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PubMed1990

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)

Animals↗

PubMed2002

Effect of nicorandil on coronary events in patients with stable angina: the Impact Of Nicorandil in Angina (IONA) randomised trial.

BACKGROUND: In addition to its anti-ischaemic effects, the antianginal drug nicorandil is thought to have cardioprotective properties. We did a randomised trial to find out whether nicorandil could reduce the frequency of coronary events in men and women with stable angina and additional risk factors. METHODS: 5126 patients were randomly assigned 20 mg nicorandil twice daily (n=2565) or identical placebo (n=2561) in addition to standard antianginal therapy. The primary composite endpoint was coronary heart disease death, non-fatal myocardial infarction, or unplanned hospital admission for cardiac chest pain. The secondary endpoint was the combined outcome of coronary heart disease death or non-fatal myocardial infarction. Other outcomes reported include all-cause mortality, all cardiovascular events, and acute coronary syndromes. Mean follow-up was 1.6 years (SD 0.5). Analysis was by intention to treat. FINDINGS: There were 398 (15.5%) primary endpoint events in the placebo group and 337 (13.1%) in the nicorandil group (hazard ratio 0.83, 95% CI 0.72-0.97; p=0.014). The frequency of the secondary endpoint was not significantly different between the groups (134 events [5.2%] vs 107 events [4.2%]; 0.79, 0.61-1.02; p=0.068). The rate of acute coronary syndromes was 195 (7.6%) in the placebo group and 156 (6.1%) in the nicorandil group (0.79, 0.64-0.98; p=0.028), and the corresponding rates for all cardiovascular events were 436 (17.0%) and 378 (14.7%; 0.86, 0.75-0.98; p=0.027). INTERPRETATION: We showed a significant improvement in outcome due to a reduction in major coronary events by antianginal therapy with nicorandil in patients with stable angina.

Aged↗

PubMed1998

Myocardial protection afforded by nicorandil and ischaemic preconditioning in a rabbit infarct model in vivo.

We previously showed that preoperative nicorandil, a hybrid potassium channel opener and nitrate compound, conferred cardioprotective effects in a hypoxia/reoxygenation model of isolated human atrial muscle by using functional recovery as an end point, and that ischaemic preconditioning surprisingly abolished the protection afforded by nicorandil. In view of this paradoxic result, this study was undertaken to assess whether ischaemic preconditioning influences any protective effect of nicorandil by using infarct size as an end point. In addition, we investigated the underlying mechanisms of the protective action of nicorandil. Rabbits underwent a midline sternotomy under anaesthesia. A left coronary branch was occluded for 30 min followed by 120 min of reperfusion. Nicorandil (100 microg/kg bolus + 10 microg/kg/min) was given intravenously 30 min before coronary occlusion and continued to the time of reperfusion (early treatment) or 5 min before reperfusion and continued throughout reperfusion (late treatment). Ischaemic preconditioning was achieved by a single episode of 5-min coronary occlusion followed by 10-min reperfusion before the 30-minute occlusion in the presence or absence of nicorandil. Risk volume and infarct volume were determined by fluorescent microspheres and tetrazolium staining, respectively. Early treatment with nicorandil conferred a significant decrease in percentage of infarct size within the risk zone (24.9 +/- 2.9%) when compared with control (39.2 +/- 4.3%; p < 0.01). Late treatment with nicorandil had no effect on infarct size (43.5 +/- 3.4%). Ischaemic preconditioning also resulted in significant reduction in infarct size (13.4 +/- 4.3%; p < 0.01 vs. control). The combination of ischaemic preconditioning with nicorandil (early treatment) showed an intermediate protective efficacy between early treatment with nicorandil alone and ischaemic preconditioning alone (18.1 +/- 4.2%; p < 0.01 vs. control). Nitroglycerin (10 microg/kg bolus + 1 microg/kg/kg/min, i.v.) given before and during ischaemia tended to reduce infarct size, but the effect was not statistically significant (28.9 +/- 2.9%; p > 0.05 vs. control). Although an adenosine triphosphate (ATP)-sensitive potassium channel blocker, 5-hydroxydecanoate (5 mg/kg, i.v.) by itself had no effect on infarct size (38.8 +/- 3.6%), the protective effect of nicorandil was abolished by 5-hydroxydecanoate (37.7 +/- 5.8%; p < 0.05 vs. early treatment of nicorandil). There were no differences in area at risk or haemodynamics between groups. Our results show that nicorandil has a protective effect against myocardial infarction in our rabbit model when infused before and during ischaemia, but not during reperfusion, and the protective effect is abolished by an ATP-sensitive potassium channel blocker. Furthermore, the addition of ischaemic preconditioning does not detrimentally influence the effect of nicorandil. This suggests that nicorandil can confer an infarct-limiting effect by opening of ATP-sensitive potassium channels with or without intermittent ischaemia, as may happen in patients with unstable angina.

