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PubMed2006

Nitric oxide and prostacyclin pathways: an integrated mechanism that limits myocardial infarction progression in anaesthetized rats.

Nitric oxide (NO) and cyclooxygenase-derived prostaglandins, such as prostacyclin (PGI2), are involved in vascular homeostasis. To better understand the reciprocal role of both NO and PGI2 on myocardial infarction in the rat, we have investigated the cardioprotective effect of nitro-naproxen, isosorbide dinitrate (ISDN), L-arginine, defibrotide and naproxen. In this study, male Wistar rats were treated orally once a day for 5 consecutive days with the compounds under investigation and then, under anesthesia, the animals were subjected to acute myocardial ischemia (30 min) and reperfusion (120 min). Systemic blood pressure, left ventricular pressure and related parameters of cardiac mechanics were recorded. Ventricular arrhythmias and infarct size of the left ventricular wall were also evaluated. Furthermore, cardiac myeloperoxidase (MPO) and plasma creatine phosphokinase (CPK) activities were determined. Defibrotide, nitro-naproxen, ISDN and L-arginine all provided a cardioprotection characterized by significant prevention of arrhythmias with high survival rate of the rats. Infarct size restriction was paralleled by reduction of both cardiac MPO and plasma CK. Cardioprotection of nitro-naproxen, ISDN and L-arginine involve nitrites/nitrates and PGI2-increased in the circulation associated to a reduction of thromboxane B2 (TXB2) in the blood. Defibrotide displays a cardioprotection by increasing PGI2 release and by reducing TXB2 in the blood. Naproxen was devoid a lower protecting activity on myocardial infarction, and PGI2 inhibition may have played a critical role in this context. The results suggested that the increase of both NO and PGI2 brings about a cascade of integrated cellular and molecular events which are of paramount importance in prevention of myocardial ischemic insult.

Animals↗
PubMed2001

Effect of obesity on endothelium-dependent, nitric oxide-mediated vasodilation in normotensive individuals and patients with essential hypertension.

The purpose of this study was to determine the interdependent and independent effects of hypertension and obesity on endothelial function in humans. We evaluated the forearm blood flow (FBF) response to acetylcholine, an endothelium-dependent vasodilator, and isosorbide dinitrate (ISDN), an endothelium-independent vasodilator, in 16 lean and 12 obese normotensive individuals and the 18 lean and 15 obese hypertensive patients with no history of smoking, hypercholesterolemia, diabetes mellitus, or renal dysfunction. The FBF was measured using a mercury-filled Silastic strain-gauge plethysmograph. The systolic and diastolic blood pressures (BP) and forearm vascular resistance were significantly greater in hypertensive patients than in the normotensive individuals. Insulin resistance, determined by a homeostatic model assessment (HOMA), was significantly greater in the obese group than in the lean group (3.59 +/- 1.68 v 1.91 +/- 1.12, P < .01). There was no significant difference in the HOMA index between normotensive and hypertensive subjects regardless of weight. The response of FBF to acetylcholine was greatest in lean normotensive individuals and least in obese hypertensive patients (40.5 +/- 8.5 and 10.4 +/- 2.8 mL/min/100 mL of tissue, P < .001 v other groups). The FBF response was similar in obese normotensive individuals and lean hypertensive patients (24.1 +/- 7.9 and 19.3 +/- 3.2 mL/min/100 mL of tissue). The vasodilatory effect of ISDN was similar in all four groups. Multiple regression analysis revealed that the maximal FBF response to acetylcholine correlated independently with age (P = .043), obesity (P = .012), HOMA index (P = .002), and mean BP (P < .001). These findings suggest that obesity and hypertension are independently involved in abnormal endothelium-dependent vasodilation by attenuated nitric oxide production.

Acetylcholine↗
PubMed1982

Unloading effects of vasodilators on peripheral circulation and cardiac hemodynamics in patients with acute myocardial infarction.

