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PubMed1987

First-line treatment of left ventricular failure complicating acute myocardial infarction: a randomised evaluation of immediate effects of diuretic, venodilator, arteriodilator, and positive inotropic drugs on left ventricular function.

A prospective randomised trial compared the immediate haemodynamic effects of intravenous diuretic (frusemide), venodilator (isosorbide dinitrate), arteriolar dilator (hydralazine), and positive inotropic stimulation (prenalterol) as first-line therapy for acute left ventricular (LV) failure following myocardial infarction. Forty-eight patients with transmural myocardial infarction and a pulmonary artery occluded pressure (PAOP) of greater than 20 mm Hg were studied within 18 h of admission to a coronary care unit. Both frusemide (-4 mm Hg; p less than 0.01) and isosorbide dinitrate (-6 mm Hg; p less than 0.01) reduced LV filling pressure without change in cardiac index and heart rate. Although both hydralazine and prenalterol increased cardiac index (p less than 0.01), the reduction in LV filling pressure (-2 mm Hg; p less than 0.05) was less than with frusemide and isosorbide dinitrate, and was associated with an increased heart rate (+8 and +13 beats min-1; p less than 0.01). These data suggest that in acute heart failure following myocardial infarction the four treatment modalities could be ranked in descending order of potential benefit as follows: venodilatation (isosorbide dinitrate)--decrease of LV pressure/work; diuretic therapy (frusemide)--decrease of LV pressure/work offset by a transient pressor effect; arteriolar dilatation (hydralazine)--decrease of LV pressure/work and of PAOP, but offset by tachycardia; and positive inotropic therapy (beta 1-agonist prenalterol)--tachycardia and augmented LV afterload. Combination of the former and latter agents, because of their differing modes of action, should offer haemodynamic advantages over monotherapy and deserves further evaluation.

Adult↗
PubMed2000

Long term consequences of regressed coronary aneurysms after Kawasaki disease: vascular wall morphology and function.

OBJECTIVES: To investigate the long term consequences of regressed aneurysms after Kawasaki disease, using follow up coronary angiography; to assess the vascular wall morphology at the site of the aneurysms by intravascular ultrasound imaging; and to evaluate the function of the affected vessels using intracoronary infusions of acetylcholine and isosorbide dinitrate. DESIGN: 33 patients were studied, 27 with previous Kawasaki disease and six with congenital heart disease. All Kawasaki disease patients were followed for more than 10 years from disease onset. The 33 patients comprised four groups: group 1 included 13 Kawasaki disease patients with a total of 23 sites of regressed large sized (>/= 4 mm) coronary aneurysms; group 2 included 13 Kawasaki disease patients with 22 sites of regressed small sized (< 4 mm) coronary aneurysms (four patients had sites of both large and small sized aneurysms); group 3 included a further five Kawasaki disease patients with 25 normal coronary angiography sites in the acute stage of Kawasaki disease; and group 4 comprised the six patients with congenital heart disease as controls, with a total of 27 normal coronary angiography sites. During coronary angiography, 15 microg of acetylcholine and 0.5 mg isosorbide dinitrate were infused into the coronary artery. The luminal diameter at the sites was measured using a cine-videodensitometric analyser, to assess the distensibility of the coronary artery wall. RESULTS: Coronary angiography in all 22 patients in groups 1 and 2 and in all the patients in group 3 was normal, with no stenoses and no irregularity of the arterial wall. However, the intravascular ultrasound imaging in groups 1 and 2 showed various degrees of the intimal thickening. In groups 1 and 2, there was significantly more vascular constriction with acetylcholine, and poorer dilatation with isosorbide dinitrate than in groups 3 or 4 (each p < 0.05, respectively). There was no difference between group 3 and group 4 in response to either acetylcholine or isosorbide dinitrate, CONCLUSIONS: There is evidence of persisting abnormal vascular wall morphology and vascular dysfunction at the site of regressed coronary aneurysms in patients with previous Kawasaki disease. These patients should be counselled to avoid potential risk factors for atherosclerosis, and long term follow up is needed into adult life.

Acetylcholine↗
PubMed1981

Effects of nitrates on R-wave variations after exercise in coronary heart disease: differences in patients with and without angina pectoris.

