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PubMed1994

The Asymptomatic Cardiac Ischemia Pilot (ACIP) study: design of a randomized clinical trial, baseline data and implications for a long-term outcome trial.

OBJECTIVES: The primary objectives of the Asymptomatic Cardiac Ischemia Pilot were 1) to compare the 12-week efficacy of three treatment strategies to suppress cardiac ischemia, and 2) to assess the feasibility of a prognosis trial in patients with asymptomatic cardiac ischemia. BACKGROUND: Cardiac ischemia has been associated with increased morbidity and mortality. However, most cardiac ischemia is asymptomatic, and although therapeutic strategies ranging from no medication to revascularization are being used to treat ischemia, no prospective study evaluating different treatment strategies has been reported. METHODS: Patients with angiographically documented coronary artery disease and ischemia on exercise and ambulatory electrocardiogram (ECG) in 11 clinical units were randomized to receive angina-guided medical therapy, angina-guided plus ambulatory ECG ischemia-guided medical therapy or revascularization (coronary angioplasty or bypass surgery). Patients were also randomized to receive either diltiazem plus isosorbide dinitrate or atenolol plus nifedipine when possible. After anti-ischemic medication adjustment to control angina, blinded medication was adjusted in the medical therapy groups to eliminate ischemia in the ischemia-guided group. The primary outcome was the absence of ischemia at 12 weeks. Follow-up was scheduled for 1 year. RESULTS: A total of 1,959 patients were screened by ambulatory ECG monitoring; 982 (49%) had asymptomatic ischemia, and 618 (65%) were enrolled in the study. Most patients were men, were > 60 years old and had two or more ischemic episodes, early positive exercise tests and multivessel disease. CONCLUSIONS: Design and baseline data for a pilot study of ischemia treatment strategies are described.

Aged↗
PubMed2007

BiDil for heart failure in black patients: implications of the U.S. Food and Drug Administration approval.

In 2005, the combination of hydralazine hydrochloride and isosorbide dinitrate was approved by the U.S. Food and Drug Administration (FDA) for treating heart failure in black patients. In departing from its long history of approving drugs for general clinical indications without regard to demographic classification, the FDA cited the need to address racial disparities in health as an important contributor to their decision. The authors argue that this decision, although perhaps well-intentioned, was based on flawed scientific interpretation of trial results that claimed differential drug response by race and ignored the considerable literature on the cause of racial disparities in health and health care. Because of its potential impact on future drug approvals, the FDA's decision is a setback in the scientific and policy discourse on medical therapeutics and race and specifically hinders the efforts aimed at eliminating health and health care disparities.

Black People↗
PubMed1999

cGMP-mediated negative-feedback regulation of endothelial nitric oxide synthase expression by nitric oxide.

Earlier studies have demonstrated that nitric oxide (NO) exerts a fast-acting inhibitory influence on endothelial NO synthase (eNOS) enzymatic activity in isolated vascular tissue preparations. The present study was designed to examine the possible effect of NO on eNOS protein expression in cultured endothelial cells and intact animals. Human coronary endothelial cells were incubated with S-nitroso-N-acetyl-penicillamine (SNAP, an NO donor), oxyhemoglobin (HGB, an NO trapping agent), SNAP plus HGB, or inactive vehicle (control). In other experiments, cells were treated with 3-isobutyl-1-methylxanthine (a phosphodiesterase inhibitor), 1H-[1,2, 4]oxadiazolo-[4,3-2]quinoxalin-1-one (ODQ, a guanylate cyclase inhibitor), SNAP plus ODQ, 8-bromo-cGMP (8-Br-cGMP, a cell-permeable cGMP compound), 8-Br-cGMP plus HGB, or inactive vehicle in order to discern the effect of cGMP. The incubations were conducted for 24 hours, and total nitrate plus nitrite production and eNOS protein abundance (Western analysis) were measured. To determine the effect of NO on eNOS expression in vivo, rats were treated with either the NO donor isosorbide dinitrate or placebo by gastric gavage for 48 hours, and aortic eNOS protein expression was examined. The NO donor SNAP markedly depressed, whereas the NO scavenger HGB significantly raised, eNOS protein expression. The downregulatory action of SNAP was completely abrogated by HGB. Phosphodiesterase inhibitor and 8-Br-cGMP downregulated, whereas the guanylate cyclase inhibitor ODQ upregulated eNOS protein expression. The downregulatory action of SNAP was completely overcome by the guanylate cyclase inhibitor ODQ, and the upregulatory action of the NO scavenger HGB was abrogated by 8-Br-cGMP. Administration of NO donor resulted in a marked downregulation of aortic eNOS protein expression in intact animals, thus confirming the in vitro findings. NO serves as a negative-feedback regulator of eNOS expression via a cGMP-mediated process.

