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PubMed1986

[Dose-response relationship of nitrate therapy of angina pectoris].

The treatment of 15 patients with coronary heart disease and exertion-related angina pectoris with isosorbide dinitrate (ISDN) tablets in 4 doses (6 X 5 mg, 6 X 20 mg, 6 X 40 mg, 6 X 80 mg) in a randomized sequence for 1 week each resulted in a dose-related improvement of ischemia (ST-segment depression during stress testing) as compared to placebo: 5 mg (30 mg/day): 24% (p less than 0.05); 20 mg (120 mg/day): 40% (p less than 0.05); 40 mg (240 mg/day): 60% (p less than 0.01); 80 mg (480 mg/day): 74% (p less than 0.01). Continuation of treatment for another 4 weeks with 480 mg/day led to a slight decrease in antianginal activity, with a 55% improvement of ST-depression. The frequency of angina pectoris was also lowered in a dose-related manner. For nitroglycerin in oral sustained release form (matrix system) a dose-related antianginal efficacy could be demonstrated in 12 patients enrolled in a double-blind cross-over trial: 2.6 mg (single dose): 23% (n.s.); 6.5 mg: 38% (p less than 0.01); 10 mg: 55% (p less than 0.001); 20 mg: 74% (p less than 0.0001). The duration of action of 20 mg was 4 hours. Transdermal nitroglycerin also proved to be effective in a dose related fashion. In 12 patients undergoing 1-week treatment periods with 5 cm2, 10 cm2 and 20 cm2-patches ST-depression was favourably influenced by 15% (n.s.), 22% (p less than 0.05) and 46% (p less than 0.001) 3 hours after administration. No antiischemic efficacy was demonstrable 24 hours after medication.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Cutaneous↗
PubMed1990

Inhibition of platelet function during in vivo infusion of isosorbide mononitrates: relationship between plasma drug concentration and hemodynamic effects.

Isosorbide monitrates (IS-2-MN and IS-5-MN), hepatic metabolites of isosorbide dinitrate, inhibit platelet function in vitro very differently, with IS-2-MN being much more potent than IS-5-MN. To assess their antiplatelet properties in vivo and to compare time and dosage requirements, we infused both IS-2-MN and IS-5-MN for 30 minutes, on 2 separate days, into nine patients with stable coronary artery disease, at rates of 4 mg/hr (n = 4) and 8 mg/hr (n = 5). Two additional patients received IS-5-MN at 16 mg/hr. Platelet aggregation and thromboxane (TX) B2 generation in response to various agonists, drug plasma concentrations, and blood pressure were monitored throughout the study. A significant decrease in platelet aggregation and TXB2 production by adenosine diphosphate and adrenaline occurred in seven of nine patients receiving IS-2-MN and in 7 of 11 patients receiving IS-5-MN. Response was dose related, with more patients responding at 8 mg/hr to IS-2-MN (five of five) than to IS-5-MN (three of five), and was maximum at the end of the infusion time, corresponding to peak plasma levels. Patients responding to drug infusions with an inhibition of platelet function were characterized by a greater vascular responsiveness compared to nonresponders, since the decrease in systolic blood pressure (mean +/- SEM) was significantly greater in the former (15.4 +/- 3.2) than in the latter (2.5 +/- 2.1, p less than 0.05). Therefore both mononitrates, when administered at infusion rates between 8 and 16 mg/hr, are accompanied by a consistent inhibition of adenosine diphosphate- and adrenaline-induced aggregation and TX generation.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary Disease↗
PubMed1990

Combined effects of nitrates on the coronary and peripheral circulation in exercise-induced ischemia.

We compared the effects of isosorbide dinitrate (ISDN) administered by intracoronary and intravenous routes in 10 patients with severe coronary artery disease, stable effort angina, and very low exercise tolerance. Supine bicycle ergometer exercise was performed under four conditions: 1) control, 2) after intracoronary administration of 0.4 mg ISDN, 3) 1 hour later (control 2), and 4) after administration of intravenous 4 mg ISDN. At rest, intracoronary ISDN caused no significant hemodynamic effects, whereas intravenous infusion of ISDN resulted in a decline in left ventricular (LV) systolic pressure (-20 +/- 5 mm Hg), LV end-diastolic volume (-27 +/- 3%), and LV end-systolic volume (-30 +/- 4%). After intracoronary infusion of ISDN, ST segment depression and the increase in LV end-diastolic pressure and LV end-systolic volume induced by exercise were significantly less abnormal than during control (0.20 +/- 0.09 vs. 0.14 +/- 0.08 mV, 36 +/- 7 vs. 24 +/- 8 mm Hg, and 91 +/- 40% vs. 40 +/- 29%, respectively). When exercise was performed after intravenous infusion of ISDN, the above-mentioned parameters were significantly improved even further: ST segment depression to 0.05 +/- 0.07 mV, end-diastolic pressure to 14 +/- 7 mm Hg, and LV end-systolic volume to 5 +/- 11% (all p less than 0.01 compared with intracoronary ISDN). Thus, in patients with severe coronary artery disease, it is suggested that intracoronary nitrates increase coronary blood supply during effort-induced ischemia, based on significant improvements in the indirect measures of ST segment depression, LV end-diastolic pressure, and LV volume.(ABSTRACT TRUNCATED AT 250 WORDS)

Angina Pectoris↗
PubMed1994

Antianginal effects of FK409, a new spontaneous NO releaser.

