Inotropic Effects of Nicorandil on Cardiac Contractility Assessed by Left Ventricular Pressure-Volume Relationship Analyses in Anesthetized Monkeys.

Nicorandil is a representative antianginal drug that has dual properties of a nitrate and adenosine triphosphate-sensitive potassium (KATP) channel agonist; however, its effects on integrated cardiac function have not been fully understood. This study was conducted to clarify the functional, hemodynamic, and electrophysiological effects of nicorandil using ventricular pressure-volume loop analysis in isoflurane-anesthetized monkeys. Nicorandil was given intravenously at therapeutic doses of 0.2 and 2 mg/kg over 10 minutes to cynomolgus monkeys (n = 5) with a pause of 10 minutes between the 2 doses. Nicorandil at 0.2 mg/kg caused decreases in systemic blood pressure and left ventricular end-diastolic pressure by its vasodilating action. Nicorandil at 2 mg/kg also exhibited positive inotropic action demonstrated by increased slopes of preload recruitable stroke work relationship, which is a load-independent inotropic parameter. In load-dependent inotropic parameters, positive inotropy of nicorandil was also indicated by the shortened QA interval and increased contractility index; however, significant changes were not observed in the maximal upstroke velocity of left ventricular pressure. Moreover, reflex tachycardia accompanied by shortening of QT/QTc intervals was observed. Overall, the isoflurane-anesthetized monkey model with pressure-volume loop analysis revealed cardiac variables of nicorandil, including a positive inotropy contributable to cardiac performance in addition to its vasodilatory effect. These findings provide useful information when considering the prescription of nicorandil in patients.

Activity of nicorandil, a nicotinamide derivative with a nitrate group, in the experimental model of pain induced by formaldehyde in mice.

Nicorandil (2-nicotinamide ethyl nitrate), an antianginal drug characterized by the coupling of nicotinamide with a nitric oxide (NO) donor, activates guanylyl cyclase and opens ATP-dependent K(+) channels. In the present study, we investigated the effects induced by per os (p.o.) administration of nicorandil (12.5, 25 or 50 mg/kg) or equimolar doses (corresponding to the highest dose of nicorandil) of N-(2-hydroxyethyl) nicotinamide (NHN), its main metabolite, or nicotinamide in the model of nociceptive response induced by formaldehyde in mice. Nicorandil, but not NHN or nicotinamide, inhibited the second phase of the nociceptive response. This activity was observed when nicorandil was administered between 30 and 120 min before the injection of formaldehyde. Ipsilateral intraplantar injection of nicorandil (125, 250 or 500 µg/paw) did not inhibit the nociceptive response. After p.o. administration of nicorandil (50 mg/kg), peak plasma concentrations of this compound and NHN were observed 0.63 and 4 h later, respectively. Nicotinamide concentrations were not increased after administration of nicorandil. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 1 or 2 mg/kg), a guanylyl cyclase inhibitor, partially attenuated the antinociceptive activity of nicorandil. However, this activity was not changed by glibenclamide (30 or 60 mg/kg), an inhibitor of ATP-dependent K(+) channels. In conclusion, we demonstrated the antinociceptive activity of nicorandil in a model of pain that exhibits both a nociceptive and an inflammatory profile. This activity is not mediated by nicotinamide or NHN. The coupling of an NO-donor to nicotinamide results in a compound with an increased potency. The NO-cGMP pathway, but not ATP-dependent K(+) channels, partially mediates the antinociceptive activity of nicorandil.

Should nicorandil infusion be adapted in dialysis-dependent patients undergoing continuous renal replacement therapy after cardiac surgery?

In this report, we studied whether plasma concentration of nicorandil is maintained effectively and safely in dialysis-dependent patients with stage 5 chronic kidney disease (CKD5D) undergoing continuous renal replacement therapy (CRRT). Participants consisted of 10 patients undergoing CRRT after cardiac surgery. CRRT was performed with an effluent flow rate of either 600 mL/h (low-flow group; n = 5) or 1800 mL/h (high-flow group; n = 5). Nicorandil was infused intravenously at 0.1 mg/kg/h for more than 15 h starting 8 h before and 7 h after the start of CRRT. Plasma nicorandil concentrations were measured from arterial blood lines 1 h before and 7 h after CRRT initiation. Nicorandil clearance by CRRT was also calculated 1 h after CRRT initiation. Nicorandil plasma concentrations before and 7 h after CRRT initiation were 68.0 ng/mL and 74.6 ng/mL, respectively. Nicorandil clearance 1 h after CRRT initiation was 20.2 mL/min. Increasing the effluent flow rate from 600 mL/h to 1800 mL/h tended to increase nicorandil clearance. When nicorandil was infused intravenously during CRRT at 0.1 mg/kg/h in patients with CKD5D, plasma nicorandil concentrations were maintained within an effective concentration range.

