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PubMed1991

Lessons from V-HeFT: questions for V-HeFT II and the future therapy of heart failure.

V-HeFT, the first mortality trial in patients with heart failure, has provided important insights regarding trial design, including patient selection and efficacy criteria. Planning of V-HeFT II, the trial comparing hydralazine-isosorbide dinitrate and enalapril, has raised additional issues regarding the power to detect mortality effects and the relative value of non-mortality endpoints for efficacy. V-HeFT has demonstrated that some vasodilator regimens can prolong life in heart failure. Hydralazine + isosorbide dinitrate reduced mortality by 27% compared to placebo in patients treated with digoxin and diuretics. The possibility of a non-vasodilator mechanism for long-term benefit of these interventions is raised by the apparently poor relationship between the magnitude of vasodilation and the favorable long-term effects. These issues need to be explored in subsequent trials. In future long-term trials, however, the need for background therapy with drugs that have been effective in reducing mortality will make the identification of life prolongation from new therapies more difficult to demonstrate.

Enalapril↗
PubMed1993

Influence of prerandomization (baseline) variables on mortality and on the reduction of mortality by enalapril. Veterans Affairs Cooperative Study on Vasodilator Therapy of Heart Failure (V-HeFT II). V-HeFT VA Cooperative Studies Group.

BACKGROUND: The effects of hydralazine plus isosorbide dinitrate were compared with those of enalapril in 804 men receiving digoxin and diuretic therapy for chronic congestive heart failure (CHF) in the Department of Veterans Affairs Cooperative Vasodilator-Heart Failure Trial (V-HeFT II). METHODS AND RESULTS: Patients were randomly assigned to receive 20 mg of enalapril or 300 mg of hydralazine plus 160 mg of isosorbide dinitrate daily. At 2 years, treatment with enalapril resulted in a significant (28%) reduction in mortality relative to the active control treatment. Baseline variables were examined to determine their impact on risk of mortality and on relative response to treatment. Mortality rates were significantly higher in patients with severe ventricular arrhythmias; in patients with low baseline ejection fractions, low peak oxygen consumption, and low systolic blood pressures; in patients with high cardiothoracic ratios, high scores indicating greater impairment on a quality-of-life questionnaire, and high plasma norepinephrine or renin levels; and in patients in New York Heart Association (NYHA) classes III and IV. Coronary artery disease, duration of CHF, and patient age were not predictive of mortality. Enalapril reduced mortality significantly compared with hydralazine/isosorbide dinitrate in patient subgroups with high plasma renin or norepinephrine levels and in patients with low cardiothoracic ratios. Furthermore, enalapril conferred significantly greater protection from mortality than hydralazine/isosorbide dinitrate in patients in NYHA classes I and II and in patients without arrhythmias or with < or = 10 premature ventricular contractions per hour. CONCLUSIONS: Of the prerandomization characteristics that were predictive of mortality in patients with CHF, only neurohormone measurements, cardiothoracic ratios, arrhythmia severity, and NYHA class identified subgroups of patients who benefited most from treatment with enalapril; a treatment interaction across strata was detected only for plasma norepinephrine and NYHA class. In no patient subgroup was the mortality with enalapril treatment significantly higher than the mortality with hydralazine/isosorbide dinitrate treatment.

Drug Therapy, Combination↗
PubMed2004

Impairment of gastrointestinal motility by nitrate administration: evaluation based on electrogastrographic changes and autonomic nerve activity.

BACKGROUND: Nitrates decrease the tone of the lower oesophageal sphincter, and may thus induce gastro-oesophageal reflux. AIM: In the present study, we evaluated electrogastrographic changes and heart-rate variability before and after the administration of nitrates. METHODS: In 15 patients with chest pain treated with nitrates, electrocardiography and percutaneous electrogastrography were performed before and after administration of nitrates. Autonomic nervous system function was evaluated by spectral analysis of heart-rate variability and serial changes in low frequency and high frequency power, and the low frequency/high frequency ratio were compared. Electrogastrograms were analysed by obtaining peak power amplitudes and their dominant frequencies. RESULTS: After the administration of nitrates (isosorbide dinitrate), high frequency power, an index of parasympathetic nervous activity, was significantly decreased, whereas the low frequency/high frequency ratio, an index of sympathetic nervous activity, was significantly increased. The mean peak amplitude of the electrogastrogram significantly increased postprandially both before and after treatment. After isosorbide dinitrate treatment, however, mean peak amplitudes after a meal were significantly lower than those obtained before treatment. The mean dominant frequency of the electrogastrogram did not vary before and after treatment. CONCLUSIONS: The present study suggests that nitrates inhibit gastrointestinal motility by decreasing autonomic nervous activity.

