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

Figures

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  Figure 1. Percentage Mean Changes in Parameters (A to D) Percentage mean changes in parameters with BMS-986231 (0.7, 2, 7 μg/kg/min) and vehicle over time. All values shown are mean ± SEM. *p < 0.05 versus baseline; †p < 0.05 versus 0.7 μg/kg/min dose infusion; ‡p < 0.05 versus vehicle. CO = cardiac output; Ei/Ai = ratio of Ei (time-velocity integral of the mitral inflow velocity waveform representing early filling) to Ai (time-velocity integral representing left atrial contraction); HR = heart rate; LVEDV = left ventricular end-diastolic volume; LVEDWS = left ventricular end-diastolic circumferential wall stress; LVFAS = left ventricular fractional area shortening; MVO2 = myocardial oxygen consumption; SVR = systemic vascular resistance.

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  Figure 2. Time Course and Dose Effects of BMS-986231 (A) Time course effects of BMS-986231 (50 μg/kg/min) in animals with normal cardiac function, and (B) dose effects of BMS-986231 (25, 50, and 75 μg/kg/min) after a 3-h infusion in animals with pacing-induced cardiomyopathy. All values shown are mean ± SEM. *p < 0.05 versus baseline; †p < 0.05 (3 h + HEX vs. 3 h); ‡p < 0.05 (vs. 25 μg/kg/min). EDPVR = end-diastolic pressure-volume relationship; ESPVR = end-systolic pressure-volume relationship; HEX = Hextend (plasma volume-expanding solution); LVEF = left ventricular ejection fraction; MAP = mean arterial pressure; PRSW = preload-recruitable stroke work; PVA = pressure-volume area; Tau = left-ventricular relaxation time-constant; other abbreviations as in Figure 1.

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  Figure 3. Representative Left Ventricular Pressure–Volume Relationships Representative left ventricular pressure–volume relationships generated via acute preload reductions in conscious healthy dogs at baseline (BASE, black) and at 3 h following BMS-986231 (BMS) administration (50 μg/kg/min intravenously), both before (BMS, red) and after (BMS + HEX, blue) acute volume expansion. (A) Steady-state (pre-occlusion) pressure–volume curves of 1 cardiac cycle (inset, showing filling phase), demarcated by both the end-systolic (ESPVR) and by the estimated (linear) end-diastolic pressure–volume relationships (EDPVR). BMS-986231 decreased preload, and load-independently increased the end-systolic elastance (slope of the ESPVR). (B) Families used to generate the pressure–volume relationships (top and middle), as well as the stroke work (SW) to end-diastolic volume relationship (bottom), showing an increase in the slope of the PRSW (Mw) induced by BMS-986231. EDV = end-diastolic volume; HEX = Hextend (plasma volume-expanding solution); LVP = left ventricular pressure; LVV = left ventricular volume; PRSW = preload-recruitable stroke work.

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  Figure 4. Representative Left Ventricular Pressure–Volume Relationships Generated Via Acute Preload Reductions in Conscious Dogs Representative left-ventricular pressure–volume relationships generated via acute preload reductions in conscious dogs with tachypacing-induced heart failure (HF), taken both at baseline (HF, black) and at 3 h following BMS-986231 (BMS) administration (50 μg/kg/min intravenously, red). (A) Steady-state (pre-occlusion) pressure–volume curves of 1 cardiac cycle (inset, showing filling phase), demarcated by both the ESPVR as well as by the estimated (linear) EDPVRs. BMS-986231 decreased pre-load, and load-independently increased the end-systolic elastance (slope of the ESPVR). (B) Families used to generate the pressure–volume relationships (top), as well as the SW to end-diastolic volume relationship (bottom), showing a BMS-986231-induced increase in the slope of the PRSW (Mw). Abbreviations as in Figure 3.