Action Of Nicorandil Research Articles

Nicorandil directly and cyclic GMP-dependently opens K+ channels in human bypass grafts

As we previously demonstrated the role of different K+ channels in the action of nicorandil on human saphenous vein (HSV) and human internal mammary artery (HIMA), this study aimed to analyse the contribution of the cGMP pathway in nicorandil-induced vasorelaxation and to determine the involvement of cGMP in the K+ channel-activating effect of nicorandil. An inhibitor of soluble guanylate cyclase (GC), ODQ, significantly inhibited nicorandil-induced relaxation, while ODQ plus glibenclamide, a selective ATP-sensitive K+ (KATP) channel inhibitor, produced a further inhibition of both vessels. In HSV, ODQ in combination with 4-aminopyridine, a blocker of voltage-gated K+ (KV) channels, did not modify the concentration-response to nicorandil compared with ODQ, whereas in HIMA, ODQ plus iberiotoxin, a selective blocker of large-conductance Ca2+-activated K+ (BKCa) channels, produced greater inhibition than ODQ alone. We showed that the cGMP pathway plays a significant role in the vasorelaxant effect of nicorandil on HSV and HIMA. It seems that nicorandil directly opens KATP channels in both vessels and BKCa channels in HIMA, although it is possible that stimulation of GC contributes to KATP channels activation in HIMA. Contrary, the activation of KV channels in HSV is probably due to GC activation and increased levels of cGMP.

Nicorandil inhibits hypoxia-induced apoptosis in human pulmonary artery endothelial cells through activation of mitoKATP and regulation of eNOS and the NF-κB pathway

Apoptosis of human pulmonary artery endothelial cells (HPAECs) is the initial step and triggering event for pulmonary hypertension (PH). However, little is known about the actions of nicorandil on HPAECs in vitro. In the present study, we investigated the anti-apoptotic effect of nicorandil on HPAECs exposed to hypoxia, and explored the underlying mechanism(s) of action. Cell viability was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Annexin V and propidium iodide staining, and Hoechst 33342 staining assay were employed to detect apoptosis. In addition, the protein expression of Bax, Bcl-2, caspase-9 and -3, endothelial nitric oxide synthase (eNOS), nuclear factor-κB (NF-κB) and IκBα were determined by western blotting to investigate the possible mechanisms. We found that exposure to hypoxia for 24 h significantly decreased cell viability and increased cell apoptosis. Pretreatment with nicorandil (100 µM) effectively abolished the influence of hypoxia on HPAECs. However, these protective effects of nicorandil were significantly inhibited by an antagonist of mitochondrial adenosine triphosphate-sensitive potassium (mitoKATP) channels, 5-hydroxydecanoate (5-HD, 500 µM), and by an eNOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 300 µM). We further observed that nicorandil could upregulate the decreased protein expression of eNOS and IκBα, and downregulate the increased protein expression of NF-κB, induced by hypoxia. In addition, nicorandil inhibited the enhancement of caspase-3 and -9 expression, and the increase in the Bax/Bcl-2 expression ratio, induced by hypoxia. However, these effects were also abolished by 5-HD and L-NAME. Collectively, these findings suggest that nicorandil inhibits hypoxia-induced apoptosis of HPAECs through activation of mitoKATP channels and increased eNOS expression, which in turn inhibits the NF-κB pathway and the mitochondrial apoptotic pathway.

2024 Diagnostic efficacy of Nicorandil in perfusion MRI for the detection of myocardial ischemia

Introduction Pharmacological stress perfusion in MRI is attracting widespread interest as a technique for the assessment of myocardial perfusion. We have reported that high-dose Nicorandil is known to increase coronary blood flow. The duration of action of Nicorandil is 2 to 3 minutes, its effects on hemodynamics are minimal. These characteristics of Nicorandil lead to expectations that it is safe and simple to use.

