Comparison of the inhibitory effects of nicorandil, nitroglycerin and isosorbide dinitrate on vascular smooth muscle of rabbit aorta

The inhibitory effects of nicorandil, nitroglycerin and isosorbide dinitrate on the contractions induced by 10(-6) M norepinephrine or by 65.4 mM K+ were compared in the vascular smooth muscle of rabbit aorta. These compounds relatively selectively inhibited the contraction induced by norepinephrine. Norepinephrine induced a sustained contraction in the aorta depolarized with high K+ and treated with 10(-6) M verapamil, and this contraction was also inhibited by these compounds. The increase in Ca2+ influx induced by norepinephrine, but not by high K+, was inhibited by the three compounds. The norepinephrine-induced transient contraction, which is due to release of stored Ca2+, was inhibited by these compounds. The inhibitory effects of nicorandil and nitroglycerin on this contraction were attenuated by high-K+ depolarization. Methylene blue (10(-5) M) antagonized and M&B 22948 (10(-5) M) potentiated the inhibitory effects of these compounds. These results suggest that nicorandil, nitroglycerin and isosorbide dinitrate have a similar mechanism of action. These compounds inhibit the norepinephrine-induced sustained contraction possibly by inhibiting the Ca2+ influx through receptor-linked Ca2+ channels, and inhibit the transient contraction by membrane hyperpolarization and also by direct inhibition of Ca2+ release although other mechanism of action may also be involved.     

Hemodynamic effects of nicorandil, isosorbide dinitrate, and dihydralazine in healthy volunteers

In this randomized, double-blind, crossover, single-dose study with 12 healthy subjects, we determined the hemodynamic changes and their time kinetics after administration of the mononitrate nicorandil (60 mg s.l.) and compared these effects with changes after administration of isosorbide dinitrate (ISDN; 20 mg s.l.), dihydralazine (10 mg i.v.), and placebo. Mechanocardiography, electrical impedance cardiography, and M-mode echocardiography measured drug effects. Dihydralazine increased heart rate, systolic pressure, and ventricular ejection time, and it decreased peripheral resistance, diastolic pressure, preejection period, end-systolic diameter and wall stress; these changes indicate an intense, pure afterload reduction. ISDN decreased systolic pressure, peripheral resistance, end-diastolic and systolic diameters and wall stress, shortened the ejection time, and prolonged the preejection period. The responses suggest ISDN causes a notable preload reduction accompanied by some afterload reduction. Nicorandil's effects were similar to those of ISDN in that the reductions in preload were equal, although the afterload reduction was more intense. Nicorandil's effects reached significance within 10 min, reached a maximum by 60 min, and had not vanished at 4 h. A drug with this profile and time kinetics should be tested further in situations requiring pre- and afterload reductions.     

Attenuation by isosorbide dinitrate of coronary occlusion-induced acidosis in the dog myocardium.

In dogs anaesthetized with pentobarbitone, the thorax was opened and myocardial pH measured continuously by the use of a glass pH electrode inserted in the left ventricular wall. The left anterior descending coronary artery (LAD) was partially occluded so that the LAD flow could be reduced to a half or one-third of the original flow (partial occlusion). LAD partial occlusion was continued for 90 min, drug or saline being infused for the last 60 min of this period. LAD occlusion decreased myocardial pH significantly by 0.41 to 0.67 pH units, and increased ST segment of the surface electrocardiogram from 11.7 to 12.1 mV. In dogs with non-ischaemic normal hearts, isosorbide dinitrate (ISDN; 1 mg kg-1) did not change markedly either the LAD flow, myocardial pH or heart rate, whereas it decreased myocardial contractile force (determined by a strain gauge arch) slightly and both the systolic and diastolic blood pressure markedly. In dogs with partial LAD occlusion, ISDN (1 mg kg-1) increased myocardial pH significantly and decreased blood pressure, but did not change ST segment elevation in an epicardial lead. These results indicate that ISDN attenuates ischaemia-induced acidosis without attenuating ischaemia-induced ST elevation in the dog myocardium.     