With the purpose of investigating the pathophysiology of changes in the R wave after exercise and its relationship with left ventricular function, we studied 44 patients with coronary heart disease. They were classified into the following three groups: group A, 11 patients with angina pectoris and no prior myocardial infarction; group B, 18 patients with angina pectoris and prior myocardial infarction; and group C, 15 patients with prior myocardial infarction but no angina. All patients performed two exercise tests; one was a control test, and the other was performed after the sublingual administration of 5 mg of isosorbide dinitrate. In group A, variations in the R-wave voltage in control test and in the test after isosorbide dinitrate were 1.5 +/- 0.8 mm and -1.2 +/- 0.9 mm (P less than 0.05), respectively. In group B, results were 1.2 +/- 0.7 mm on the control test and -0.7 +/- 0.6 mm after isosorbide dinitrate (P less than 0.002), and in group C were -1.6 +/- 1.2 mm on the control test and -0.7 +/- 0.7 mm after isosorbide dinitrate (not significant). Thus, the two groups of patients with angina showed an increase of the R-wave after exercise in the control test but a decrease after the administration of nitrates, whereas the patients without angina showed a reduced R-wave after exercise both before and after the administration of nitrates (like normal subjects). This study suggests that ischemic ventricular dysfunction with exercise results in an increase in the R-wave, while exercise after nitrates results in a decrease in the R-wave consistent with less or no ventricular dysfunction due to nitrate therapy.

Administration, Topical↗
PubMed1988

Relationship of pharmacokinetic and pharmacodynamic properties of the organic nitrates.

Glyceryl trinitrate (nitroglycerin), isosorbide dinitrate and isosorbide mononitrate are, in various formulations, available for clinical use. The pharmacokinetics of glyceryl trinitrate are complex and only 1% of the drug administered orally can be detected in the plasma due to a pronounced arteriovenous concentration gradient, hydrolysis in the blood, and rapid denitration in the liver. There is a poor and usually transient correlation between plasma concentrations and therapeutic effects, due in part to the complex pharmacokinetics of glyceryl trinitrate, but primarily due to development of tolerance during continuous administration, either via the intravenous or cutaneous route. Isosorbide dinitrate kinetics are complicated by its extensive metabolism into 2- and 5-mononitrates, which are pharmacologically active, and which also accumulate more than the parent drug during long term treatment. These facts, combined with development of tolerance during long term therapy, preclude the establishment of a concentration-response relationship. Isosorbide-5-mononitrate has ideal and dose-linear kinetics and is nearly 100% bioavailable after oral administration. However, tolerance develops during long term therapy, and therefore a relationship between plasma concentrations and clinical effects cannot be established. On the basis of available data, plasma concentrations of various nitrates do not reliably predict clinical effects.

Angina Pectoris↗
PubMed1987

Mononitrates as monotherapy in the prophylactic treatment of angina pectoris.

This article reviews the results of double-blind comparative studies on the therapeutic use of isosorbide 5-mononitrate as monotherapy in the prophylaxis of angina pectoris. Isosorbide 5-mononitrate appears at least as effective as the same dosage of isosorbide dinitrate and is probably superior to the calcium antagonists. Recent data have shown that isosorbide 5-mononitrate in a controlled-release formulation given once daily has a significantly better antianginal effect than placebo without inducing the development of tolerance.

Angina Pectoris↗
PubMed2006

Use of antihypertension agents for the suppression of arterial pulse pressure waveforms in patients with intracranial aneurysms.