Effects of three representative vasodilators on peripheral and cardiac hemodynamics were studied in 20 patients with heart failure due to acute myocardial infarction (PCWP greater than 18 mmHg, C1 greater than 2.20 L/min/m2) using venous occlusion plethysmography and a Swan-Ganz catheter. Sublingual isosorbide dinitrate (ISDN) significantly increased calf venous capacitance (CVC) from 5 to 60 min (p less than 0.01) and calf blood flow (CBF) in the initial 15 min (p less than 0.05), while simultaneously lowering PCWP (p less than 0.05) and central venous pressure (p less than 0.05). Calf vascular resistance (CVR), cardiac index, blood pressure, and total systemic peripheral resistance (TSPR) were not affected significantly. Nitroglycerin ointment (NGO) significantly decreased CVR (p less than 0.05) and increased CVC (p less than 0.05) from 60 to 240 min, simultaneously with lowering of PCWP (p less than 0.01), central venous pressure (p less than 0.05), and TSPR (p less than 0.05). Oral prazosin (Pz) increased CBF (p less than 0.01) and CVC (p less than 0.05) from 60 to 240 min, simultaneously with significant lowering of PCWP (p less than 0.01) and TSPR (p less than 0.05), resulting in increased stroke work index (p less than 0.05). These data confirm that ISDN predominantly causes capacitance vessel dilatation and reduce excessive venous return, while Pz and NGO dilate not only capacitance vessels but also resistance vessels, consequently reducing systemic vascular resistance and resulting in increased peripheral blood flow and cardiac performance. It was observed that the higher the base-line calf vascular resistance rose, the better the response to the vasodilator treatment appeared in terms of a decrease in calf vascular resistance.

Adult↗
PubMed2000

Three minute, but not one minute, ischemia and nicorandil have a preconditioning effect in patients with coronary artery disease.

OBJECTIVES: This study focused on 1) the determination of the optimal preconditioning (PC) duration, and 2) the protective effect of nicorandil (NC), a hybrid nitrate with a KATP channel opening effect, during a percutaneous transluminal coronary angioplasty (PTCA) model in humans. BACKGROUND: The ischemic PC effect is induced in 180 s ischemia, but not in 120 s ischemia in rabbit hearts. However, the duration of ischemia that induces PC effect and the role of the KATP channel in the PC effect in humans are still unclear. METHODS: Forty-six patients with stable angina were randomly allocated to four groups: the duration of the first inflation as PC ischemia was 60 s in the PC60 group (n = 12), and 180 s in the PC180 group (n = 12). In the other groups, NC (80 microg/kg) was intravenously given for 1 min in the NC group (n = 12), and isosorbide dinitrate (ISDN) (40 microg/kg) was given in the ISDN group (n = 10). Five minutes after first inflation or drug administration, a second inflation was conducted for 120 s in each group. In the ECG, the lead with the largest shift in ST segment (deltaST max), and the sum of elevated ST levels in all leads (sigmaST) were determined. RESULTS: In the PC60 group, no significant difference was observed in either deltaST max or sigmaST between the first and second inflation. However, the second inflation in the PC180 group showed significantly lower levels of deltaST max and sigmaST compared with those of the first inflation. In the NC group, both deltaST max and sigmaST measured at 30 s and 60 s after balloon inflation were significantly lower than those of the first inflation in the PC60 and PC180 control groups. In the ISDN group, no significant difference was observed in deltaST max or sigmaST. CONCLUSION: In human PTCA models, a PC effect is observed in 180 s ischemia, but not in 60 s ischemia. A pharmacological PC effect is induced by NC, a KATP channel opener with a nitrate-like effect but not ISDN. This suggests that the opening of KATP channels plays an important role in the protecting effect of NC.

Angina Pectoris↗
PubMed1991

Angiographic evolution of coronary atherosclerosis in patients receiving propranolol. A two-year follow-up.