1. The aim of this study was to compare antianginal effects of (+/-)-(E)-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexeneamide (FK409), a new spontaneous nitric oxide releaser, with those of isosorbide dinitrate (ISDN). We used two types of rat angina model; methacholine- and arginine vasopressin (AVP)-induced coronary vasospasm models. 2. In the in vitro study, FK409 showed 80 times more potent vasorelaxant effect in dog isolated coronary artery than ISDN (EC50 = 16.7 +/- 4.8 and 1340 +/- 320 nM, respectively). 3. In the rat methacholine-induced coronary vasospasm model, FK409 suppressed the elevation of ST segment dose-dependently and significantly at 0.1 mg kg-1, i.d. On the other hand, ISDN suppressed it significantly at 3.2 mg kg-1, i.d. In addition, the efficacy of 3.2 mg kg-1 ISDN in the model was almost the same as that of 0.1 mg kg-1 FK409. 4. In the above experiments, FK409 and ISDN decreased mean blood pressure significantly at the maximum dose tested (1.0 mg kg-1, i.d. and 3.2 mg kg-1, i.d., respectively) but did not change heart rate at these doses. Therefore, the hypotensive effect of FK409 was 10 times weaker than the antianginal effect of the compound, while those of ISDN were almost the same. 5. In the rat AVP-induced coronary vasospasm model, 32 mg kg-1 FK409 significantly inhibited the depression of ST segment 60 min after oral administration. On the other hand, 32 mg kg-1 ISDN did not inhibit it at 60 and 120 min after oral administration. 6. In conclusion, FK409 inhibits coronary vasospasm more potently in two types of rat angina models than ISDN. In addition, FK409 shows an antianginal effect more selectively that a hypotensive effect,compared with ISDN.

Angina Pectoris, Variant↗
PubMed1998

The impact of beta-receptor blocker addition to high-dose angiotensin-converting enzyme inhibitor-nitrate therapy in heart failure.

BACKGROUND: The natural history of heart failure is one of continued worsening of cardiac function. Beta-receptor blocker therapy has been effective in improving clinical status and left ventricular function in patients with heart failure. Similarly, high doses of angiotensin-converting enzyme (ACE) inhibitors with nitrates partially reverse the ventricular remodeling of heart failure. HYPOTHESIS: We tested the hypothesis that beta-blocker therapy added to high-dose ACE inhibitor-nitrates would potentiate the reversal of heart failure. METHODS: Thirteen patients, aged 52 +/- 8 years, with moderate to severe heart failure, 12 of whom were referred for transplant consideration, with heart failure duration of 4.8 +/- 2.2 years, were prospectively followed for 12 months. Baseline echocardiographic ejection fraction was 19 +/- 8%, and presenting New York Heart Association class was 2.9 +/- 0.7. Angiotensin-converting enzyme inhibitors and nitrates were uptitrated over 6 months to a final dose of lisinopril 53 +/- 31 mg/day, and isosorbide dinitrate 217 +/- 213 mg/day. At 6 months, beta-blocker therapy with atenolol was initiated and titrated to a final dose of 46 +/- 23 mg/day. Two-dimensional Doppler echocardiography and metabolic stress testing were performed at baseline, at 6 months on lisinopril-nitrates only, and at 12 months on combined ACE inhibitor-nitrate and beta-blocker therapy. RESULTS: New York Heart Association classification improved from 2.9 +/- 0.7 to 1.8 +/- 0.8 on lisinopril-nitrates (p < 0.05), and to 1.5 +/- 0.5 with the addition of beta blockade (p = NS). On follow-up, peak oxygen consumption rose from 17 +/- 7 ml O2/kg/min at baseline to 21 +/- 5 ml O2/kg/min at 6 months on lisinopril-nitrates (p = 0.06) without further change on beta blockade. Ejection fraction rose from 19 +/- 8 to 33 +/- 14% on lisinopril-nitrates at 6 months (p = 0.005) and to 36 +/- 18% on beta blockade at 12 months (p = NS). CONCLUSION: High-dose ACE inhibitor-nitrate therapy significantly improved patient clinical status and left ventricular systolic function in heart failure. The addition of beta-receptor blockade over and above high-dose ACE inhibitor-nitrates was well tolerated but had no further impact on symptomatic status, exercise tolerance, or left ventricular systolic function. The potential for pharmacologic reversal of heart failure remodeling may be finite despite the use of complementary therapies. Larger placebo-controlled and randomized trials of beta-receptor blockade added to high-dose ACE inhibitor-nitrate therapy are needed to confirm these observations.