OBJECT: Patients with intracranial aneurysms tend toward raised blood pressure and abnormal pulse pressure profiles. The authors have investigated the influence of three antihypertension agents on blood pressure and pulse pressure waveforms in patients with known intracranial aneurysms, with a view to assessing the potential benefits of longterm antihypertension therapy on the progression of unruptured intracranial aneurysms. METHODS: Nineteen patients with a mean age of 56 years (range 38-76 years) were recruited for this study. All patients had confirmed intracranial aneurysms. A double-blind, randomized, crossover study was performed using perindopril, irbesartan, isosorbide mononitrate, and a placebo. Blood pressure and pulse pressure waveforms were assessed at the end of each 4-week treatment period. Perindopril and irbesartan were well tolerated. For all measured parameters except heart rate (p = 0.03), no significant difference between baseline and placebo was identified. Each drug when compared with placebo reduced peripheral arterial blood pressure. Perindopril significantly decreased mean blood pressure by 10 mm Hg (p = 0.004), irbesartan by 9 mm Hg (p = 0.004), and isosorbide mononitrate by 13 mm Hg (p = 0.005). The administration of each drug effected a significant reduction in the carotid artery augmentation index (AIX) compared with baseline values (perindopril p = 0.01, irbesartan p = 0.0002, and isosorbide mononitrate p = 0.03). There was also a significant difference in the AIX between irbesartan and the placebo (p = 0.05). Compared with the placebo, there was a significant difference in AIX (adjusted for heart rate) following the administration of irbesartan (p = 0.003) and isosorbide mononitrate (p = 0.01), but not with perindopril (p = 0.17). CONCLUSIONS: Irbesartan appears to be the most effective treatment for the combined suppression of blood pressure and AIX in patients with intracranial aneurysms and has a high degree of patient tolerance.

Adult↗
PubMed2007

BiDil for heart failure in black patients: The U.S. Food and Drug Administration perspective.

Critics of the U.S. Food and Drug Administration (FDA) approval of the fixed combination of hydralazine hydrochloride, 37.5 mg, and isosorbide dinitrate, 20 mg, for treating heart failure in black patients have suggested that data were insufficient to distinguish treatment effects in black and white people; that distinctions based on race, rather than pathophysiology, were scientifically unreasonable; and that a "race-based" approval could be a commercial ploy to avoid a more expensive and prolonged full evaluation of a drug. The criticisms acknowledge that data supporting the approval came from a well-designed clinical trial in which self-identified black patients with heart failure who took hydralazine hydrochloride-isosorbide dinitrate with standard therapy experienced a statistically significant 43% (95% CI, 11% to 63%) reduction in mortality compared with those who took only the standard therapy. The criticisms do not always recognize that the decision to conduct the trial in only black patients reflected careful analyses of 2 previous trials in racially mixed patient populations that compared hydralazine hydrochloride-isosorbide dinitrate with placebo or with enalapril. Both trials showed little or no overall effect of hydralazine hydrochloride-isosorbide dinitrate in the mostly white patient population but hinted at a substantial effect in subsets of black patients. Perhaps most critically, the criticisms do not appreciate the urgency of strong scientific evidence of a substantial survival benefit in black patients. A serious attempt to avoid race-based approval by mandating study of a mixed population to identify a possible white patient-responder subset, particularly without a plausible hypothesis as to what that subset might be, would have required years of work, many thousands of patients, and wholly unreasonable delay in approval of a treatment whose effectiveness had been well-documented in the group for which it was intended.

Black People↗
PubMed2005

[Pharmacological stress echocardiography for diagnosing of viable myocardium in severe left ventricular dysfunction].

OBJECTIVE: To compare the safety, sensitivity, specificity and accuracy of low dose dobutamine (Dob), isosorbide dinitrate and their combination in stress echocardiography to predict regional movement recovery after coronary revascularization (CRV) in patients with old myocardial infarction (OMI) and severe left ventricular dysfunction. METHODS: Fourty patients (mean age 52 +/- 8 years, male 39, female 1) with OMI waiting for CRV with mean left ventricular ejection fraction (LVEF) (39.4 +/- 5.1)%, underwent Dob (3, 5 and 10 microg.kg(-1).min(-1)), isosorbide dinitrate (270 +/- 56) microg/min and their combination (nitrate plus Dob 3, 5 microg.kg(-1).min(-1)) stress echocardiography. Twenty-six patients completed follow-up rest two dimension echocardiography (2DE) (6.8 +/- 2.9) months after CRV. RESULTS: During Dob 2DE, side effects rates increased by dosage, the drug even induced ischemia at a dosage of 10 microg.kg(-1).min(-1). When Dob was combined with nitrate, no ischemia happened. Among 272 abnormal segments in 26 patients after CRV, 156 segments showed contractile improvement. In Dob 2DE, both the sensitivity (46.8% to 88.6%) and accuracy (64.1% to 77.9%) increased by dosage gradient, while the specificities decreased from 87.1% to 64.2%. When combined with nitrate, the sensitivities and accuracy were higher than either drugs used alone (P < 0.05). The detecting effect in isosorbide dinitrate + Dob 5 microg 2DE was comparable to that of Dob 10 microg.kg(-1).min(-1) 2DE. CONCLUSIONS: In identifying myocardial viability in patients with OMI and severe left ventricular dysfunction, Dob 5-10 microg.kg(-1).min(-1) 2DE have good detecting effects, but could induce ischemia. When nitrate was combined with Dob, no ischemia happened, and the sensitivity and accuracy improved significantly. Isosorbide dinitrate + Dob 5 microg.kg(-1).min(-1) 2DE has identifying effect comparable to Dob 10 microg.kg(-1).min(-1) 2DE.