Myocardial Distribution and Biotransformation In Vitro and In Vivo of Nicorandil in Rats, with Special Reference to Mitochondria

This study reports subcellular localization of nicorandil in the myocardium and metabolism in mitochondria after oral dosing of 3 mg/kg nicorandil to rats. In the in vitro experiments, nicorandil, which was incubated with tissue homogenates (liver, kidney, heart, and small intestine), was metabolized to its denitrated compound, SG-86, and unknown substances. In the absence of a NADPH-generating system in the heart, the metabolic activity existed only in the mitochondrial fraction, but not in cytosolic and microsomal fractions. In the presence of the system, the activity in the mitochondrial fraction became much higher. To examine subcellular distribution of nicorandil in the myocardium, [14C]nicorandil was orally given to rats. Fifteen minutes after oral dosing of 3 mg/kg [14C]nicorandil, of which myocardial concentration reached a peak, nicorandil and SG-86 were found in mitochondrial fractions as well as in cytosolic and microsomal ones of the heart. Electron-microscopic autoradiograms, 15 min after oral dosing of 3 mg/kg [3H]nicorandil to rats, also showed the existence of the silver grains (showing radioactivity) in mitochondria of the heart. We conclude that nicorandil given orally is distributed in mitochondria of the heart, being partly transformed into SG-86, and that the myocardial mitochondria may be a potential site of action of nicorandil, an opener of KATP channels, which have been demonstrated to be present in this subcellular particle.

Analysis of relaxation and repolarization mechanisms of nicorandil in rat mesenteric artery.

1. The mechanisms by which nicorandil causes relaxation of rat isolated small mesenteric arteries mounted on a Mulvany myograph was investigated by use of a combination of putatively mechanism-specific antagonists. 2. In arteries precontracted by the thromboxane-mimetic, U46619, the EC50 for cromakalim and levcromakalim-induced relaxation curves were raised by 36 and 17 fold by glibenclamide (3 microM) while the EC50 for nicorandil-induced relaxation was unaffected by either glibenclamide or methylene blue (10 microM). A combination of these antagonists raised the EC50 for nicorandil by 8 fold. 3. In U46619-contracted arteries, nifedipine (100 nM) did not affect the cromakalim relaxation curve but it raised the EC50 for nicorandil by 5 fold. The combination of methylene blue, glibenclamide and nifedipine further inhibited the maximum relaxation to nicorandil. 4. In separate experiments, membrane potential (Em) and force responses were measured simultaneously. In arteries depolarized and contracted by U46619 both nicorandil and cromakalim repolarized (delta Em, 35 mV) and relaxed (100%) the vessels. Glibenclamide (3 microM) did not alter the relaxation-concentration curve to nicorandil but reduced the maximum repolarization to delta 10.8 mV. In contrast to Em and relaxation-response curves to cromakalim were shifted to the right by glibenclamide by 30-100 fold. 5. In unstimulated arteries, nicorandil (but not cromakalim) -induced hyperpolarization was significantly antagonized by methylene blue (10 microM) (6.6 fold rightward shift) or nifedipine (100 nM) (2.6 fold). In depolarized arteries (U46619), nifedipine but not methylene blue inhibited the nicorandil-induced hyperpolarization. 6. In arteries precontracted to 50% tissue maximum by either KCl or U46619, nifedipine (100 nM) relaxed the artery but failed to repolarize the Em. Presumably voltage-operated calcium channels (VOCC) were blocked preventing contraction but the artery remained depolarized, presumably through non VOCC mechanisms. 7. These data suggest that nicorandil may relax small arteries through 3 parallel pathways, (i) NO-donor mediated stimulation of guanylate cyclase and increase in cyclic GMP, (ii) K+ATP channel opening, and (iii) nifedipine-sensitive VOCC inhibition. Em data suggest that nicorandil-induced repolarization is caused principally through opening K+ATP channels. Blockade of this hyperpolarization by glibenclamide is not sufficient to alter the relaxation, indicating dissociation of nicorandil-induced changes in membrane potential and relaxation. 8. These results highlight the 'chameleon' actions of nicorandil where there is no apparent association of Em repolarization with relaxation, in contrast to the parallel responses for cromakalim.

