Effect of transdermal nitroglycerin or N-acetylcysteine, or both, in the long-term treatment of unstable angina pectoris

OBJECTIVES: This study was designed to evaluate whether the addition of transdermal nitroglycerin or oral N-acetylcysteine, or both, to conventional medical therapy improves the natural history of unstable angina pectoris. BACKGROUND: Transdermal nitroglycerin is widely used to treat angina pectoris, but the development of tolerance is a major problem that may reduce its clinical efficacy. It has been suggested that the addition of N-acetylcysteine to nitroglycerin reverses the development of tolerance, potentiates the hemodynamic response to nitroglycerin and may improve in-hospital prognosis in unstable angina. METHODS: We assessed the efficacy of adding transdermal nitroglycerin or oral N-acetylcysteine, or both, to conventional medical therapy in a randomized, double-blind, placebo-controlled trial involving 200 patients with unstable angina who were followed up for 4 months. RESULTS: Outcome events--death, myocardial infarction or refractory angina requiring revascularization--occurred in 31% of patients receiving nitroglycerin, 42% of those receiving N-acetylcysteine, 13% of those receiving nitroglycerin plus N-acetylcysteine and 39% of those receiving placebo (p = 0.0052). Kaplan-Meier curves showed a higher probability (p < 0.01) of no failure of medical treatment in the group receiving both nitroglycerin and N-acetylcysteine than in those receiving placebo, N-acetylcysteine or nitroglycerin alone. The combination of nitroglycerin and N-acetylcysteine was associated with a high incidence of side effects (35%), mainly intolerable headache, which was almost twice as frequent as in patients receiving nitroglycerin alone. CONCLUSIONS: The combination of nitroglycerin and N-acetylcysteine, associated with conventional medical therapy in the long-term treatment of patients with unstable angina, reduces the occurrence of outcome events. However, the high incidence of side effects limits the clinical applicability of this therapeutic strategy at least at the dosage used in the present study.     

Na-K-Cl cotransport in normal and glaucomatous human trabecular meshwork cells

PURPOSE: Previous results from this laboratory showed that intracellular volume of trabecular meshwork (TM) cells is regulated by the Na-K-Cl cotransport system. Other studies suggest that TM cell volume, in turn, is a determinant of permeability across the TM. Given that a decrease in outflow facility across the TM is thought to be the primary cause of elevated intraocular pressure in primary open-angle glaucoma, the present study was conducted to investigate the possibility that Na-K-Cl cotransport function may be altered in glaucomatous TM cells compared with normal TM cells. METHODS: Normal and glaucomatous human TM cells were cultured from donor eyes and trabeculectomy specimens, respectively. Trabecular meshwork cell monolayers were evaluated for Na-K-Cl cotransport activity, assessed as ouabain-insensitive, bumetanide-sensitive K influx using 86Rb as a tracer for K. Cotransporter protein expression was determined by western blot analysis, and intracellular volume was determined radioisotopically using [14C]urea and [14C]sucrose as markers of total and extracellular water space, respectively. RESULTS: Na-K-Cl cotransport activity of glaucomatous TM cells was found to be reduced by 32% +/- 2% compared with that of normal TM cells, whereas western blot analyses showed that cotransporter protein expression in glaucomatous TM cells was reduced by 64% +/- 14% compared with expression in normal TM cells. Also, exposure of normal TM cells to 10 microM norepinephrine or 50 microM 8-bromo-3',5'-cyclic adenosine monophosphate was found to diminish Na-K-Cl cotransport activity, whereas these agents were without effect on glaucomatous TM cell cotransport. Finally, resting cell volume of glaucomatous TM cells was found to be increased compared with that of normal TM cells, whereas intracellular volume of both cell types was reduced after exposure to 10 microM benzmetanide or 10 microM bumetanide. CONCLUSIONS: These findings indicate that Na-K-Cl cotransport function and regulation are altered in glaucomatous TM cells compared with that of normal TM cells. However, the observation that cell volume of glaucomatous TM cells is greater than that of normal TM cells, despite reduced Na-K-Cl cotransport activity, suggests that other volume-regulatory ion flux pathways may be involved in the reduced outflow of glaucoma.     