1-Methyl-3-isobutylxanthine↗
PubMed2000

Inhibitory effects of stress-activated nitric oxide on antioxidant enzymes and testicular steroidogenesis.

The messenger role of nitric oxide (NO) in immobilization stress-induced inhibition of testicular steroidogenesis has been previously suggested. In accord with this, here, we show that the intratesticular injection of isosorbide dinitrate (ISDN; 2x2.5 mg/testis), an NO donor, mimicked the action of stress on serum testosterone concentrations and hCG-stimulated testosterone production in rat testicular tissue. When added in vitro, ISDN inhibited testicular 3beta-hydroxysteroid dehydrogenase and 17alpha-hydroxylase/lyase. Immobilization stress and injections of ISDN also decreased the activity of catalase, glutathione peroxidase, glutathione transferase, and glutathione reductase in the interstitial compartment of testis. When stressed rats were treated concomitantly with bilateral intratesticular injections of N(omega)-nitro-L-arginine methyl ester, a non-selective NOS inhibitor (2x600 microg/testis), the activities of antioxidative enzymes, as well as serum testosterone concentration, were partially normalized. These results indicate that stress-induced stimulation of the testicular NO signalling pathway leads to inhibition of both steroidogenic and antioxidant enzymes.

Animals↗
PubMed1995

Escalating nitrate dose overcomes early attenuation of hemodynamic effect caused by nitrate tolerance in patients with heart failure.

This study was performed to examine the hypothesis that an early attenuation of nitrate effect caused by nitrate tolerance can be overcome by dose increase. We compared hemodynamic effects of constant dose (40 to 120 mg) of oral isosorbide dinitrate (ISDN) given every 6 hours for three doses followed by 12 hours of nitrate washout interval with those of escalating dose (40 mg, 80 mg, and 120 mg) in two similar groups of patients with chronic congestive heart failure. Escalating ISDN dose resulted in a progressive increase in ISDN blood level and overcame early attenuation of effect occurring with a constant dose. At peak effect of the third ISDN dose, a significantly greater reduction was seen in mean right atrial pressure (-59% +/- 27% vs -20% +/- 22%, p < 0.01), mean pulmonary artery pressure (-29% +/- 11% vs -11% +/- 15%, p < 0.01) and mean pulmonary artery wedge pressure (-39% +/- 19% vs -19% +/- 23%, p < 0.05) with the escalating dose. These findings demonstrate that early attenuation of hemodynamic effect caused by nitrate tolerance can be overcome by dose escalation.

Adult↗
PubMed2003

Limitations of medical therapy in patients with pure coronary spastic angina.