STUDY OBJECTIVE: To test whether propranolol may influence the progression of coronary atherosclerosis. DESIGN: Repeat coronary angiography after two year treatment and evaluation of changes in coronary narrowings. SETTING: Subjects with effort angina of recent onset requiring coronary angiography and medical treatment. PATIENTS: 80 untreated patients, with a greater than or equal to 50 percent focal narrowing on a major coronary branch associated or not with a less than 50 percent stenosis of other major branches. They were randomized to isosorbide dinitrate (40 mg bid) (group 1, control group) or to propranolol (80 mg qid) (group 2, treatment group). RESULTS: At restudy, there were more diseased vessels and These narrowings per patient in both groups. Multivessel involvement and greater than or equal to 50 percent obstructions were also augmented. These changes were not statistically significant. Patients with progression of the stenotic tracts (both greater than or equal to 50 percent and less than 50 percent were 19 (48 percent) in group 1 and 28 (70 percent) in group 2 (p less than 0.05). Narrowings with progression were 25 in group 1 and 48 in group 2. Thirteen narrowings in group 1 and 15 in group 2 were newly detected at restudy. Eighteen patients (45 percent) in group 1 and nine (23 percent) in group 2 had a steady disease. Smoking, high blood pressure, family history of coronary disease, blood glucose values and lipid levels were considered; the only significant group differences were 31 percent rise of total triglyceride and 23 percent decrease of HDL cholesterol in patients who were treated with propranolol. CONCLUSIONS: Propranolol showed an adverse influence on coronary atherosclerosis, regarding the evolution of both greater than or equal to 50 percent and less than 50 percent narrowings and not the formation of new stenoses. Changes in serum lipid values might have a role.

Angina Pectoris↗
PubMed1984

Blood vessel uptake and metabolism of organic nitrates in the rat.

Recent reports have suggested that the unusual pharmacokinetics observed for nitroglycerin (NTG) and isosorbide dinitrate (ISDN) may be partially explained by extensive uptake and/or metabolism of these drugs by vascular and other extrahepatic tissues. Using the rat as an animal model, this hypothesis was examined by in vivo intravessel NTG and [14C]ISDN infusion and injection into various vessel segments, viz. the femoral vein, inferior vena cava [IVC: lower, middle and upper) and the aorta. NTG and [14C]ISDN concentrations were determined in these blood vessels and in plasma. Blood vessel segments nearest the input site had the greatest amounts of nitrate, whereas segments further away from the input site had progressively less nitrate, with the exception of aorta, which appeared to take up NTG less extensively, on a per weight of vessel basis, than the IVC. Blood vessel NTG concentrations (nanogram per gram) were generally higher (10-fold) and declined about twice as slowly as NTG plasma concentrations (nanograms per milliliter). [14C]NTG and [14C]ISDN were also incubated with cofactors in IVC, aorta, abdominal muscle, lung and liver. The amounts of nitrate metabolites formed from parent drug were larger in each extrahepatic tissue incubation than in the controls (P less than .05). The results are consistent with the hypothesis that vascular and other extrahepatic tissues can take up and/or metabolize organic nitrates. The data appear to provide a partial explanation for the large systemic clearance seen with nitrates and appear consistent with existing mechanistic hypotheses for the vascular action of these compounds.

Animals↗
PubMed1996

Regulation of endothelin receptors by nitric oxide in cultured rat vascular smooth muscle cells.