Simultaneous quantitation of nicorandil and its denitrated metabolite in plasma by LC-MS/MS: application for a pharmacokinetic study.

A liquid chromatography-electrospray ionization tandem mass spectrometry method was developed and validated for the simultaneous quantitation of nicorandil and its denitrated metabolite, N-(2-hydroxyethyl)-nicotinamide, in rat plasma. After a liquid-liquid extraction step, chromatographic separation was performed on a ShinPack C(18) column with an isocratic mobile phase composed of methanol and 2 mM aqueous ammonium acetate containing 0.03% (v/v) formic acid (33:67 v/v). Procainamide was used as an internal standard (IS). Selected reaction monitoring was performed using the transitions m/z 212 → m/z 135, m/z 166 → m/z 106 and m/z 236 → m/z 163 to quantify nicorandil, its denitrated metabolite and IS, respectively. Calibration curves were constructed over the range of 5-15,000 ng.ml(-1) for both nicorandil and its metabolite. The mean relative standard deviation (RSD%) values for the intra-run precision were 5.4% and 7.3% and for the inter-run precision were 8.5% and 7.3% for nicorandil and its metabolite, respectively. The mean accuracy values were 100% and 95% for nicorandil and its metabolite, respectively. No matrix effect was detected in the samples. The validated method was successfully applied to a pharmacokinetic study after per os administration of nicorandil in rats.

Pharmacokinetics of nicorandil in dogs with mild mitral regurgitation.

The aim of this study was to examine the pharmacokinetics of nicorandil, a hybrid of an adenosine triphosphate-sensitive potassium channel opener and a nitrate, and to estimate its clinical doses in dogs with mild mitral valve regurgitation (MR). Nicorandil (0.1, 0.3, and 1.0 mg/kg) was administered orally to normal dogs and those with experimentally-induced MR, and its plasma concentrations were analyzed using high-performance liquid chromatography. Plasma concentrations increased dose-dependently after the administration of nicorandil, and were not different between normal dogs and those with MR. Similar to the effective plasma values obtained in cardiac disease in humans, the findings of this pharmacokinetic study may indicate that a dose of 0.3-1.0 mg/kg has the same effectiveness in dogs with cardiac dysfunction.

Nicorandil attenuates FeCl(3)-induced thrombus formation through the inhibition of reactive oxygen species production.

BACKGROUND: Although nicorandil has a number of beneficial cardiovascular actions, its effects on endothelial cells in the context of thrombosis have not been elucidated. METHODS AND RESULTS: Arterial thrombosis was induced by endothelial injury caused by FeCl(3) in the mouse testicular artery. Thrombus growth led to complete occlusion 12 min after endothelial injury in control mice. The antiplatelet agent, tirofiban, and nicorandil significantly slowed the growth of thrombi, resulting in arterial occlusion after 58 min and 55 min, respectively. In the absence of endothelial cells, nicorandil did not inhibit platelet aggregation. Diazoxide and high-dose isosorbide dinitrate both showed a similar effect to that of nicorandil. The beneficial effect of nicorandil was prevented by 5-hydroxydecanoate, but not by L-NAME. The production of reactive oxygen species by FeCl(3) treatment was measured with the specific fluorescent probe, dihydrorhodamine 123. After FeCl(3) treatment, nicorandil significantly inhibited the increase in fluorescence. In further experiments, incubation of human umbilical vein endothelial cells with nicorandil did not change the endothelial nitric oxide synthase (eNOS) mRNA levels, eNOS phosphorylation or nitrite production. CONCLUSIONS: Nicorandil attenuates FeCl(3)-induced thrombus formation in the mouse testicular artery, which suggests that it may inhibit the generation of reactive oxygen species by FeCl(3)-treated endothelial cells through activation of the mitochondrial ATP-sensitive potassium channels.

An estimation method of the half-life for a one-compartment model of a single bolus intravenous injection by a single sampling.

In clinical trials, sometimes only a single drug concentration can be measured from a patient because of the patient's burden. In this case, the sampling point is usually identical for all patients. From a single concentration, we cannot generally obtain point-estimates of each pharmacokinetic parameter. In this paper, we propose a method to estimate the half-life of a one-compartment model of a single bolus intravenous injection from a single concentration at a sampling point of or after three half-lives. We analytically show that the later the sampling point is the better estimate of the half-life we can get. This approach is illustrated by simulated concentration-data and nicorandil concentration-data. Therefore, we compared the performance of the proposed method with that of the Bayesian approach.