Inhalation of carbon dioxide enhances the coronary vasodilating action of isosorbide dinitrate in the dog

Two kinds of inspiratory gases, 100% O2 and 81% O2 + 19% CO2, were used for the artificial respiration. Elevating the inspiratory CO2 tension enhanced the decrease in coronary vascular resistance caused by isosorbide dinitrate (100 micrograms/kg), without any change in heart rate and systemic arterial pressure. Such a change in coronary vascular resistance was prevented by indomethacin. The results suggested an interaction between isosorbide dinitrate and CO2, which was mediated by prostaglandins.     

Effects of molsidomine,nitroglycerin, and isosorbide dinitrate on the coronary circulation,myocardial oxygen consumption,and haemodynamics in anaesthetized dogs

Summary The effects of i.v. molsidomine administration on the coronary circulation, myocardial oxygen consumption, and haemodynamics were studied in open-chest dogs with non-constricted coronary arteries, and compared to those of nitroglycerin and isosorbide dinitrate. Molsidomine (50, 100, 250 g/kg) reduced coronary flow while nitroglycerin (5, 10, 20 g/kg) and isosorbide dinitrate (50, 100, 250 g/kg) augmented coronary flow indicating coronary dilatation. Coronary resistance remained unaffected by molsidomine but fell after both nitrates. Molsidomine decreased myocardial oxygen consumption whereas nitroglycerin and isosorbide dinitrate initially increased oxygen consumption followed by a reduction. A decrease in stroke work was calculated after all three drugs. Minute work fell after molsidomine and nitroglycerin but not after isosorbide dinitrate.Heart rate and contractility remained unchanged by molsidomine but were both significantly enhanced by both nitrates. Stroke volume and cardiac output fell after molsidomine but increased immediately after both nitrates when administered with a subsequent decrease. Peripheral resistance was unchanged by the low dose of molsidomine but significantly decreased by the two nitrates immediately after administration indicating precapillary vasodilatation. The fall in blood pressure after molsidomine followed the reduction in cardiac output as sequel of lowered preload and venous return to the heart. The same mechanism decreased heart work after both nitrates but in addition vasodilatation of the coronary arteries and arterial vessel occurred.The effects of the three compounds are mainly the consequence of extracardiac effects, i.e. increased capacity of postcapillary vessels (molsidomine) plus arteriolar vasodilatation of short (nitroglycerin) and long duration (isosorbide dinitrate), respectively. Whereas molsidomine exerts no effects on the heart and coronary circulation both nitrates dilate coronary arteries and change heart performance thus indicating direct effects on the entire heart.     

Hypotensive effects and biotransformation of nicorandil, a new antianginal agent, administered to rats by different routes: comparison with nitroglycerin and isosorbide dinitrate

The effects of nicorandil, N-(2-hydroxyethyl)nicotinamide nitrate (ester), in reducing systemic blood pressure (SBP) in rats were studied in comparison with isosorbide dinitrate and nitroglycerin. The drugs were administered to pentobarbitone-anaesthetized rats by jugular vein (i.v.), portal vein (p.v.), intrajejunal (i.j.), intraperitoneal (i.p.) and subcutaneous (s.c.) routes.Nicorandil was absorbed rapidly through all routes, and caused marked hypotension dose-dependently. With isosorbide dinitrate and nitroglycerin, unlike nicorandil, the p.v. dose required to induce a vasodepressor response was significantly greater than that required to cause a comparable response after i.v. administration. In non-recirculating rat liver perfusion experiments, nicorandil was reduced only 5-10% during a single passage through the liver, while nitroglycerin was reduced over 95%. In recirculating liver perfusion experiments, the progressive decrease of nicorandil in the blood recirculated was accompanied by a corresponding increase of SG-86, a dinitrate compound of nicorandil (its main metabolite). Sixty min after dosing, nicorandil was decreased by approximately 73% of the initial nicorandil blood concentration and SG-86 was increased by approximately 70%. The extent of degradation of nicorandil in liver homogenates, examined by thin-layer chromatography, was in the following order: rat = guinea-pig greater than dog = monkey greater than pig. In these species a close inverse relationship is apparent between the rate of liver nicorandil degradation and hypotensive effects of nicorandil.     