Animals↗

PubMed1986

The relaxant action of nicorandil in guinea-pig isolated trachealis.

Nicorandil (1-1000 mumol l-1) caused concentration-dependent relaxation of guinea-pig isolated trachealis. Propranolol (1 mumol l-1) did not modify the relaxant action of nicorandil but antagonized isoprenaline. Among K+-channel inhibitors tested, apamin (0.1 mumol l-1) and procaine (5 mmol l-1) did not modify the relaxant action of nicorandil. In contrast, tetraethylammonium (TEA, 8 mmol l-1) caused five fold antagonism. Trachealis exposed to K+-rich (120 mmol l-1) Krebs solution developed near-maximal tension. Nicorandil relaxed the K+-depolarized tissue though its concentration-effect curve was shifted markedly to the right. In tissues in which tone was induced by histamine, methylene blue (100 mumol l-1) antagonized nicorandil and sodium nitroprusside but did not modify the relaxant action of aminophylline. Intracellular electrophysiological recording showed that nicorandil (1 mumol l-1) could evoke some relaxation in the absence of electrical changes. Higher concentrations (10-1000 mumol l-1) reduced the amplitude and frequency of spontaneous electrical slow waves. Nicorandil also caused concentration-dependent hyperpolarization and relaxation. When the hyperpolarization was sufficiently pronounced slow wave activity was abolished. TEA (8 mmol l-1) induced slow waves which were surmounted by a spike potential. TEA slightly reduced the maximal hyperpolarization induced by nicorandil and increased the time required for nicorandil to abolish slow wave discharge. Procaine (5 mmol l-1) induced slow waves of relatively low frequency. Sometimes these were surmounted by a spike potential Procaine markedly reduced the hyperpolarization induced by nicorandil and increased the time required for abolition of slow waves. In studies of the efflux of 86Rb+ from muscle-rich strips of trachea, nicorandil (1000 mumol l-1) increased the efflux rate constant, whereas isoprenaline (1 mumol l-1) was without effect. It is concluded that nicorandil-induced relaxation does not involve the activation of beta-adrenoceptors but is partly attributable to the formation of nitric oxide from the nitrate moiety in its molecular structure. Nicorandil can evoke relaxation in the absence of membrane potential change but towards the upper end of its effective concentration range, nicorandil increases membrane K+ conductance and thereby evokes hyperpolarization of trachealis cells. The K+ channels opened by nicorandil are permeable to 86Rb, insensitive to apamin and TEA but may be inhibited by procaine.

Aminophylline↗

PubMed1997

Hyperpolarized cardioplegic arrest with nicorandil: advantages over other potassium channel openers.

BACKGROUND: Our laboratory has demonstrated that the potassium channel openers (PCOs) aprikalim and pinacidil are effective cardioplegic agents but exhibit toxicity at high doses. In this study, the effectiveness of another PCO, nicorandil, was investigated for several reasons. The chemical structure of nicorandil is distinct from other PCOs, in part because of a nitrate moiety, which may confer additional cardioprotection. Moreover, nicorandil has been approved for human use and has not been shown to exhibit significant toxicity in clinical trials. METHODS AND RESULTS: Using a blood-perfused, parabiotic, isolated rabbit heart model, 45 hearts underwent 30 minutes of global normothermic ischemia after infusion of 50 mL of cardioplegia, followed by 30 minutes of reperfusion. Cardioplegia consisted of Krebs-Henseleit solution either alone (control) or with nicorandil (100 micromol/L, 300 micromol/L, or 1 mmol/L), 20 mmol/L KCl, or nicorandil (100 micromol/L) plus glibenclamide (10 micromol/L), a potassium channel blocker. Over a wide range of volumes, left ventricular systolic function and diastolic compliance were measured at baseline and after reperfusion. The percentage of recovery of developed pressure (mean+/-SEM) for control, glibenclamide plus nicorandil, 100 micromol/L nicorandil, 1 mmol/L nicorandil, and 20 mmol/L KCl was 44.1+/-3.4%, 44.9+/-2.9%, 61.1+/-4.7%, 58.4+/-3.0%, and 63.2+/-1.5%, respectively. Postreperfusion end-diastolic pressures were significantly increased in control, 300 micromol/L nicorandil, and nicorandil plus glibenclamide groups. CONCLUSIONS: Nicorandil (100 micromol/L and 1 mmol/L) significantly improved functional recovery compared with control and was as effective as KCl cardioplegia. The protective effect of nicorandil was eliminated by glibenclamide, indicating that nicorandil is cardioprotective primarily through its capability as a PCO. In contrast to other PCOs, nicorandil produced mechanical arrest as quickly as KCl and did not show toxicity.

