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PubMed1991

Reactivity of eccentric and concentric coronary stenoses in patients with chronic stable angina.

Dynamic coronary stenoses may be the cause of a variable angina threshold and rest angina in patients with chronic stable angina. It has been suggested that eccentric but not concentric coronary artery stenoses have the potential for dynamic changes of caliber in response to vasoactive stimuli. The vasomotor response of eccentric (asymmetric narrowing) and concentric (symmetric narrowing) coronary stenoses to ergonovine (20 micrograms intracoronary or 300 micrograms intravenous) and isosorbide dinitrate (1 mg intracoronary) was studied in 51 patients with chronic stable angina. Diameter of reference segments (angiographically normal segments proximal to the stenoses) and that of eccentric (n = 30) and concentric (n = 35) coronary stenoses that ranged from 50% to 90% luminal diameter reduction were measured by computerized quantitative angiography before and after ergonovine and isosorbide dinitrate. Ergonovine reduced stenosis diameter (by greater than or equal to 10%) in 80% of eccentric stenoses and 42% of concentric stenoses (p less than 0.05). Mean (+/- SEM) diameter reduction with ergonovine was 19 +/- 3% and 9.5 +/- 2% for eccentric and concentric stenoses, respectively (p less than 0.05). Isosorbide dinitrate increased coronary diameter (by greater than or equal to 10%) in 70% of eccentric and 43% of concentric stenoses (p less than 0.05). Mean diameter of eccentric stenoses increased from 1.15 +/- 0.05 to 1.35 +/- 0.06 mm after nitrate (18.6 +/- 2.5%), whereas diameter of concentric stenoses increased from 1.05 +/- 0.05 to 1.14 +/- 0.05 mm (10 +/- 2.5%) (p less than 0.05). Average dilation of reference segments with administration of isosorbide dinitrate and constriction with ergonovine were not significantly different in patients with concentric and eccentric stenoses.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Substance P for evaluation of coronary endothelial function after cardiac transplantation.

The endothelium-dependent vasodilator substance P dilates normal and diseased coronary vessels in humans in vivo and produces a maximal response similar to that seen with intracoronary isosorbide dinitrate. Twelve cardiac transplant recipients underwent intracoronary infusion of substance P after routine annual investigations. All patients were well, with no evidence of rejection and with angiographically normal coronary arteries. Substance P was infused at 2 ml/min for 2 min into the coronary artery, starting at a dose of 1.4 pmol/min and increasing by doubling increments, and followed by isosorbide dinitrate (1 mg/min) infused over 2 min. Coronary artery diameter was measured in 23 vessel segments from 12 transplant recipients. The following doses were infused: saline solution (1 ml/min), substance P (0.7 [three patients], 1.4, 2.8, 5.6, 11.2, 22.4 pmol/min) and isosorbide dinitrate (1 mg/min). The mean percent increase in diameter (+/- SEM) in response to increasing doses of substance P was as follows: 0, 6.5 +/- 2.9%, 10.9 +/- 2.9%, 12.1 +/- 2.9%, 16.5 +/- 2.6%, 19.2 +/- 3.1% and 25.8 +/- 2.2%, respectively. Half maximal dilation was produced with 1.4 to 2.8 pmol/min of substance P; the maximal response (mean percent diameter change) was 22 +/- 2.5%. This was not significantly different from that achieved with isosorbide dinitrate. It is concluded that coronary endothelial function as assessed by response to substance P is preserved in cardiac transplant recipients with angiographically normal coronary arteries. Substance P may be a suitable agent for testing endothelial function in these patients.

Coronary Angiography↗
PubMed1985

Relation of antianginal efficacy of nifedipine to degree of coronary arterial narrowing and to presence of coronary collateral vessels.

Thirty-six patients with chronic stable angina pectoris or with stable and vasospastic components of angina pectoris were classified by coronary arteriographic findings into 4 groups. Patients in group A had a single stenotic coronary artery; patients in groups B, C and D had occluded arteries, but these arteries had been collateralized to varying degrees, and an epicardial coronary steal phenomenon was possible. All patients underwent multiple exercise tests before and after randomized, double-blind, crossover treatment with 20 mg of nifedipine, 20 mg of isosorbide dinitrate, a combination of both, and placebo. Maximal and mean ST-segment depression, occurrence of angina pectoris and heart rate were evaluated. After nifedipine treatment, mean ischemic ST-segment depression was reduced 21% in group A (p less than 0.05), but was not significantly altered in the other groups (group B, 2% decrease; group C, 10% increase; group D, 3% decrease). However, isosorbide dinitrate reduced ST-segment depression significantly in all groups (group A, 29%, p less than 0.001; group B, 18%, p less than 0.01; group C, 19%, p less than 0.05; group D, 33%, p less than 0.05). The combination with nifedipine did not further improve the effect of isosorbide dinitrate. Maximal ST-segment depression and angina pectoris paralleled the changes in mean ST depression during the different medications. Heart rate at rest was not significantly changed after nifedipine treatment in any group, but increased significantly after isosorbide dinitrate treatment in groups B and C (group B, 12%, p less than 0.01; group C, 9%, p less than 0.05); heart rate during exercise did not differ significantly in any group or after any form of medication from placebo.