Comparative effects of captopril and isosorbide dinitrate on the arterial wall of hypertensive human brachial arteries

Blood pressure, diameter, volume distensibility, and compliance of brachial artery were measured noninvasively in patients with sustained essential hypertension before and after Captopril in 11 patients and before and after isosorbide dinitrate (ISDN) in 11 other patients. Both drugs caused a similar significant decrease in mean arterial pressure (MAP) (p less than 0.001) and increase in arterial compliance (p less than 0.001), defined as the product of arterial volume by distensibility. ISDN increased arterial compliance through a dominant increase in arterial diameter (0.524 +/- 0.029 vs. 0.455 +/- 0.022 cm; p less than 0.001) and hence volume, whereas Captopril increased compliance through an increase in volume distensibility (0.20 +/- 0.02 vs. 0.12 +/- 0.02% change volume/mm Hg; p less than 0.001) with minimal changes in arterial diameter. The study provided evidence that of the two vasodilating drugs, ISDN and Captopril, only Captopril caused a predominant pharmacological relaxing effect on the wall of hypertensive human brachial arteries studied in situ.     

静滴硝酸异山梨酯与硝酸甘油治疗急性心肌梗死的比较

硝酸异山梨酯(Iso)组30例(男性24例,女性6例;年龄69±16a)采用Iso 20mg+5％葡萄糖液500mL持续静脉滴注72h,按35-40μg/min滴速治疗。硝酸甘油(Nit)组16例(男性12例,女性4例;年龄65±11a)采用Nit 20mg+5％葡萄糖液500mL,方法同上。结果:2组疗效相似,但Iso对血压影响小,对心率可略减慢,更适用于血压偏低和(或)伴有心功能不全者。     

Responses of isolated dog coronary arteries to tyramine

In isolated dog coronary arteries contracted with prostaglandin F2 alpha, tyramine in concentrations of 10(-6) and 5 x 10(-6) M caused relaxations, but it produced contractions at 2 x 10(-5) M or higher. The relaxant response to tyramine was attenuated, but the contractile response was enhanced at the second trial as compared with the responses at the first. Relaxations induced by low concentrations of tyramine were reversed to contractions by treatment with propranolol (10(-6) M) or sotalol (10(-5) M), and were abolished by cocaine (3 x 10(-6) M) or bretylium (2 x 10(-5) M). In coronary arteries isolated from reserpine (0.5 mg/kg)-pretreated dogs, tyramine produced only a contraction. Under resting conditions, contractions induced by tyramine (5 x 10(-6) to 2 x 10(-3) M) were potentiated by cocaine and propranolol, and were inhibited by phentolamine. Norepinephrine produced a dose-dependent relaxation in the arteries contracted with prostaglandin F2 alpha. In the presence of propranolol, the arteries under resting conditions were contracted by norepinephrine, the contraction being suppressed by treatment with phentolamine. It may be concluded that relaxations of dog coronary arteries induced by tyramine are mediated by liberation of norepinephrine from adrenergic nerves which stimulates beta-adrenoceptors in the smooth muscle. It seems likely that the tyramine (2 x 10(-5) M or higher)-induced contraction is not mediated by norepinephrine released, but it is partly due to a direct action on alpha-adrenoceptors.     

