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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 30min 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 Ca+2 re-uptake and enhanced myocyte relaxation in isolated cardiomyocytes from ISO rats. Compared to milrinone, CXL-1020 more effectively improved Ca+2 reuptake in ISO rats without concomitant chronotropy, and did not enhance Ca+2 entry via L-type Ca+2 channels nor increase myocardial arrhythmias/ectopic activity. Acute-therapy with CXL-1020 improved ventricular relaxation and Ca+2 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. [ABSTRACT FROM AUTHOR]

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To evaluate potential mechanisms of clinical hepatotoxicity, 4 endothelin receptor antagonists (ERAs) were examined for substrate activity and inhibition of hepatic uptake and efflux transporters in sandwich-cultured human hepatocytes. The 4 transporters studied were sodium-dependent taurocholate cotransporter (NTCP), organic anion transporter (OATP), bile salt export pump (BSEP), and multidrug resistance-associated protein 2 (MRP2). ERA transporter inhibition was examined using the substrates taurocholate (for NTCP and BSEP), [3H]estradiol-17β-d-glucuronide (for OATP), and [2-d-penicillamine, 5-d-penicillamine]enkephalin (for MRP2). ERA substrate activity was evaluated using probe inhibitors ritonavir (OATP and BSEP), bromosulfalein (OATP), erythromycin (P-glycoprotein), probenecid (MRP2 and OATP), and cyclosporin (NTCP). ERAs were tested at 2, 20, and 100 µmol·L-1 for inhibition and at 2 µmol·L-1 as substrates. OATP, NTCP, or BSEP transport activity was not reduced by ambrisentan or darusentan. Bosentan and sitaxsentan attenuated NTCP transport at higher concentrations. Only sitaxsentan decreased OATP transport (52%), and only bosentan reduced BSEP transport (78%). MRP2 transport activity was unaltered. OATP inhibitors decreased influx of all ERAs. Darusentan influx was least affected (84%-100% of control), whereas bosentan was most affected (32%-58% of control). NTCP did not contribute to influx of ERAs. Only bosentan and darusentan were shown as substrates for both BSEP and P-glycoprotein efflux. All ERAs tested were substrates for at least one hepatic transporter. Bosentan and sitaxsentan, but not ambrisentan and darusentan, inhibited human hepatic transporters, which provides a potential mechanism for the increased hepatotoxicity observed for these agents in the clinical setting. Afin d’évaluer les mécanismes potentiels de l’hépatotoxicité clinique, on a examiné quatre antagonistes des récepteurs de l’endothéline (ARE) relativement à l’activité de substrats et à l’inhibition de transporteurs de capture et d’efflux hépatiques (NTCP, OATP, BSEP, MRP2), en utilisant des hépatocytes humains cultivés en configuration sandwich. On a examiné l’inhibition des transporteurs par les ARE en utilisant les substrats taurocholate (NTCP et BSEP), E2-17βG (OATP) et DPDPE (MRP2). On a évalué l’activité de substrats des ARE en utilisant les inhibiteurs ritonavir (OATP et BSEP), bromosulfaléine (OATP), érythromycine (P-glycoprotéine) et probénécide (MRP2 et OATP). On a examiné la capacité d’inhibition à 2, 20 et 100 µmol/L, et l’activité de substrats à 2 µmol/L. L’ambrisentan et le darusentan n’ont pas diminué l’activité de transport d’OATP, de NTCP ou de BSEP. Le bosentan et le sitaxsentan ont atténué le transport de NTCP aux concentrations élevées. Seul le sitaxsentan a diminué le transport d’OATP (52 %) ; seul le bosentan a diminué l’activité de transport de BSEP (78 %). L’activité de transport de MRP2 n’a pas été modifiée. Les inhibiteurs d’OATP ont diminué l’influx de tous les ARE. L’influx de darusentan a été le moins touché (84 %-100 % des valeurs témoins), alors que celui de bosentan a été le plus affecté (32 %-58 % des valeurs témoins). Le NTCP n’a pas contribué à l’influx des ARE. Seuls le bosentan et le darusentan se sont démarqués comme substrats des efflux de BSEP et de P-glycoprotéine. Tous les ARE examinés ont été des substrats d’au moins un transporteur hépatique. Le bosentan et le sitaxsentan, mais pas l’ambrisentan ni le darusentan, ont inhibé les transporteurs hépatiques humains, ce qui fournit un mécanisme potentiel de l’augmentation d’hépatotoxicité de ces agents en milieu clinique. [ABSTRACT FROM AUTHOR]