CK‐2289 and milrinone in dogs with propranolol‐induced heart failure: Effect of ouabain

We examined the interaction between ouabain and CK‐2289, a new bivalent inodilator, and compared their effect with that of milrinone on the hemodynamic and myocardial energetic parameters of anesthetized dogs with propranolol‐induced heart failure (PIHF). Mongrel dogs (13–19 kg) of either sex were anesthetized with pentobarbital sodium (35 mg/kg, i. v.) and instrumented for routine hemodynamic measurements using an open‐chest, artificially ventilated preparation. PIHF was produced by decreasing left ventricular (LV) dP/dT max by 50% from control values with an initial infusion of 0.5 mg/kg of propranolol followed by continuous infusion of 0.02 to 0.08 mg/kg of propranolol to maintain PIHF. This was followed by infusion of saline (2 ml, i. v., n = 12/group) or ouabain (25 μg/kg, i. v., n = 12/group). Thirty min later saline and ouabain‐treated animals (4/group) were given 2 doses of saline (1 and 2 ml, i. v.), CK‐2289 (0.01 and 0.03 mg/kg, i. v.) or milrinone (0.03 and 0.1 mg/kg, i. v.) 30 min apart. Hemodynamic parameters were monitored continuously. Myocardial oxygen consumption (MVO 2 ) was monitored 15 and 30 min after each dose of drug. CK‐2289 increased LV dP/dT max and LV dP/dT min by 60 and 120% and 42 and 43%, respectively. Mean arterial pressure decreased by 12% after the high dose of CK‐2289. CK‐2289 did not affect heart rate, while LV end diastolic pressure decreased by 5 mmHg. CK‐2289 increased LV work and did not affect or decrease LV contractile efficiency. Ouabain enhanced the myocardial energetic profile of CK‐2289 by allowing CK‐2289 to stimulate more work at a lower MVO 2 , thereby increasing myocardial efficiency. Milrinone had a profile similar to CK‐2289 but in ouabain‐pretreated animals with PIHF milrinone stimulated less work at the same MVO 2 , thus decreasing contractile efficiency. Thus, ouabain may enhance the myocardial energetic effects of CK‐2289.