Two important mediators of endothelium-dependent regulation of vascular smooth muscle tone and proliferation are nitric oxide (NO) and endothelin (ET-1). An imbalance between NO and ET-1 may contribute to the alterations in vascular tone characteristic of cardiovascular disease. The objective of this study was to determine whether NO regulates ET receptors in cultured rat superior mesenteric artery vascular smooth muscle cells (RVSMC). Chronic treatment of quiescent RVSMC with any one of three chemically dissimilar NO-generating drugs, S-nitroso-N-acetyl penicillamine (SNAP), sodium nitroprusside (SNP), and isosorbide dinitrate (ISDN) produced a significant dose- and time-dependent increase in the number of ET-A receptors, while concomitantly increasing the affinity of ET-1 for this receptor. This effect was mimicked by both 8-bromo-cGMP and 8-bromo-cAMP. The requirement of both protein and RNA synthesis and activation of a cAMP-dependent protein kinase (A-kinase) was demonstrated following inhibition of this regulation by cycloheximide, actinomycin D and KT5720 (a specific A-kinase inhibitor), respectively. In addition, the cytokine interleukin 1 beta (IL-1 beta) which induced NOS activity with subsequent NO synthesis in vascular smooth muscle, also caused a similar upregulation of ET receptors. This effect was attenuated in the presence of the specific NOS inhibitor, L-NAME. To assess the possible functional consequences of this NO-mediated upregulation, the effect of SNAP pretreatment on isolated vessel reactivity was determined. In both superior mesenteric artery and thoracic aorta rings, SNAP pretreatment caused a significant increase in the maximal force of contraction to ET-1. Collectively, these data suggest that NO regulates ET-A receptors in vitro through a cGMP-dependent mechanism via activation of the cAMP-dependent protein kinase. We conclude that a similar interaction between NO and ET-1 may be operational in vivo.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2001

Dobutamine as bridge to angiotensin-converting enzyme inhibitor-nitrate therapy in endstage heart failure.

BACKGROUND: Intravenous inotropic intervention in congestive heart failure is generally associated with a poor prognosis and is largely used as a "bridge" to mechanical support or heart transplantation. HYPOTHESIS: We hypothesized that the inotropic support afforded by dobutamine may serve as a bridge to the introduction and intensification of angiotensin-converting enzyme (ACE) inhibitor-nitrate therapy. METHODS: We studied the efficacy of transitioning inotrope-dependent patients in endstage heart failure from intravenous dobutamine to high-dose ACE inhibitor-nitrates, with 1-year follow-up. Forty-nine sequential dobutamine-dependent patients with left ventricular ejection fraction (LVEF) 17+/-17% were treated with increasing lisinopril (1.9+/-1.5 to 46+/-28 mg/day) and isosorbide dinitrate (7+/-6 to 229+/-161 mg/day). Outpatient dobutamine was continued or repeat infusions pursued, as indicated, and dobutamine was tapered when feasible. RESULTS: During the following year, 14 of 49 patients required repeat dobutamine, with home treatment with dobutamine for 6.3+/-3.7 months (n = 5). At 1 year, New York Heart Association (NYHA) classification improved from 3.6+/-0.5 to 1.9+/-1.0, p < 0.0001; yearly hospitalizations fell from 2.7+/-2.3 to 1.2+/-3.0, p = 0.02; and LVEF rose from 17+/-7% to 24+/-11%, p < 0.0001. At 1 year, 14 patients who remained dobutamine dependent had significantly more severe symptoms than dobutamine-independent patients (n = 35). Transplant or death occurred in 7 of 14 patients with follow-up dobutamine, and in 5 of 35 patients free of subsequent dobutamine, p = 0.03. Patients with poor outcome (transplant n = 10, death n = 12) continued to be more limited (NYHA 2.7+/-0.9 vs. 1.7+/-0.9, p = 0.0002), with more follow-up hospitalizations (3.6+/-5.4 vs. 0.6+/-0.8, p = 0.0004), and no improvement in LVEF (17+/-8vs. 28+/-11%, p = 0.003). CONCLUSIONS: Of the patients on dobutamine inotropic support, 70% were successfully transitioned to ACE inhibitor-nitrate therapy, with improved symptoms and LVEF, and with reduced hospitalizations and follow-up dobutamine or transplant. Thirty percent of patients with continued need for dobutamine had a significantly poorer 1-year clinical outcome.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1986

Acute and sustained effects of isosorbide 5-mononitrate in stable angina pectoris.