Rapid and sensitive liquid chromatography-tandem mass spectrometry method for the estimation of nicorandil in human plasma.

A rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed and validated for the estimation of nicorandil in human plasma. Nicorandil was extracted from human plasma using solid-phase extraction technique. Imipramine was used as the internal standard. A Betasil C18 column provided chromatographic separation of analytes followed by detection with mass spectrometry. The method involves a rapid solid-phase extraction from plasma, simple isocratic chromatography conditions and mass spectrometric detection that enables detection at nanogram levels. The proposed method has been validated for a linear range of 1.0-500.0 ng/mL with a correlation coefficient of > or =0.9993. The intra-run and inter-run precision and accuracy was within 10.0%. The overall recovery for nicorandil was 63.81%. The total run time was just 3.0 min.

In vivo evaluation of limonene-based transdermal therapeutic system of nicorandil in healthy human volunteers.

Hydroxypropyl methylcellulose (HPMC) gel drug reservoir system prepared with 70:30 v/v ethanol-water solvent system containing 6% w/w of limonene was effective in promoting the in vitro transdermal delivery of nicorandil. The objective of the present study was to fabricate and evaluate a limonene-based transdermal therapeutic system (TTS) for its ability to provide the desired steady-state plasma concentration of nicorandil in human volunteers. The in vitro permeation of nicorandil from a limonene-based HPMC gel drug reservoir was studied across excised rat skin (control), EVA2825 membrane, adhesive-coated EVA2825 membrane and adhesive-coated EVA2825 membrane-excised rat skin composite to account for their effect on the desired flux of nicorandil. The flux of nicorandil from the limonene-based HMPC drug reservoir across EVA2825 membrane decreased to 215.8 +/- 9.7 microg/cm(2).h when compared to that obtained from control, indicating that EVA2825 was effective as a rate-controlling membrane. The further decrease in nicorandil flux across adhesive-coated EVA2825 membrane and adhesive-coated EVA2825 membrane-excised rat skin composite showed that the adhesive coat and skin also controlled the in vitro transdermal delivery. The limonene-based drug reservoir was sandwiched between adhesive-coated EVA2825-release liner composite and a backing membrane. The resultant sandwich was heat-sealed as circle-shaped patch (20 cm(2)), trimmed and subjected to in vivo evaluation in human volunteers against immediate-release tablets of nicorandil (reference formulation). The fabricated limonene-based TTS of nicorandil provided a steady-state plasma concentration of 21.3 ng/ml up to 24 h in healthy human volunteers. It was concluded that the limonene-based TTS of nicorandil provided the desired plasma concentration of the drug for the predetermined period of time with minimal fluctuations and improved bioavailability.

Bioavailability of nerodilol-based transdermal therapeutic system of nicorandil in human volunteers.

The objective of the present investigation was to design and evaluate a nerodilol-based transdermal therapeutic system (TTS) for finding its ability in providing the desired steady-state plasma concentration of nicorandil in human volunteers. The influence of EVA2825 membrane, adhesive-coated EVA2825 membrane and adhesive-coated EVA2825-rat skin composite on the in vitro permeation of nicorandil from a nerodilol-based HPMC gel drug reservoir was studied against a control (excised rat skin alone). The flux of nicorandil from the nerodilol-based HMPC drug reservoir across excised rat skin (control) was 384.0+/-4.6 microg/cm2 h and this decreased to 222.7+/-7.1 microg/cm2 h when studied across EVA2825 membrane indicating that EVA2825 membrane was effective as rate controlling membrane. The flux of the drug decreased to 183.8+/-5.7 microg/cm2 h on application of a water-based acrylic adhesive (TACKWHITE A 4MED) coat to EVA2825 membrane. However, the flux of nicorandil across adhesive-coated EVA2825-membrane-rat-skin composite was 164.8+/-1.8 microg/cm2 h, which was 1.74-times of the required flux that prompted for preparation of TTS. The nerodilol-based drug reservoir system was sandwiched between a composite of adhesive-coated EVA2825 membrane-release liner and a backing membrane. The resultant sandwich was heat-sealed to produce circle-shaped TTS (20 cm2) that were subjected to bioavailability study in human volunteers against immediate release nicorandil tablet. The nerodilol-based TTS provided a steady-state plasma concentration of 25.5 ng/ml for 24 h in human volunteers. It was concluded that the nerodilol-based TTS of nicorandil provided the desired plasma concentration of the drug for the predetermined period of time with minimal fluctuations.