Animals↗

PubMed2000

Cardioprotective effects of nicorandil in rabbits anaesthetized with halothane: potentiation of ischaemic preconditioning via KATP channels.

1. The roles of ATP-sensitive K+ channels (KATP channels) in ischaemic or pharmacological preconditioning in the rabbit heart remain unclear. Infarct limitation by ischaemic preconditioning was abolished by the KATP channel blocker glibenclamide under ketamine/xylazine anaesthesia, but not under anaesthesia induced by pentobarbital. Infarct limitation by the KATP channel opener pinacidil was detected under ketamine/xylazine anaesthesia, but not under pentobarbital anaesthesia. Thus, these effects appear to be anaesthetic dependent. 2. In the present study, we examined whether nicorandil (a KATP channel opener nitrate) exhibits cardioprotective actions under halothane anaesthesia, another commonly used volatile anaesthetic. Control animals were subjected to 40 min coronary occlusion and 120 min reperfusion. Before 40 min ischaemia, the nicorandil group received nicorandil (100 microg/kg per min, i.v., for 10 min), the 5' preconditioning (PC) group received 5 min ischaemia/20 min reperfusion, the 2.5'PC group received 2.5 min preconditioning ischaemia/20 min reperfusion, the nicorandil +2.5'PC group received both nicorandil and 2.5 min ischaemia/20 min reperfusion, the nicorandil +2.5'PC + 5-hydroxydecanoate (5HD) group received both nicorandil and 2.5 min ischaemia/20 min reperfusion in the presence of 5-hydroxydecanoate (5HD; a KATP blocker) and the 5HD group received 5 mg/kg, i.v., 5HD alone. Myocardial infarct size in control (n = 7), nicorandil (n = 5), 5'PC (n = 8), 2.5'PC (n = 5), nicorandil + 2.5'PC (n = 5), nicorandil + 2.5'PC + 5HD (n = 5) and 5HD (n = 4) groups averaged 44.4 +/- 3.6, 41.7 +/- 5.7, 17.8 +/- 3.2,* 34.1 +/- 4.8, 21.3 +/- 4.2,* 39.1 +/- 5.6 and 38.9 +/- 5.0% of the area at risk, respectively (*P <0.05 vs control). 3. Thus, nicorandil alone did not have an infarct size-limiting effect in halothane-anaesthetized rabbits. However, the results suggest that even when nicorandil alone does not demonstrate a direct cardioprotective effect, it may enhance ischaemic preconditioning via KATP channels. Key words: ATP-sensitive K+ (KATP) channel, ischaemic preconditioning, myocardial infarction, nicorandil, rabbit.

ATP-Binding Cassette Transporters↗

PubMed1992

Pharmacokinetic profile of nicorandil in humans: an overview.

Nicorandil is rapidly and almost completely absorbed from the gastrointestinal tract. Nicorandil is not metabolized significantly by the liver during passage through the portal system (lack of first-pass effect). Thus, it easily enters the systemic blood flow, resulting in almost complete bioavailability (75-100%). The concomitant food intake decreases the rate of absorption of the drug, resulting in a delay of peak plasma concentration, but has little or no effect on maximal plasma concentration or total amount of absorbed nicorandil. After oral administration of a 5-, 10-, 20-, or 40-mg dose, there is a linear relationship between the doses and increases of maximum plasma concentrations and area under the curve, demonstrating that the pharmacokinetics of nicorandil are linear. Steady-state plasma concentrations of nicorandil usually are reached within approximately 96-120 h after continuous dosing (20 mg b.i.d.), probably due to its distribution and metabolism patterns. On average, the Cmax then is approximately 300 ng/ml, which is achieved rapidly within 30 min after drug intake. Nicorandil is bound weakly to human albumin and other plasma proteins (approximately 25%). After oral (and i.v.) administration of the drug, the apparent volume of distribution is approximately 1.0 L/kg body weight. Nicorandil is metabolized extensively, and the major route of elimination is the kidney: Less than 2% of the dose is excreted through the biliary route. As a consequence, the parent drug is excreted poorly in urine (very low renal clearance), whereas 2-nicotinamidoethanol, a pharmacologically inactive denitrated metabolite, is the major nicorandil-related compound excreted in urine. The nicotinamide/nicotinic acid biotransformation pathway contributes to the accumulation of nicorandil and 2-nicotinamidoethanol (denitrated metabolite) during repeated dosing because of the saturable merging of nicotinamide/nicotinic acid derivatives (from the nicorandil metabolism) into the NAD/NADP endogenous pool of coenzymes. The apparent elimination half-life is short (approximately 1 h), and total body clearance is close to 1.15 L/min, which is lower than the liver blood flow. Especially during repeated dosing, a slower elimination process appears that is related to only approximately 10% of the amount of nicorandil found in plasma. Most of the nicorandil metabolites are excreted during the 24-h period after dosing, with the remainder excreted more slowly (as nicotinamide derivatives). The pharmacokinetics of nicorandil are not altered significantly in elderly persons and in patients who have chronic renal impairment or liver insufficiency. Furthermore, its disposition profile is not modified when concomitant drugs such as drug-metabolizing enzyme inducers or inhibitors are given.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗

