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

Figures

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  Figure 1. Effects of CXL-1020 on systemic, energetic, and left-ventricular hemodynamic indices in instrumented normal anesthetized rats. (A) Percent change vs. baseline following 30 min of continuous IV infusion of CXL-1020 (100 μg/kg/min, n = 31). (B) Schematic of the experimental design with black block indicating data acquisition. (C) Representative PV loops and % change from baseline comparing CXL-1020 (n = 7) to volume matched vehicle control (7% Captisol, n = 8) (D) before and (E) during volume expansion with Hextend (~1–1.5 mL). (F) Representative PV loops and % change from baseline comparing CXL-1020 (n = 7) to SNP (25 μg/kg/min, n = 6) (G) before and (H) during afterload restoration with PE (5 μg/kg/min). *P < 0.05 vs. corresponding baseline.

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  Figure 2. Effects of clinically established drugs and CXL-1020 when administered in combination on estimated mechanical energy and LV hemodynamics indices in instrumented anesthetized normal rats. Summary data as % change from baseline of CXL-1020 administered with an (A) ACE inhibitor, (ENA, 1 mg/kg/hr, n = 5), (B) β-AR blocker, MET (1 mg/kg/h, n = 7), and β-AR 1 agonist, DOB (5 μg/kg/min, n = 7). Experimental design schematic with black block indicating data acquisition is below each corresponding graph. *P < 0.05 vs. corresponding baseline, #P < 0.05 vs. corresponding CXL-1020 alone.

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  Figure 3. Effect of CXL-1020 on systemic and LV hemodynamics indices in instrumented anesthetized RW and ISO rat models. (A) Echocardiographic evaluation on systolic and diastolic indices in RW (n = 15) and ISO rats (n = 6). (B) Cardiovascular profiles of CXL-1020 (100 μg/kg/min, n = 8) as shown as % change from baseline following 5 weeks of renal wrapping. (C) Representative single PV loop of the diastolic portion. (D) Cardiovascular profile of CXL-1020 (100 μg/kg/min, n = 6) as shown as % change from baseline following 4 weeks of chronic ISO. (E) Representative single PV loop of the diastolic portion. Experimental design schematic with black block indicating data acquisition is below each corresponding graph. *P < 0.05 vs. corresponding baseline.

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  Figure 4. Effect of CXL-1020 on isolated cardiomyocyte function in the ISO rat model. (A) Representative trace of Ca2+ transients (CaT) and myocyte shortening (as the % resting cell length (RCL)). (B) Summary data as % change from baseline of contractile changes (n = 14 cells/7 hearts) (CaT and shortening amplitude) and relaxation (CaT and relengthening RT50), *P < 0.05 vs. corresponding baseline.

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  Figure 5. Comparison of CXL-1020 and MIL effects on systemic and LV hemodynamic indices in instrumented anesthetized rats and cardiomyocyte function. Summary data comparing as % change from baseline of (A) Tau (n = 6) and (B) myocyte function (n = 14–17 cells/7–8 hearts) in ISO rats. (C) Summary data as % change from baseline of a dose response of CXL-1020 and MIL in normal rats on contractile changes (CaT and shortening amplitude) and (D) relaxation (CaT and relengthening RT50), 7–25 cells/5–8 hearts. (E) Summary data as % change from baseline of CXL-1020 and MIL on heart rate in normal, RW and ISO rats (n = 5–7). (F) The time course of ectopic beats/per minute from the LV-pressure curve during IV infusion (n = 12–13). *P < 0.05 vs CXL-1020.

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  Figure 6. Effects of L-Type Ca2+ Channel blockade on systemic and LV hemodynamics indices in instrumented anesthetized normal rats. (A) Schematic of the experimental design with black block indicating data acquisition. Summary data as % change vs. baseline of the cardiovascular profiles of verapamil (VER) alone, CXL-1020 (100 μg/kg/min, n = 7) and MIL (10 μg/kg/min, n = 7) with and without VER on (B) heart rate, (C) Tau, and (D) preload recruitable stroke work. *P < 0.05 vs. corresponding baseline.