Potentiating Effect of Nicorandil, an Antianginal Agent, on Relaxation Induced by Isoproterenol in Isolated Rat Aorta

In rat aortic rings, isoproterenol (ISO) 10(-9)-3 x 10(-6)M relaxed the contraction induced by phenylephrine (PE) 3 x 10(-7)M. Pretreatment with nicorandil 3 x 10(-7) and 3 x 10(-6) M potentiated the relaxation induced by ISO. Nicorandil 3 x 10(-6) M also potentiated the relaxations induced by forskolin 3 x 10(-9) - 10(-6) M and dibutylyl-cyclic AMP 3 x 10(-6) - 3 x 10(-4) M. Nitroglycerin (NTG) 10(-8) M, but not cromakalim 3 x 10(-8) M, also potentiated the ISO relaxation. Pretreatment with glyburide 10(-6) M or apamin 10(-6) M did not affect the potentiating action of nicorandil 3 x 10(-6) M. Pretreatment with methylene blue (MB) 10(-6) M, but not with NG-monomethyl-L-arginine (NMMA), however, markedly inhibited the potentiating effect of nicorandil. Removal of endothelium impaired the relaxation induced by ISO but did not inhibit the potentiating effect of nicorandil. In addition, in the presence of MCl-154 (10(-7) M), which itself potentiated ISO-induced relaxation, nicorandil 3 x 10(-6) M did not further potentiate the relaxing response to ISO. Furthermore, nicorandil 3 x 10(-6) M potentiated the increase in the tissue level of cyclic AMP caused by ISO 3 x 10(-7) M, whereas the nicorandil-induced increase in cyclic GMP levels were not affected by ISO. These results suggest that the potentiating effect of nicorandil on the relaxation induced by ISO is most likely due to inhibition of phosphodiesterase III (PDE III) by increased cyclic GMP levels.

A further study of the vasodilator and negative inotropic mechanisms of action of nicorandil and its congeners in the canine heart.

The vasodilator and negative inotropic mechanisms of action of nicorandil and its congeners (SG-209, SG-103, and SG-86) were investigated in isolated canine papillary muscle preparations cross-circulated through the anterior septal artery with support dogs. SG-209, SG-103, and SG-86 were obtained by replacement of the nitroxyl group of nicorandil by acetoxyl, nicotinoyloxyl, and hydroxyl groups, respectively. Nicorandil (0.03-10 mumol), SG-209 (0.1-10 mumol), SG-103 (1-30 mumol), and SG-86 (3-100 mumol) all produced an increase in coronary blood flow through the anterior septal artery. Both nicorandil and SG-209 produced a near-maximal increase in coronary blood flow, the latter being about 5.5 times less potent than the former. SG-103 and SG-86 were far less potent than SG-209 in that order. The vasodilator actions of nicorandil and SG-209 were antagonized by glibenclamide given IV to support dogs, but those of SG-103 and SG-86 were not. The pKB values of glibenclamide were 6.34 toward nicorandil and 6.49 toward SG-209. Developed tension of the papillary muscle was reduced by nicorandil, SG-209, and SG-103, but not by SG-86. In this respect SG-209 was about 4.7 times less potent than nicorandil, and SG-103 was much less potent than SG-209. The negative inotropic effects of nicorandil and SG-209 were antagonized by glibenclamide, but that of SG-103 was not.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanism of the vasodilatory action of nicorandil on coronary circulation in dogs

Nicorandil possesses hybrid properties as a nitrate and a potassium (K) channel opener. We have previously reported that large coronary arteries responded to nicorandil at low plasma concentrations, while dilatation of small coronary arteries only occurred at higher plasma concentrations (above 200 ng/ml) in chronically instrumented dogs. In this study we examined the effects of intravenous nicorandil on epicardial coronary artery diameter (CoD) and coronary blood flow (CBF) in the absence and presence of glibenclamide, a K+ channel blocker, as well as the effects of nitroglycerin and cromakalim as reference drugs. The increase in CBF induced by nicorandil and cromakalim was significantly suppressed by glibenclamide. However, the increase in CoD induced by nicorandil and nitroglycerin was not suppressed by glibenclamide. These findings suggest that nicorandil-induced dilatation of the large coronary arteries was related to its nitrate action, while nicorandil-induced dilatation of the small coronary arteries was closely related to its effect as a K+ channel opener. In addition, the former response to nicorandil occurred at low concentrations, while the latter occurred at higher concentrations.