Cardiotonic Agents↗
PubMed1986

Sorption of four drugs to polyvinyl chloride and polybutadiene intravenous administration sets.

Sorption of nitroglycerin, isosorbide dinitrate, diazepam, and clomethiazole edisylate (chlormethiazole) to polyvinyl chloride (PVC) i.v. administration sets with and without cellulose propionate burettes and to polybutadiene (PBD) sets with and without methacrylate butadiene styrene (MBS) burettes was studied. All drugs (except chlormethiazole) were diluted with 0.9% sodium chloride injection (NS) in glass bottles or in the burette chambers. Initial samples of each solution were obtained from the bottle or from the burette, and effluent samples were collected at various times up to 240 minutes from the sets without burettes and up to 90 minutes from the sets with burettes. For nitroglycerin, flow rates of 0.5 and 1.0 mL/min were used without the burette. The effect of priming the tubing before adding drug to the burette was studied for diazepam. Triplicate samples were analyzed for nitroglycerin and isosorbide dinitrate by high-performance liquid chromatography and for diazepam and chlormethiazole by ultraviolet spectrophotometry. Up to 50% potency of chlormethiazole and nitroglycerin, 15-25% of isosorbide dinitrate, and 13-20% of diazepam was lost to PVC sets without burettes, and an additional 10-15% loss of each drug resulted when PVC sets with burettes were used. Less sorption of nitroglycerin to the PVC sets occurred at the higher flow rate, but flow rate through the PBD sets did not affect sorption. Priming the tubing before adding diazepam to the burette did not affect final drug delivery. No loss to PBD sets was observed for nitroglycerin, isosorbide dinitrate, and diazepam; loss of chlormethiazole to PBD was 7-13%. Drug potency in effluent from PBD sets was not affected by presence or absence of a burette.(ABSTRACT TRUNCATED AT 250 WORDS)

Adsorption↗
PubMed1978

Nitrate therapy for congestive heart failure.

A randomized double-blind crossover trial included 16 patients with severe congestive heart failure who received isosorbide dinitrate or placebo for eight weeks, and then the opposite treatment for eight more weeks. All patients received their usual maintenance therapy with digitalis and diuretics. Seven morbid events occurred during 85 patient-weeks of isosorbide dinitrate therapy compared with 17 during 76 patient-weeks of placebo. Severity of congestive heart failure improved in all eight patients who received isosorbide dinitrate compared with two patients who showed improvement and five whose symptoms became worse with placebo. No significant differences in physical findings, cardiac dimensions, or resting hemodynamics were observed. Maximal exercise duration increased significantly by 2.54 minutes with isosorbide dinitrate therapy, and rose insignificantly by 1.24 minutes with placebo. This preliminary trial suggests that long-term vasodilator therapy may be clinically beneficial in congestive heart failure.

Adult↗
PubMed1986

[The diameter of arterial and venous abdominal vessels during acute and chronic administration of nitrates. A sonographic study].

