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, 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.
Kamijo
T
T
Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan.
Kamei
K
K
Sugo
I
I
Kamiyama
T
T
Sudo
H
H
Ohba
Y
Y
D000208:Acute Disease; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood; D002303:Cardiac Output, Low / Q000188:drug therapy*; D019806:Cromakalim / Q000494:pharmacology; D004285:Dogs; D004621:Embolization, Therapeutic; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D006728:Hormones / Q000378:metabolism; D008297:Male; D008863:Microspheres; D017202:Myocardial Ischemia / Q000503:physiopathology* / Q000628:therapy; D020097:Natriuretic Peptide, Brain / Q000097:blood; D020108:Nicorandil / Q000494:pharmacology*; D005996:Nitroglycerin / Q000494:pharmacology; D015221:Potassium Channels / Q000819:agonists; D012083:Renin / Q000097:blood; D014665:Vasodilator Agents / Q000494:pharmacology*
D006728:Hormones; D015221:Potassium Channels; D014665:Vasodilator Agents; D019806:Cromakalim; D020097:Natriuretic Peptide, Brain; D020108:Nicorandil; D009320:Atrial Natriuretic Factor; D012083:Renin; D005996:Nitroglycerin