Coronary haemodynamics and vasodilatory profile of a potassium channel opener in patients with coronary artery disease

Previous studies have indicated that nicorandil reduces both preload and afterload, clearly distinguishing nicorandil from conventional nitrates, whose predominant action is that of preload reduction. In association with the decrease in afterload following nicorandil, the contractile responses during isovolumic contraction and relaxation improved significantly, indicating that nicorandil does not demonstrate negative inotropic actions. Furthermore, despite a marked decrease in mean aortic pressure after nicorandil, coronary sinus blood flow remains unchanged. Therefore, coronary vasodilatation must have taken place, while myocardial oxygen consumption decreased significantly. The vasodilatory action of nicorandil on the epicardial coronary artery has also been demonstrated in our previous study. Nicorandil, at a dose of either 20 or 40 mg, induces a significant increase in coronary artery diameter favourably by acting not only on the non-stenotic but also on the stenotic coronary segments. In our recent study, the effects of intracoronary nicorandil (6 mu.kg-1) and isosorbide dinitrate (2 mg) on the epicardial coronary arteries were investigated in patients undergoing coronary angioplasty. In non-stenotic coronary artery segments, the mean coronary diameter increased significantly after either nicorandil (+12%) or isosorbide dinitrate (+17%). In stenotic segments, however, increase in the diameter of the obstructed segment by 20% after intracoronary nicorandil was much more pronounced when compared to that of 8% after isosorbide dinitrate. There was a significant additional increase of 13% in the diameter of the obstructed segment when nicorandil was administered following isosorbide dinitrate, while no such additional effect was observed when isosorbide dinitrate was given after nicorandil.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic tolerance and pharmacokinetics of nicorandil in experimental heart failure.

We tested whether nicorandil (NCR), a nitrovasodilator which also possesses K+ channel action, will produce in vivo hemodynamic tolerance commonly observed with other nitrovasodilators such as nitroglycerin (NTG). NCR was infused at 50 micrograms/kg/min for 10 h through a femoral cannula into conscious rats (n = 5) with congestive heart failure (CHF). Left ventricular end-diastolic pressure (LVEDP), LV peak-systolic pressure (LVPSP), and heart rate (HR) were measured periodically through an implanted catheter. Under these conditions, NCR produced a 40% reduction (p < 0.05) in LVEDP from baseline at 40 min after the start of the infusion. This reduction lasted approximately 6 h, followed by a slow return to baseline between 6 and 10 h. LVPSP was reduced (p < 0.05) from 2 h and leveled at approximately 8 h. HR increased by 12% from baseline at 40 min (p < 0.05). Plasma NCR concentrations were identical at 5 h (pretolerant state) and at 10 h (tolerant state) in these animals, suggesting that plasma pharmacokinetics were unrelated to NCR pharmacodynamics. NCR kinetics were not changed by the presence of CHF. Thus, in this animal model, tolerance to NCR developed in LVEDP but not LVPSP, and the K+ channel action of NCR apparently could not prevent tolerance development to venodilation arising from nitrate action.

Spasmolytic action of nicorandil in canine conductive coronary arteries in vivo is not modified by glibenclamide.