PubMed1996

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.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2001

[Pharmaceutical evaluation of fast-disintegrant tablet containing nicorandil-loaded particles].

AIM: To improve the bioavailability and taste of fast-disintegrating tablet (FD tablet) containing nicorandil-loaded particles. METHODS: A FD tablet containing nicorandil-loaded particles with 1%-4% croscarmellose sodium in addition of D-mannitol and lactose (9:1) was prepared and the dissolution and absorption characteristics were examined, in comparison with FD tablet and commercial tablets of nicorandil. In vivo absorption of nicorandil from FD tablet was evaluated in beagle dogs. RESULTS: The disintegration time of FD tablets containing 1% croscarmellose sodium with 6 mm and 10 mm in diameter were about 12 and 23 seconds, respectively. When nicorandil-loaded particles consist of myristyl alcohol and stearyl alcohol were put in FD tablet, nicorandil release from FD tablet continued until 6 h while nicorandil release from Sigmart and FD tablet containing nicorandil crystals finished within 5 min. In vivo absorption of nicorandil from Sigmart and FD tablet containing nicorandil crystals was very similar after oral administration in beagle dogs and no statistic difference in AUC, Tmax, Cmax was observed between these tablets. However pharmacokinetics parameters of nicorandil after oral administration of FD tablet containing nicorandil-loaded particles showed that nicorandil was delivered into the body at a suitable absorption rate with similar AUC, delayed Tmax and lower Cmax. CONCLUSION: The reports suggest that the modification of properties of myristyl alcohol and stearyl alcohol released from the drug-loaded particles system would lead to more acceptable bioavailability of the system. However, The formulation of particles and may have a masking effect against the bitter taste and irritation of the drug.

Administration, Oral↗

PubMed1992

Clinical profile of nicorandil: an overview of its hemodynamic properties and therapeutic efficacy.

Nicorandil is a new vasodilator agent. Efficacy and safety of nicorandil in the treatment of angina pectoris have been evaluated through an extensive clinical program with a total of 1,680 patients who received the product. Results of hemodynamic studies provide clear evidence of the vasodilatory effect of nicorandil. In a population of patients with normal left ventricular function, a reduction in preload was apparent from a decrease in left ventricular end-diastolic pressure from 7.4 +/- 1.7 to -3.2 +/- 1.5 mm Hg. Furthermore, nicorandil produced marked reductions in total peripheral resistance (19%) and aortic blood pressures with decreases in systolic pressure of 34% and in diastolic pressure of 21%. At antianginal doses, nicorandil has a coronary vasodilating effect as well as a balanced peripheral action that leads to decreases in both preload and afterload. Therefore, nicorandil affects two of the main hemodynamic determinants of oxygen demand without impairing myocardial contractility or atrioventricular conduction. In addition, its strong spasmolytic activity is of particular interest when dynamic coronary obstruction is considered. Nicorandil clearly has demonstrated K(+)-channel-opening activity. In addition, the range of plasma concentrations in humans at therapeutic doses is similar to that of experimental models in which the K(+)-channel activity has been determined. This mechanism of action may explain the different hemodynamic profiles of nicorandil and nitrates in humans. Nicorandil is an effective and potent antianginal agent at a dose of 10-40 mg, which in monotherapy controls 69-80% of patients with stable chronic angina. Comparative trials have shown that the efficacy of nicorandil compares with that of drugs from the main classes of antianginal drugs--beta-blockers (atenolol, propranolol) and a Ca2+ antagonist (diltiazem). Patients treated for as long as 3 months or 1 year have shown sustained efficacy with no evidence of development of tolerance to the drug. The long duration of action allows effective treatment with a well-tolerated b.i.d. regimen. At the recommended doses, the main side effects were limited to headaches. They usually occurred early in the course of treatment and can be diminished by a progressive titration. From the large safety data base, there is no evidence that nicorandil induced exacerbation of myocardial ischemia or abrupt withdrawal syndrome. Nicorandil does not adversely affect the lipid profile or the glucose level. As an antianginal drug with a novel mechanism of action, nicorandil provides a useful alternative to existing antianginal agents in the long-term management of patients with angina pectoris.

