The pharmacologic profiles of
nicorandil in the cardiovascular system have been characterized by K-channel opening and
nitrate activities. However, the effects of
nicorandil on acute
heart failure have yet to be elucidated. To investigate the effects of
nicorandil under such pathophysiologic conditions, we administered
nicorandil intravenously to dogs with acute ischemic
heart failure induced by coronary embolization and compared the results with those induced by
cromakalim and
nitroglycerin. The
heart failure in this experiment 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); Vmax, an index of the contractility of the left ventricle, from 105.5+/-4.4 to 49.9+/-1.8 1/s (p < 0.01), and 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 ventricular relaxation, from 38.3+/-0.8 to 62.4+/-2.8 ms (p < 0.01). Furthermore, 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), whereas
brain natriuretic peptide (BNP) remained unchanged (from 23.1+/-2.2 to 26.9+/-1.4 pg/ml).
Nicorandil (10-40 microg/kg/min, i.v. infusion for 20 min for each dosing) or
cromakalim (0.25-1 microg/kg/min) decreased MBP, systemic vascular resistance (SVR), RAP, and LVEDP, and increased CO, SV, and Vmax. However, the reduction of RAP in
cromakalim was significantly smaller than those of
nicorandil and
nitroglycerin in comparison at similar hypotensive doses.
Nitroglycerin (2.5-10 microg/kg/min) decreased MBP, RAP, and LVEDP, and increased Vmax but did not change CO or SV. Increased plasma
ANP levels, an index of cardiac filling pressure after induction of acute ischemic
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 produces the reduction of both preload and afterload followed by an improvement of cardiac contractility in this model. The increase in CO may be mediated mainly by the
drug's K-channel opening activities and the reduction of venous tone by its
nitrate properties.
Nicorandil may prove to be useful in the treatment of acute ischemic
heart failure.