Controlled comparison of the pharmacodynamic effects of nicorandil (SG-75) and isosorbide dinitrate in man

Summary Nicorandil (SG-75) is a long acting mononitrate. A randomized, double-blind, crossover study in 10 healthy subjects has compared the haemodynamic actions of single sublingual doses of nicorandil 15, 30 and 60 mg with Isosorbide dinitrate (ISDN) 5 mg and placebo. Heart rate, blood pressure, systolic time intervals (STI) and left ventricular echocardiograms were used to assess haemodynamics over a 6 h period. Within 15 min of nicorandil administration, heart rate increased and peripheral resistance decreased (dose-dependent); the preejection period (corrected; PEPc) and the ratio of PEP to left ventricular ejection time (LVET) — PEP/LVET — were shortened by the 60 mg dose; the heart rate corrected electromechanical systole (QS₂c) was almost unchanged; left ventricular end diastolic and systolic diameters (EDD and ESD) were diminished. The effects on certain parameters had not completely disappeared after 6 h. ISDN produced a similar pattern with somewhat less intense effects; although PEPc and PEP/LVET were prolonged. The effects of both drugs can be attributed to vasodilatation on both the arteriolar and venous sides. The predominant action of ISDN was to reduce preload and thereby to lengthen PEPc and PEP/LVET; in addition, it lessened afterload. Although nicorandil caused a distinct reduction in preload, as shown by the smaller EDD, the effects of afterload reduction were predominant at the high dose induced shortening of PEPc and PEP/LVET. The profile of action of nicorandil should encourage clinical testing to evaluate its ability to induce ventricular unloading.     

Comparative pharmacokinetics of isosorbide nitrates after repeated doses of sustained release isosorbide dinitrate

The plasma kinetics of isosorbide dinitrate (ISDN), isosorbide-5-nitrate (IS-5-N) and isosorbide-2-nitrate (IS-2-N) were investigated in 20 healthy male and female volunteers, after b.i.d. administration over 2 days of sustained release ISDN 20 mg and 40 mg capsules (Iso Mack Retard 20 mg and 40 mg) and of a 40 mg sustained release ISDN tablet as reference formulation. The means of the individual maximum ISDN concentrations during the complete 2-day treatment amounted to 10.4 ng/ml after the 40 mg capsule, 5.3 ng/ml after the 20 mg capsule and 5.3 ng/ml after the reference tablet. The corresponding figures of the metabolically generated IS-5-N were 355.5 ng/ml, 168.8 ng/ml and 161.5 ng/ml, respectively. The measured amounts of IS-5-N are expected to contribute to the overall antianginal effect of at least the 40 mg capsule. According to the b.i.d. schedule, ISDN and the two mononitrates accumulated in the plasma after all three tested formulations. However, during the treatment with the 20 mg and the 40 mg capsules, accumulation was practically completed at the second day, while it was found to be more extended during treatment with the reference product. In terms of areas under the curve, the mean bioavailability of the 40 mg sustained release capsule relative to the reference formulation was 198% with respect to ISDN, and 197% both with respect to IS-2-N and IS-5-N. On the other hand, perfect dose-linearity of all relevant pharmacokinetic parameters of all three measured isosorbide nitrates was observed for the 20 mg and the 40 mg dose of the capsule.(ABSTRACT TRUNCATED AT 250 WORDS)     

Responsiveness and high-energy phosphate metabolism of isolated dog coronary arteries

The relationship between responsiveness and high-energy phosphate metabolism was observed in isolated dog coronary arterial strips before and after equilibration, under aerobic conditions. The strips responded slowly to potassium, norepinephrine, isoproterenol and 5-hydroxytryptamine before being equilibrated but did respond quickly to these drugs after being equilibrated for 1 hour under aerobic conditions. The contents of ATP, creatine phosphate (CP) and lactate were not significantly altered before and after equilibration for 1 hr. It is proposed that, before being equilibrated under aerobic conditions, coronary arteries may be unable to utilize ATP and CP due to injury of contractile or relaxant mechanisms resulting in a weak vascular responsiveness.     

Saliva concentrations of isosorbide dinitrate, isosorbide 2-mononitrate and isosorbide 5-mononitrate.

