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

Abstract

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.

Intravenous Infusion of the Novel HNO Donor BMS-986231 Is Associated With Beneficial Inotropic, Lusitropic, and Vasodilatory Properties in 2 Canine Models of Heart Failure

“…Earlier in vitro nuclear magnetic resonance studies (data not shown) demonstrated that BMS-986231 in phosphate-buffered saline was converted stoichiometrically to HNO and its inactive by-product, BMT-284730; furthermore, when this conversion in phosphate-buffered saline took place in the presence of excess glutathione, stoichiometric trapping of HNO as a glutathione adduct occurred. In addition, a study of CXL-1020 in rats reported hemodynamic effects that were not only similar to those seen with BMS-986231 in the present studies with dogs, but were different to those of the NO donor sodium nitroprusside (13) . Regarding the biochemical effects of BMS-986231 in humans, in the phase 2a study, BMS-986231 (3 to 12 μg/kg/min) was not associated with adverse changes in laboratory parameters, including brain natriuretic peptide, troponin I, serum creatinine, liver enzymes, hemoglobin, or platelet count (22) .…”

“…Nitroxyl (HNO) donors are a class of molecules with unique biochemical and pharmacological properties that have been investigated over several years for their potential therapeutic applications. Although related to nitric oxide (NO), the pharmacological effects of HNO are different from NO; these effects produce arterial and venous dilation, as well as direct, beneficial, cAMP/protein kinase A-independent lusitropic and inotropic effects, in both the normal and failing myocardium 8 , 10 , 12 , 13 . HNO enhances sarcoplasmic reticular calcium uptake and release through modulation of sarcoplasmic reticulum calcium 2+ adenosine triphosphatase (SERCA2a), phospholamban (PLN), and the ryanodine receptors.…”

Effect of Loading Changes on the Intraventricular Pressure Measured by Color M-Mode Echocardiography in Rats

“…A 24G intravenous catheter was introduced through the jugular vein. In the first experiment, after the acquisition of echocardiographic images at baseline (BL), milrinone (MIL) (Maruishi Pharmaceutical, Osaka, Japan) was administered intravenously at a constant rate of 10 µL kg −1 min −1 according to the previously reported protocol [27]. Echocardiographic examinations were repeated 20 min after MIL infusion.…”

Regulation of Cardiac PKA Signaling by cAMP and Oxidants

“…The latter has been attributed to general disulfide induction in oxidant-susceptible proteins that culminate in the enhancement of sarcomere shortening and cardiac myocyte relaxation. This includes an increase in Ca 2+ -reuptake into the SR and an acceleration of cross-bridge cycling by disulfide crosslinking of proteins localized to the SR—PLN and SERCA2a—and the myofilament—tropomyosin and the myosin light chains—compartment [ 204 , 205 , 206 , 207 , 208 ]. Recently, disulfide formation in PKA and PP2A subunits has been described to contribute to this scenario and to occur independently of β-adrenoceptor activation [ 44 ].…”