Diltiazem↗

PubMed1990

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.

Animals↗

PubMed1989

Effects of nicorandil on coronary circulation and myocardial ischemia.

The effect of the new antianginal drug, nicorandil, was studied in several models of myocardial ischemia in anesthetized dogs. In animals subjected to an acute or chronic coronary artery occlusion, nicorandil produced increases in collateral perfusion when changes in aortic pressure were minimized. In a model of irreversible ischemia, nicorandil produced a marked (50%) decrease in myocardial infarct size. In several models of reversible ischemia-reperfusion injury, the "stunned myocardium," nicorandil was shown to enhance the recovery of systolic segment shortening after a brief period (15 to 30 minutes) of coronary occlusion. Other vasodilators such as nitroglycerin or nifedipine were not as efficacious as nicorandil. In a model of multiple (n = 3) coronary occlusion (5 minutes) with intermittent (30 minutes) reperfusion, nicorandil improved the recovery of systolic segment shortening during reperfusion and prevented the loss of adenosine triphosphate and tissue edema that occurred in untreated hearts. The beneficial effects of nicorandil on functional and metabolic recovery after recurrent ischemia was shown to be partially the result of an energy-sparing effect of nicorandil to reduce free fatty acid use during the ischemic period. Cyclooxygenase blockade with indomethacin did not block the beneficial effects of nicorandil in the stunned myocardium. These results suggest that nicorandil does not promote an increase of prostacyclin. Finally, nicorandil was found to inhibit superoxide anion production by human neutrophils stimulated by formyl-methionyl-leucyl-phenylalanine plus cytochalasin B. These results suggest that part of the beneficial actions of nicorandil may occur during reperfusion and may be the result of a reduction in oxygen free radical production.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1998

Potassium channel activation and relaxation by nicorandil in rat small mesenteric arteries.

1. We used whole-cell patch clamp to investigate the currents activated by nicorandil in smooth muscle cells isolated from rat small mesenteric arteries, and studied the relaxant effect of nicorandil using myography. 2. Nicorandil (300 microM) activated currents with near-linear current-voltage relationships and reversal potentials near to the equilibrium potential for K+. 3. The nicorandil-activated current was blocked by glibenclamide (10 microM), but unaffected by iberiotoxin (100 nM) and the guanylyl cyclase inhibitor LY 83583 (1 microM). During current activation by nicorandil, openings of channels with a unitary conductance of 31 pS were detected. 4. One hundred microM nicorandil had no effect on currents through Ca2+ channels recorded in response to depolarizing voltage steps using 10 mM Ba2+ as a charge carrier. A small reduction in current amplitude was seen in 300 microM nicorandil, though this was not statistically significant. 5. In arterial rings contracted with 20 mM K+ Krebs solution containing 200 nM BAYK 8644, nicorandil produced a concentration-dependent relaxation with mean pD2 = 4.77+/-0.06. Glibenclamide (10 microM) shifted the curve to the right (pD2 = 4.32+/-0.05), as did 60 mM K+. LY 83583 caused a dose-dependent inhibition of the relaxant effect of nicorandil, while LY 83583 and glibenclamide together produced greater inhibition than either alone. 6. Metabolic inhibition with carbonyl cyanide m-chlorophenyl hydrazone (30 nM), or by reduction of extracellular glucose to 0.5 mM, increased the potency of nicorandil. 7. We conclude that nicorandil activates KATP channels in these vessels and also acts through guanylyl cyclase to cause vasorelaxation, and that the potency of nicorandil is increased during metabolic inhibition.

Aminoquinolines↗

PubMed2002

Long-term administration of nicorandil abolishes ischemic and pharmacologic preconditioning of the human myocardium: role of mitochondrial adenosine triphosphate-dependent potassium channels.