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 microg.kg(-1).min(-1)) (blood concentration: 0.53 +/- 0.14 and 1.48 +/- 0.21 microg/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 microg.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).

Ventricular arrhythmias with left bundle branch block pattern and inferior axis: assessment of their mechanisms on the basis of response to ATP, nicorandil and verapamil.

The present study investigated the mechanism of ventricular arrhythmias showing left bundle branch block (LBBB) pattern with an inferior axis. The effects of 3 drugs, adenosine triphosphate (ATP), nicorandil and verapamil, were evaluated in 17 patients. ATP suppressed the arrhythmias in 14 patients and nicorandil suppressed them in 8 of those 14. Verapamil suppressed 5 of the 6 ATP-nicorandil-sensitive arrhythmias. Four patients with ATP- or nicorandil-sensitive arrhythmias were not sensitive to verapamil. On the other hand, 3 of the ATP-insensitive arrhythmias were sensitive to neither nicorandil nor verapamil. The QT intervals and QTc were shortened by nicorandil in 5 of the 6 patients who were sensitive to all 3 drugs. One mechanism of suppression by nicorandil could be related to less Ca++ entering the myocardium, which would decrease the duration of the action potential as indicated by the shortened QT intervals. The results suggest that the mechanism of some ventricular arrhythmias is related to triggered activity. Arrhythmias that are sensitive to ATP or nicorandil, but not to verapamil, may be caused by abnormal automaticity. On the other hand, arrhythmias that are insensitive to all 3 drugs might be related to reentry. The features of ventricular arrhythmias with LBBB pattern and inferior axis differ and therefore the causative mechanisms are not the same.

Effects of intravenous nicorandil on coronary circulation in humans: plasma concentration and action mechanism.

We investigated the cardiovascular profile of nicorandil, an antianginal agent, in humans. Pharmacologically, nicorandil acts as both an adenosine triphosphate (ATP)-sensitive K+ (K(ATP)) channel opener and a nitrate. We examined which of these mechanistic components has a predominant vasodilatory effect at clinical doses. Fourteen patients underwent cardiac catheterization. The effects of the continuous intravenous infusion of nicorandil (12 mg/45 min) were examined in angiographically normal coronary arteries. Coronary vascular resistance was calculated from coronary artery diameter and coronary blood flow velocity measured using an intravascular Doppler catheter. We compared the hemodynamic responses to nicorandil with those to the intracoronary injection of nitroglycerin (250 microg) and papaverine (12 mg). The epicardial coronary arteries responded to nicorandil at the lowest plasma concentration examined (dilation of +14.0 +/- 3.3% at approximately 170 ng/ml), whereas dilation of the coronary resistance arteries (i.e., a decrease in coronary vascular resistance) took place only at higher concentrations (>200 ng/ml). Nitroglycerin caused no further changes in coronary artery diameter or coronary vascular resistance. Papaverine caused no further increase in coronary artery diameter, but markedly decreased coronary vascular resistance (1.6 +/- 0.3 to 0.4 +/- 0.1 mm Hg/ml/min; p < 0.05). Nicorandil significantly decreased pulmonary capillary wedge pressure (i.e., reduced cardiac preload) at a plasma level of >200 ng/ml, but did not change either systemic or pulmonary vascular resistance. Thus nicorandil preferentially dilated epicardial coronary arteries rather than coronary resistance arteries, and had a stronger effect on preload than on afterload. These changes in human coronary hemodynamics suggest that the nitrate actions of nicorandil as a coronary vasodilator predominate over those as a K(ATP) opener.

Routine and sensitive method for determination of nicorandil in human plasma developed for liquid chromatography with ultraviolet and mass spectrometric detection.

A rapid and sensitive method using HPLC has been developed for the quantification of nicorandil (SG-75) in human plasma samples for routine bioequivalence studies. The sample preparation needs two liquid-liquid extractions, first with CH3Cl and HClO4 as denaturation reagent and second with addition of ethyl acetate and Na2CO3(aq). Detection wavelength was 256 nm. The obtained correlation coefficient for weighted linear curve in the range from 5.0 to 300 ng/ml was higher than 0.9950. The limit of quantitation (LOQ) was established at 5.0 ng/ml. The HPLC separation was accomplished on Nucleosil Phenyl (5 microm) stainless steel column within 7 min. The mixture of 0.01 M ammonium acetate buffer (pH 6.2) and acetonitrile 10:3 (v/v) was used as the mobile phase. The same separation method was examined on HPLC-MS system. Using this system, the LOQ was established at 1.0 ng/ml and the linearity was obtained in the range from 1.0 to 150 ng/ml.