OBJECTIVES: To assess the efficacy of medication for the treatment of pure coronary spastic angina, 71 consecutive patients with this diagnosis who had undergone coronary arteriography in a hospital with a follow-up of at least 2 years were studied. METHODS AND RESULTS: All 71 patients without significant organic stenosis were treated with long-acting calcium antagonists. The disappearance of chest pain attacks while receiving medical therapy was observed in 27 patients (38%), whereas the remaining 44 patients (62%) had chest pain attacks. Of special interest, 30 patients had more than one attack per month irrespective of the administration of calcium antagonists or isosorbide dinitrate. Medical treatment showed a good response in female patients (63% vs 31%, respectively; p < 0.05) and those with ST-segment elevation during selective spasm provocation tests (63% vs 30%, respectively; p < 0.05). In contrast, patients with a longer history of chest pain attacks before hospital admission and those with diffuse spasms (77% vs 34%, respectively; p < 0.01) had poor responses to medical treatment. In this study, neither sudden death nor acute myocardial infarction was observed during the follow-up periods. CONCLUSION: The limitations of medical therapy, including the administration of long-acting calcium antagonists, were observed in 30 of 71 patients (42%) with pure coronary spastic angina. Medical treatment was effective in only 38% of patients with pure coronary spastic angina in Japan.

Acetylcholine↗
PubMed1993

Nitrates improve detection of ischemic but viable myocardium by thallium-201 reinjection SPECT.

Thallium-201 reinjection imaging improves myocardial viability detection when compared to standard 3-4-hr redistribution imaging, however, the extent of ischemic but viable myocardium is still underestimated. We tested whether the sensitivity of reinjection imaging could be increased by giving nitrates postexercise to improve blood flow during the redistribution period. Twenty patients with coronary artery disease were included, 11 of them with a recent myocardial infarction. All patients underwent two exercise/4-hr redistribution 201Tl SPECT protocols: one with reinjection alone and the other with nitrates and reinjection. In the latter case, 20 mg of Isosorbide Dinitrate were given to patients immediately after postexercise imaging. Fifteen patients had reversible defects with reinjection alone, three additional patients were defined as ischemic with nitrates/reinjection protocol. Reinjection alone identified 41 reversible segmental defects, all except one were also evaluated as reversible with nitrates/reinjection. However, among the 54 segments showing fixed defects after reinjection only, 14 (26%) presented as reversible with the nitrates/reinjection protocol. The redistribution extent (segments/patient) was 2.05 +/- 0.41 segments with reinjection alone and 2.75 +/- 0.38 (p < 0.01) with nitrates/reinjection. In 15 patients showing reversible defects with both protocols, the redistribution extent was 2.73 +/- 0.41 segments with reinjection alone and 3.20 +/- 0.40 (p < 0.05) with nitrates/reinjection. Thallium-201 SPECT with nitrates and reinjection improves the detection of ischemic but viable myocardium in comparison to SPECT with reinjection alone.

Coronary Disease↗
PubMed1988

Effects of atrial natriuretic polypeptide and organic nitrates on levels of relaxation and cyclic nucleotide of canine coronary artery with and without endothelial injury.

We studied the effects of organic nitrates and human atrial natriuretic polypeptide (hANP) on relaxation and tissue cyclic guanosine monophosphate (cGMP) levels using isolated canine coronary arteries with and without endothelial injury. Glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), pentaerythritol tetranitrate (PETN), and hANP relaxed both the injured and control coronary arteries, and they increased tissue cGMP levels in a dose-dependent fashion without changing tissue adenosine 3':5'-cyclic phosphate (cAMP) levels. The extent of relaxation was larger and the increase in cGMP was greater in the injured coronary artery than in the control artery. Methylene blue inhibited relaxation induced by GTN and hANP, and decreased tissue cGMP levels in both the injured and control groups. M&B 22,948 enhanced relaxation induced by GTN and hANP and increased tissue cGMP levels in both groups. The results suggest that organic nitrates and hANP relax the coronary artery by directly activating the guanylate cyclase in coronary smooth muscle and that such activation is independent of the endothelium-dependent vasodilator system.

Animals↗
PubMedDate not supplied

Doppler flow wire evaluation of renal blood flow reserve in hypertensive patients with normal renal arteries.