Adrenergic beta-Antagonists↗
PubMed1996

Impaired effectiveness of nitric oxide-donors in resistance arteries of patients with arterial hypertension.

OBJECTIVE: To assess the dilatory effectiveness of nitric oxide donors in resistance arteries of patients with arterial hypertension in comparison with that in those of normotensive controls. BACKGROUND: Endothelium-dependent vasodilation has been demonstrated to be impaired in arterial hypertension. Besides disturbances in endothelial nitric oxide production a reduced vasodilatory effectiveness of nitric oxide might contribute to this phenomenon of endothelial dysfunction. We therefore investigated the dilatory responsiveness of resistance arteries to exogenous nitric oxide by means of administration of the nitric oxide donors glycerol trinitrate (GTN), isosorbide dinitrate (ISDN) and sodium nitroprusside (SNP) in hypertensive patients. METHODS: Forearm blood flow was measured by venous occlusion plethysmography at rest and during intra-arterial infusion of nitric oxide donors at increasing doses in 11 patients with arterial hypertension and in 10 age-matched normotensive controls. RESULTS: Forearm blood flow at rest was comparable in the two groups and was dose-dependently increased by administration of either nitric oxide donor. In patients with arterial hypertension, blood flow responses to infusions of organic nitrates were significantly impaired over the entire dose-response curve compared with those of normotensive controls (220 nmol/min GTN 13.1 +/- 1.3 and 8.6 +/- 0.3 ml/min per 100 ml tissue; 212 nmol/min ISDN 9.9 +/- 0.7 and 5.8 +/- 1.0 ml/min per 100 ml tissue). Blood flow responses to infusion of the nitric oxide donor SNP were also profoundly impaired in the hypertensive patients, the extent of which impairment equalled that found with the organic nitrates. Within the entire set of normotensive and hypertensive subjects, maximal flow responses to either nitric oxide donor were inversely correlated with mean arterial blood pressure. CONCLUSIONS: Dilation of resistance arteries in response to infusion of nitric oxide donors is impaired in hypertensive patients and the degree of this impairment depends critically on the severity of arterial hypertension. The reduced effectiveness of nitric oxide appears to be independent of the class of nitric oxide donor and thus of the mode of intravascular nitric oxide generation. These findings are likely to have important implications not only for our understanding of the pathophysiological mechanisms of endothelial dysfunction but also for nitric oxide donor therapy in arterial hypertension.

Adult↗
PubMed1998

Morphological and functional changes in coronary vessel evoked by repeated endothelial injury in pigs.

OBJECTIVE: We examined the morphological changes induced by repeated endothelial denudation in coronary artery (CA), as well as functional changes in the endothelium-dependent and smooth muscle responses to various vasoactive agents during the process of intimal thickening. METHODS: We observed vascular responses in denuded and non-denuded portions of pig CA while being fed a normal diet (n = 11, N group) or 2% cholesterol diet (n = 25, C group) to intracoronary acetylcholine (ACh), 5-hydroxytryptamine (5-HT), substance P (SP), and isosorbide dinitrate (ISDN) with and without the nitric oxide synthesis inhibitor N omega-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg i.v.) over a period of 8 weeks. Balloon endothelial denudation of the left anterior descending CA was carried out every 2 weeks. RESULTS: In N group, maximum vasoconstriction was obtained with ACh 2 weeks after the first denudation [26 +/- 5% vs. 1 +/- 1% pre-denudation, p < 0.05]. L-NAME did not affect ACh-induced CA diameter changes. Thereafter, the response to ACh was attenuated by repeated denudation in N groups. However, the degree of 5-HT-induced CA narrowing at the denuded portion increased from 7 +/- 4% (0 week) to 88 +/- 8% (8 weeks) (p < 0.05). The changes resulted in severe myocardial ischaemia, and suggested that endothelium-dependent vasodilation was progressively attenuated while hyperreactivity of vascular smooth muscle simultaneously increased. Vasodilation induced by SP was attenuated somewhat, but ISDN-induced vasodilation was preserved. Although mild hypercholesterolaemia was induced in C group, the vascular responses to these vasoactive agents did not differ from those of N group. CONCLUSIONS: Repeated CA endothelial injury and regeneration induce the change of morphology and vascular reactivity in the denuded portion regardless of atherogenic diet. This study strongly suggests that intimal thickening caused by repeated endothelial injury and regeneration induces specific vascular responses to vasoactive agents. Moreover, it is also suggested that during the progression of intimal thickening, increased vascular smooth muscle contraction and decreased endothelium-dependent dilation appear in a stimulus-dependent manner, often leading to severe coronary vasoconstriction accompanied with definitive ECG ST change.