BACKGROUND: Acute administration of mitochondrial adenosine triphosphate-dependent potassium channel openers preconditions the heart, but whether their long-term administration induces a permanent state of protection is unknown. These studies investigate the effect of long-term treatment with the mitochondrial adenosine triphosphate-dependent potassium channel opener nicorandil on the response of the human myocardium to ischemia and preconditioning. METHODS: Right atrial tissue obtained from patients regularly treated with or without nicorandil (mean of 20 mg/d for 18.6 +/- 2.5 months) and undergoing cardiac surgery was sliced and equilibrated for 30 minutes and then subjected to 90 minutes of simulated ischemia, followed by 120 minutes of reoxygenation. In study 1 the following groups were studied to investigate the effect of nicorandil on the susceptibility of the myocardium to ischemia and on the protective effect of ischemic and pharmacologic preconditioning: (1) aerobic control; (2) simulated ischemia and reoxygenation alone; (3) ischemic preconditioning with 5 minutes of simulated ischemia and 5 minutes of reoxygenation; and (4) phenylephrine (0.1 micromol/L) for 5 minutes and 5 minutes' washout before simulated ischemia and reoxygenation. In study 2 the following groups were studied to investigate the effect of nicorandil on the responsiveness of mitochondrial adenosine triphosphate-dependent potassium channels: (1) aerobic control; (2) simulated ischemia and reoxygenation; (3) ischemic preconditioning; (4) diazoxide (100 micromol/L) for 10 minutes before simulated ischemia and reoxygenation, and (5) 5-hydroxydecanoate (1 mmol/L) for 10 minutes before simulated ischemia and reoxygenation. In study 3 the following groups were included to investigate the effect of the long-term administration of nicorandil on the kinase pathway involved in preconditioning: (1) aerobic control; (2) simulated ischemia and reoxygenation alone; (3) ischemic preconditioning; (4) phorbol 12-myristate 13-acetate (1 micromol/L), a protein kinase C activator, for 10 minutes before simulated ischemia and reoxygenation; and (5) anisomycin (1 nmol/L), a p38 mitogen-activated protein kinase activator, for 10 minutes before simulated ischemia and reoxygenation. At the end of each protocol, the leakage of creatine kinase (in units per gram wet weight) and the reduction of 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide into insoluble formazan dye (in millimoles per gram wet weight) were measured. RESULTS: In study 1 the leakage of creatine kinase and the reduction of 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide induced by simulated ischemia and reoxygenation were similar in the groups with or without nicorandil (creatine kinase, 3.4 +/- 0.1 and 3.5 +/- 0.2, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 74.6 +/- 3.9 and 67.9 +/- 7.3, respectively; P >.2 in each instance). Ischemic preconditioning and pharmacologic preconditioning protected the myocardium from patients without nicorandil (creatine kinase, 2.3 +/- 0.1 and 2.4 +/- 0.1, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 131.4 +/- 4.9 and 128.4 +/- 5.6, respectively; P < 0.001 vs simulated ischemia and reoxygenation alone in each instance) but not the myocardium from patients receiving nicorandil (creatine kinase, 3.3 +/- 0.1 and 3.3 +/- 0.2, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 89.7 +/- 6.5 and 86.4 +/- 5.2, respectively; P >.2 vs simulated ischemia and reoxygenation alone in each instance). In study 2 the administration of diazoxide had identical protection to that of ischemic preconditioning in the myocardium of patients not receiving nicorandil (creatine kinase, 2.1 +/- 0.2 and 2.3 +/- 0.1, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 141.4 +/- 7.4 and 131.4 +/- 4.9, respectively; P < 0.001 vs simulated ischemia and reoxygenation alone in each instance) but failed to precondition the myocardium from patients treated with nicorandil (creatine kinase, 3.3 +/- 0.2 and 3.4 +/- 0.1, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 90.1 +/- 7.2 and 86.4 +/- 5.2, respectively; P > 0.2 vs simulated ischemia and reoxygenation alone in each instance). In study 3 phorbol 12-myristate 13-acetate or anisomycin given for 10 minutes before simulated ischemia and reoxygenation afforded similar protection to that of ischemic preconditioning in the myocardium from patients with (creatine kinase, 1.5 +/- 0.3 and 1.4 +/- 0.1, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 147.0 +/- 4.9 and 160.0 +/- 16.1, respectively; P < 0.001 vs simulated ischemia and reoxygenation alone in each instance) and without nicorandil (creatine kinase, 1.7 +/- 0.4 and 1.4 +/- 0.2, respectively; 3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide, 160.3 +/- 13.6 and 158.3 +/- 11.8, respectively; P <.001 vs simulated ischemia and reoxygenation alone in each instance). CONCLUSION: The myocardium of patients chronically treated with nicorandil cannot be preconditioned either by ischemia or pharmacologically, and this is because of unresponsive mitochondrial adenosine triphosphate-dependent potassium channels. However, protection can be obtained by protein kinase C and p38 mitogen-activated protein kinase activation, which are downstream of mitochondrial adenosine triphosphate-dependent potassium channels in the signaling transduction pathway of preconditioning.

