Hemodynamic and hormonal responses to nicorandil in a canine model of acute ischemic heart failure: A comparison with cromakalim and nitroglycerin

The pharmacologic profiles of nicorandil in the cardiovascular system have been characterized by K-channel opening and nitrate activities. However, th e effects of nicorandil on acute heart failure have yet to be elucidated. T o investigate the effects of nicorandil under such pathophysiologic conditi ons, we administered nicorandil intravenously to dogs with acute ischemic h eart failure induced by coronary embolization and compared the results with those induced by cromakalim and nitroglycerin. The heart failure in this e xperiment was demonstrated by a reduction of mean blood pressure (MBP) from 143 +/- 3 to 129 +/- 2 mm Hg (p < 0.01); cardiac output (CO) from 2.18 +/- 0.10 to 1.06 +/- 0.05 L/min (p < 0.01); stroke volume (SV) from 12.7 +/- 0 .6 to 6.8 +/- 0.3 ml/min (p < 0.01); V-max, an index of the contractility o f the left ventricle, from 105.5 +/- 4.4 to 49.9 +/- 1.8 l/s (p < 0.01), an d an increase in right atrial pressure (RAP) from 2.9 +/- 0.3 to 5.3 +/- 0. 3 mm Hg (p < 0.01); left ventricular end-diastolic pressure (LVEDP) from 2. 5 +/- 0.4 to 26.0 +/- 1.4 mm Hg (p < 0.01); and T, time constant of left ve ntricular relaxation, from 38.3 +/- 0.8 to 62.4 +/- 2.8 ms (p < 0.01). Furt hermore, plasma renin activity (PRA) and plasma atrial natriuretic peptide (ANP) increased (from 1.72 +/- 0.29 to 5.03 +/- 0.68 ng AngI/ml/h, p < 0.01 ; from 103.9 +/- 5.8 to 411.5 +/- 29.4 pg/ml, p < 0.01, respectively), wher eas brain natriuretic peptide (BNP) remained unchanged (from 23.1 +/- 2.2 t o 26.9 +/- 1.4 pg/ml). Nicorandil (10-40 mu g/kg/min, i.v. infusion for 20 min for each dosing) or cromakalim (0.25-1 mu g/kg/min) decreased MBP, syst emic vascular resistance (SVR), RAP, and LVEDP, and increased CO, SV, and V -max. However, the reduction of RAP in cromakalim was significantly smaller than those of nicorandil and nitroglycerin in comparison at similar hypote nsive doses. Nitroglycerin (2.5-10 mu g/kg/min) decreased MBP, RAP, and LVE DP, and increased V-max but did not change CO or SV. Increased plasma ANP l evels, an index of cardiac filling pressure after induction of acute ischem ic heart failure, were decreased significantly by cromakalim and tended to decrease by nicorandil or nitroglycerin. Plasma BNP levels and PRA were not influenced by any of these drugs. These results suggest that nicorandil pr oduces the reduction of both preload and afterload followed by an improveme nt of cardiac contractility in this model. The increase in CO may be mediat ed mainly by the drug's K-channel opening activities and the reduction of v enous tone by its nitrate properties. Nicorandil may prove to be useful in the treatment of acute ischemic heart failure.