The spasmolytic effects of nicorandil, cromakalim, and nitroglycerin on coronary arteries were investigated by angiographic technique in anesthetized dogs. With intracoronary arterial (i.a.) U 46619, a thromboxane A2 mimetic, the diameter of coronary arteries decreased in a sustained manner by 36.1 +/- 1.6% from control levels (coronary spasm). With a successive i.a. injection of nicorandil (300 micrograms), cromakalim (30 micrograms), or nitroglycerin (3 micrograms), the diameter recovered control levels (102.9 +/- 3.9, 96.8 +/- 5.6, and 100.1 +/- 4.3%, respectively). In dogs treated intravenously (i.v.) with glibenclamide, a pharmacologic antagonist of K-channel openers, the spasmolytic effect of cromakalim was significantly reduced, whereas the activity of nicorandil or nitroglycerin remained unaffected. We also investigated a possible modification by glibenclamide of the increase in coronary blood flow (CBF) induced by i.a. nicorandil and cromakalim in anesthetized dogs. The dose-dependent blood flow responses to cromakalim and nicorandil were significantly attenuated by glibenclamide, whereas the response to nitroglycerin remained unaffected. These results suggest that the spasmolytic effect of nicorandil on canine conductive coronary vessels is not mediated by K-channel opening but by a nitroglycerin-like action and that the dilatation of resistive coronary vessels induced by nicorandil may be largely due to its action as a K-channel opener.

The group at C2 of N-ethylnicotinamide determines the vasodilator potencies and mechanisms of action of nicorandil and its congeners in canine coronary arteries

The relaxant mechanisms of action of nicorandil and its congeners (SG-86, SG-103, SG-209 and SG-212) on large coronary arteries were investigated in isolated canine circumflex arteries contracted with 25 mmol/l KCl or 10(-7) mol/l U46619, a thromboxane A2 analogue. SG-212, SG-86, SG-209 and SG-103 were obtained by replacement of the nitroxy group of nicorandil by bromine, the hydroxy, acetoxy and nicotinoyloxy groups, respectively. Nicorandil (10(-6)-10(-3) mol/l), SG-212 (3 x 10(-4)-10(-2) mol/l), SG-209 (10(-4)-10(-2) mol/l), SG-103 (3 x 10(-4)-10(-2) mol/l), and SG-86 (10(-3)-10(-2) mol/l) all produced a concentration-dependent relaxation in KCl- or U46619-contracted arteries. The order of relaxant potency was as follows: Nicorandil much greater than SG-209 greater than SG-212 = SG-103 greater than SG-86. The relaxant effect of nicorandil was not affected by glibenclamide but antagonized by methylene blue. In the presence of glibenclamide, the concentration-relaxation curves for SG-209 underwent rightward parallel shifts. The relaxant effect of SG-209, however, was not affected by methylene blue. The concentration-relaxation curves for SG-212 underwent rightward parallel shifts only to a limited extent in the presence of glibenclamide, but they were not affected by methylene blue. The relaxant effect of SG-103 was affected by neither glibenclamide or methylene blue. The relaxant effect of SG-86 was not affected by glibenclamide. The relaxant effect of nicorandil accompanied an increase in cyclic-GMP levels but that of SG-209 did not.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Nicotinamidoethyl acetate (SG-209) is a potassium channel opener: structure activity relationship among nicorandil derivatives.

The mechanism of the vasodilating action of 2-nicotinamidoethyl acetate (SG-209), a derivative of nicorandil, was examined in the isolated rabbit aorta. Comparison was made using 2-nicotinamidoethyl alcohol (SG-86) and 2-nicotinamidoethyl nitrate (nicorandil; SG-75) to reveal any structure-activity relationships. SG-209 and nicorandil caused concentration-dependent relaxation in preparations precontracted with phenylephrine (10(-7) mol/l), while SG-86 produced a relaxation only at very high concentrations. The pD2 values (-log[EC50]) of SG-209 and nicorandil were 3.59 +/- 0.07 and 5.95 +/- 0.10, respectively. The vasorelaxant activity of nicorandil was associated with significant increases in cyclic GMP content, while that of SG-209 was not. Methylene blue (10(-5) mol/l) attenuated the relaxant effect of nicorandil, but had no effect on that of SG-209. Furthermore, the relaxant effect of nicorandil was not affected by glibenclamide (10(-5) mol/l), whilst the relaxant effect of SG-209 was abolished by this compound. In the presence of methylene blue (10(-5) mol/l), however, glibenclamide (10(-5) mol/l) attenuated the relaxant effect of higher concentrations of nicorandil (greater than or equal to 10(-5) mol/l). These results indicate that the relaxant effect of SG-209 is mostly if not exclusively due to the activation of potassium channels, while this action contributes to the vasodilating action of nicorandil only at higher concentrations.

