Haemodynamic effects of the nitroxyl donor cimlanod (<scp>BMS</scp>‐986231) in chronic heart failure: a randomized trial

Lang, Ninian N.; Ahmad, Faheem; Cleland, John G.F.; O’Connor, Christopher M; Teerlink, John R.; Voors, Adriaan A.; Täubel, Jörg; Hodes, Anke R; Anwar, Mohamed; Karra, Ravi; Sakata, Yasushi; Ishihara, Shiro; Senior, Roxy; Khemka, Abhishek; Prasad, Narayana; DeSouza, Mary M.; Seiffert, Dietmar; Ye, June Y; Kessler, Paul D.; Borentain, Maria; Solomon, Scott D.; Felker, G. Michael; McMurray, John J.V.

doi:10.1002/ejhf.2138

Cited by 17 publications

(16 citation statements)

References 21 publications

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“…40 Interestingly, in HF patients with reduced ejection fraction, the pure nitroxyl donor cimlanod lowered blood pressure mostly by inducing venodilation, in a similar manner to nitroglycerin. 41 Nitroglycerin has been shown to lower blood pressure at least partly by the oxidative activation of PKGI. 42 Whether differential CXL-1020-mediated MAP lowering in KI and WT occurs as well in response to other stimuli than Ang II such as endothelin-1 or α1-adrenoceptor agonists, remains the topic of future investigations.…”

Section: Discussionmentioning

confidence: 99%

Nitroxyl Donor CXL-1020 Lowers Blood Pressure by Targeting C195 in Cyclic Guanosine-3’,5’-Monophosphate-Dependent Protein Kinase I

et al. 2022

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Background: We previously demonstrated that nitroxyl causes vasodilation, at least in part, by inducing the formation of an intradisulfide bond between C117 and C195 in the high affinity cyclic guanosine monophosphate-binding site of PKGI (cyclic guanosine monophosphate-dependent protein kinase I). The aim of this study was to determine whether nitroxyl donors lower blood pressure via this novel PKGI activation mechanism in vivo. Methods: To determine this, a C195S PKGI knock-in mouse model was generated that ubiquitously and constitutively expresses a mutant kinase resistant to nitroxyl-induced intradisulfide activation. Results: Knock-in and wild-type littermates did not differ in appearance, body weight, in PKGI protein expression or blood gas content. Organ weight was similar between genotypes apart from the cecum that was significantly enlarged in knock-in animals. Mean arterial pressure and heart rate monitored in vivo over 24 hours by radio-telemetry revealed neither a significant difference between genotypes at baseline nor during angiotensin II–induced hypertension or sepsis. CXL-1020, a clinically relevant nitroxyl donor, did not lower blood pressure in normotensive animals. In contrast, administering CXL-1020 to hypertensive wild-type mice reduced their blood pressure by 10±4 mm Hg ( P =0.0184), whereas the knock-in littermates were unaffected. Conclusions: Oxidation of C195 in PKGI contributes to the antihypertensive effects observed in response to nitroxyl donors, emphasising the potential importance of nitroxyl donors in pathological scenarios when cyclic guanosine monophosphate levels are reduced and insufficient to activate PKGI.

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Section: Discussionmentioning

confidence: 99%

Nitroxyl Donor CXL-1020 Lowers Blood Pressure by Targeting C195 in Cyclic Guanosine-3’,5’-Monophosphate-Dependent Protein Kinase I

et al. 2022

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“…Both drugs had similar effects, namely venodilatation and preload reduction, without additional inotropic or lusitropic effects. 9 Cardiac contractility modulation (CCM) may improve functional capacity and reduce CV and HF hospitalizations. 10,11 Long-term effects of CCM were evaluated in a European prospective registry including 503 patients.…”

Section: New Treatmentsmentioning

confidence: 99%

July 2021 at a glance: focus on blood volume distribution, haemodynamics and adherence to therapy

Tomasoni

Adamo

Metra

2021

European J of Heart Fail

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“…Interest in azanone donors and in the biological chemistry of HNO has increased significantly during the last 2 decades, due to the beneficial pharmacological effects of its donors in the treatment of heart failure. Currently, an HNO donor cimlanod (BMS-986231, CXL-1427) is in clinical trials for heart failure treatments ( Felker et al, 2019 ; Felker et al, 2021 ; Greenberg and Urey, 2021 ; Lang et al, 2021 ). This review focuses on the chemistry of aqueous solutions of HNO, with emphasis on the reaction kinetics and mechanisms.…”

Section: Introductionmentioning

confidence: 99%

The Chemistry of HNO: Mechanisms and Reaction Kinetics

et al. 2022

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Azanone (HNO, also known as nitroxyl) is the protonated form of the product of one-electron reduction of nitric oxide (•NO), and an elusive electrophilic reactive nitrogen species of increasing pharmacological significance. Over the past 20 years, the interest in the biological chemistry of HNO has increased significantly due to the numerous beneficial pharmacological effects of its donors. Increased availability of various HNO donors was accompanied by great progress in the understanding of HNO chemistry and chemical biology. This review is focused on the chemistry of HNO, with emphasis on reaction kinetics and mechanisms in aqueous solutions.

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Haemodynamic effects of the nitroxyl donor cimlanod (BMS‐986231) in chronic heart failure: a randomized trial

Cited by 17 publications

References 21 publications

Nitroxyl Donor CXL-1020 Lowers Blood Pressure by Targeting C195 in Cyclic Guanosine-3’,5’-Monophosphate-Dependent Protein Kinase I

Nitroxyl Donor CXL-1020 Lowers Blood Pressure by Targeting C195 in Cyclic Guanosine-3’,5’-Monophosphate-Dependent Protein Kinase I

July 2021 at a glance: focus on blood volume distribution, haemodynamics and adherence to therapy

The Chemistry of HNO: Mechanisms and Reaction Kinetics

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