Phylogenetically distant intracellular symbionts in termites

Nitric oxide (NO), a gaseous molecule synthesized in the arteriolar endothelium from the amino acid L-arginine (L-arg), has been identified as the previously described Endothelium-Derived Relaxing Factor (EDRF): nitroderivatives such as nitroglycerin are known to induce vasodilation via NO release. The aim of this study was to evaluate by Transcranial Doppler (TCD) monitoring any changes in cerebral hemodynamics induced by both the infusion of L-arg and the sublingual administration of nitroglycerin in 20 healthy subjects. L-arg infusion induced a significant increase in blood velocity compared to the baseline value (mean +/- S.D. percent change = 18 +/- 8.71; p<0.0001 ) and a slight but significant decrease in Pulsatility Index. By contrast, nitroglycerin was able to cause a significant decrease in blood velocity (mean +/- S.D. percent change = 24.8 +/- 7.68; p<0.0001), while leaving Pulsatility Index unchanged. These data suggest that L-arg and nitroglycerin, both hypothesized to use NO as the final product at the vascular level, result in opposite blood velocity patterns within the cerebral circulation. This may be due to the particular type of artery and/or to the local endothelial environment whereby the released NO may act.     

The cumulative normalised rim/disc area ratio curve

BACKGROUND: The assessment of the cup of the optic disc depends, among other criteria, on the disc area. A small cup in a small optic disc can indicate an advanced glaucomatous lesion, while on the other hand a large cup in a large optic disc can be normal. Therefore, a cumulative normalised rim/disc area ratio curve could help to distinguish between glaucomatous and normal optic cups. The aim of our study was to calculate normalised rim/disc area ratio curve. METHODS: Heidelberg Retina Tomograph examinations of the optic nerve head of 100 randomly selected eyes of 100 normal subjects were evaluated. We calculated the disc area-adjusted normalised rim/disc area ratio in sectors of 10 degrees. The 95th, 90th and 50th percentiles of each of the 36 sectors were displayed in descending order. RESULTS: In relation to the normal percentile curves, it is possible to display an individual normalised rim/disc area ratio curve. We obtained such curves for a normal optic disc, optic nerve heads with moderate and advanced lesions and a small optic disc with glaucomatous damage. CONCLUSION: We present a new display mode for the results of Heidelberg Retina Tomograph optic nerve head examination, which may be helpful for easy and reliable assessment of the local, diffuse and combined components of glaucomatous optic nerve head damage depending on optic disc size.     

Differential in vivo effects of alpha-naphthoflavone and beta-naphthoflavone on CYP1A1 and CYP2E1 in rat liver, lung, heart, and kidney

Tenascin is a large extracellular matrix glycoprotein expressed in neural and non-neural tissues. In the central nervous system, tenascin is synthesized by astrocytes during development and wound healing, forming barriers and affecting neurite outgrowth. In this study we examined tenascin expression in optic nerve heads of normal and glaucomatous eyes and found that there is upregulation of tenascin mRNA and protein in reactive astrocytes from human glaucomatous optic nerve heads compared to normal age-matched controls. In the prelaminar region there was a band of tenascin immunoreactivity around the blood vessels of glaucomatous, but not in normal eyes. However, tenascin mRNA was only localized to astrocytes, suggesting that astrocytes are the cellular source of tenascin. In the lamina cribrosa, tenascin immunoreactivity and gene expression were localized to astrocytes in the cribriform plates and inside the nerve bundles. In the post-lamina region, tenascin immunoreactivity and gene expression were localized to astrocytes lining the pial septum immediately adjacent to the lamina cribrosa. In normal optic nerve heads, tenascin expression at the mRNA and protein levels was confined to clusters of astrocytes at the level of Bruch's membrane in the prelaminar optic nerve head. In glaucoma, enhanced expression of tenascin may be protective to the axons of the retinal ganglion cells by providing a barrier for humoral and/or blood-borne factors that may cause further neural damage. However, the precise role of tenascin in glaucomatous optic neuropathy is not yet elucidated.     