Acetylcholine↗
PubMed2002

Anal achalasia after pull-through operations for Hirschsprung's disease -- preliminary experience with topical nitric oxide.

INTRODUCTION: Following definitive pull-through for Hirschsprung's disease (HD), a minority of patients develop constipation, incontinence and enterocolitis. The cause for these symptoms in some of the patients is believed to be "internal sphincter achalasia" related to abnormal innervation of the sphincter, with an absent anorectal relaxation reflex. Transanal myectomy, posterior sagittal rectal myectomy, anal dilatation and even intrasphincter injection of botulinum toxin have been used to solve this problem. Nitric oxide (NO) has been identified as the chemical messenger of the intrinsic non-adrenergic, non-cholinergic pathway mediating relaxation of the normal internal anal sphincter when applied topically. BACKGROUND/PURPOSE: To evaluate the effect of topical isosorbide dinitrate (DTN) applied to the anus and its role in the management of patients with HD after pull-through who have ongoing difficulties in stool evacuation. MATERIAL AND METHODS: Four children, aged 2, 5, 7 and 13 years, who all underwent the Soave operation for Hirschsprung's disease, were assessed. Three patients had recurrent episodes of enterocolitis, and all had symptoms of difficulty in rectal/colonic evacuation. Conservative treatment of repeated anal dilatation under anaesthesia had failed to improve symptoms. A rectal myectomy and conversion of Soave to Duhamel procedure had been done in 2 without significant improvement in symptoms. In all patients, ano-rectal manometry was performed before and after application of DTN paste (1 mg/kg/day in two separate doses) which was continued for a minimum period of 3 weeks. Results. Marked symptom improvement was noted in all 4 children. On manometric assessment the median maximum pressure (pre-DTN application) was 165 mm Hg (range 96 - 250), the median sphincter length 2.7 cm (range 2.3 - 3.1) and the high-pressure zone (HPZ) median length 1.6 cm (range 1.2 - 2.1). After application of DTN paste, the maximum pressure dropped by a median of 88 mm Hg (range 46 - 90), total sphincter length shortened to a median of 2.1 cm and the HPZ by a median total length of 1.4 cm (range 0.01 - 0.9). In addition, vector volume was reduced by a median of 59 % (range 40.5 - 77). CONCLUSION: From these results, it is evident that DTN paste is not only an adjunct in the investigation, but can also be used as a temporary form of treatment of obstructive symptoms in Hirschsprung's disease patients.

Administration, Topical↗
PubMed1990

Comparison of low-dose aspirin and coronary vasodilators in acute unstable angina.

Episodic platelet activation has been shown to occur in unstable angina, and aspirin should have an important therapeutic role in the management of these patients. The response to aspirin alone or to aspirin in combination with vasodilators such as heparin and beta-blockers has been assessed in 41 patients with unstable angina. Therapy was added sequentially in the event of recurrence of transient myocardial ischemia. Patients were randomly assigned to two groups. Group 1 (21 patients) received an intravenous infusion of isosorbide dinitrate and oral diltiazem, and group 2 (20 patients) received intravenous aspirin (60 mg the first day and 20 mg on successive days). This dose of aspirin reduced serum thromboxane B2 from 160 +/- 88 ng/ml (mean +/- SD) to undetectable values (less than 6 ng/ml, p less than 0.01). If episodes of ischemic ST segment shift continued, the therapy of group 1 was added to that of group 2 or vice versa; if further ST segment changes were documented, intravenous heparin and oral beta-blockers were added; if episodes of myocardial ischemia persisted, urgent coronary arteriography and myocardial revascularization were performed. Nine patients in group 1 and six in group 2 (p = 0.8) had no further episodes of myocardial ischemia on their initial therapy; 12 additional patients had no further episodes when taking combined therapy of aspirin and vasodilators. Thus, the administration of aspirin alone was not superior to coronary dilators; 30% of all patients continued to have episodes of myocardial ischemia or had a myocardial infarction develop when heparin and beta-blockers were added. Myocardial infarction occurred in one patient on vasodilator therapy alone, in two on combined therapy, and in two on full therapy. These results suggest that in some patients, the stimulus to coronary thrombosis and vasoconstriction occasionally becomes so strong that it cannot be inhibited by certain antagonist drugs. The unstable tendency to continuation of ischemia or evolution to myocardial infarction is not related to the severity of the persisting stenosis. Those patients not promptly responding to combined therapy immediately from admission should have early coronary angiography and aggressive treatment.

Angina Pectoris↗
PubMed1985

Improved coronary supply: prevailing mechanism of action of nitrates in chronic stable angina.