Adult↗
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↗
PubMed1997

Interactions between endothelin-I-induced contractions and bronchodilators in human isolated bronchi.

1. The aim of this study was to compare the ability of four different bronchodilators (atrial natriuretic peptide, salbutamol, sodium nitroprusside and isosorbide dinitrate) to reverse and also to protect against contractions evoked by the spasmogens endothelin-1 and methacholine in human isolated bronchial rings. 2. Contractions evoked by either endothelin-1 or methacholine were reversed by atrial natriuretic peptide (10(-9)-10(-6) mol/l), salbutamol (10(-9)-10(-5) mol/l), sodium nitroprusside (10(-9)-10(-5) mol/l) and isosorbide dinitrate (10(-7)-10(-4) mol/l). 3. Sodium nitroprusside produced a significantly (P < 0.05 for data points) greater mean maximal inhibition of endothelin-1-induced tone than methacholine-induced tone; however, the other dilators were equally effective at reversing either endothelin-1- or methacholine-induced contractions. Comparing sodium nitroprusside and salbutamol, sodium nitroprusside was significantly (P < 0.05 for data set) less effective than salbutamol at reversing either endothelin-1- or methacholine-induced contractions. 4. To compare the ability of these bronchodilator substances to protect against spasmogen challenge, cumulative concentration-response curves to either endothelin-1 (10(-10)-3 x 10(-7) mol/l) or methacholine (10(-9)-3 x 10(-4) mol/l) were constructed in the presence and absence of each bronchodilator. Atrial natriuretic peptide, at a concentration of 10(-6) mol/l, significantly attenuated contractions evoked by methacholine. In contrast, contractions evoked by endothelin-1 were enhanced by atrial natriuretic peptide at concentrations of 3 x 10(-7) and 10(-6) mol/l. Preincubation of salbutamol at a concentration of 10(-6) mol/l significantly attenuated methacholine-induced contractions, but responses to endothelin-1 were not altered by preincubation of salbutamol at concentrations of 3 x 10(-7), 10(-6) and 3 x 10(-6) mol/l. Sodium nitroprusside (10(-6) mol/l) and isosorbide dinitrate (3 x 10(-5) mol/l) did not alter responses evoked by subsequent addition of either endothelin-1 or methacholine. At a concentration of 10(-4) mol/l, however, isosorbide dinitrate significantly attenuated endothelin-1-evoked contractions. 5. These results show that drugs which reverse agonist-induced tone in isolated bronchial rings may not necessarily protect against subsequent challenge with this agonist. This suggests that the pharmacology of relaxation may be dissimilar to that of protection.

Albuterol↗
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↗
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↗
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↗
PubMed1990

Relationship between the inhibition of receptor-induced increase in cytosolic free calcium concentration and the vasodilator effects of nitrates in patients with congestive heart failure.

Nitroglycerin, isosorbide dinitrate and sodium nitroprusside, like nifedipine, were found to inhibit the receptor-provoked increase of cytosolic free calcium concentration in human platelets loaded with 2-[(2-amino-5-methylphenoxy)methyl]-6-methoxy-8-aminoquinoline-N,N,N',N' - tetraacetate. Sodium nitroprusside and nitroglycerin induced elevation of cyclic guanosine 3',5'-monophosphate content in platelets which correlated with their calcium-blocking activity. Methylene blue and epinephrine decreased the calcium-blocking effect and the influence of nitroglycerin on cyclic guanosine 3'-5'-monophosphate content, but failed to suppress the inhibitory effect of sodium nitroprusside. Ascorbic acid increased the calcium blocking effect of sodium nitroprusside and its influence on cyclic guanosine 3'-5'-monophosphate content, but did not alter the inhibitory effect of nitroglycerin. In order to evaluate the relationship between the mode of action of nitrates at cellular level and their vasodilatory effectiveness, we studied the circulatory response of the forearm to isosorbide dinitrate and the influence of nitroglycerin on free calcium concentration in the platelets in 10 patients with chronic heart failure. We established a significant positive correlation between the basal values for venous tone and its peak decrease after administration of the 10-mg dose of isosorbide dinitrate. A correlation was also found between the deviation of maximal decrease of venous tone by this dose of isosorbide dinitrate from the regression line (the relationship between the basal venous tone and its lowering by the drug) and mean inhibitory concentration values for nitroglycerin in blocking that proportion of the rise of calcium ion concentration in platelets due to blocking of the platelet-activating factor. Thus, nitrates, like calcium antagonists, inhibit the receptor-provoked calcium supply to the contractile system of the cells so neutralizing the effects of increased concentrations of vasoconstrictors. This suggests that the effectiveness of nitrates appears to be positively related to the contribution of receptor-induced increase of cytosolic free calcium concentration in vasoconstriction together with their capacity to raise cyclic guanosine 3',5'-monophosphate.