PURPOSE: To study the vasomotor responses of the renal microcirculation in patients with essential hypertension. METHODS: We studied the reactivity of the renal microcirculation to papaverine, with intraarterial Doppler and quantitative arteriography, in 34 renal arteries of 19 hypertensive patients without significant renal artery stenosis. Isosorbide dinitrate was given to maximally dilate proximal renal arteries. APV (average peak blood flow velocity) was used as an index of renal blood flow. RESULTS: Kidneys could be divided into two distinct subgroups based on their response to papaverine. An increase in APV of up to 55% occurred in 21 kidneys, an increase > 55% in 13 kidneys. Within each group the values were normally distributed. Both baseline APV and the effect of papaverine on mean velocity differed significantly between groups. CONCLUSION: There seems to be a subgroup of patients with essential hypertension that has an impaired reactivity to papaverine, consistent with a functional impairment of the renal microcirculation. Further studies are required to determine whether this abnormality contributes to or results from elevated blood pressure.

Analysis of Variance↗
PubMed1999

Clinical experience of long-term transdermal treatment with nitric oxide donor for women with preeclampsia.

Isosorbide dinitrate (ISDN), a nitric oxide donor, was applied transdermally for 4-16 days to 4 preeclamptic women with oligohydramnios, intrauterine fetal growth retardation (IUGR), and elevated resistance of blood flow in the uterine arteries. Pulsed Doppler ultrasonography revealed immediate and drastic improvement of pulsatility index (PI) of uterine arteries following treatment with ISDN. The average PI in uterine arteries of the 4 patients was reduced to approximately 67% of that of the untreated state. In 2 patients the amniotic fluid gradually increased over a few days which suggested improvement of fetoplacental circulation during administration of ISDN. This study suggests that long-term transdermal ISDN is an effective therapy, at least in a portion of preeclamptic women, to avoid maternal hypertension, fetal distress, oligohydramnios, and IUGR, and consequentially to prolong the gestational period.

Administration, Cutaneous↗
PubMed1986

Effect of slow-release ISDN on cardiac function in patients with coronary heart disease during bicycle ergometry.

In 10 patients with coronary heart disease (CHD), the effect of a single doses of slow-release isosorbide dinitrate (ISDN) on cardiac function was investigated. Haemo-dynamics was examined by right heart catheterization and thermodilution measurement of cardiac output. After placebo and after 2 and 6 hours with 40 mg ISDN, the heart rate (HR), cardiac index (CI), pressure values in the pulmonary artery (PASP, PAMP, PAEDP) and in the aorta (AoSP, AoMP, AoEDP) and systemic vascular resistance (SVR) were measured at rest and during bicycle ergometry. At rest, PASP and PAMP were significantly reduced only 6 hours after ISDN. Under exercise conditions, significantly reduced pressure values in the pulmonary artery were found 2 and 6 hours after ISDN. AoSP was likewise reduced 2 and 6 hours after ISDN. HR, CI and SVR showed no significant differences compared with placebo values. Thus, an effective reduction of left ventricular preload and afterload was seen in patients with CHD during bicycle ergometry.

Adult↗
PubMed2003

Nitric oxide donors inhibit the coxsackievirus B3 proteinases 2A and 3C in vitro, virus production in cells, and signs of myocarditis in virus-infected mice.

The antiviral effect of nitric oxide (NO)-releasing compounds was investigated. Using bacterially expressed and purified proteinases 2A and 3C of coxsackievirus B3, in vitro assays demonstrated the inhibition of the 2A proteinase activity in the presence of S-nitroso- N-acetyl-penicillamine (SNAP), 3-morpholinosydnonimine (SIN-1), 4-phenyl-3-furoxancarbonitrile (PFC), glyceryl trinitrate (GTN), and isosorbide dinitrate (ISDN). Sodium nitroprusside (SNP), which releases NO after metabolization, had no effect. The 3C proteinase was inactivated by SNAP, GTN, and ISDN. The vasodilators GTN and ISDN, widely used in the treatment of angina pectoris, exhibited antiviral activity in CVB3-infected GMK cells. CVB3-infected NMRI outbred mice showed significantly reduced signs of myocarditis after treatment with GTN or ISDN. Inhibitors of the cellular inducible NO synthase (iNOS) such as N(G)-nitro-L-arginine methyl ester (L-NAME), N(G)-nitro-L-arginine (L-NNA), and S-methyl-isothiourea (SMT), had no deleterious effect on CVB3-infected NMRI mice, indicating that endogenous NO synthesis is unlikely to be a major defense mechanism after enterovirus infection of outbred mice.