Exercise tolerance before and after sublingual isosorbide dinitrate (ISDN), 10 mg, was assessed in 217 consecutive patients with stable angina, positive exercise test, and angiographically proved coronary artery disease. In 65 patients (30%), ISDN prevented exercise-induced ST segment depression and/or increased exercise time to 1 mm ST segment depression (greater than or equal to 3 minutes), despite the significantly higher (greater than or equal to 25 X 10(2) increment) rate-pressure product attained (increased coronary reserve). On the contrary, in 40 other patients, exercise test remained positive, and neither time to 1 mm ST segment depression nor rate-pressure product increased significantly (fixed coronary reserve). The remaining 106 patients had an intermediate response. To assess the mechanisms underlying the beneficial action of nitrates, we further investigated 13 patients with increased coronary reserve (group 1) and five with fixed coronary reserve (group 2) by the exercise response to ISDN and verapamil, the changes in left ventricular volumes after ISDN and verapamil, the ECG response to intravenous ergonovine, and the changes in coronary stenosis severity following intravenous ergonovine and intracoronary nitrates. ISDN dramatically improved exercise capacity only in group 1 patients. However, it induced a significant reduction of left ventricular volumes in both groups (p less than 0.01). Ergonovine provoked angina and ST segment depression in 62% of group 1 patients and significantly increased the severity of their coronary stenoses (p less than 0.01). In all group 2 patients, ergonovine was negative, and no significant increase in stenosis severity was observed. Intracoronary nitrates reduced stenosis severity in group 1 (p less than 0.01) but not in group 2.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

[Effect of low-dosage intravenous nitrate therapy on the anticoagulant effect of heparin].

BACKGROUND AND AIM: Controversial studies concerning the fact that simultaneous i.v. administration of heparin and glyceroltrinitrate (GTN) might reduce the anticoagulatory effect of heparin have been published. In a controlled and comparative study we therefore investigated the influence of the nitrates GTN or isosorbide dinitrate (ISDN) in comparison to placebo on the anticoagulatory effect of a constant heparin infusion in patients with CAD. PATIENTS AND METHODS: 22 stable and mobile inpatients (two female, 20 male; aged 47 to 80; documented CAD in 20 patients, one patient with atrial fibrillation, one patient with suspected CAD), kept on a therapeutic heparin infusion for several days (prolongation of the partial thromboplastin time [PTT] by 1.5 to two-fold), were included. Study course: Day 1: Discontinuation of nitrate medication, optimization of heparin therapy and fixation of the heparin dose (mean dose 33,800 E/24 h in the GTN group and 32,700 E/24 h in the ISDN group). Day 2: Intravenous simultaneous administration of 0.9% NaCl solution as placebo (3 ml/h) with heparin over 24 hours. Day 3: Substitution of NaCl solution by randomised single-blind intravenous administration of GTN (n = 10; 0.1%, solved in NaCl; dose 2.8 +/- 0.5 mg/h) or ISDN (n = 12; 0.1%, solved in NaCl, dose: 4.8 +/- 0.8 mg/h) for 24 hours. Day 4: Discontinuation of nitrates. RESULT: As compared to placebo, the intravenous simultaneous administration of GTN or ISDN and heparin over 24 hours had no influence on the anticoagulatory effect of heparin when the areas under the curve of PTT values on days 2 and 3 were compared (PTT measurements at 8, 10 a.m., 1, 3, 6, 11 p.m.; Mann-Whitney test). After GTN or ISDN had been discontinued, no change in PTT values was seen during the following five hours. CONCLUSION: There is no indication of a pharmacodynamic relevant interaction between heparin and low-dose intravenous nitrate therapy in patients with CAD.

Aged↗
PubMed1977

Acute drug testing with nitrates: angina relief during treadmill exercise.

To evaluate the effect of sublingual nitroglycerin (N) and chewable isosorbide dinitrate (I) in patients with angina pectoris, 12 subjects underwent treadmill exercise to the point of onset of angina. At that juncture, N or I or placebo (P) was administered and walking was continued until moderately severe angina recurred. For those patients who completed the initial 10-minute exercise period, testing was repeated until moderately severe angina recurred or until a total test time of three hours elapsed. Retesting ensured that each patient was tested separately with N, I and P within a two-week period. Within the I group, four patients experienced the onset of angina relief (AR) at 10 minutes (') 6 seconds (*) +/- 3' 4" with a mean recurrence time (RT) of 154' 3" +/- 4' 27" (P less than or equal to 0.05), for a significant difference. Within the N group, six patients had AR of 8' 3" +/- 1' 1" with an RT of 49' 39" +/- 1' 15" (P less than or equal to 0.01), for a significant effect. Within the P group, only one patient experienced AR. For all other patients in each group, testing was terminated because of moderately severe angina in the 5-8' period of the first test. In comparing subgroups for RT during I therapy (4 patients) versus N therapy (6 patients), a significant difference was noted (154' 3" +/- 27" versus 49' 39" +/- 1' 15") (P less than 0.05). The data suggest a possible benefit of I in selected patients. The effect may last as long as three to four hours. There is also an enhanced benefit of N with the patient in the upright position. This effect may last as long as 40-50'. Treadmill testing is recommended with nitrate administration to determine which drug (I or N) is the more suitable for the specific patient.