Comparison of antihypertensive effects of nicardipine with nitroglycerin for perioperative hypertension

BACKGROUND: To compare the efficacy of intravenous (iv) nicardipine with nitroglycerin for the treatment for patients with perioperative hypertension. METHODS: Forty patients with perioperative hypertension randomly divided into two groups were treated with intravenous calcium entry blocker, nicardipine, or vasodilator, nitroglycerin. Haemodynamic measurements including mean arterial and pulmonary arterial pressure, central venous and pulmonary capillary wedge pressure, and cardiac output were recorded; peripheral and pulmonary vascular resistance were calculated. RESULTS: Both medications were effective in reducing blood pressure and controlling haemodynamics. During the maintenance by continuous iv infusion, nicardipine controlled hypertension more rapidly than nitroglycerin (nicardipine 10.5 +/- 2.5 min and nitroglycerin 18.7 +/- 2.8 min, p < 0.05) without significant alteration in heart rate. The total frequency of dose adjustments required to achieve therapeutic response was significantly less in the nicardipine-treated group (2.5 +/- 0.3 for nicardipine and 6.2 +/- 1.4 for nitroglycerin, p < 0.05). Incidence of hypotensive episodes during the infusion were observed in both groups [nicardipine 5% (1/20) and nitroglycerin 30% (6/20), p < 0.05]. CONCLUSIONS: Intravenous nicardipine is as effective as nitroglycerin in the treatment of perioperative hypertension. Specific advantages have been identified such as stable dose-response effect, less hypotensive and tachycardial effects during the use of iv nicardipine in treatment of hypertensive patients.     

Parapapillary chorioretinal atrophy in patients with ocular hypertension. II. An evaluation of progressive changes

OBJECTIVE: To determine whether parapapillary chorioretinal atrophy in patients with ocular hypertension remained stationary or progressed along with glaucomatous optic nerve damage. METHODS: The morphometric parameters and progression of parapapillary atrophy were retrospectively investigated, using serial photographs, in 350 eyes of 175 patients with ocular hypertension. The association of parapapillary atrophy progression with subsequent glaucomatous conversion and with other baseline patient- and eye-specific characteristics was analyzed. RESULTS: Progression in the area and extension of parapapillary atrophy before noticeable optic disc or visual field changes was observed in 48 (49.0%) of 98 eyes that converted to glaucoma, while parapapillary atrophy progression was noted in 25 (9.9%) of 252 ocular hypertensive eyes that did not develop glaucomatous damage (P<.001). The predictive sensitivity and specificity of this observation were 49% and 90%, respectively. In a logistic multiple regression model, the progression of parapapillary atrophy was associated with a family history of glaucoma (odds ratio, 2.7) and the initial size of zone beta (odds ratio, 1.64, for an increase of 0.10 of the zone beta area-disc area ratio). CONCLUSION: The progression of parapapillary chorioretinal atrophy may be an early glaucomatous finding in some patients with ocular hypertension.     

Comparison of psychophysical and electrophysiological testing in early glaucoma

PURPOSE: To compare the sensitivity and specificity of a wide range of psychophysical and electrophysiological tests in the detection of early glaucomatous damage. METHODS: Forty-three normals and 43 patients with early glaucoma, some still without field defects, were tested with differential light threshold perimetry, short-wavelength automated perimetry, high-pass resolution perimetry, motion detection, flicker contrast sensitivity, flickering and isoluminantly matched letter tests, and pattern and flash electroretinography, including photopic, scotopic, oscillatory potentials, and 30 Hz flicker. Receiver operating characteristic analysis was applied to continuous variables derived from each of the tests. RESULTS: Most parameters reflected glaucomatous loss to some degree, even though only single variables were analyzed separately in the receiver operating characteristic analysis. The pattern electroretinogram and some of the letter acuity tests had the best sensitivity and specificity, followed by short-wavelength automated perimetry and high-pass resolution-perimetry. Motion detection, flicker contrast, and flash electroretinogram parameters scored poorly. Six patients with normal results on the Humphrey field test had abnormal results on many of the other tests. CONCLUSIONS: Applying different psychophysical and electrophysiological tests may add to our ability to detect early glaucomatous damage.     