Aged↗
PubMed1991

Effects of vasodilators on venous tone in vivo in dogs.

The authors investigated, in vivo, the effects of four vasodilators on venous tone in dogs. Baseline venous tone was determined from the pressure: diameter relationships in the inferior vena cava (VSIVC) and femoral vein (VSFV) as measured during several seconds of occlusion of the proximal inferior vena cava. All of the slopes were nearly linear. All vasodilators were administered in dosages sufficient to lower blood pressure by approximately 20%; these dosages also decreased systemic vascular resistance by 15% to 30%. Isosorbide dinitrate reduced VSIVC from 7.17 +/- 0.81 to 5.81 +/- 0.73 mmHg/mm and VSIVC from 59.4 +/- 13.5 to 37.2 +/- 6.6 mmHg/mm. Neither nifedipine nor nisoldipine altered VSIVC or VSFV. However, prazosin decreased VSIVC from 13.2 +/- 3.3 to 10.7 +/- 2.7 mmHg/mm and VSFV from 43.5 +/- 11.3 to 29.9 +/- 8.8 mmHg/mm. These results suggest that isosorbide dinitrate and prazosin decrease venous tone in vivo, whereas nifedipine and nisoldipine do not.

Animals↗
PubMed1982

Treatment of patients with chest pain in a large city hospital.

A subspecialty clinic was established in a large city hospital in order to evaluate and treat patients with chest pain syndromes and to assess the relative efficiency of isosorbide dinitrate and propranolol in the treatment of angina pectoris. The intensive subspecialty approach proved superior to the standard evaluation and treatment that these patients received in the general medicine clinics. Almost 50 percent of referred patients with the diagnosis of longstanding angina pectoris did not have this disease. Of the patients with chest pain due to coronary artery disease, the clinic provided an expedient, efficient, and effective means of evaluation and treatment. Isosorbide dinitrate was shown to be as effective an antianginal drug as propranolol.

Angina Pectoris↗
PubMed1998

Effects of intravenous administration of L-arginine on autonomic nervous activities. Analysis of heart rate variability.

We studied the differences between isosorbide dinitrate (ISDN) and L-arginine (L-Arg), the precursor of nitric oxide, regarding autonomic nervous function by assessing changes in heart rate variability and blood levels of various vasoactive substances. Healthy volunteers received infused L-arginine (L-Arg group) or isosorbide dinitrate (ISDN group). ECGs were monitored and analyzed. Blood levels of catecholamines, endothelin, renin activity, angiotensin, human atrial natriuretic peptide, aldosterone, arginine, and citrulline were examined. Time-domain analyses of heart rate variability showed no significant changes in occurrence of R-R variability or coefficient of R-R variability, indicators of parasympathetic activity, after administration of ISDN. By contrast, both measures showed significantly more variation following administration of L-Arg. Frequency-domain analyses showed that high frequency power, an indicator of parasympathetic activity, was significantly elevated in the L-Arg group, whereas there was no significant change in the ISDN group. The blood levels of the measured vasoactive substances in L-Arg and ISDN groups were significantly different. The differences in autonomic nervous function and various kinds of vasoactive substances between the L-Arg and ISDN groups suggest that L-Arg had other actions on humoral factors in addition to vasodilation. Thus, arginine/nitric oxide may act as a neurotransmitter, altering parasympathetic nervous tension.

Adult↗
PubMed2003

Delayed adverse reactions to iodinated radiographic contrast media after coronary angiography: a search for possible risk factors.