Adult↗
PubMed2001

Topical application of nitrates onto the papilla of Vater: manometric and clinical results.

BACKGROUND AND STUDY AIMS: Systemic administration of nitrates inhibits motility of the sphincter of Oddi (SO) but is hampered by a decrease of the arterial blood pressure. We evaluate whether topical application of glyceril trinitrate (GTN) onto the papilla can facilitate cannulation of the common bile duct during routine endoscopic retrograde cholangiopancreatography (ERCP) and compare the effect of topical GTN with that of isosorbide dinitrate (ISDN) on SO motility. PATIENTS AND METHODS: A total of 80 patients undergoing routine ERCP for suspected biliary obstruction received topical application of either saline (n = 40) or 10 mg of GTN (n = 40) onto the papilla of Vater in a randomized, double-blind fashion. Thereafter, selective bile-duct cannulation was attempted with a 0.035" hydrophilic guide wire. In another trial, 16 biliary type III patients underwent endoscopic SO-manometry and received in a randomized fashion either 10 mg of GTN (n = 8) or 10 mg of ISDN (n = 8) which was infused topically onto the papilla via the manometric catheter. Thereafter, the manometric recording was continued for a further 5 minutes. RESULTS: A spontaneous opening of the papilla with concurrent transpapillary bile flow was observed in 24/40 patients after topical GTN, and in only 8/40 patients after topical saline (P < 0.01). However, neither the number of cannulation attempts nor the time until successful cannulation differed significantly between the groups. In addition, the pre-cut rate was nearly identical in the two groups. Topical GTN showed no significant influence on the mean arterial blood pressure. The SO-baseline pressure was significantly lowered by topical GTN (28.2+/-12.9 mm Hg before ISDN vs. 22.5+/-13.7 mmHg after P<0.01). The phasic SO motility was also strongly inhibited by both drugs. However, the effect of GTN completely wanes after 3 minutes, whereas ISDN inhibited SO motility for > 5 minutes in all patients. CONCLUSIONS: Both topically administered GTN and ISDN evoked a profound inhibition of SO motility, but the effect of ISDN was longer lasting than that of GTN. However, locally administered GTN did not facilitate selective bile-duct access during routine ERCP.

Administration, Topical↗
PubMed1995

Nitric oxide increases cellular glutathione levels in rat lung fibroblasts.

Nitric oxide (NO) has been demonstrated to play a protective role in cell injury. In this study, we have explored the effect of NO and two NO donors (sodium nitroprusside [SNP] and isosorbide dinitrate [ISDN]) on cellular glutathione (GSH) levels in a rat lung fibroblast cell line (RFL6 cells). SNP and ISDN significantly increased cellular GSH in RFL6 cells (5 x 10(-4) M SNP: 21.9 +/- 3.6 nmol/10(6) cells and 5 x 10(-3) M ISDN: 27.6 +/- 1.7 nmol/10(6) cells versus control: 13.2 +/- 0.4 nmol/10(6) cells; P < 0.05). The stimulatory effect of SNP and ISDN on GSH was first seen at 6 h and peaked at 12 to 24 h. A similar increase in GSH was observed in RFL6 cells exposed to 400 ppm NO for 7.5 h (NO: 20.5 +/- 3.4 nmol/10(6) cells versus control: 11.9 +/- 2.4; P < 0.05). SNP and ISDN also increased cellular GSH in bovine pulmonary artery smooth muscle cells (BPSMC) and bovine pulmonary artery endothelial cells (BPAEC). Buthionine sulfoximine (BSO) (0.01 mM), an inhibitor of the GSH synthetic enzyme gamma-glutamyl cysteine synthetase, blocked the increase in GSH in RFL6 cells seen with both SNP and ISDN. In BPAEC, exposure to NO donors for 24 h stimulated glutamate uptake (SNP: 441 +/- 19 pmol/10 min/10(6) cells and ISDN: 677 +/- 48 pmol/10 min/10(6) min/10(6) cells versus control: 222 +/- 9 pmol/10 min/10(6); P < 0.05). This effect paralleled the increase in GSH. In RFL6 cells, only SNP increased glutamate uptake after 24 h of incubation. In summary, NO and NO donors increase cellular GSH in RFL6 cells, BPAEC, and BPSMC. The mechanism of this effect is unclear but may involve upregulation of the normal GSH synthetic pathways. This observation may explain in part the protective effect of NO seen in some cell culture systems and may contribute to a protective effect against oxidant injury in vivo.