Lack of cross-tolerance to short-term linsidomine in forearm resistance vessels and dorsal hand veins in subjects with nitroglycerin tolerance

BACKGROUND: Therapy with nitroglycerin is widely used in the treatment of angina pectoris, but development of tolerance is a major problem. Nitrovasodilators other than nitroglycerin may be less prone to induce vascular tolerance. This investigation was designed to test whether the alternative nitric oxide donor linsidomine maintains its vasodilator effects in the presence of nitroglycerin tolerance. METHODS: We tested the vascular effects of nitroglycerin and linsidomine (SIN-1) in forearm resistance arteries (venous occlusion plethysmography) and hand veins (venous compliance technique) using a randomized, double-blind placebo-controlled regimen in 33 healthy subjects (age range, 22 to 38 years; mean age, 26 years) before and after 7 days of assignment to either 1 week of nitroglycerin administration (0.83 mg/hr) for induction of tolerance or placebo administration. RESULTS: Vascular responses of both vascular beds to nitroglycerin (in veins: mean difference, 42.3%; confidence interval [CI], 3% to 81.7%; p < 0.05; in arteries: mean difference, 65.0%; CI, 38.9% to 91.1%; p < 0.01) but not to linsidomine (in veins: mean difference, -13.8%; CI, -53.5 to 25.8%; not significant; in arteries: -19.7%; CI, -33.7% to -5.6%; not significant) were attenuated in the nitroglycerin patch group, whereas the placebo group showed no differences to either nitroglycerin (in arteries: mean difference, -7.5%; CI, -44.6% to 29.6%; in veins: -10.6%; CI, -58.2% to 36.9%) or linsidomine (in arteries: 4.5%; CI, -12.8% to 21.7%; in veins: -13.1%; CI, -4.5% to 29.8%). CONCLUSION: These results suggest that short-term administration of sydnonimines can overcome the loss of vascular relaxation associated with long-term nitroglycerin therapy.     

Neurochemical mechanisms of nitroglycerin-induced neuronal activation in rat brain: a pharmacological investigation

Nitroglycerin is a nitric oxide donor which induces sustained expression of Fos protein, a marker of neuronal activation, in specific neuronal groups in the central nervous system. The mechanisms which underlie nitroglycerin-induced neuronal activation are elusive at this time, although a precise role has been suggested for the pool of neurons containing nitric oxide synthase as well as for catecholaminergic and peptidergic pathways. The aim of this study was to provide further details on the central effect of nitroglycerin by means of a pharmacological manipulation of nitroglycerin-induced neuronal activation with inhibitors of the nitric oxide synthase, modulators of the sympathetic drive and mediators of pain perception. Adult male Sprague-Dawley rats received L-NGnitro-arginine methyl ester, 7-nitro-indazole, ephedrine sulfate, indomethacin, capsaicin or vehicle before the subcutaneous injection of nitroglycerin (10 mg/kg b.w.). They were sacrificed 4 hr after nitroglycerin administration and brain sections were processed for immunocytochemical visualization of Fos. All the pharmacological treatments administered before injecting nitroglycerin selectively influenced Fos expression in the different brain nuclei. The data obtained suggest that nitroglycerin-induced neuronal activation is mediated by nociceptive and barosensitive mechanisms. Nitric oxide seems to represent the most important mediator of this phenomenon. The sympathetic system and prostaglandin synthesis are also likely to be involved.     

Exercise test and nitrates

The use of sublingual nitroglycerin in the stress test is a precious tool in everyday clinical cardiology. It has several indications in this context: 1) Confirmation of the diagnosis of myocardial ischaemia by eliminating a large number of false-positives with no marked variation of ST depression and performance after sublingual nitroglycerin in contrast with patients presenting authentic myocardial ischaemia on effort. 2) Teaching of the preventive and opportunistic use of nitroglycerin before intense effort and before physical training which, in the long-term, is one of the most effective treatments of exertional angina pectoris. 3) Demonstration of potentiation of the effect of certain antianginal drugs such as beta-blockers. 4) In therapeutic trials, the stress test performed with sublingual nitroglycerin is used as a reference and to select patients capable of a fairly marked progression, so that they can be included in a protocol. It has the advantage of demonstrating a functionally measurable improvement of the stress test with an appropriate drug. 5) Progression with sublingual nitroglycerin during the stress test is related to regression of ischaemia i.e. restoration of functional viability of hibernating or shocked ischaemic segments of myocardium. It is probably the only realistic way to predict possible improvement after revascularization compared to other tests, which may be over-sensitive, as they detect zones with little capacity of regaining a viability which really contributes to cardiac output on exertion.     