Adenosine Triphosphate↗

PubMed1992

Nicorandil. A review of its pharmacology and therapeutic efficacy in angina pectoris.

Nicorandil belongs to the class of compounds known as potassium channel activators which are characterised by their arterial vasodilator properties. In addition, nicorandil has venodilating properties which are attributable to a nitrate group in its chemical structure. Therefore, by combining these two vasodilator mechanisms, nicorandil represents a novel type of compound for use in the treatment of angina pectoris. Furthermore, increasing experimental evidence suggests that potassium channel activation may also exert a direct cytoprotective effect by augmenting normal physiological processes which protect the heart against ischaemic events. Comparative studies of up to 3 months' duration suggest that nicorandil is equivalent in efficacy to isosorbide dinitrate, propranolol, atenolol, nifedipine or diltiazem in the treatment of stable angina. Preliminary evidence suggests that an improvement of anginal and ischaemic symptoms is maintained for up to 1 year. Whilst the efficacy of nicorandil in other types of angina has not been extensively studied, preliminary results indicate that intravenous nicorandil is as effective as isosorbide dinitrate in the treatment of unstable angina and is also effective in patients with variant angina. In addition, the limited data available indicate that nicorandil may be effective in patients with unstable and variant angina who are refractory to therapy with conventional antianginal agents, a potentially important area for further study. Headache, mostly of mild to moderate intensity was the most commonly reported adverse event, occurring in one-third of patients receiving the recommended therapeutic regimen of nicorandil 10 to 20mg twice daily. In comparative trials involving a total of 84 patients who received nicorandil, the incidence of headache was similar to that produced by isosorbide mononitrate and isosorbide dinitrate. Headache was most frequent on initiating therapy but declined with continued treatment. To date, approximately 5% of patients participating in European trials have withdrawn due to headache, although this rate may be reduced by using a lower starting dose of nicorandil (5 mg twice daily). In summary, clinical experience thus far indicates that nicorandil, with its novel combination of two distinct vasodilator mechanisms, offers an effective alternative to established vasodilator therapy with conventional nitrates and calcium antagonists in the long term treatment of stable angina pectoris. Further studies are warranted to establish whether the unique pharmacodynamic profile of nicorandil is advantageous for the treatment of other types of angina and/or the ischaemic myocardium.

Angina Pectoris↗

PubMed2000

Nicorandil. An updated review of its use in ischaemic heart disease with emphasis on its cardioprotective effects.

Nicorandil is a drug with both nitrate-like and ATP-sensitive potassium-channel (K+ ATP) activating properties. By virtue of this dual mechanism of action, the drug acts as a balanced coronary and peripheral vasodilator and reduces both preload and afterload. The K+ ATP channel has been shown to be involved in the phenomenon of myocardial preconditioning, and studies in animal models of ischaemia-reperfusion-induced myocardial stunning or infarction indicate that nicorandil has cardio-protective effects. Studies in patients undergoing percutaneous transluminal coronary angioplasty (PTCA) have shown that the administration of nicorandil reduces ST-segment elevation during ischaemia. Nicorandil significantly improved the results of exercise tolerance tests versus baseline in patients with stable effort angina pectoris in early noncomparative trials. The drug also improved the results of exercise tolerance tests relative to placebo in early randomised, double-blind, placebo-controlled trials. In randomised, double-blind comparative studies in patients with angina pectoris, nicorandil has demonstrated equivalent efficacy, as measured by exercise tolerance testing, to isosorbide di- and mononitrate, metoprolol, propranolol, atenolol, diltiazem, amlodipine and nifedipine. The effects of nicorandil on various aspects of myocardial recovery from ischaemic damage caused by acute myocardial infarction have been investigated in the short term. Regional left ventricular (LV) wall motion, a marker of myocardial function, was significantly improved in nicorandil recipients relative to control. The main adverse event associated with nicorandil as treatment for angina pectoris is headache. This can be minimised by commencing nicorandil at a low dose in patients prone to headache. There have been infrequent case reports of mouth ulcers in patients receiving nicorandil; causality has not been conclusively established, but product prescribing information indicates that an alternative treatment should be considered if persistent aphthous or severe mouth ulceration occurs. Thus, nicorandil remains a useful background therapy for patients with angina pectoris. The drug has also demonstrated potential cardioprotective effects when used as part of an intervention strategy directly after acute myocardial infarction in high-risk patients. Further large scale longer term studies of nicorandil in this latter indication are awaited with interest.

