Long-term Aspirin Administration Research Articles

Long-term aspirin administration suppresses inflammation in diabetic cystopathy.

Diabetic cystopathy (DCP) is one of the most common and troublesome urologic complications of diabetes mellitus, characterized by chronic low-grade inflammatory response. However, the correlation between inflammation and disease progression remains ambiguous and effective drugs interventions remain deficient. Herein, during 12-week study, 48 male Sprague-Dawley rats were randomly assigned to four groups: negative control (NC), NC treated with aspirin (NC+Aspirin), DCP, and DCP treated with aspirin (DCP+Aspirin). Type 1 diabetes mellitus was established by intraperitoneal injection of streptozotocin (65 mg/kg). After 2 weeks modeling, the rats in treatment groups received daily oral aspirin (100 mg/kg/d). After 10 weeks of treatment, aspirin ameliorated pathological weight loss and bladder weight increase in diabetic rats, accompanied by a 16.5% decrease in blood glucose concentrations. H&E, Masson, immunohistochemistry and transmission electron microscopy revealed that a dilated bladder with thickened detrusor smooth muscle (DSM) layer, inflammatory infiltration, fibrosis and ultrastructural damage were observed in diabetic rats, which were obviously ameliorated by aspirin. The dynamic investigations at 4, 7 and 10 weeks revealed inflammation gradually increased as the disease progresses. After 10 weeks of treatment, the expression of TNF-α, IL-1β, IL-6, and NF-κB has been decreased to 78%, 39.7%, 44.1%, 33.3% at mRNA level and 67.6%, 76.7%, 71.4%, 67.1% at protein level, respectively (DCP+Aspirin vs. DCP, p < 0.01). Aspirin partially restored the increased expression of inflammatory mediators in bladder DSM of diabetic rats. The study provided insight into long-term medication therapies, indicating that aspirin might serve as a potential strategy for DCP treatment.

Aspirin Affects MDA-MB-231 Vesicle Production and Their Capacity to Induce Fibroblasts towards a Pro-Invasive State.

Long-term administration of aspirin (ASA, acetylsalicylic acid) in oncogenic patients has been related to a reduction in cancer risk incidence, but its precise mechanism of action is unclear. The activation of cancer-associated fibroblasts (CAFs) is a key element in tumor progression and can be triggered by cancer-derived extracellular vesicles (EVs). Targeting the communication between cancer cells and the surrounding tumor microenvironment (TME) may control cancer progression. Our aim was to investigate the effect of ASA on breast cancer cells, focusing on EV secretion and their effect on the biological properties of CAFs. As a result, ASA was shown to reduce the amount and alter the size distribution of EVs produced by MDA-MB-231 tumor cells. Fibroblasts stimulated with EVs derived from MDA-MB-231 treated with ASA (EV-ASA) showed a lower expression of alpha-smooth muscle actin (α-SMA), matrix metalloproteinase-2 (MMP2) but not fibroblast activation protein (FAP) in respect to the ones stimulated with EVs from untreated breast cancer cells (EV-CTR). Furthermore, invasion assays using a three-dimensional (3D) fibroblast spheroid model showed reduced MDA-MB-231 invasion towards fibroblast spheroids pretreated with EV-ASA as compared to spheroids prepared with EV-CTR-stimulated fibroblasts. This suggests that ASA partially inhibits the ability of tumor EVs to stimulate CAFs to promote cancer invasion. In conclusion, ASA can interfere with tumor communication by reducing EV secretion by breast tumor cells as well as by interfering with their capacity to stimulate fibroblasts to become CAFs.

Alleviating Aspirin-Induced Gastric Injury by Binding Aspirin to β-Lactoglobulin.

PurposeGastric injury is a major issue for long-term administration of aspirin. In this work, we tried to explore the possibility of using BLG to alleviate aspirin-induced gastric injury, because of excellent abilities of BLG in loading drug molecules.MethodsVarious spectroscopic techniques and molecular docking methods were applied to investigate the interaction mechanism between BLG and aspirin. Animal experiments were performed to figure out the effects of taking aspirin-BLG on the stomach.ResultsOur results demonstrate that aspirin could bind with BLG to form stable aspirin-BLG complex (the binding constant Kb= 2.051 × 103 M−1). The formation process is endothermic (∆H>0) and the main acting force is hydrophobic force. Our data also show that the aspirin-BLG complex is formed with a higher affinity in simulated gastric fluid and could remain stable for several hours, which might arise from its special binding mode under acidic condition and the resistance of BLG to gastric digestion. Furthermore, animal models (rats with aspirin-induced gastric damage) were built. The results of animal experiments reveal that the oral administration of aspirin-BLG could cause less damage to gastric tissue, and it also hardly triggers obvious inflammatory responses.ConclusionThis study would contribute to an in-depth understanding of the interaction mechanism between BLG and aspirin. It is reasonable to believe that using BLG to bind with aspirin would be a potential way to alleviate the aspirin-induced gastric injury.