Animals↗
PubMed2006

Nicorandil but not ISDN upregulates endothelial nitric oxide synthase expression, preventing left ventricular remodeling and degradation of cardiac function in Dahl salt-sensitive hypertensive rats with congestive heart failure.

Cardiac endothelial nitric oxide synthase (ecNOS) was suppressed and inducible NOS (iNOS) enhanced at the decompensated heart failure stage in 18-week-old Dahl salt-sensitive (DS) hypertensive rats to which a high-salt diet had been administered from the age of 6 weeks. Nicorandil (NIC) enhanced ecNOS by activating Adenosine triphosphate-sensitive potassium channels (K-ATP channels) in the normal rat left ventricle. In this study, left ventricular hypertrophy, remodeling, function, cardiac ecNOS, and iNOS were compared between NIC and isosorbide dinitrate (ISDN) treatments in DS hypertensive rats with congestive heart failure. We examined DS hypertensive rats of 18 weeks of age to which 8% NaCl had been administered from the age of 6 weeks, and to which subdepressor doses of NIC (6 mg/kg/d), ISDN (6 mg/kg/d), and vehicle (CON) were administered from the age of 11 weeks. Contractility (Ees), stiffness (Eed), left ventricular end-diastolic volume, and left ventricular end-systolic volume were measured by conductance catheter and micromanometer on the basis of the pressure-volume relationship, and mRNA and protein levels of ecNOS and iNOS in the left ventricle were measured by reverse transcription-polymerase chain reaction and Western blot analysis at 18 weeks. LV mass index and LV dimensions were smaller in the NIC and ISDN groups than in the CON group (P < 0.01), and the first parameter was lower in the NIC than in the ISDN group (P < 0.01). Ees was also better maintained in the NIC and ISDN groups than in the CON group (NIC: 3349 +/- 649; ISDN: 2950 +/- 577, P < 0.05 vs. NIC; CON: 1424 +/- 375 mL/mmHg, P < 0.01 vs. treatments). Eed was exacerbated only in the ISDN group. NIC enhanced whereas ISDN suppressed ecNOS mRNA and protein levels (NIC 2.0-fold and 1.8-fold, ISDN 0.70-fold and 0.8-fold vs. CON; P < 0.01, respectively). However, no intragroup differences in iNOS mRNA or protein levels were observed for the 3 groups. More significant improvements in cardiac function and LV hypertrophy regression were observed in an NIC group than in an ISDN group of DS hypertensive rats. Activation of the K-ATP channel seems to induce this beneficial effect, which may be mediated in part by enhanced ecNOS expression in the heart in DS hypertensive congestive heart failure rat model.

Animals↗
PubMed1998

Use of a hemoglobin-trapping approach in the determination of nitric oxide in in vitro and in vivo systems.

We describe methods for measuring the release of nitric oxide (NO) derived from organic nitrates in vitro, using triple wavelength and difference spectrophotometry in the presence and absence of concentric microdialysis probes. These methods are based on the ability of NO to oxidize oxyhemoglobin (OxyHb) to methemoglobin (MetHb) quantitatively in aqueous solution. Isosorbide dinitrate (ISDN), a thiol-dependent organic nitrate, increased MetHb concentration in 45 min from 2.47 +/- 0.47 to 4.15 +/- 0.12 microM (p < 0.05) and decreased OxyHb concentration from 2.13 +/- 0.35 to 0.33 +/- 0.26 microM (p < 0.05) at 37 degrees C. At 27 degrees C, the OxyHb concentration was not significantly altered (2.04 +/- 0.23 to 1.60 +/- 0.04 microM) by ISDN, nor was the MetHb concentration (from 2.68 +/- 0.50 to 2.59 +/- 0.25 microM). Sodium nitroprusside (SNP), a thiol-independent organic nitrate, increased MetHb concentrations in 30 min from 4.21 +/- 0.26 to 6.00 +/- 0.56 microM (p < 0.05) at 37 degrees C, and from 4.23 +/- 0.39 to 5.90 +/- 0.43 microM (p < 0.01) at 27 degrees C. SNP also decreased OxyHb concentrations in 30 min from 1.99 +/- 0.32 to 0.13 +/- 0.12 microM (p < 0.01) at 37 degrees C, and from 2.25 +/- 0.31 to 0.13 +/- 0.09 microM (p < 0.01) at 27 degrees C. Difference spectrophometry indicated that 0.25-5 mM SNP significantly increased NO production in a dose-dependent fashion. This hemoglobin-trapping technique was also useful in quantifying the concentrations of NO released from SNP in aqueous solution in vitro, using concentric microdialysis probes. The NO concentration following exposure to SNP was 530 +/- 50 nM, as determined using the difference spectrophotometric technique. To demonstrate the applicability of this technique to in vivo microdialysis, we implanted concentric microdialysis probes into hippocampus and cerebellum of conscious and anesthetized rats. Baseline NO concentrations in hippocampus of conscious and anesthetized rats were 11 +/- 2 nM and 23 +/- 9 nM, respectively, while in the cerebellum NO concentrations were 28 +/- 9 nM and 41 +/- 20 nM, respectively. These results demonstrate that microdialysis using a novel hemoglobin-trapping technique possesses adequate sensitivity to measure the NO levels produced from organic nitrates in aqueous solutions, and further document the applicability of this approach to in vivo systems.