Adult↗
PubMed2000

Tilt testing in neurocardiogenic syncope: isosorbide versus isoproterenol.

OBJECTIVE: To compare the diagnostic value of pharmacological stimulation with sublingual isosorbide dinitrate and intravenous isoproterenol during tilt testing in patients with neurocardiogenic syncope and with a negative tilt test without pharmacological provocation. METHODS AND RESULTS: One hundred and twenty patients with a history of neurocardiogenic syncope (aged 15 to 77 years) and 50 healthy volunteers (aged 25 to 70 years) were prospectively submitted to head-up tilt (HUT). Those who did not develop syncope or presyncope during passive HUT for 30 minutes underwent repeated HUT with isoproterenol infusion at 4 microg/min (ISOP HUT), for 10 minutes, and, subsequently, were tilted after sublingual administration of 5 mg of isosorbide dinitrate (ISDN HUT) for another 12 minutes. ISDN HUT was always performed after ISOP HUT. Sensitivity and specificity of passive HUT were 41% (95% C.I. 32.9% to 51.0%) and 100%, respectively. Sensitivity of ISOP HUT was 51.4% (95% C.I. 39.2% to 63.6%) and specificity 70% (95% C.I. 55.4% to 82.1%) and for ISDN HUT were 70% (95% C.I. 57.9% to 80.4%) and 88% (95% C.I. 75.7% to 95.5%), respectively. The accuracy of ISDN HUT was significantly higher than the accuracy of ISOP HUT 77.5% (95% C.I. 68.9% to 84.6%). There were fewer side effects during ISDN HUT. CONCLUSION: Sublingual isosorbide dinitrate is at least as sensitive as isoproterenol to assess patients with suspected neurocardiogenic syncope and with a negative tilt test without provocation. The low rate of side effects and the higher accuracy of ISDN HUT, along with the simplicity of this challenge compared to ISOP HUT, suggest that sublingual isosorbide dinitrate should be preferred as a provocative agent to evaluate neurocardiogenic syncope after a negative passive tilt test.

Administration, Sublingual↗
PubMed1985

Nitrates and endothelial prostacyclin production: studies in vitro.

The hypothesis that nitrates evoke prostacyclin production by vascular endothelium has been reevaluated on cultured umbilical vein endothelial cells and in vascular fragments, both obtained from humans. Endothelial cell monolayers (passages 1 and 2) were washed free of culture medium and exposed for 3 to 5 min to buffer or nitroglycerin (NTG), isosorbide dinitrate (ISDN), or isosorbide-5-mononitrate (ISMN) over a range of concentrations (10(-9)M to 10(-6)M) encompassing those usually attained in vivo, with or without 25 microM sodium arachidonate. Basal prostacyclin production, measured by radioimmunoassay of the stable metabolite 6-keto-PGF1 alpha, depended on cell density in the endothelial monolayer (being higher in preconfluent cultures) and on incubation time. Basal prostacyclin, however, was not altered by incubation with NTG (3.3 +/- 2.0 pg/1000 cells without drug vs 3.9 +/- 3.8 pg/1000 cells with drug, mean +/- SD), ISDN (3.1 +/- 1.9 vs 3.1 +/- 2.2), or ISMN (2.0 +/- 0.9 vs 2.3 +/- 1.5) at 10(-7)M (all differences NS). Also, long-term incubation (2, 6, and 24 hr) with ISDN and ISMN did not alter prostacyclin production over control. Over a 30-fold increase (p less than .001) in prostacyclin production was obtained with arachidonate stimulation, but incubation with nitrates did not significantly modify the stimulated production. Saphenous vein, mesenteric artery, and atrial appendage fragments incubated at 37 degrees C for 20 min in a shaking water bath with a control buffer produced 27.8 +/- 13.9, 189.7 +/- 75.2, and 662.3 +/- 390.6 pg 6-keto-PGF1 alpha/mg tissue, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1984

[Long-term therapy with nitrates. Relation between dosage and tolerance effect].