Effect of aspirin to intentionally induce leaky gut on performance, inflammation, and carcass characteristics of feedlot cattle

The negative impacts of stress on gastrointestinal tract (GIT) barrier function can result in compromised animal growth and health. Aspirin is known to cause mucosal injury leading to increased gut permeability and tight junction damage and can be used as a model to study leaky gut in cattle. The objective of this study was to determine the long-term impact of aspirin-induced chronic leaky gut on cattle growth and carcass attributes. Two treatments were evaluated in two studies: control (no aspirin) or 0.25% of the diet dry matter (DM) aspirin fed daily. Diets consisted of 50% corn, 24% dried distillers grains, 20% corn silage, and 6% supplement on a DM basis. In experiment 1, sixteen Angus × Simmental heifers, allotted by body weight (BW) and breed composition, were fed diets for 154 d. On day 155, heifers were dosed with 1 liter of a 180-mM Cr-ethylenediaminetetraacetic acid solution using an esophageal tube and had urine collected every 1.5 to 3 h for 48 h for analysis of Cr as a measure of gut leakiness. In experiment 2, ninety-six Simmental × Angus steers (355.0 ± 14.8 kg) were allotted by BW and breed composition and fed treatment diets for 159 d. Weight was recorded monthly and serum was collected on day 159 and analyzed for lipopolysaccharide-binding protein (LBP), interleukin-6 (IL-6), serum amyloid A (SAA), haptoglobin, and aspartate aminotransferase (AST). Data were analyzed using the MIXED procedure of SAS. Heifers fed 0.25% aspirin in experiment 1 excreted more Cr into urine compared with heifers not fed aspirin (overall treatment effect, P = 0.01). In experiment 2, aspirin tended to increase serum LBP (P = 0.06) but had no effect on concentrations of IL-6, haptoglobin, SAA, or AST (P ≥ 0.25). Aspirin tended to decrease average daily gain (P = 0.10), decreased hot carcass weight and rib-eye area (P ≤ 0.05), and increased fat thickness, marbling score, and yield grade (P ≤ 0.02). Aspirin tended to increase kidney, pelvic, and heart fat percentage (P = 0.10) and had no effect on liver abscesses (P ≥ 0.80). This study indicates that leaky gut induced by long-term administration of aspirin has negative impacts on feedlot performance and carcass composition. The negative impact of aspirin-induced leaky gut on animal performance suggests that chronic leaky gut caused by other factors (subacute acidosis, stress) may be a significant problem for the feedlot industry.

PSII-12 Effect of aspirin to intentionally induce leaky gut on performance, blood markers of stress, and carcass characteristics of feedlot cattle

Abstract The negative impacts of stress on gastrointestinal (GIT) barrier function can result in compromised animal health. Aspirin (acetylsalicylic acid) is known to cause mucosal injury leading to increased gut permeability and tight junction damage. The objective of this study was to determine the long-term impact of leaky gut on animal physiology. In this experiment, 96 Simmental x Angus steers (355 ± 14.8 kg) were allotted by body weight and breed into two treatments: control (no aspirin) or aspirin fed at 50 mg/kg/d for 159 d. Steers were housed in 16 pens (8 pens/treatment) with 6 steers in each pen. Weight was recorded monthly and serum was collected on d 159 to be analyzed for lipopolysaccharide binding protein (LBP), interleukin-6 (IL-6), serum amyloid A (SAA), haptoglobin, and aspartate aminotransferase (AST). Data were analyzed using the MIXED procedure of SAS. Average daily gain (ADG) tended to decrease in cattle fed aspirin (P= 0.10). Aspirin decreased hot carcass weight (P= 0.05) and rib-eye area (P= 0.01)and increased fat thickness (P= 0.02), marbling score (P = 0.003), and yield grade (P = 0.01). Percent KPH tended to increase (P= 0.10) for steers fed aspirin. Aspirin had no effect on body weight, dry matter intake, gain:feed, days on feed, dressing percentage, liver abscess score, or percent liver abscesses. Aspirin tended to increase serum LBP (P= 0.07), but had no effect on serum concentrations of IL-6, haptoglobin, SAA, and AST (P≥ 0.30). This study indicates that leaky gut induced by long-term administration of aspirin has negative impacts on feedlot performance and carcass leanness. The negative impact of aspirin induced leaky gut on animal performance suggests that leaky gut caused by other factors (subacute acidosis, stress) may be a significant problem for the feedlot industry.