Isosorbide 5-mononitrate (IS 5-MN) is an active metabolite of isosorbide dinitrate and is widely used as an antianginal agent. The acute and subacute (2 weeks) effects of IS 5-MN, 40 mg twice daily, were evaluated in 18 patients with stable angina pectoris using computerized exercise testing and a placebo-controlled, double-blind, randomized trial protocol. There were 2 phases of 2 weeks each in which patients received placebo or active IS 5-MN. Acute testing (8 patients) was performed 2 hours after the first dose and subacute testing 2 hours after the morning dose on day 14. Acute testing showed an increase in exercise time from a mean (+/- standard error of mean) of 8.2 +/- 0.6 minutes to 11.1 +/- 0.5 minutes (p less than 0.001) after a single dose of IS 5-MN. Time to 1 mm of ST depression increased significantly and peak exercise ST-segment depression decreased significantly. Rest and peak exercise heart rate increased significantly during acute testing with IS 5-MN; blood pressure did not change significantly. After 2 weeks of therapy, exercise time had not changed (9.9 +/- 0.6 with placebo to 9.7 +/- 0.6 minutes). The beneficial effects on ST-segment variables were sustained at 2 weeks. The data suggest that there is an attenuation of effect with respect to exercise time and sustained beneficial effect on the ST-segment variables. This may be a result of development of partial tolerance to IS 5-MN after 2 weeks of therapy.

Adult↗
PubMed1992

[Analysis of circulatory responses to orthostatic stress in the elderly].

An active orthostatic stress test was conducted on 32 elderly patients over 65 years (elderly group) and 17 normal adults, for a comparative evaluation of their blood pressure, heart rates, and plasma catecholamine responses. In addition, 8 patients in the elderly group underwent a study of orthostatic responses with or without sublingual administration of isosorbide dinitrate (ISDN). The results of the orthostatic responses were evaluated by Schellong's method. The elderly group produced a positive reaction in one (3.1%), and a weakly positive reaction in two (6.3%), while the remaining 29 (90.6%) and all of the normal adults showed negative responses. The systolic blood pressure pattern that developed in response to rising among the elderly group was significantly different (p less than 0.001) from that of the normal adult group, but the response pattern seen in the heart rates of the former approximated that of the latter. The plasma norepinephrine concentration 10 minutes after rising increased significantly (p less than 0.001) in both the elderly and normal adult groups. This increase amounted to 1.5-fold in the elderly group and 2-fold in normal subjects, with a less prominent increase shown by the elderly. The norepinephrine levels of the elderly group were significantly higher than those of the normal adults both before and 10 minutes after rising (p less than 0.001 and p less than 0.01, respectively). In the elderly, ISDN caused a significant drop in the systolic blood pressure immediately after rising and a significant increase in the heart rate. Sublingual ISDN administration resulted in a significant increase in the norepinephrine level (p less than 0.05) in association with rising. These findings indicated that the circulatory responses to orthostatic stimuli are inappropriate as clinical data among the elderly and the administration of ISDN exaggerates this shortcoming further.

Aged↗
PubMed1989

Reduction of portal pressure by isosorbide-5-mononitrate in patients with cirrhosis. Effects on splanchnic and systemic hemodynamics and liver function.

The results of a study to characterize the effects of the oral administration of isosorbide-5-mononitrate (Is-5-Mn), the active metabolite of isosorbide dinitrate, on portal hypertension in 23 patients with cirrhosis are reported. Patients received 20 mg of Is-5-Mn (n = 10), 40 mg (n = 9), or a placebo (n = 4). No significant changes were observed after the administration of the placebo. However, both doses of Is-5-Mn significantly reduced portal pressure, as evaluated by measurements of the hepatic venous pressure gradient. The fall in portal pressure averaged 10% after the 20-mg dose and 18% after 40 mg and was maintained for the 2 h of observation. Reduction of portal pressure was due to a decrease in the wedged hepatic vein pressure, with no changes in the free hepatic venous pressure. After the 20-mg dose, the decrease in portal pressure was associated with an increase in hepatic blood flow (16%), suggesting a fall in hepatic vascular resistance. However, after the 40-mg dose, a reflex splanchnic vasoconstriction elicited by the fall in arterial pressure (-19%) appeared to contribute to the greater reduction in portal pressure, as suggested by a significant decrease in azygos blood flow (-15%). These beneficial effects on portal pressure were not associated with adverse effects on liver function, as evaluated by measurements of the hepatic clearance of indocyanine green and the hepatic intrinsic clearance. Neither dose of Is-5-Mn caused significant changes in these quantitative parameters of liver function. These findings suggest that Is-5-Mn could be a potentially useful and safe agent in the treatment of portal hypertension.