OBJECTIVE: The incidence of and risk factors for delayed adverse events (DAEs) that appear from 1 h to 7 days after injection of radiographic contrast media were investigated in patients who had undergone coronary angiography (CAG). METHODS: DAEs were monitored by questionnaire in 155 patients who received iomeprol. Isosorbide dinitrate was injected in every case. Risk factors for DAEs were analysed by a logistic regression model. RESULTS: Of 118 patients who returned questionnaires, 54 complained of DAEs, although no severe or fatal reactions occurred. Erythema, rash and nausea were frequent events. Female gender, total dose of isosorbide dinitrate <2 mg, and execution of acetylcholine provocation test were found to be the major risk factors, and the incidence of DAEs increased as the number of risk factors increased. CONCLUSION: Care should be taken when CAG is performed on female patients who undergo acetylcholine provocation tests and receive low-dose nitric oxide donor injections.

Aged↗
PubMed1994

Coronary endothelial function in cardiac transplant recipients with accelerated coronary disease.

BACKGROUND: Previous studies with the endothelium-dependent vasodilator substance P have shown a preserved vasodilator response in cardiac transplant recipients with angiographically normal coronary arteries. Although endothelial dysfunction is known to occur in cardiac transplant recipients with accelerated coronary disease, the degree to which the endothelium is affected is not known precisely. The aim of the present study was to examine endothelial function in accelerated coronary disease following cardiac transplantation. METHODS: Thirteen cardiac transplant recipients with epicardial coronary disease underwent substance P infusion. The response to incremental doses of substance P was measured in smooth segments of affected coronary arteries. Substance P was infused over 2 min with a starting dose of 1.4 pmol/min and a maximum of 22.4 pmol/min, reached by doubling the dose in steps, followed by an infusion of 2 mg isosorbide dinitrate over 2 min. RESULTS: Substance P caused less vasodilation at lower concentrations, with a significantly higher dose required to achieve half maximal dilation compared with cardiac transplant recipients with no coronary disease. The mean maximal dilatation achieved with substance P was 22.98 +/- 4.62% compared to 21.95 +/- 4.9% with isosorbide dinitrate; the latter value was not significantly different from the maximal dilation achieved in cardiac transplant recipients without coronary disease. CONCLUSIONS: In cardiac transplant recipients with accelerated coronary disease the functional vasodilatory ability of the coronary endothelium is impaired in segments of apparently unaffected epicardial arteries, which may lead to an increase in the resting vasoconstrictor tone and have important functional and therapeutic implications.

Adult↗
PubMed2000

[Intravascular Doppler for the evaluation of renal blood flow: validation and demonstration of vessel reactivity].

AIM: To assess the feasibility and to demonstrate the potential clinical application of intravascular doppler in the evaluation of renal blood flow in patients with hypertension and normal renal arteries. MATERIALS AND METHODS: Intravascular doppler was used to measure renal blood flow in 19 patients (34 kidneys) during arteriography to rule out renovascular hypertension. Arteriography showed no evidence of renal artery stenosis in any patient. Hemodynamic parameters, renal artery diameter, and doppler measurements were undertaken at baseline, after injection of a bolus (10 ml) of normal (0.9%) saline, and after injection of isosorbide dinitrate (1 mg diluted in 10 ml normal saline). RESULTS: Repeated measurements of renal blood flow confirmed the reproducibility of the technique. Basal blood flow was similar in both right and left kidneys; injection of vehicle solution (10 ml normal saline) had no effect on doppler parameters. Injection of isosorbide dinitrate resulted in a significant increase in renal blood flow velocity reflecting an increase in renal blood flow; this demonstrates the existence of a renal flow reserve. The degree of increase in renal blood flow varied significantly between kidneys. CONCLUSIONS: Intravascular doppler is a safe, effective, and reproducible technique for measurement of renal blood flow. It allows evaluation of variations in renal blood flow in response to diverse vasoactive drugs or other vasomotor stimuli. The present study demonstrated the heterogenous response of renal blood flow in response to vasodilator stimuli.

Angiography↗
PubMed1997

Anal ultra slow waves: a smooth muscle phenomenon associated with dyschezia.