Angina Pectoris↗

PubMed1988

Nicorandil shortens action potential duration and antagonises the reduction of Vmax by lidocaine but not by disopyramide in guinea-pig papillary muscles.

Conventional microelectrode techniques were used to examine whether or not nicorandil, which shortens action potential duration (APD), modifies the lidocaine- or disopyramide-induced time-dependent reduction of Vmax in guinea-pig papillary muscles. First, effects of 0.1 and 1 mmol/l nicorandil were examined on the frequency dependence of Vmax and on the recovery process of Vmax. Second, the frequency-dependent reduction of Vmax by 20 mumol/l antiarrhythmic drugs was examined in the presence and absence of 1 mmol/l nicorandil at stimulation frequencies of 1/120 Hz - 5 Hz. Third, the recovery process of Vmax in the presence of 20 mumol/l antiarrhythmic drugs was examined, with and without 1 mmol/l nicorandil, by applying test stimuli at various diastolic intervals after conditioning stimuli. 1 mmol/l nicorandil greatly shortened APD90 to 30-40% of control without changing the frequency dependence of Vmax, the recovery process of Vmax, and the resting potential. The lidocaine-induced, frequency-dependent reduction of Vmax was significantly antagonised by 1 mmol/l nicorandil, but the disopyramide-induced reduction was not. The recovery process of Vmax slowed in the presence of lidocaine was antagonised by 1 mmol/l nicorandil as follows: the time to get the full recovery of Vmax was shortened by nicorandil with a significant decrease in the zero time-intercept (from 0.54 to 0.38) but with an insignificant change in the recovery time constant (from 130 ms to 121 ms). In contrast, the recovery process of Vmax slowed in the presence of disopyramide (a zero time intercept of 0.13 and a recovery time constant of 50 s) was not significantly antagonised by 1 mmol/l nicorandil. In conclusion, nicorandil having an action potential-shortening action antagonises the lidocaine-induced, time-dependent reductions of Vmax, but not the disopyramide-induced reductions. These results suggest that: (1) lidocaine and disopyramide preferentially bind to inactivated and activated sodium channels, respectively, because lidocaine's effects are dependent on and disopyramide's effects are independent of APD (during which sodium channels are in the inactivated state); and (2) nicorandil is a useful drug for estimating whether a sodium channel-blocking action of class I antiarrhythmic drugs is due to an inactivated channel block or an activated channel block. These time-dependent reductions of Vmax by both lidocaine and disopyramide were well simulated by the guarded receptor hypothesis.

Action Potentials↗

PubMed1991

Analysis of cromakalim-, pinacidil-, and nicorandil-induced relaxation of the 5-hydroxytryptamine precontracted rat isolated basilar artery.

The effects of the K+ channel activators cromakalim, pinacidil, and nicorandil were investigated in endothelium intact, 5-hydroxytryptamine (5-HT) precontracted rat isolated basilar artery. Cromakalim, pinacidil, and nicorandil produced concentration-dependent relaxation of rat isolated basilar artery precontracted with 5-HT with a rank order of potency of cromakalim greater than pinacidil greater than nicorandil. All compounds produced full or nearly full relaxation. The calculated Hill coefficients for cromakalim-, pinacidil-, and nicorandil-induced relaxation of 5-HT-precontracted rat isolated basilar artery were 2.20 +/- 0.36, 1.30 +/- 0.07, and 1.00 +/- 0.01, respectively. Under conditions of increased tone produced by 50 mmol/l KCl (which inhibits cromakalim-induced relaxation) pinacidil and nicorandil produced marked reversal of spasm, with pinacidil being more potent than nicorandil. In arteries precontracted with 5-HT, preincubation with glibenclamide (0.1-1 mumol/l) produced concentration-related inhibition of relaxation with calculated mean pA2 values (and slopes of Schild regression) +/- SEM of 6.84 +/- 0.20 (1.1 +/- 0.20) against cromakalim. 6.60 +/- 0.14 (0.95 +/- 0.23) against nicorandil, and 6.57 +/- 0.26 (1.04 +/- 0.18) against pinacidil. For cromakalim, pinacidil, and nicorandil the slopes of Schild regression were not significantly different from unity. Tolbutamide 10 mumol/l was without effect against the cromakalim-, pinacidil-, or nicorandil-induced relaxation. Tetraethylammonium (TEA; 1-10 mmol/l) produced noncompetitive inhibition of the cromakalim-induced relaxation, but appeared to produce competitive inhibition of the pinacidil- and nicorandil-induced relaxations. We conclude that cromakalim, pinacidil, and nicorandil produce relaxation of the 5-HT precontracted rat basilar artery by similar mechanisms to those identified in other peripheral vascular and visceral smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