Action of nicorandil on ATP‐sensitive K+ channel in guinea‐pig ventricular myocytes

1. Patch-clamp techniques were used to study the effects of nicorandil (2-nicotinamiodethyl nitrate) on the adenosine 5'-triphosphate (ATP)-sensitive K+ channel current (IK.ATP) in guinea-pig ventricular myocytes. 2. Nicorandil activated the time-independent outward current. This effect was dependent on intracellular ATP concentration ([ATP]i) showing a larger effect at 2 mM than at 10 mM [ATP]i. The nicorandil-induced outward current was inhibited by application of 0.3 microM glibenclamide. 3. In the inside-out patch configuration, 0.3-1.0 mM nicorandil increased the open-stage probability of IK.ATP without a change in its conductance value (about 90pS). This effect was inhibited by glibenclamide. Analysis of the open and closed time distributions showed that nicorandil had no effect on open and closed distributions shorter than 5 ms. On the other hand, nicorandil increased the life time of bursts and decreased the interburst intervals. 4 The inward rectifier K+ channel current was not influenced by internal application of nicorandil. 5 Therefore, we conclude that IK.ATP is the only K+ current activated by nicorandil, and the main effect of nicorandil is on the kinetics of the IK.ATP bursting behaviour. These actions are similar to that of pinacidil on this preparation.

Nicorandil-Induced Vasorelaxation

Using a series of functional criteria, we wished to evaluate the K+ conductance mechanism and the cyclic GMP mechanism implicated in the actions of nicorandil (NIC) as a vasodilator. In rabbit isolated superior mesenteric artery, NIC exhibited two relaxation dose-response curves (DRCs): one with a lower IC50 of 4.8 x 10(-6) M for norepinephrine (NE 5 microM) contraction, and another with a higher IC50 of 1.4 x 10(-4) M for 80 mM K+ contraction. K+ channel blockers (TEA 1-10 mM), Ba2+ (0.1-0.5 mM), glyburide (1 microM), and increased [K+]ex (20 mM), all caused significant attenuations in the ability of NIC to relax NE contraction, but did not influence the ability of NIC to relax high-K+ contraction. Pretreatment with 5 microM methylene blue, a guanylate cyclase inhibitor, produced a pronounced inhibition of nitroglycerine (NTG) relaxation, but only a marginal inhibitory effect on the NIC relaxation DRC for NE contraction. Functional studies demonstrated that the inhibitory effect of NIC on NE-sensitive intracellular Ca2+ release occurred in the same concentration range as that required for relaxation of 80 mM K+ contractions (10(-5)-10(-3) M). Furthermore, NIC also caused increases in cellular cyclic GMP levels at this higher concentration range. Finally, NIC relaxation of NE contraction was not prone either to self-tolerance (30 mM NIC preexposure) or cross-tolerance (0.55 mM NTG preexposure) development. In contrast, a modest but significant degree of self-tolerance to NIC could be demonstrated under high-K+ contraction condition. These studies thus show the existence of both cellular mechanisms for NIC in the same vascular preparation and further show that these two mechanistic components are separate and independent. The K+ channel-dependent component occurs at lower concentrations, is blocked by K+ channel blockers, is not inhibited by methylene blue, is not associated with increases in cyclic GMP, and is not prone to tolerance development. In this, NIC resembles other K+ channel openers. The cyclic GMP-dependent component is evident at relatively higher concentrations, is associated with inhibition of [Ca2+]i release, is associated with increases in cyclic GMP levels, and is prone to tolerance development. In this, NIC resembles other nitrovasodilators. A combination of these characteristics of the actions of NIC may contribute to the differences in the acute versus chronic hemodynamic profile of NIC.

