis AA, Nemirovsky NE, Mennenga SE, Camp BW, Bimonte-Nelson HA, Bode J, Italiano K, Morrison R, Daniels JS, Niswender CM, Olive MF, Lindsley CW, Jones CK, Conn PJ
(2012) J Neurosci 32: 8532-44
MeSH Terms: Animals, Arrestins, Behavior, Animal, Benzamides, Biphenyl Compounds, Brain, CHO Cells, Calcium, Cell Line, Corpus Striatum, Cricetinae, Cricetulus, Extracellular Signal-Regulated MAP Kinases, Extracellular Space, Fear, Gene Expression Profiling, Hippocampus, Humans, Male, Maze Learning, Membrane Potentials, Mice, Mice, Inbred C57BL, Muscarinic Agonists, Phosphorylation, Prefrontal Cortex, Rats, Rats, Sprague-Dawley, Receptor, Muscarinic M1
Show Abstract · Added March 7, 2014
M(1) muscarinic acetylcholine receptors (mAChRs) represent a viable target for treatment of multiple disorders of the central nervous system (CNS) including Alzheimer's disease and schizophrenia. The recent discovery of highly selective allosteric agonists of M(1) receptors has provided a major breakthrough in developing a viable approach for the discovery of novel therapeutic agents that target these receptors. Here we describe the characterization of two novel M(1) allosteric agonists, VU0357017 and VU0364572, that display profound differences in their efficacy in activating M(1) coupling to different signaling pathways including Ca(2+) and β-arrestin responses. Interestingly, the ability of these agents to differentially activate coupling of M(1) to specific signaling pathways leads to selective actions on some but not all M(1)-mediated responses in brain circuits. These novel M(1) allosteric agonists induced robust electrophysiological effects in rat hippocampal slices, but showed lower efficacy in striatum and no measureable effects on M(1)-mediated responses in medial prefrontal cortical pyramidal cells in mice. Consistent with these actions, both M(1) agonists enhanced acquisition of hippocampal-dependent cognitive function but did not reverse amphetamine-induced hyperlocomotion in rats. Together, these data reveal that M(1) allosteric agonists can differentially regulate coupling of M(1) to different signaling pathways, and this can dramatically alter the actions of these compounds on specific brain circuits important for learning and memory and psychosis.
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29 MeSH Terms
Albuminuria and blood pressure, independent targets for cardioprotective therapy in patients with diabetes and nephropathy: a post hoc analysis of the combined RENAAL and IDNT trials.
Holtkamp FA, de Zeeuw D, de Graeff PA, Laverman GD, Berl T, Remuzzi G, Packham D, Lewis JB, Parving HH, Lambers Heerspink HJ
(2011) Eur Heart J 32: 1493-9
MeSH Terms: Aged, Albuminuria, Amlodipine, Angiotensin Receptor Antagonists, Biphenyl Compounds, Blood Pressure, Calcium Channel Blockers, Cardiotonic Agents, Diabetes Mellitus, Type 2, Diabetic Angiopathies, Diabetic Nephropathies, Female, Heart Failure, Humans, Hypertension, Irbesartan, Losartan, Male, Middle Aged, Myocardial Infarction, Randomized Controlled Trials as Topic, Retrospective Studies, Risk Factors, Stroke, Tetrazoles, Treatment Outcome
Show Abstract · Added December 10, 2013
AIMS - The long-term cardioprotective effect of angiotensin receptor blockers (ARBs) is associated with the short-term lowering of its primary target blood pressure, but also with the lowering of albuminuria. Since the individual blood pressure and albuminuria response to an ARB varies between and within an individual, we tested whether the variability and discordance in systolic blood pressure (SBP) and albuminuria response to ARB therapy are associated with its long-term effect on cardiovascular outcomes.
METHODS AND RESULTS - The combined data of the RENAAL and IDNT trials were used. We first investigated the extent of variability and discordance in SBP and albuminuria response (baseline to 6 months). Subsequently, we assessed the combined impact of residual Month 6 SBP and albuminuria level with cardiovascular outcome. In ARB-treated patients, 421 patients (34.5%) either had a reduction in SBP but no reduction in albuminuria, or vice versa, indicating substantial discordance in response in these parameters. The initial reduction in SBP and albuminuria independently correlated with cardiovascular protection: HR per 5 mmHg SBP reduction 0.97 (95% CI 0.94-0.99) and HR per decrement log albuminuria 0.87 (95% CI 0.76-0.99). Across all SBP categories at Month 6, a progressively lower cardiovascular risk was observed with a lower albuminuria level. This was particularly evident in patients who reached the guideline recommended SBP target of ≤130 mmHg.
CONCLUSION - The SBP and albuminuria response to ARB therapy is variable and discordant. Therapies intervening in the renin-angiotensin-aldosterone system with the aim of improving cardiovascular outcomes may therefore require a dual approach targeting both blood pressure and albuminuria.
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26 MeSH Terms