Anesthesia, General↗
PubMed2002

[Comparative evaluation of the clinical effectiveness and the adverse effects of three different forms of nitrates in high oral doses in patients with stable angina pectoris].

UNLABELLED: The aim of this study was the comparative evaluation of antianginal efficacy and the adverse effects of 3 nitrates in oral doses: isosorbide dinitrate 80 mg in slow release form (ISDN-80), nitroglycerin 15 mg--slow release (NITRO-15) and pentaerythritol tetranitrate 100 mg in normal tablets (PENTA-100) in patients (pts) with stable angina pectoris. In a randomized, double-blind, cross-over and placebo (P) controlled study 15 men, with mean age 54.8 +/- 8.0 years, with stable angina, received single doses of: ISDN-80, NITRO-15, PENTA-100 or P. Clinical efficacy of the drugs was evaluated by analysis of the walking times: total (TT), to angina (TA), and to ischemia (TI) on treadmill during stress tests performed 2 and 6 hours (h) after drug ingestion; the adverse effects were registered during 6 h follow up. RESULTS: 2 h after ingestion all 3 study drugs improved significantly: TT, TA and TI in comparison to P. After 6 h the same parameters were improved by: ISDN-80 and NITRO-15, but PENTA-100 improved only TT and TA. After 6 h ISDN-80 significantly improved in comparison to NITRO-15: TT by 19.7% (p < 0.01), TA by 21.2% (p < 0.01) ant TI by 25.0% (p < 0.05), and in comparison to PENTA-100: TT by 32.1% (p < 0.001), TA by 33.4% (p < 0.001) and TI by 41.1% (p < 0.01). After 6 h NITRO-15 significantly improved TI in comparison to PENTA-100 by 13.1% (p < 0.05). The headaches, the most frequent adverse effects, occurred after ingestion of ISDN-80 in 6 pts, NITRO-15 in 4 pts, PENTA-100 in 3 pts and P in 1 pt. Among three evaluated nitrates ISDN-80 significantly improved the effort tolerance and the coronary reserve in the strongest way, NITRO-15 was intermediate in the clinical efficacy, but PENTA-100, the drug with the weakest antianginal efficacy, was the reason of the least number of the adverse effects.

Angina Pectoris↗
PubMed1994

Acute effects of nitrates on exercise testing in patients with syndrome X. Clinical and pathophysiological implications.

BACKGROUND: Sublingual nitrates are much more effective in relieving angina pectoris in patients with coronary artery disease than in patients with syndrome X, but it is not known whether their effect on exercise tolerance is also different in these two groups of patients. METHODS AND RESULTS: Treadmill exercise testing was performed before and after administration of sublingual isosorbide dinitrate (ISDN, 5 mg) in 18 patients with syndrome X (effort angina and normal coronaries, group X) and in 33 patients with documented coronary artery disease (group C). As a selection criterion, all patients had ST-segment depression > or = 1 mm on the control exercise test. Compared with the control test, the main differences in the two groups observed during the exercise test after administration of ISDN were (1) heart rate at 1-mm ST-segment depression was higher (126 +/- 25 versus 104 +/- 15 beats per minute [bpm], P < .01) in group C, whereas it was not different (125 +/- 15 versus 126 +/- 16 beats per minute) in group X; (2) the rate-pressure product at 1-mm ST-segment depression, the time to 1-mm ST-segment depression, and the exercise duration were significantly improved in group C (P < .01 for all) but were worsened in group X (18,047 +/- 4159 versus 20,535 +/- 4507 bpm . mm Hg, P = .014; 268 +/- 312 versus 429 +/- 214 seconds, P < .01; 494 +/- 279 versus 622 +/- 194 seconds, P = .013, respectively); (3) a normalization of the ECG (no ST-segment depression) was obtained in 10 patients (30%) of group C but in only 1 (5%) of group X (P < .01); (4) angina was prevented in 10 of 19 patients of group C but in no patient of group X (P < .01). CONCLUSIONS: In patients presenting with anginal chest pain, the effects of sublingual nitrates on exercise testing appear to be clinically useful to distinguish patients with coronary artery stenoses from patients with syndrome X. Indeed, worsening of exercise tolerance is highly predictive of normal coronary arteries. Furthermore, the failure of nitrates to improve exercise tolerance in patients with syndrome X suggests that a deficiency in coronary prearteriolar nitric oxide production is unlikely to play a key role in the pathophysiology of the syndrome.

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