Adult↗
PubMed2003

Low body mass index is a risk factor for impaired endothelium-dependent vasodilation in humans: role of nitric oxide and oxidative stress.

OBJECTIVES: The purpose of this study was to evaluate the relationship between body mass index (BMI), including low BMIs, and endothelial function. BACKGROUND: Epidemiologic study has demonstrated that not only obesity but also a low BMI may be a risk factor for cardiovascular disease. METHODS: The forearm blood flow (FBF) response to acetylcholine (ACh) and isosorbide dinitrate (ISDN) was measured in 87 healthy young men (15 low BMI, 51 normal, 14 obese, and 7 extremely obese). RESULTS: Plasma concentrations of 8-hydroxy-2'-deoxyguanosine and serum concentrations of malondialdehyde-modified low-density lipoprotein were higher in low BMI, obese, and extremely obese subjects than in normal subjects and were similar among the low BMI, obese, and extremely obese groups. The FBF response to ACh was greater in the normal group than in the other groups (p < 0.001), and was lower in the extremely obese group as compared with the other groups (p < 0.001). The ACh-stimulated vasodilation was similar between the low BMI group and the obese group. The ISDN-stimulated vasodilation was similar in all four groups. There were no significant differences in ACh-stimulated vasodilation between the four groups after the nitric oxide (NO) synthase inhibitor NG-monomethyl-L-arginine infusion. Co-infusion of vitamin C augmented the FBF response to ACh in low BMI, obese, and extremely obese groups--but not in normal BMI group. CONCLUSIONS: These findings suggest that not only obesity but also a low BMI may be a risk factor for impaired endothelium-dependent vasodilation through the increased oxidative stress, leading to the reduced bioavailability of NO.

Acetylcholine↗
PubMed1983

Long-term responses to nifedipine in patients with coronary spasm who have an initial favorable response.

Twenty-six patients with angina and coronary spasm participated in a randomized crossover trial comparing nifedipine with isosorbide dinitrate. Eighteen patients had a short-term beneficial response to nifedipine, and 14 of these were followed up for an average period of 9.4 months. During follow-up study, nifedipine was the primary therapy in these 14 patients, but other drugs were added when clinically necessary to control angina. There was an overall 86% beneficial response rate (greater than 50% decrease in angina frequency). However, 2 patients had a large increase (greater than 10 times) and 4 patients had a slight increase (transient) in angina frequency over the long term compared with the short-term response. The other 8 patients had a similar angina frequency compared with the short-term response. Of the 12 patients with a good response (transient slight increase or no change), 8 (67%) required additional drug therapy to maintain angina control. Nifedipine was discontinued in 2, and the dose was decreased in 3 of the 14 patients because of adverse effects. Three patients had a marked increase in angina at 9, 14, and 3 months, requiring hospitalization; 1 patient had coronary bypass for symptom control. Thus, patients with coronary spasm selected because of a favorable short-term response to nifedipine were effectively treated over the long term with nifedipine; however, additional therapy was often needed to control symptoms. Adverse effects were common, but simple reduction of nifedipine dose usually diminished the unwanted effects of the drug.

Angina Pectoris↗
PubMed2000

Statistical methods to improve the precision of the treadmill exercise test.