Anal ultra slow waves (USWs) have been described in a variety of anorectal disorders, all of which may be associated with constipation. We investigated whether they represent a marker for dyschezia and whether their occurrence can be modified. Manometric and endosonographic studies were performed in 25 patients with dyschezia, in 25 age- and sex-matched controls, and in an equal number of patients with hemorrhoids. Patients exhibiting ultra slow waves were repeatedly studied with and without local administration of isosorbide dinitrate. In addition, we determined whether stimulatory maneuvers modify the occurrence of USWs. Anal USWs were persistently found in 56% of patients with dyschezia, in 8% of patients with hemorrhoids, and in none of the healthy controls. They were stimulated by anal squeeze and completely abolished by local administration of isosorbide dinitrate. Ultra slow waves always occurred in conjunction with an increase in anal resting pressure and were tightly associated with a fluctuation in slow wave amplitude. Anal sphincter morphology was similar in patients with dyschezia and in controls. We conclude that anal USWs occur most frequently in patients with dyschezia and indicate smooth muscle dysfunction. Treatment directed at abolishing this motor phenomenon may represent a novel approach to the management of patients with dyschezia.

Adult↗
PubMed2002

Effect of a nitric oxide donor on the ophthalmic artery flow velocity waveform in preeclamptic women.

OBJECTIVE: To evaluate the effects of an antihypertensive agent on the orbital circulation of preeclamptic women. METHODS: We studied the ophthalmic arteries of 10 healthy pregnant women and 10 women with severe preeclampsia by pulsed Doppler ultrasonography and evaluated the effect of transdermal isosorbide dinitrate, a nitric oxide donor, on preeclamptic women. RESULTS: The average pulsatility index and resistive index were significantly lower, whereas the average end-diastolic velocity, time-averaged mean peak velocity, and peak ratio, which quantifies characteristic changes in the ophthalmic artery flow velocity waveform, were higher in preeclamptic women. Transdermal isosorbide dinitrate significantly reduced the average end-diastolic velocity (P < .05) and peak ratio of the ophthalmic artery (P < .01), whereas it did not significantly affect other indices. CONCLUSIONS: Orbital circulation was altered in preeclamptic women. A nitric oxide donor affected orbital circulation. Peak ratio was a sensitive index for evaluating orbital circulation in preeclampsia.

Administration, Cutaneous↗
PubMed1997

Elevation of oxygen release by nitroglycerin without an increase in blood flow in the hepatic microcirculation.

The effect of nitroglycerin on oxygen (O2) release in the microcirculation was investigated by examining single, unbranched hepatic sinusoids of rats using dual-spot microspectroscopy. Nitroglycerin significantly increased O2 release from erythrocytes flowing in the sinusoids. Differences in O2 saturation of hemoglobin per unit length of the sinusoid were significantly enhanced, while there were no significant changes in erythrocyte velocity, hemoglobin concentration or oxyhemoglobin flow into the sinusoids, or in regional hepatic blood flow measured with a laser tissue blood flow meter. No change was noted for hepatic O2 consumption measured in isolated liver perfused with hemoglobin-free oxygenated buffer. Isosorbide dinitrate showed a similar but slower effect. These findings suggest that nitroglycerin and isosorbide dinitrate enhance O2 release from erythrocytes without significantly increasing tissue blood flow.

Animals↗
PubMed1995

Late endothelial function of free and pedicled internal mammary artery grafts.

The internal mammary artery has greater long-term patency than the saphenous vein when used for coronary bypass grafting. Therefore, bilateral use of the internal mammary artery for grafting with the right internal mammary artery used as a "free" graft may result in improved graft survival. The study objectives were to compare the endothelial-dependent and -independent vasodilatory response in free and pedicled internal mammary artery grafts in patients who had previously undergone coronary surgery. Free (group 1, n = 8) and pedicled (group 2, n = 7) internal mammary artery grafts were studied by comparing the response to selective infusion of the endothelial-dependent vasodilator substance P (1.4 up to 22.4 pmol/min in doubling dose increments) followed by isosorbide dinitrate (2 mg over 2 minutes), in patients undergoing coronary angiography, 1 month to 6 years after coronary surgery. Maximal dilatory response to substance P was 8.7% +/- 1.8% in pedicled grafts compared with 8.8% +/- 2.3% in free grafts (p = not significant), with the dose response for both groups being similar. Infusion of isosorbide dinitrate produced only minimal further dilatation in both groups. No significant difference was found in endothelium-dependent and -independent vasodilatory response between free and pedicled internal mammary artery grafts, suggesting that the use of the free right internal mammary artery and other arterial grafts may enhance graft survival.