Fourteen male patients with coronary heart disease were randomly assigned to treatment periods with isosorbide dinitrate (ISDN) 120 mg/day (6 X 20 mg) and placebo for 4 weeks each, according to a double-blind protocol with intraindividual cross-over. The luminal diameters of the superior mesenteric artery, the hepatic artery, the superior mesenteric vein and the portal vein were determined sonographically in the supine position on days 1, 14 and 28 of both treatment periods 90 min after drug intake. The measurements were repeated after 1.6 mg sublingual nitroglycerin. On day 1 of drug intake the vessel diameters increased significantly after ISDN as compared to placebo: superior mesenteric artery: +11%; hepatic artery: +26%; superior mesenteric vein: +17%; portal vein: +11% (p less than 0.05). No differences in luminal diameters between both drug regimens were found on days 14 and 28. Additional nitroglycerin caused a marked diameter increase during the placebo period (14-21%; p less than 0.001) and on days 14 and 28 of ISDN therapy, while the drug effects were absent after maximal ISDN-induced vasodilatation on day 1. Thus, nitroglycerin and isosorbide dinitrate administered acutely caused a comparable vasodilatation of arterial and venous vessels in the splanchnic region. During sustained therapy with isosorbide dinitrate the vasodilatory effects of the drug were lost. It is supposed that a decrease of blood pooling in the splanchnic region occurs during sustained ISDN therapy. Despite this tolerance development to the circulatory effects of isosorbide dinitrate, nitroglycerin remained effective with regard to arterial and venous vasodilatation.

Adult↗
PubMed1985

[Methodological approaches to assessing the effectiveness of anti-angina preparations in stenocardia patients using paired bicycle ergometry loads].

Paired bicycle ergometry was used in 24 anginal patients to compare the efficiency of 10-20 mg isosorbide dinitrate, 20-30 mg corinfar and 40-80 mg propranolol. Isosorbide dinitrate showed maximum efficiency in half of the patients, corinfar in 1/4, propranolol in 1/6. Isosorbide dinitrate produced an effect with the very first dose more frequently, as compared to other drugs. Heart rate patterns at rest and under the action of corinfar and isosorbide dinitrate varied in different individuals and were related to the time of onset of an exercise-induced anginal attack.

Angina Pectoris↗
PubMed1977

[Effectiveness of nifedipine on exercise tolerance in patients with angina pectoris. Comparison with a nitroderivative and a beta-blocking agent].

The effect of nifedipine on effort angina was investigated by means of exercise tests with bycicle ergometer and compared, in the same patients, with the effects of a nitroderivative and a betablocking agent. Five patients with stable effort angina entered the study, after an hemodynamic and contrasto-graphic control. According to the protocol of a latin square 5 X 5, all the patients received in a random sequence the following treatments: placebo, 1 c. orally; isosorbide dinitrate, 5 mg sublingually; propranolol, 40 mg orally; nifedipine, 10 mg sublingually; nifedipine, 10 mg orally. No significant change of any of the considered parameters was observed after the placebo. Isosorbide dinitrate and nifedipine produced significant increases of the duration of work before appearance of pain and EKG positivity, and of total work performed before anginal pain. Only the duration of work before EKG positivity was improved by propranolol. The comparisons between treatments showed no significant difference of the effects of the administered doses of isosorbide dinitrate and nifedipine. The improvements observed after propranolol were significantly lower than that observed after isosorbide dinitrate and oral nifedipine. On the basis of the observed changes of cardiac rate, maximal arterial pressure, ejection time index and triple product, the authors evaluate the possible mechanism of action of nifedipine.

Adolescent↗
PubMed1983

[Congestive cardiomyopathy: value of short and long-term vasodilator treatment and prognosis].

Vasodilator therapy in congestive heart failure has proven an effective adjunct to conventional treatment with digitalis and diuretics. In this study dipyridamole was used in combination with isosorbide dinitrate to treat twelve patients (mean age 55 years) with idiopathic congestive cardiomyopathy. All patients were in N.Y.H.A. class III or IV and were already treated with digitalis and diuretics. This conventional therapy was not discontinued for the study. Acute studies were performed during diagnostic right and left heart catheterization. Hemodynamics were obtained at rest, after intravenous administration of 40 mg dipyridamole and after 5 mg isosorbide dinitrate sublingually. An increase in cardiac index and stroke volume index was noted, while left ventricular enddiastolic pressure and systemic vascular resistance decreased significantly. The twelve patients were then treated with 4 X 150 mg dipyridamole and 4 X 40 mg isosorbide dinitrate per day while also continuing the digitalis and diuretic treatment. They were followed up clinically for a period of 8 to 24 months. Three patients died but the other nine showed a clinical improvement (mean of 1.45 N.Y.H.A. classes). It was possible to perform a second right and left heart catheterization in four patients. Cardiac index, stroke volume index and maximum and minimum DP/dt were significantly higher, and left ventricular enddiastolic pressure was significantly lower, than before vasodilator therapy. These results suggest a sustained effect of dipyridamole and isosorbide dinitrate. The postextrasystolic modification of maximum DP/dt could be of prognostic value in congestive cardiomyopathy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1978

Treatment of ruptured interventricular septum with afterload reduction.