OBJECTIVES: The study systematically compared different measures of ST segment depression from the treadmill exercise test. BACKGROUND: The value of the treadmill exercise test for objectively measuring treatment effects is limited by random error in the measurement of ST depression and may be biased by regression to the mean or by the decision to terminate the test. METHODS: Treadmill exercise was performed in 21 subjects with ischemic heart disease 1 h after isosorbide dinitrate 10 mg or placebo in a double-blind randomized crossover study. A 12-lead electrocardiogram (ECG) was recorded every 30 s during and at peak exercise. The relative sample size needed to detect the nitrate effect was compared for different summary measures of ST depression. RESULTS: The ST depression measured from a single unmatched lead at longest equivalent sub-maximal exercise needed the lowest sample size to detect the nitrate effect in paired comparisons (p = 0.000006). Averaging over multiple leads or times did not improve detection of the nitrate effect. The rate of increase in ST depression (in mm/min) calculated by linear regression needed a similar sample size (x1.32, 95% CI 0.62 to 2.58). A larger sample size was needed for ST depression at peak exercise (x2.9, CI 1.3, 11.1) and exercise duration (x4.5, CI 1.5, 38). Time to 1-mm ST depression was the least efficient measurement (relative sample size x15.5, CI 1.6, >1,000). Comparison of matched leads resulted in >2-fold differences in estimates of the nitrate effect because of bias from regression to the mean. CONCLUSIONS: Maximal ST depression at longest equivalent sub-maximal exercise and the maximal rate of increase in ST depression had less bias and random variation than did other commonly used measures. The rate of increase in ST depression is preferred because it can be calculated in either paired or unpaired studies.

Administration, Oral↗
PubMed2002

African-American Heart Failure Trial (A-HeFT): rationale, design, and methodology.

BACKGROUND: Hydralazine and isosorbide dinitrate combination (H+ISDN), angiotensin-converting enzyme inhibitors, and beta-blockers have improved outcomes in heart failure (HF). Analysis of previous trials has shown that H+ISDN appears especially beneficial in African American patients. METHODS AND RESULTS: The African-American Heart Failure Trial (A-HeFT) is double-blind, placebo-controlled, and includes African American patients with stable New York Heart Association Class III-IV HF on standard therapy. Patients must have prior HF-related events and left ventricular ejection fraction (LVEF) < or = 35% or LVEF <45% with left ventricular internal diastolic dimension >2.9 cm/m(2). Randomization to addition of placebo or BiDil (Nitro Med, Inc., Bedford, MA), a fixed combination of H+ISDN, is stratified for beta-blocker usage. All patients are treated and followed until the last patient entered completes 6 months of follow-up. The primary efficacy endpoint is a composite score including quality of life, death, and hospitalization for HF. At least 600 patients will be randomized; the first was randomized in June 2001. CONCLUSIONS: In addition to providing additional information on BiDil efficacy in HF, A-HeFT is the first HF trial aimed at a selected subgroup of patients and the first to use a new composite HF score as its primary efficacy endpoint.

Adolescent↗
PubMed1988

[New approaches to the study of the mechanism of action of nitrates].

The effects of nitrates on a Ca+2 increase and the content of cyclic nucleotides in human platelets were studied. Nitroglycerin (GTN), isosorbide dinitrate (ISDN) and sodium nitroprusside (NP) were found to inhibit dose-dependently the intracellular Ca+2 increase induced by the platelet activating factor (PAF). The inhibiting effect of NP was at lower concentrations than those of GTN and ISDN. GTN calcium blocking action did not change significantly regardless of vasopressin, serotonin or PAF used as inducers of the intracellular Ca+2 increase. GTN suppressed the PAF provoked Mn+2 entering into the cells. NP and GTN induced increase of the cGMP content correlated with their calcium blocking activity. They did not augment the level of cAMP. Methylene blue (MB), a guanylate cyclase and glutathione reductase inhibitor, decreased the calcium blocking effect of GTN and its influence on the cGMP content but failed to suppress the inhibitory effect of NP. Ascorbic acid increased the calcium blocking effect of NP but did not influence the inhibitory effect of GTN. An increase in Ca+2 content induced by PAF in platelets from patients with chronic congestive heart failure was significantly higher in the group with dilatation cardiomyopathy. The effect of 10 mg of ISDN sublingually on forearm venous tone was higher in patients with initially elevated venous tone. There was a direct statistical correlation between the IC50 of GTN calcium blocking effects in platelets and the elevation of a forearm venous tone reaction from a statistic mean reaction to ISDN.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Platelets↗
PubMed1997

Comparison of coronary flow reserve between focal and diffuse vasoconstriction induced by ergonovine in patients with vasospastic angina.