The dualistic mode of action of the vasodilator drug, nicorandil, differentiated by glibenclamide in 86Rb flux studies in rabbit isolated vascular smooth muscle

(1) In rabbit isolated aorta, the effects of the antianginal drug, nicorandil, of the K+ channel opener, cromakalim, and of the nitrovasodilator, sodium nitroprusside, on 86Rb efflux and on contractile force were compared. (2) In ion flux studies using 86Rb as a marker of K+ ions, both nicorandil and cromakalim, but not sodium nitroprusside, increased the efflux of 86Rb in non-stimulated preparations. The increase of membrane K+ conductance induced by nicorandil and cromakalim was totally suppressed by 10(-5) mol/l of the sulfonylurea derivative, glibenclamide. (3) The vasoconstrictor drug, noradrenaline (3 x 10(-7) mol/l), effectively increased the rate of 86Rb efflux. This stimulatory response was unaffected by glibenclamide, but was totally inhibited by Ca2+ depletion suggesting that the activation of Ca2(+)-sensitive K+ channels was responsible for this action of noradrenaline. (4) Sodium nitroprusside and nicorandil, the latter in the presence of glibenclamide to suppress the glibenclamide-sensitive stimulatory component on 86Rb efflux, antagonized the noradrenaline-induced increase in 86Rb efflux, while cromakalim in the presence of glibenclamide had no effect. (5) All of the vasodilators relaxed rabbit aortic strips contracted by 10(-7) mol/l noradrenaline in a concentration-dependent manner. (6) The vasodilatory response to cromakalim was antagonized by glibenclamide, whereas the relaxant action of nicorandil and of sodium nitroprusside remained unaffected. (7) These results demonstrate that under particular experimental circumstances, nicorandil can behave in vascular smooth muscle both as an opener of glibenclamide-sensitive K+ channels, and as a directly acting nitrovasodilator which acts via reduction of cellular calcium levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Left ventricular effects of nicorandil in comparison with nitroglycerin in chronic conscious dogs

Nicorandil is a new coronary vasodilator possessing beneficial properties. However, its detailed cardiovascular effects, especially on left ventricular (LV) preload, have not yet been fully elucidated. The purpose of this study was to assess the effects of nicorandil on LV hemodynamics in conscious dogs and to examine the mechanisms of its antiischemic action. Nine mongrel dogs were instrumented for instantaneous and continuous measurements of LV diameters, and aortic and LV pressures. The effects of nicorandil (0.2 mg/kg, intravenously) were compared with those of nitroglycerin (15 micrograms/kg, intravenously) in conscious dogs. Mean aortic pressure decreased similarly with both nicorandil and nitroglycerin (-20.1 +/- 3.1% vs. 21.6 +/- 2.8%, ns). Heart rate was elevated with both drugs. Both nicorandil and nitroglycerin significantly decreased LV systolic pressure to the same extent (-11.3 +/- 0.5% vs. -10.5 +/- 11.6%, ns). LV max dp/dt was not significantly changed by either drug. Although both nicorandil and nitroglycerin significantly increased fractional shortening, nicorandil had a greater effect on fractional shortening than nitroglycerin (20.0 +/- 3.0% vs. 10.2 +/- 2.3%, p less than 0.05). In this study, nicorandil, administered intravenously, had a salutary effect on cardiac function. LV end-diastolic diameter decreased with nicorandil and nitroglycerin (-6.5 +/- 1.5% vs. -12.6 +/- 2.6%, p less than 0.01), respectively. In conclusion, nicorandil decreased LV end-diastolic diameter in conscious dogs, indicating a decrease in venous return and preload of the heart. In addition, nicorandil decreased LV afterload to the same extent as nitroglycerin. The decrease in preload and afterload on the heart is thought to be one of the mechanisms of the antiischemic action of nicorandil.