Two patients with a ruptured interventricular septum complicating acute myocardial infarction were treated with isosorbide dinitrate. The first patient recovered from cardiogenic shock after sublingual administration of 5 mg of isosorbide dinitrate every two hours and was successfully operated on. The second patient recovered from severe pulmonary edema during the acute stage of the infarction with sublingual isosorbide dinitrate. Moreover, she experienced a considerable symptomatic improvement when a 5 mg sublingual dose of isosorbide dinitrate every three hours was added to her long-term treatment. Analysis of hemodynamic data showed that the most striking change following administration of the drug was the substantial reduction of pulmonary wedge pressure. The striking symptomatic and hemodynamic improvement was achieved by the favorable effect of afterload reduction on left ventricular performance and not by reduction in left to right shunt.

Aged↗
PubMed1994

Nitric oxide and castor oil-induced diarrhea.

The effect of NG-nitro-L-arginine methyl ester (L-NAME) on castor oil-induced diarrhea was studied in control rats and those treated with isosorbide dinitrate or isosorbide-5-mononitrate. Castor oil (2 ml) produced diarrhea that lasted at least 8 h. Pretreatment of the rats with L-NAME (1-25 mg/kg i.p.) 15 min before castor oil did not block the castor oil-induced diarrhea beyond 3 h after challenge but delayed its appearance (P < .05-.001). However, diarrhea was inhibited (P < .01-.001) during the entire 8 h if rats were treated twice with L-NAME (25 mg/kg) (15 min before and 3 h after castor oil). These findings suggest that L-NAME, once administered, loses its activity 3 h after its administration. The nitric oxide synthase substrate, L-arginine (150-600 mg/kg), reversed (P < .05-.01) the inhibitory effect of L-NAME on diarrhea induced by castor oil. This effect is enantiomer-specific because D-arginine (900 mg/kg) was without an effect. These results suggest that castor oil-induced diarrhea in rats involves the L-arginine nitric oxide pathway. This is further supported by the effect of isosorbide dinitrate (0.6-120 mg/kg) and isosorbide-5-mononitrate (0.6-120 mg/kg). When administered to castor oil-treated rats, these two nitric oxide-generating agents prevented in a dose-dependent fashion (P < .01-.001) the inhibitory effect of L-NAME (25 mg/kg).

Animals↗
PubMed2004

[Therapy with NO donors-antiatherogenic and antioxidant actions].

