CXL-1020, a Novel Nitroxyl (HNO) Prodrug, Is More Effective than Milrinone in Models of Diastolic Dysfunction—A Cardiovascular Therapeutic: An Efficacy and Safety Study in the Rat

The nitroxyl (HNO) prodrug, CXL-1020, induces vasorelaxation and improves cardiac function in canine models and patients with systolic heart failure (HF). HNO's unique mechanism of action may be applicable to a broader subset of cardiac patients. This study investigated the load-independent safety and efficacy of CXL-1020 in two rodent (rat) models of diastolic heart failure and explored potential drug interactions with common HF background therapies. In vivo left-ventricular hemodynamics/pressure-volume relationships assessed before/during a 30 min IV infusion of CXL-1020 demonstrated acute load-independent positive inotropic, lusitropic, and vasodilatory effects in normal rats. In rats with only diastolic dysfunction due to bilateral renal wrapping (RW) or pronounced diastolic and mild systolic dysfunction due to 4 weeks of chronic isoproterenol exposure (ISO), CXL-1020 attenuated the elevated LV filling pressures, improved the end diastolic pressure volume relationship, and accelerated relaxation. CXL-1020 facilitated Ca2+ re-uptake and enhanced myocyte relaxation in isolated cardiomyocytes from ISO rats. Compared to milrinone, CXL-1020 more effectively improved Ca2+ reuptake in ISO rats without concomitant chronotropy, and did not enhance Ca2+ entry via L-type Ca2+ channels nor increase myocardial arrhythmias/ectopic activity. Acute-therapy with CXL-1020 improved ventricular relaxation and Ca2+ cycling, in the setting of chronic induced diastolic dysfunction. CXL-1020's lusitropic effects were greater than those seen with the cAMP-dependent agent milrinone, and unlike milrinone it did not produce chronotropy or increased ectopy. HNO is a promising new potential therapy for both systolic and diastolic heart failure.

• Publication year

  2017

• Venue

  Frontiers in Physiology

• Publication date

  2017-11-10

• Fields of study

  Medicine

• Identifiers
  DOI 10.3389/fphys.2017.00894PMID 29209225PMCID 5701606
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• Compared with milrinone, CXL-1020 more effectively improved Ca2+ reuptake in ISO rats without concomitant chronotropy, and it did not increase L-type Ca2+ channel entry or myocardial arrhythmias/ectopic activity.

  Confidence 0.95

  박진우 (dztg5apj7m) extractionKiller Whale (322360f1c1) reviewB (s683577b42) reviewmexicorea (qjvnbu8xg3) review
• In rat models of diastolic heart failure, CXL-1020 attenuated elevated left-ventricular filling pressures, improved the end-diastolic pressure-volume relationship, and accelerated relaxation.

  Confidence 0.96

  박진우 (dztg5apj7m) extractionKiller Whale (322360f1c1) reviewB (s683577b42) reviewmexicorea (qjvnbu8xg3) review
• CXL-1020 produced acute load-independent positive inotropic, lusitropic, and vasodilatory effects in normal rats during a 30 min IV infusion.

  Confidence 0.97

  박진우 (dztg5apj7m) extractionKiller Whale (322360f1c1) reviewB (s683577b42) reviewmexicorea (qjvnbu8xg3) review

• bilateral renal wrapping

  animal model, disease model

  A rat model of isolated diastolic dysfunction created by wrapping both kidneys to induce the phenotype.

  Aliases: RW

  박진우 (dztg5apj7m) extractionKiller Whale (322360f1c1) reviewB (s683577b42) reviewmexicorea (qjvnbu8xg3) review
• ca2+ reuptake

  cellular process, physiologic process

  The process of clearing cytosolic calcium back into intracellular stores during cardiomyocyte relaxation, measured in isolated cells from ISO rats.

  Aliases: calcium reuptake

  박진우 (dztg5apj7m) extractionKiller Whale (322360f1c1) reviewB (s683577b42) reviewmexicorea (qjvnbu8xg3) review
• chronic isoproterenol exposure

  animal model, disease model

  A rat model induced by four weeks of isoproterenol treatment that produces diastolic dysfunction with mild systolic impairment.

  Aliases: ISO model

  박진우 (dztg5apj7m) extractionKiller Whale (322360f1c1) reviewB (s683577b42) reviewmexicorea (qjvnbu8xg3) review
• cxl-1020

  compound, therapeutic agent

  A nitroxyl prodrug administered by intravenous infusion and tested as the intervention in the rat heart-failure models.

  박진우 (dztg5apj7m) extractionKiller Whale (322360f1c1) reviewB (s683577b42) reviewmexicorea (qjvnbu8xg3) review
• diastolic heart failure

  disease, condition

  A heart-failure phenotype characterized by impaired ventricular relaxation and elevated filling pressures, represented by the rat models used here.

  Aliases: HF with diastolic dysfunction

  박진우 (dztg5apj7m) extractionKiller Whale (322360f1c1) reviewB (s683577b42) reviewmexicorea (qjvnbu8xg3) review
• milrinone

  drug, comparator

  A cAMP-dependent inotropic comparator drug used to benchmark CXL-1020's cardiac effects.

  박진우 (dztg5apj7m) extractionKiller Whale (322360f1c1) reviewB (s683577b42) reviewmexicorea (qjvnbu8xg3) review
• nitroxyl (hno) prodrug

  compound class, prodrug

  A drug class that releases nitroxyl, the active species underlying CXL-1020's pharmacology in the abstract.

  Aliases: HNO prodrug

  박진우 (dztg5apj7m) extractionKiller Whale (322360f1c1) reviewB (s683577b42) reviewmexicorea (qjvnbu8xg3) review

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