In 56 patients with angiographically-documented coronary artery disease, the longterm effects of isosorbide dinitrate (ISDN) and isosorbide 5-mononitrate (5-ISMN) on exercise hemodynamics and exercise capacity were assessed. The hemodynamic and antianginal acute and longterm effects of the respective agents were objectively analyzed on the basis of the tested parameters of mean pulmonary artery pressure and work capacity (watts X minutes). These parameters are unaffected by placebo and show reproducible changes at rest and during exercise after drug administration. After the standard 20 mg dose of ISDN or 5-ISMN, both at rest and during exercise, there was a marked decrease in pulmonary artery pressure as well as an increase in exercise capacity. The acute effects of 60 mg ISDN or 50 mg 5-ISMN were not substantially more marked than those of the 20 mg doses. During longterm treatment with 20 mg ISDN or 5-ISMN three times daily there was no attenuation of the hemodynamic effects, that is, no tolerance development; the increase in exercise capacity was maintained. In contrast, at the end of the four-week treatment period with 60 mg ISDN or 50 mg 5-ISMN three times daily there was a marked attenuation of the hemodynamic effects as well as the associated exercise capacity. The results of this study do not enable delineation of the mechanism responsible for the attenuated effect during high-dose treatment. Most probably, it is due to a complex process, in which, in addition to pharmacokinetics and pharmacodynamics, alterations in various reflex and adaptive mechanisms also play a role.

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↗
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↗
PubMed1997

Comparison of proarrhythmogenic effects of two potassium channel openers, levcromakalim (BRL 38227) and nicorandil (RP 46417): a high-resolution mapping study on rabbit heart.

This study was designed (a) to test and (b) to compare proarrhythmic effects of levcromakalim and nicorandil; and (c) determine the mechanism of arrhythmia initiation by using high-resolution ventricular epicardial mapping on 44 Langendorff-perfused rabbit hearts. Eighteen hearts were kept intact and received incremental doses (1-500 microM) of levcromakalim, nicorandil, and isosorbide dinitrate. In 26 hearts, a thin layer of epicardium was obtained after endocardial cryotechnique (frozen hearts). In intact hearts, isosorbide dinitrate did not produce any arrhythmia. In contrast, levcromakalim induced spontaneous ventricular fibrillation (VF) in all hearts at 50 microM, whereas only one VF occurred at 500 microM nicorandil. These three drugs produced a dose-dependent bradycardia in intact hearts. In frozen hearts, arrhythmias were induced by 5 microM levcromakalim and 50 microM nicorandil. Isosorbide dinitrate had no proarrhythmogenic effect. Epicardial mapping showed that most of induced ventricular tachycardias were based on reentry around an arc of functional conduction block. Ventricular conduction velocities did not change, but levcromakalim and nicorandil shortened ventricular effective refractory period. We conclude that (a) levcromakalim and nicorandil, used in toxic concentrations, have direct proarrhythmic effects; (b) nicorandil proarrhythmogenic effects are 10 times less marked than those of levcromakalim (arrhythmia is solely the result of the potassium channel opener property of nicorandil); and (c) most of ventricular tachycardias induced are based on reentry.

Animals↗
PubMed1985

Nitrate tolerance.

Nitrate tolerance may be defined as that condition in which increasing nitrate doses are required to induce a given hemodynamic or antianginal effect. Tolerance may be due to changes in pharmacokinetics or to alterations in the property of target tissues, making them less sensitive to the nitrate effect. The question of nitrate tolerance has been addressed using 4-times-a-day therapy with oral isosorbide dinitrate, daily therapy with long-acting isosorbide dinitrate ointment and once-a-day therapy with nitroglycerin patches. Each of these treatment modalities is associated with initial beneficial effects, but during sustained therapy, there is marked attenuation of the effect both in magnitude and duration. Thus the concept that stable nitroglycerin blood levels over 24 hours are desirable appears to be incorrect. Preliminary hemodynamic studies suggest that short periods of nitrate withdrawal restore the hemodynamic effect of the nitrates, and it is postulated that intermittent nitrate therapy may be desirable in the management of angina. Transmucosal nitroglycerin administration for a 15-hour period with a 9-hour washout period was recently undertaken. The results demonstrated that this method of nitrate administration is not associated with development of tolerance to its antianginal effects. Large doses of transdermal nitroglycerin, varying from 45 to 100 mg during short-term studies, have been shown to result in only minimal increases in exercise tolerance at 24 hours. These findings, plus evidence that with smaller doses tolerance occurs after only 1 week of once-a-day therapy, challenge the concept that larger nitroglycerin dosages, administered once a day by transdermal patches, could be effective throughout a 24-hour period in patients with angina pectoris.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Topical↗