Hemodynamic and Hormonal Responses to Nicorandil in a Canine Model of Acute Ischemic Heart Failure: A Comparison with Cromakalim and Nitroglycerin

Abstract

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.

Positive inotropic effect of nicorandil in adult rats in situ

“…In the acute ischemic heart failure canine model, nicorandil at similar concentrations to the present ones increased cardiac output and SV mediated by the drug's K-channel opening activities and by the reduction of venous tone by its nitrate properties [6]. Furthermore, in the canine acute congestive heart failure model, nicorandil may exert beneficial hemodynamic effects mainly due to decrease in both afterload and preload rather than the coronary vasodilator effect [7].…”

“…The increase in EDV induced by nicorandil is not likely due to venous contractions, because nicorandil dilates capacitance vessels, as does nitroglycerin, but does not contract capacitance vessels [6]. Neither elongation of relaxation time nor the enhancement of lusitropy in the left ventricle seems likely to increase EDV, because the left ventricular end-diastolic pressure-volume curve at the filling phase was not affected by nicorandil (our observation).…”

“…It was actually reported that at high concentrations nicorandil exerted negative inotropic effects on human left ventricular papillary muscles predominantly by opening the K ATP channels [5]. In acute ischemic and congestive heart failure canine models, nicorandil was considered to improve cardiac contractility due to the reduction of both preload and afterload mediated by K ATP channel opening actions with NO-like actions [6,7]. No positive inotropic effects of nicorandil on the normal heart model, however, have been reported.…”

Nicorandil Promotes Myocardial Capillary and Arteriolar Growth in the Failing Heart of Dahl Salt-Sensitive Hypertensive Rats

“…3 Acute administration of nicorandil has indeed been shown to be effective in the treatment of heart failure, predominantly as a result of its vasodilator effects. 4,5 A single oral dose of nicorandil increased coronary blood flow and ameliorated exercise-induced LV dysfunction in patients with previous myocardial infarction. 6 Intravenous administration of nicorandil also attenuated exercise-induced LV diastolic dysfunction in individuals with hypertrophic cardiomyopathy, probably as a result of its beneficial effect on abnormal coronary microcirculation.…”

Effects of Intravenous Nicorandil on the Mid-Term Prognosis of Patients With Acute Heart Failure Syndrome

“…By virtue of the well-balanced decrease in both preload and afterload it induces, nicorandil improves the hemodynamics of patients with AHFS. 7, 16 It is recommended that intravenous nicorandil therapy be initiated with a bolus injection to ensure prompt improvement of hemodynamics. Although prompt improvement of hemodynamics should improve the prognosis of patients with AHFS, 4 it has been reported that treatment with the natriuretic peptide analog, nesiritide, may cause deterioration of renal function and thus the prognosis of patients with decompensated HF, possibly via induction of hypotension by bolus administration or continuous infusion of a high dose.…”