Correlations between saliva and plasma concentrations of isosorbide dinitrate (ISDN), and its active metabolites, isosorbide 2-mononitrate (2-ISMN) and isosorbide 5-mononitrate (5-ISMN) were examined. In the case of 5-ISMN (r = 0.98, P less than 0.01), saliva concentrations are probably reliable indices of the plasma concentrations of this drug and their measurement should provide a useful non-invasive procedure to assess compliance during the clinical use of products containing either ISDN or 5-ISMN: it may also be helpful in assessing the clinical pharmacokinetics of 5-ISMN. Less satisfactory correlations were obtained for ISDN (r = 0.84) and 2-ISMN (r = 0.83).     

Comparisons of the effects of nicorandil, pinacidil, nicardipine and nitroglycerin on coronary vessels in the conscious dog: role of the endothelium.

1. The vasodilator properties of nicorandil on large and small coronary arteries were compared to those of nicardipine, pinacidil, nitroglycerin and acetylcholine in six conscious dogs. 2. Intravenous bolus injections of acetylcholine (0.1 micrograms kg-1), nitroglycerin (0.3-3 micrograms kg-1), pinacidil (10-100 micrograms kg-1), nicardipine (3-30 micrograms kg-1) and nicorandil (10-100 micrograms kg-1) dose-dependently increased circumflex coronary artery diameter and decreased coronary vascular resistance, indicating vasodilator effects on both conduit and resistance coronary arteries. 3. Three days after removal of the endothelium of the circumflex coronary artery (balloon angioplasty), pinacidil- and nicardipine-induced dilation of large coronary arteries was greatly reduced (both -76%, P < 0.01) whereas that produced by nitroglycerin and nicorandil was decreased only slightly and to a similar extent for both drugs (-19%, P < 0.01 and -28%, P < 0.05, respectively). 4. Thus in conscious dogs, nicardipine- and pinacidil-induced dilatation of large coronary arteries is endothelium-dependent. In contrast, the vasodilator effects of nitroglycerin and nicorandil on conduit vessels are endothelium-independent. 5. Finally, our results demonstrate that nicorandil dilates the large coronary arteries through its nitrate-like action and that the ATP-potassium channel opening properties of the drug are not involved in this effect in the conscious dog.     

Effects of glutathione S-transferase inhibitors on nitroglycerin action in pig isolated coronary arteries

1. The present study was designed to clarify the role of glutathione S-transferase (GST) in the vasorelaxation response and development of tolerance to nitroglycerin (GTN) using GST inhibitors. 2. In pig isolated coronary arteries, GST activity was significantly changed to 77 and 82, or 69% of the control level (100%) following treatment with bromosulphophthalein (BSP; 10-3 and 10-4 mol/L) or ethacrynic acid (ETA; 10-4 mol/L), both GST inhibitors, respectively, but not following treatment with 10-3 and 10-4 mol/L GTN (GST activity 97 and 98% of control, respectively). 3. In KCl-contracted coronary artery strips pre-incubated with 10-5 and 10-4 mol/L GTN, 10-4 and 10-3 mol/L BSP or 10-4 mol/L ETA, concentration-dependent relaxations produced by GTN were significantly decreased compared with control. 4. 8-Bromo cGMP (8-Br-cGMP), a membrane-permeable cGMP analogue, produced concentration-dependent relaxations in GTN-pretreated arterial strips that were identical to control responses. However, there was weak but significant decrease in concentration-dependent relaxations in response to 8-Br-cGMP in BSP- and ETA-pretreated arteries. 5. The cGMP content in coronary arteries was significantly increased with GTN, GTN + BSP or GTN + ETA to similar high levels compared with control. 6. The results of the present study show that BSP and ETA decrease GTN- and 8-Br-cGMP-induced vasorelaxation, but have no effect on the GTN-induced increase in cGMP content in coronary arteries, suggesting a possibility that the GST inhibitors may have depressant actions on GTN- and 8-Br-cGMP-induced vasorelaxation through direct inhibition of the vasorelaxation of vascular smooth muscle themselves, in addition to having inhibitory effects GST activity.     