Nitrate Tolerance Induced by Nicorandil or Nitroglycerin is Associated with Minimal Loss of Nicorandil Vasodilator Activity

In the current study, the vasodilator and tolerance-inducing actions of a recently developed organic nitrate vasodilator, nicorandil, were compared to nitroglycerin (NTG) in an isolated coronary artery preparation. The order of potency for relaxing U46619-constricted bovine-isolated coronary artery rings was NTG greater than isosorbide dinitrate (ISDN) greater than nicorandil. NTG was approximately 250-fold more potent than nicorandil (mean EC50 values for relaxation; 0.044 and 11.2 microM, respectively; n = 6-8). Coronary artery rings preexposed for 60 min to NTG (30 microM) were subsequently markedly less responsive to the relaxant effects of NTG (7.5-fold increase in mean EC50 value, 68.4% decrease in Emax; p less than 0.001) and ISDN (14.1-fold increase in mean EC50 value; p less than 0.001), although only marginally less responsive to nicorandil (1.75-fold increase in mean EC50 value; p less than 0.05). Thus, the coronary artery relaxant actions of nicorandil were significantly less affected by NTG-induced tolerance than were the relaxant actions of the related organic nitrate compounds, NTG and ISDN. To compare the tolerance-inducing actions of NTG and nicorandil, the relaxant actions of a series of nitric oxide (NO)-containing vasodilators were determined in control coronary artery rings and in rings preexposed for 60 min to either 30 microM NTG or 5,000 microM nicorandil. Quantitatively, similar changes in coronary artery ring responsiveness were produced by tolerance induced by NTG and nicorandil; marked attenuation of responsiveness to NTG and to the nonnitrate compound 3-morpholinosydnonimine (SIN-1), but only marginal attenuation of responsiveness to nicorandil and NO.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of N-(2-hydroxyethyl)nicotinamide Nitrate (Nicorandil; SG-75) and its Derivatives on Pancreatic Exocrine Secretion in the Dog

Nicorandil, a compound containing a nitrate moiety, can act as a K+ channel opener. Previously we reported stimulatory effects of an intraarterial injection of nicorandil on pancreatic exocrine secretion in the isolated, blood-perfused pancreas under a constant perfusion pressure. To clarify this mechanism in relation to the chemical structure we studied the effects of nicorandil and its derivatives [nitrate containing structure, N-(3-hydroxy-propyl)nicotinamide nitrate (SG-89); nitrate lacking structure, N-(2-acetoxyethyl)nicotinamide (SG-209)], in addition to nitroglycerin (TNG) and pinacidil (a potent K+ channel opener) under a constant perfusion flow rate to the pancreas. Nicorandil, SG-89, and TNG elicited a dose-dependent increase in pancreatic fluid secretion, showing increases in bicarbonate and amylase concentrations. In contrast, SG-209 and pinacidil did not stimulate pancreatic secretion. Furthermore, stimulatory action of nicorandil was not inhibited by treatment with an intraarterial infusion of tetraethylammonium (TEA). These results suggest that nicorandil has direct secretory properties on pancreatic exocrine glands and its nitrate moiety has an important role in the stimulation of pancreatic exocrine secretion, but increasing flow rate and K+ channel opening action do not participate in the secretion.

Effect of Cyclooxygenase Blockade on the Beneficial Actions of Nicorandil in the Stunned Myocardium of Dogs

The effects of nicorandil, indomethacin and nicorandil + indomethacin on subendocardial segment shortening (%SS), regional myocardial blood flow and coronary venous thromboxane (TxA2) and prostacyclin (PGI2) levels were compared to those of a saline-treated group in anesthetized dogs subjected to a 15-min coronary artery occlusion and 3 h of reperfusion. During reperfusion, nicorandil markedly improved %SS in the ischemic-reperfused region compared to saline- and indomethacin-treated dogs. Indomethacin did not antagonize the beneficial effects of nicorandil. These results suggest that the beneficial actions of nicorandil in this model are not the result of an increase in PGI2 or decrease in TxA2 synthesis.