Adult↗
PubMed1980

Assessment of function of contractile segments in patients with left ventricular aneurysms by quantitative first pass radionuclide ventriculography. Haemodynamic correlation at rest and exercise.

Thirteen patients with left ventricular aneurysms complicating myocardial infarction were studied by contrast angiography and by first pass radionuclide ventriculography. The ejection fraction of the contractile segment (EFCS) was measured from both studies using a double hemishperoid model, and the values correlated closely. There was a monotonic relation between EFCS and stroke volume index measured from thermodilution cardiac outputs carried out simultaneously with the radionuclide study. When radionuclide ventriculography was performed at submaximal supine exercise, changes in EFCS paralleled changes in the total left ventricular ejection fraction in 10 of the 13 cases. In nine patients, changes in EFCS paralleled changes in stroke volume index and the relation between EFCS and stroke volume index was maintained at exercise. After administration of the vasodilator isosorbide dinitrate to 12 patients, repeat exercise radionuclide ventriculography showed an improvement in left ventricular ejection fraction and in eight patients EFCS improved. First pass radionuclide ventriculography can accurately estimate EFCS, which may be an important factor in predicting the likely response to aneurysmectomy. Changes in EFCS on exercise are reflected in changes in total left ventricular ejection fraction and stroke volume index. Isosorbide dinitrate may improve contractile segment function on exercise.

Adult↗
PubMed1994

Differences in vasoreactivity between gastroepiploic artery grafts late after bypass surgery and grafted coronary arteries.

BACKGROUND: The gastroepiploic artery is increasingly used as an alternative arterial coronary bypass conduit. In vitro studies have reported differences in vasoreactivity among various types of coronary graft conduits, susceptible to influencing the adaptation of myocardial blood flow and long-term patency rate. METHODS AND RESULTS: To evaluate in vivo the vasoreactivity of gastroepiploic artery grafts implanted long-term, nine angiographically smooth grafts implanted to the distal right or to the left circumflex coronary artery were studied with quantitative angiography 6 to 36 months after surgery. Angiograms were obtained on 35mm cinefilms in basal conditions, after injection of methylergometrine (0.4 mg IV), and after intragraft injection of 1 mg isosorbide dinitrate. In basal conditions, there was no difference in luminal diameter between gastroepiploic and coronary arteries (1.64 +/- 0.32 versus 1.51 +/- 0.31 mm; P = NS). After methylergometrine, a constriction was observed in all gastroepiploic artery grafts (-14 +/- 6% of basal diameter) and in all but one grafted coronary artery (-6 +/- 5%). After isosorbide dinitrate, a dilation was consistently observed in all gastroepiploic artery grafts (+26 +/- 9%) and grafted coronary arteries (+14 +/- 7% of basal). Changes in lumen diameter in response to these constrictor and dilator stimuli, either expressed in absolute values or in percentage of control were significantly greater (P < .001) in gastroepiploic artery grafts than in grafted coronary arteries. CONCLUSIONS: Gastroepiploic artery grafts implanted long-term are more reactive than grafted coronary arteries to ergometrine and nitrates. This response differs from that previously reported of internal mammary artery grafts to the same pharmacological vasoactive stimuli. This suggests that the concept of a more efficient endothelium-dependent control of vasomotor tone contributing to better long-term functional results of internal mammary artery grafts cannot be directly extrapolated to gastroepiploic artery grafts.

Arteries↗
PubMed1997

Improvement of alveolar-capillary membrane diffusing capacity with enalapril in chronic heart failure and counteracting effect of aspirin.