Response of PUVA-induced keratoses to etretinate

Maximal, reproducible, and thus "standardized" dilation of epicardial coronary arteries can be easily achieved with intracoronary bolus administration of 0.1 mg nitroglycerin without considerable decrease in blood pressure. The addition of other nitrocompounds or calcium antagonists cannot increase coronary dilation after nitroglycerin, but may be hampered by adverse effects.     

Glaucoma, capillaries and pericytes. 1. Blood flow regulation

Blood flow autoregulation may be deficient in patients with glaucoma, making the optic nerve circulation susceptible to the challenge of intraocular pressure (IOP). Adequacy or inadequacy of autoregulation may be a factor that decides whether a patient with elevated IOP develops glaucomatous optic nerve damage. Hypothetically, capillaries may assist arteries and veins in the regulation of blood flow. Our attention has become focused on the pericytes, particularly abundant in the optic nerve and retina, which are a contractile component of capillaries and may therefore be the cells responsible for the capillary's role in autoregulation.     

Action of intracoronary nitroglycerin in refractory coronary artery spasm

Coronary artery spasm usually responds to sublingual nitroglycerin. This report describes four patients with variant angina and one patient with rest angina who had coronary spasm that was refractory to sublingual or i.v. nitroglycerin. In four patients, spasm occurred spontaneous and in one patient after 0.05 mg of ergonovine. In each case, 25-100 micrograms of intracoronary nitroglycerin promptly (30-45 seconds) resulted in reopacification of the vessel involved in spasm and resolution of evidence for ischemia. Thus, intracoronary nitroglycerin can reverse coronary artery spasm that does not respond to systemic nitroglycerin administration.     

Long-term epinephrine therapy of ocular hypertension

Nineteen patients with symmetrical ocular hypertension and symmetrical cupping of the optic nerves were made asymmetric with respect to intraocular pressure for one to five years by unilateral topical treatment with epinephrine hydrochloride. Development of glaucomatous visual field defects was observed in 32% of the untreated eyes and in none of the treated eyes (P less than .05). Progressive cupping of the optic nerve was noted in 53% of the untreated eyes and in 11% of the treated eyes (P less than .025). Evidence of glaucomatous damage was observed more frequently in subjects maintained on this regimen for longer periods and in subjects with initial horizontal cup/disc ratios greater than 0.4 (P less than .05). None of the eyes, either treated or untreated, with mean intraocular pressures less than 24 mm Hg developed glaucomatous damage during the period of this study.     

Sensitivity and specificity of optic disc variables and analysis of a new variable (MP/D) for glaucoma diagnosis with the Glaucoma-Scope

AIM: In an attempt to use the quantitative optic disc measurements of the Glaucoma-Scope (OIS Sacramento, CA, USA) to distinguish glaucomatous from normal optic discs, a new variable was investigated, the mean disc corrected for the disc size by dividing by the disc area: MP/D. METHODS: Glaucoma-Scope disc evaluation was performed on 81 eyes of 51 patients split into the following groups based on Humphrey 24-2 visual field and clinical criteria of glaucoma: chronic glaucoma n = 27 (including only early, n = 17, and low tension glaucoma, n = 10), ocular hypertension n = 24, pseudoglaucomatous large discs, n = 12, and normal eyes, n = 18. Classic optic disc variables (the vertical and horizontal c/d ratios, and the c/d area) were compared with the new MP/D index calculating receiver operating characteristic curves. RESULTS: The MP/D ratio was able to identify the glaucomatous eyes more easily than other ratios. Areas under the curves were: 0.91 (MP/D); 0.87 (c/d area); 0.85 (c/d vertical); and 0.80 (c/d horizontal). The MP/D index was also correlated with the mean deviation (r = 0.466; p = 0.001). CONCLUSION: MP/D may prove useful in detecting glaucomatous optic nerve damage and could be an interesting screening tool for primary open angle glaucoma.     