3C Viral Proteases↗
PubMed1980

[Comparative study of three oral nitrate derivatives. A hemodynamic assessment in 10 patients with chronic heart failure (author's transl)].

The efficacy of three long-acting, orally administered nitrate derivatives was assessed in 10 patients with chronic heart failure. The compounds were: isosorbide dinitrate (ID) 5 mg, nitroglycerin microcapsules (NGMC) 7.5 mg and pentaerythritol tetranitrate (PETN) 160 mg. Pulmonary blood pressures were measured at regular intervals until the 6th hour following oral administration of all three compounds successively to 7 patients and of two compounds (ID and NGMC) to 3 patients. In addition, a hemodynamic study was performed in 3 of these patients while under placebo. The results showed a significant decrease in pulmonary artery diastolic pressure with all three compounds. The effects appeared after 30 minutes with ID and NGMC and after 1 hour with PETN. They lasted 1 hour with ID and 3 to 4 hours with NGMC and PETN. Maximal effect occured at 1 hour with ID (-28%; p < 0.001), at 1.5 hour with NGMC (-18%; p (< 0.01) and at 3 hours with PETN (-21%; p <0.01).

Administration, Oral↗
PubMed1981

Pharmacokinetics of intravenous and oral isosorbide - 5 - mononitrate.

The pharmacokinetics of isosorbide-5-mononitrate (IS-5-MN) has been studied in two groups of healthy volunteers after oral (n = 20) and intravenous (n = 11) administration of 20 mg, which had previously been proved to be as effective as 20 mg sustained-release isosorbide dinitrate (ISDN). IS-5-MN in serum was measured by gas chromatography using capillary columns. The kinetic calculations were carried out with a newly developed model, which assumes a virtual volume of distribution dependent on time. IS-5-MN is rapidly (invasion half-life 4.1 min) and completely absorbed from the gastro-intestinal tract without any first pass metabolism. The maximum concentration of 480 micrograms/l was reached 1.2 h after oral administration of 20 mg. The substance was distributed throughout the total body water (distribution coefficient: 0.62), and was eliminated with a terminal t1/2 of 4.1 and 4.6 h after oral and intravenous administration, respectively. Total body clearance was 115ml/min. Thus, IS-5-MN is unlike ISDN with respect to the absence of first-pass metabolism and an 8-times longer half-life. The consequences for therapy are discussed.

Administration, Oral↗
PubMed1983

[Does long term treatment with high dose nitrates affect prognosis in coronary heart disease?].

The daily dose of nitrates was determined in 293 patients who had undergone coronary angiography seven years earlier. A questionnaire was filled out by those still living; medical records and information provided by family physicians were used for those who had died during the intervening period. The dose could be ascertained in a total of 168 patients. Patients were divided into two groups: in group I were those with a daily isosorbide dinitrate dose of less than 40 mg (n = 46), in group II those with a dose greater than 40 mg (n = 72). 56 patients had died. Two-thirds of them had been on the low-dose regimen, whereas only one-third were in the high-dose group. The extent of ventricular impairment was comparable in both groups. Seven-year mortality in group I was 39% with a mean daily nitrate dose of 14 mg. In group II, however, only 26% died with a mean daily dose of 55 mg. The difference can already be seen during the first year. Age, extent of coronary sclerosis, degree of ventricular damage, and cardiac size were identical in both groups. Thus mortality rate in group II was reduced by 30-40%. A causal relation to the height of the nitrate dose should be considered.

Aged↗
PubMed1981

Determinants of drug response in severe chronic heart failure. 1. Activation of vasoconstrictor forces during vasodilator therapy.