BACKGROUND: KII ACE, the enzyme that converts angiotensin I and inactivates bradykinin, is highly concentrated in the lungs; its blockade reduces exposure to angiotensin II and enhances exposure to prostaglandins generated by local kinin hyperconcentration. Our hypothesis is that ACE inhibitors improve pulmonary function in chronic heart failure (CHF) by readjusting lung vessel tone and permeability or alveolar-capillary membrane diffusion. METHODS AND RESULTS: In 16 CHF patients and 16 normal volunteers or mild untreated hypertensives, pulmonary function and exercise tests with respiratory gas analysis were assessed on placebo, enalapril (10 mg BID), enalapril plus aspirin (325 mg/d), or aspirin, in random order and double blind, for 15 days each. In CHF, enalapril increased pulmonary carbon monoxide diffusion (DLCO), oxygen consumption (VO2), and exercise tolerance and reduced the ratio of dead space to tidal volume (VD/VT) and the ventilatory equivalent for carbon dioxide production (VE/VCO2). On enalapril, VO2 (r = .80, P < .0001) and VD/VT (r = -.69, P = .003) changes from placebo correlated with those in DLCO. These effects were inhibited by aspirin and were absent in control subjects. In 8 additional patients, hydralazine-isosorbide dinitrate, as an alternative treatment for reducing pulmonary capillary wedge pressure (PCWP) and increasing exercise capacity, were more effective than enalapril for the PCWP but did not affect DLCO and VE/VCO2; amelioration in VO2 and VD/VT was unrelated to DLCO and was not modified by aspirin. CONCLUSIONS: ACE inhibition improved pulmonary diffusion in CHF. Hydralazine-isosorbide dinitrate failed to provide this result. Counteraction by aspirin, a prostaglandin inhibitor, bespeaks prostaglandin participation while on enalapril that might readjust capillary permeability or alveolar-capillary membrane diffusion.

Aged↗
PubMed1978

[Effectiveness of two Ca-antagonistic drugs on angina pectoris: nifedipine and verapamil versus nitroderivative and beta-blocking drugs (author's transl)].

The Authors, using cycle ergometer tests, assess the effectiveness of two Ca-antagonistic drugs, nifedipine and verapamil, administered full strength to patients suffering from typical angina from effort. The true effectiveness of these drugs was tested by comparing the results with those obtained with placebo, isosorbide dinitrate and propranolol. The effect of nifedipine proved statistically significant (p less than 0.01) with respect to the parameters: double product, time of insurgence of angor and time of appearance of electrocardiographic anomalies. Verapamil proved slightly significant (p less than 0.05) only with regard to time of appearance of electrocardiographic anomalies. There follows a brief discussion of the differences between these results. Isosorbide dinitrate and propranolol increase tolerance to effort with respect to placebo treatment. These results are statistically significant on all parameters used.

Angina Pectoris↗
PubMed1985

Nitrate tolerance.

The nitrate group of drugs is one of the most commonly used therapeutic modalities. The application of the nitrates is generally directed at ameliorating the symptoms of occlusive coronary artery disease (angina) and/or congestive heart failure. Although studies are available that attempt to refute the concept of nitrate-induced tolerance in angina pectoris, well-designed and well-controlled reports are appearing that convincingly establish the occurrence of one or more expressions of tolerance (e.g., shorter duration of action, loss of intensity of effect) with long-term dosing in this clinical setting. The type and degree of tolerance to nitrate therapy in angina pectoris depend on a number of pharmaceutic-pharmacokinetic considerations, including route of administration, dose strength, dosing frequency, and magnitude and duration of drug delivery. Reports concerning the development of tolerance to nitrates in congestive heart failure are also somewhat conflicting. However, one form and dose of nitrate therapy has been studied rather extensively: isosorbide dinitrate at 40 mg orally every 6 hours. The administration of this preparation over 3 months to a population with heart failure resulted in the development of tolerance to the systemic arterial-arteriolar effects, whereas the pulmonary vascular and venous dilative effects were maintained throughout the long-term dosing period. Exercise tolerance improved for the long-term isosorbide dinitrate group compared to the group receiving long-term placebo therapy. The mechanism(s) of tolerance to the nitrates is not known; altered disposition of reduced sulfhydryl groups at receptor and intracellular sites is the leading hypothesis.

Administration, Oral↗