Nitric acid esters such as glyceryl trinitrate were introduced into therapy more than a century ago and are still widely used for the treatment of myocardial ischemia and its main symptom angina pectoris. The basic mechanisms responsible for the vasodilatory and anti-ischemic action of organic nitrates involve bioactivation of, and nitric oxide (NO) release from, these compounds which have therefore been termed NO donors. The organic nitrate pentaerythritol tetranitrate (PETN) is known to possess antioxidant properties that are thought to be the underlying cause for its specific pharmacological profile. In contrast to other long-acting nitrates, PETN induces tolerance- free vasodilation in humans and was reported to prevent endothelial dysfunction as well as atherogenesis in cholesterol- fed rabbits. However, the exact nature of the vasoprotective signaling pathways triggered by PETN has remained obscure. The present study demonstrates that the active PETN metabolite PETriN stimulates protein expression of the antioxidant defense protein heme oxygenase-1 (HO-1; Figures 1 and 2). Additionally, PETriN enhanced the enzymatic activity of HO-1 measured as formation of the HO-1 metabolites bilirubin (Figure 3) and carbon monoxide (Figure 4) in lysates from endothelial cells. HO-1 induction subsequently led to a marked increase in protein expression of a second antioxidant protein, ferritin, via the HO-1-dependent release of free iron from endogenous heme sources (Figures 1 and 5). Pretreatment of endothelial cells with PETriN was followed by increased cellular resistance to oxidant injury mediated by hydrogen peroxide (Figure 6). Endothelial protection by PETriN was mimicked by exogenous bilirubin which led to an almost complete reversal of hydrogen peroxide-induced toxicity (Figure 8). Increased HO-1 and ferritin expression as well as endothelial protection occurred at micromolar concentrations of PETriN which are well within the range of plasma or tissue levels that can be expected during oral therapy. The capacity to protect the endothelium in vitro may translate into and explain the previously observed antiatherogenic actions of PETN in vivo. In this study, another long-acting nitrate, isosorbide dinitrate (ISDN), did not protect endothelial cells from oxidant damage (Figure 6). The absence of significant cytoprotection in the presence of ISDN was paralleled by a lack of HO-1 and ferritin stimulatory capacity (Figures 2 and 5). ISDN had no significant effect on carbon monoxide release or bilirubin formation (Figures 3 and 4). These observations are in agreement with results demonstrating small or nondetectable amounts of NO released from ISDN and its active metabolite isosorbide mononitrate (ISMN) measured as cyclic GMP formation in RFL-6 reporter cells (Figure 7). Interestingly and in contrast to PETN, isosorbide nitrates are known to induce tolerance to their cardiovascular effects, presumably via oxidant stress. Moreover, in earlier investigations aimed at assessing the antiatherogenic potential of nitrates, PETN but not isosorbide nitrates prevented plaque formation and endothelial dysfunction in animal models of atherosclerosis. Thus, the ability to activate HO-1 induction and associated antioxidant pathways apparently distinguishes PETN from other long-acting nitrates and may explain their different patterns of action in vivo (Figure 9).

Animals↗
PubMed2005

Treatment of chronic anal fissure by application of L-arginine gel: a phase II study in 15 patients.

PURPOSE: Local application of exogenous nitric oxide donors, such as isosorbide dinitrate and glyceryl trinitrate, promotes fissure healing by reducing anal resting pressure and improving anodermal blood flow. The major drawback of these nitric oxide donors is headache. The overall incidence of this side effect is approximately 40 percent. Recently we have shown in healthy volunteers that L-arginine, being an intrinsic precursor of nitric oxide, reduces anal resting pressure without headache as a side effect. The aim of the present study was to evaluate the effect of L-arginine on anal resting pressure, anodermal blood flow, and fissure healing in patients with chronic anal fissure. METHODS: Fifteen patients with a chronic anal fissure were included in the present study. Before entering the study 10 patients were unsuccessfully treated by local application of isosorbide dinitrate. Six of these patients experienced severe headache during treatment with isosorbide dinitrate. All patients were treated for at least 12 weeks by local application of a gel containing L-arginine 400 mg/ml five times a day. In patients with a persistent fissure, treatment was continued until 18 weeks. Anal manometry and laser Doppler flowmetry of the anoderm were performed before treatment, 20 minutes after local application of the first dose, and after 12 weeks of treatment. A visual analog scale was used to assess fissure-related pain and headache. RESULTS: One patient dropped out after one day of treatment, and one was excluded because of violation of the study protocol. After 12 weeks of treatment complete fissure healing was observed in 3 of 13 (23 percent) patients, and after 18 weeks the healing rate was 8 of 13 (62 percent) patients. None of the 13 patients experienced typical nitric oxide-induced headache. The pressure recordings showed a significant reduction of maximum anal resting pressure (mean +/- SD): pretreatment 89 +/- 17 mmHg; 20 minutes after application of the first dose 67 +/- 17 mmHg; 12 weeks after treatment 74 +/- 14 mmHg (P < 0.005). Recordings of anodermal blood flow showed a significant increase in flow: pretreatment 0.36 +/- 0.25 volts; 20 minutes after application of the first dose 0.59 +/- 0.27; 12 weeks after treatment 0.64 +/- 0.33 (P < 0.005). CONCLUSIONS: Local application of L-arginine promotes fissure healing without headache as a side effect, and L-arginine is effective even in patients not responding to isosorbide dinitrate treatment.

Administration, Topical↗