Decreased coronary flow reserve has been reported in patients with ergonovine-induced coronary vasoconstriction by the thermodilution method. To assess the difference of coronary flow reserve between patients with focal and diffuse vasospasm, after the vasospasm is discontinued by injection 3 mg of isosorbide dinitrate, phasic flow velocities of the diseased coronary artery were recorded at rest and during hyperemia (140 microg/kg/min of adenosine infusion intravenously) using a 0.014-inch, 15-MHz Doppler guidewire in 26 patients with ergonovine-induced coronary vasospasm (0.2-mg ergonovine injection intravenously), including 12 patients with focal (>90% stenosis), 14 patients with diffuse vasospasm (>50%), and 11 controls with normal coronary arteries without vasospasm. Although time-averaged peak velocity in cases with diffuse and focal vasospasm was not significantly different compared with that in controls at baseline (22 +/- 7, 18 +/- 5 vs 20 +/- 7 cm/s, respectively, NS), it was significantly lower in patients with diffuse vasospasm than in cases with focal vasospasm and in controls during hyperemia (43 +/- 13 vs 64 +/- 18, 61 +/- 19 cm/s, respectively, p <0.01). As a result, coronary flow reserve obtained from the ratio of hyperemic/baseline time-averaged peak velocity was significantly lower in patients with diffuse vasospasm than that in controls (1.9 +/- 0.4 vs 3.1 +/- 0.4, p <0.01), although it was not significantly different between the subjects with focal vasospasm and controls (3.5 +/- 0.7 vs 3.1 +/- 0.4, NS). Thus, coronary flow reserve is maintained normally in patients with focal vasospasm and limited in those with diffuse vasospasm. Microvascular impairment could exist further in cases with diffuse vasospasm, although similar endothelial dysfunction of the epicardial coronary artery is observed in focal and diffuse vasospasm.

Adult↗
PubMed1983

Unloading effects of molsidomine on peripheral circulation and cardiac hemodynamics in patients with acute myocardial infarction.

The unloading mechanisms and side of peripheral action of the new antianginal drug molsidomine was compared with isosorbide dinitrate (ISDN) in 14 patients with acute myocardial infarction using a Swan-Ganz catheter and venous occlusion plethysmography. Sublingual molsidomine (2-4 mg) increased calf venous capacitance (CVC) (0.42 +/- 0.18 to 0.64 +/- 0.09 ml/100 ml, p less than 0.05) from 30 to 240 minutes, while simultaneously lowering of PCWP (25.9 +/- 4.9 to 15.8 +/- 7.3 mmHg, p less than 0.05) and CVP (9.3 +/- 3.7 to 5.8 +/- 3.5 cmH2O, p less than 0.05). Calf blood flow (CBF), calf vascular resistance (CVR), CI, TSPR and SWI were not affected significantly. Molsidomine reduced preload more than 240 minutes after its administration. Sublingual ISDN increased CBF into the initial 15 minutes (1.19 +/- 0.49 to 1.83 +/- 0.98 ml/100ml/min, p less than 0.05) and CVC from 5 to 60 minutes (0.42 +/- 0.19 to 0.68 +/- 0.24 ml/100ml p less than 0.01) while simultaneously lowering PCWP (24.3 +/- 2.2 to 14.6 +/- 4.5 mmHg, p less than 0.01) and CVP (9.0 +/- 2.8 to 5.5 +/- 3.5 cmH2O, p less than 0.05). Neither drug affected cardiac index, blood pressure or systemic vascular resistance. These data suggest that molsidomine significantly lowered elevated preload (PCWP/PCP) by dilating venous capacitance vessels. Its length of action was 240 minutes compared with 60 minutes obtained with ISDN, which suggests this new agent may be of marked benefit in the AMI patients suffering from backward failure uncomplicated by forward failure in whom continued preload reduction is necessary. (Results are expressed as the mean +/- standard deviation).

Adult↗