Pattern electroretinogram and optic nerve topography in ocular hypertension

It is known that changes in pattern electroretinogram (PERG) and optic disk morphology may both precede the onset of visual field damage in glaucomatous disease. However, the relationship between PERG and optic disk morphometry in ocular hypertension (OHT) has not yet been evaluated in detail. This study of PERG amplitude in a group of OHT patients indicates its significant correlation with various optic disk morphometric parameters, in particular, those of optic disk sectors considered at risk for early glaucomatous damage. Analysis of individual data points to the possibility that, while functional abnormalities may often precede optic disk morphologic changes, in a much lower number of cases it seems to be the other way around.     

Streptozotocin-induced diabetic cynomolgus monkey is a model of hypertriglyceridemia with low high-density lipoprotein cholesterol

BACKGROUND: Cardiac allograft rejection is accompanied by cellular infiltration and tissue edema resulting in myocardial relaxation abnormalities. Doppler tissue imaging is capable of measuring myocardial relaxation velocities and is useful in the detection of heart rejection. However, the influence of ventricular loading conditions on myocardial relaxation velocities has not been studied. This study is performed to determine whether myocardial relaxation velocities are affected by left ventricular loading conditions. METHODS: Twenty heart transplant recipients without evidence of rejection by endomyocardial biopsy underwent preload and afterload reduction with nitroglycerin. The pulmonary wedge pressure was reduced from 18.2+/-0.9 to 12.0+/-0.9 mm Hg 9 (p=0.001) and the mean blood pressure from 130.0+/-5.6 to 116.1+/-7.0 mm Hg (p=0.001). Pulsed-wave Doppler tissue imaging was performed before and after administration of nitroglycerin, and the peak myocardial relaxation velocities of the inferior wall were measured. RESULTS: Myocardial relaxation velocities did not change with the administration of nitroglycerin; 0.188+/-0.009 to 0.178+/- 0.006 m/sec (p=0.4) in spite of a significant reduction in pulmonary capillary wedge pressure. Furthermore, there was no correlation between pulmonary capillary wedge pressure, mean arterial pressure, wall stress, and myocardial relaxation velocities. CONCLUSIONS: Loading conditions on the left ventricle have no influence on myocardial relaxation velocities. Therefore in heart transplant recipients changes in myocardial relaxation velocities by Doppler tissue imaging may be useful in the diagnosis of rejection, in spite of diverse loading conditions.     

Effects of sublingual nitroglycerin on the gas exchange response to exercise in stable angina pectoris

To quantitate changes in gas exchange variables that occur after administration of sublingual nitroglycerin in patients with stable angina pectoris, a randomized double-blind 2-period crossover study was performed with continuous expired gas exchange analysis and progressive exercise using individualized ramp treadmill protocols. Significant reductions in minute ventilation and respiratory rate were observed at 5 minutes of exercise during nitroglycerin therapy. Gas exchange variables i.e., minute ventilation, carbon dioxide production and oxygen uptake were significantly increased at the onset of angina after nitroglycerin administration. When techniques for optimizing the assessment of cardiopulmonary function were used, significant improvements in gas exchange variables were demonstrated in stable angina pectoris after administration of sublingual nitroglycerin.     

Preoperative radiotherapy for prevention of heterotopic ossifications after hip endoprosthesis]

Glaucoma is a leading cause of blindness worldwide and the second leading cause of irreversible blindness in the United States. The most common form of glaucoma, primary open angle glaucoma, is characterized by a chronically elevated intraocular pressure in the absence of any demonstrable structural abnormalities in the eye. The pathologic hallmark of glaucomatous optic neuropathy is the selective death of retinal ganglion cells, generally attributed to an elevated intraocular pressure. However, the histopathology of glaucomatous injury is strikingly similar to the pattern seen with the administration of toxic levels of glutamate. We have found that glaucoma is associated with elevated levels of intraocular glutamate-to a level toxic to ganglion cells. We propose that an elevation of vitreal glutamate may be responsible, at least in part, for the loss of ganglion cells seen in open angle glaucoma.