Vasomotor responses of isolated human coronary arteries to magnesium, nitroglycerin and verapamil: a comparison with coronary arteries from cat and rat

The vasomotor responses in vitro to magnesium, nitroglycerin and verapamil were investigated in human coronary arteries. In order to examine possible species differences in reactivity to these agents, experiments were performed also on cat and rat coronary arteries. Potassium (124 mM) regularly produced stable contractions suitable for experiments with dilator agents. The order of potency for eliciting relaxation was the same in all three species; verapamil greater than nitroglycerin greater than magnesium. Maximum relaxation induced by nitroglycerin or magnesium was significantly lower in arteries from cat as compared to that obtained in coronary artery segments from man and rat. Spontaneous rhytmic activity was often present in human coronary arteries but never in arterial segments from cat or rat. The rhytmic activity was frequently enhanced by the addition of prostaglandin F2 alpha (3 microM) to the tissue bath, on the other hand the rhythmic activity was depressed, or even abolished, by potassium (124 mM), magnesium (1.2-13.2 mM), nitroglycerin (2.2 X 10(-5) M) or verapamil (10(-8)-10(-7) M). The magnitude of the vasomotor response of feline coronary arteries to nitroglycerin or verapamil was dependent on the extracellular concentration of magnesium; in the presence of a high concentration of magnesium (4.4 mM) the dilator effect of nitroglycerin was enhanced while that of verapamil was slightly depressed. The dilator activity of the two agents was not changed by incubation of the vessel segments in a magnesium-free medium as compared to that obtained in the standard (1.2 mM Mg) buffer solution.     

Comparative study of the haemodynamic effects of oral molsidomine and isosorbide dinitrate in man

Summary The haemodynamic effects of oral molsidomine 4 mg and sustained-release isosorbide dinitrate (ISDN) 40 mg have been compared in 10 patients recovering from acute myocardial infarction. After both drugs pulmonary arterial, pulmonary capillary wedge and systemic arterial blood pressure were reduced to about the same extent. The maximum effect was reached 1.5 to 2 h after ingestion of both drugs, but the effect of molsidomine declined during the following 2 h and control values were almost reached after 4 h. After ISDN there was no rebound during the observation period of 6 h. Unlike molsidomine, ISDN reduced total peripheral resistance, so cardiac output and stroke volume index remained constant despite the reduction in cardiac preload. It is concluded that sustained release ISDN 40 mg and molsidomine 4 mg are about equieffective doses in terms of reduction of cardiac preload, but that the effect of molsidomine is of shorter duration. Since molsidomine alone causes venous pooling, cardiac output and stroke volume index are reduced, which may be an untoward side effect in patients with severe heart failure.     

Comparative antianginal, hemodynamic and pharmacokinetic effects of isosorbide-2-mononitrate and isosorbide dinitrate in the rat

The effect of isosorbide 2-mononitrate (IS-2-MN) was compared with that of isosorbide dinitrate (ISDN) in rats regarding the antianginal, haemodynamic and pharmacokinetic properties. The antianginal effect of IS-2-MN in equal oral dose persisted 3 times longer in the rat than did ISDN. In the same oral dosage, the two compounds caused the equal reduction of the number of deaths after an acute myocardial infarction. The intravenous or enteral administration of a single IS-2-MN dose caused an increasingly dose-dependent reduction of the systolic and mean arterial blood pressure in anaesthetized rats. The amounts of IS-2-MN required for the purpose were identical for both kinds of application. The fall of the systolic and mean arterial blood pressure due to ISDN is approx. 22 times weaker after enteral administration than it is after intravenous application. The hypotensive effect of ISDN or IS-2-MN could be antagonized by pre-treatment of the animals with i.v. dihydroergotamine (DHE). The half-life of IS-2-MN in the rat was unchanged after increase of the oral doses. The bioavailability of IS-2-MN in the rat was 100%. 1 h after oral or intravenous administration of IS-2-MN to the rat, the concentrations in the walls of aorta abdominalis and aorta thoracica and in the walls of vena cava caudalis and vena thoracica were distinctly greater than in the blood or in the other tissues examined.