Vasodilator drugs activate neurohumoral forces that produce peripheral vasoconstriction and tachycardia and probably cause the rebound events observed upon abrupt withdrawal of therapy. To determine their role in limiting therapeutic vasodilator responses, these reactive forces were measured in 40 patients with severe chronic heart failure by quantifying the magnitude of rebound change (MRC) after nitroprusside withdrawal. Group 1 patients (n = 22), who had minimal reactive vasoconstriction (MRC less than or equal to 27%), showed marked hemodynamic effects with nitroprusside (4.5 microgram/kg/min) and isosorbide dinitrate (40 mg orally), associated with significant decreases in heart rate with both drugs (p less than 0.001). Despite administration of the same doses of both drugs, group 2 patients (n = 18), who had marked rebound changes (MRC greater than 27%), showed significantly smaller changes in cardiac index, systemic vascular resistance and mean arterial pressure (p less than 0.001), associated with no change or increases in heart rate. Rebound events were attenuated and the responses to nitroprusside and nitrates were enhanced in four patients in whom these drugs were readministered after pretreatment with i.v. phentolamine (0.3mg/min). We conclude that activation of neurohumoral forces can limit the hemodynamic responses to vasodilator administration; this supports the use of combination therapy of direct-acting vasodilators and neurohumoral antagonists in selected patients with severe chronic heart failure.

Administration, Oral↗
PubMed1980

Effects of vasodilators on renal function in severe heart failure.

UNLABELLED: Changes in renal function associated with heart failure (HF) and the response to vasodilator therapy were investigated in 21 patients (pts) with ischemic heart disease. Serial measurements of systemic arterial pressure (AP), pulmonary arterial end diastolic pressure, cardiac index (CI) and effective renal plasma flow (ERPF) were obtained before and after isosorbide dinitrate (ISD) or prazosin (PZ). Baseline ERPF values measured by 131-I-orthoiodohippurate clearance correlated well with CI (r = 83). Pts with low ERPF (< 300 ml/min) had an increase of 20 to 80% in response to vasodilatation. This improvement in ERPF was not dependent on an increase in the Cl. Pts on nonic ISD/PZ with systolic AP < 90 mmHg developed edema and ascites that responded to spironolactone. These data indicate that vasodilators can significantly improve ERPF in pts with low Cl and suggests a specific beneficial effect on the renal vascular bed. SUMMARY: In pts with low cardiac output HF : 1) the ERPF is reduced in proportion to the Cl; 2) vasodilation will improve ERPF independently of the cardiac response although; 3) persistent hypotension and vasodilation may result in a clinical picture of secondary hyperaldosteronism.

Adult↗
PubMed1989

Sustained effect of and lack of development of tolerance to controlled-release isosorbide-5-mononitrate in chronic stable angina pectoris.

Tolerance has been shown to develop when nitrate preparations are used in such a manner as to produce plasma levels within the therapeutic range continuously over a 24-hour period. However, a period of reduced or low nitrate plasma levels of a few hours per day may limit or completely prevent tolerance development. In 18 patients with chronic stable angina pectoris, a single 60-mg daily dose of a controlled-release preparation of isosorbide-5-mononitrate (ISMN) was compared with the administration of 30 mg, 4 times daily, of immediate-release isosorbide dinitrate (ISDN) in a double-blind, randomized, placebo-controlled, crossover study. The comparisons were carried out on the first day of therapy and after 11 to 14 days of continuous therapy to assess the duration of effectiveness and the development of tolerance. On short-term therapy, both drugs produced a significant improvement in treadmill walking times to moderate angina in comparison with placebo. The values for ISMN were 87 +/- 99 seconds (23%) at 12:30 P.M., 72 +/- 91 seconds (19%) at 5 P.M. and 51 +/- 81 seconds (13%) at 8:30 P.M. For ISDN, the respective values were 71 +/- 83 seconds (19%), 89 +/- 98 seconds (24%) and 79 +/- 87 seconds (21%). There were no significant differences between drugs. Plasma nitrate levels for each drug paralleled the improvements in exercise performance.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