Positive inotropic effect of nicorandil in adult rats in situ

Purpose

Although the cardiac protective and negative inotropic effects of nicorandil via opening the sarcolemmal or mitochondrial K_ATP channel and NO-like action are well known, positive inotropic effects of nicorandil in normal hearts have not been reported. The aim of the current study was to investigate how nicorandil affects left ventricular (LV) function of in situ adult rat hearts through the entire cardiovascular system.

Methods

We performed simultaneous and continuous measurements of LV pressure (P) by a catheter-tip micromanometer and LV volume (V) using a conductance catheter. We obtained steady-state LV P-V loops and intermittent curvilinear LV end-systolic pressure–volume relations (ESPVRs), LV end-systolic pressure (ESP_mLVV), and systolic pressure–volume area (PVA_mLVV) at midrange LVV (mLVV). We evaluated the effects of nicorandil on LV function by these mechanical indexes sensitively reflecting changes in LV contractility and work capability, preload (end-diastolic volume, EDV), and afterload (effective arterial elastance, Ea).

Results

Nicorandil (10 and 20 µg·kg⁻¹·min⁻¹) (blood concentration: 0.53 ± 0.14 and 1.48 ± 0.21 µg/ml) largely shifted ESPVR upward and thus significantly increased ESP_0.06, PVA_0.06, stroke volume due to increase in EDV, and ejection fraction without significant changes in Ea and heart rate. In contrast, an NO donor, nitroglycerin (1 µg·kg⁻¹ · min⁻¹), significantly decreased Ea but did not change ESP_0.06, PVA_0.06, and EDV. Furthermore, either a nonselective K_ATP channel blocker, glybenclamide, or a mitochondrial K_ATP channel blocker, 5-hydroxydecanoate, abolished these nicorandil-induced positive inotropic actions.

Conclusion

These results suggest that nicorandil exhibited positive inotropic actions on LV function of in situ hearts in adult rats with resultant increased preload (EDV).

Authors and Affiliations

1. Department of Physiology II, Nara Medical University, 840 Shijo-cho, Kashihara, 634-8521, Japan

   Kazuyoshi Nakahashi, Yutaka Kitagawa, Haruo Ito & Miyako Takaki

2. Department of Anesthesiology, Nara Medical University, Kashihara, Japan

   Kazuyoshi Nakahashi, Naoya Kuzumoto & Hitoshi Furuya