Long-Term Aspirin Administration Has No Effect on Erectile Function: Evidence from Adult Rats and Ageing Rat Model

As the broad spectrum pharmacological action, aspirin has been one of the most widely used medicines since its initial synthesis; however, the association between aspirin and erectile function is still controversial. We aim to explore whether long-term aspirin administration deteriorates or preserves erectile function from adult rats and ageing rat model. Twenty adult rats (10 weeks of age) and twenty ageing rats (80 weeks of age) were randomly divided into four groups as follows: Adult-Control (normal saline [NS]), Adult-Aspirin (aspirin, 10 mg/kg/d), Ageing-Control (NS), and Ageing-Aspirin (aspirin, 10 mg/kg/d) groups (n = 10 per group). For all rats, erectile function was assessed by maximum intracavernous pressure (ICP), total area under ICP curve (AUC), ICP/mean arterial pressure (MAP) ratio, and MAP. The total treatment duration was one month. Protein expression levels of cyclooxygenase-1 (COX-1), COX-2, endothelial nitric oxide synthase (eNOS), and nNOS of the corpus cavernosum were detected by Western blot. ELISA kits were used to determine 6-keto PGF1a, PGE2, TXB2, cyclic adenosine monophosphate (cAMP), and cyclic guanosine monophosphate (cGMP) levels. Total nitric oxide (NO) concentration was measured using a fluorometric assay kit. As a result, Ageing-Control rats revealed significantly decreased ICP, AUC, and ICP/MAP ratios compared to Adult-Control rats, and these effects were accompanied by reduced eNOS protein expression and lower total NO and cGMP levels; however, no difference was found in nNOS protein expression. For adult rat groups, aspirin significantly inhibited the production of 6-keto PGF1a, PGE2, and TXB2; however, it neither changed the ICP, AUC, or ICP/ MAP ratios nor altered the protein expression of eNOS, nNOS, COX-1, and COX-2. Meanwhile, aspirin did not influence the concentrations of total NO, cAMP, or cGMP. The same tendency was also found in the ageing rat model, which confirmed that aspirin did not alter erectile function. Our data suggested that long-term aspirin administration did not strengthen or weaken erectile function in adult rats or ageing rat model. Thus, it had no impact on erectile function.

Aspirin blocks formation of metastatic intravascular niches by inhibiting platelet-derived COX-1/thromboxane A2.

Because metastasis is associated with the majority of cancer-related deaths, its prevention is a clinical aspiration. Prostanoids are a large family of bioactive lipids derived from the activity of cyclooxygenase-1 (COX-1) and COX-2. Aspirin impairs the biosynthesis of all prostanoids through the irreversible inhibition of both COX isoforms. Long-term administration of aspirin leads to reduced distant metastases in murine models and clinical trials, but the COX isoform, downstream prostanoid, and cell compartment responsible for this effect are yet to be determined. Here, we have shown that aspirin dramatically reduced lung metastasis through inhibition of COX-1 while the cancer cells remained intravascular and that inhibition of platelet COX-1 alone was sufficient to impair metastasis. Thromboxane A2 (TXA2) was the prostanoid product of COX-1 responsible for this antimetastatic effect. Inhibition of the COX-1/TXA2 pathway in platelets decreased aggregation of platelets on tumor cells, endothelial activation, tumor cell adhesion to the endothelium, and recruitment of metastasis-promoting monocytes/macrophages, and diminished the formation of a premetastatic niche. Thus, platelet-derived TXA2 orchestrates the generation of a favorable intravascular metastatic niche that promotes tumor cell seeding and identifies COX-1/TXA2 signaling as a target for the prevention of metastasis.

Metabolism of liver CYP450 and ultrastructural changes after long-term administration of aspirin and ibuprofen.

Worldwide, aspirin and ibuprofen are the most commonly used non-steroidal anti-inflammatory drugs (NSAIDs). Some adverse reactions, including gastrointestinal reactions, have been concerned extensively. Nevertheless, the mechanism of liver injury remains unclear. In the present study, we focused on the metabolism of liver cytochrome P450 (CYP450) and ultrastructural morphology of liver cells. A total of thirty rats were divided into three groups of 10. Rats in the aspirin and ibuprofen groups were given enteric-coated aspirin (15 mg/kg) and ibuprofen (15 mg/kg), respectively by gavage for four weeks. The body weights were recorded every two days. Liver function and metabolic capacity of CYP450 were studied on days 14 and 28. We then conducted ultrastructural examinations. Body weights in the Ibuprofen group were lower than those of the Control group, and ALT and AST levels were significantly higher (P < 0.05). There were no significant differences in terms of body weight, ALT or AST between the Aspirin and Control groups. The metabolic capacity of CYP450 was evaluated using five probe drugs, phenacetin, tolbutamide, metoprolol, midazolam, and bupropion. We found that ibuprofen and aspirin induced metabolism of the probe drugs. Moreover, according to the pharmacokinetic data, the Control, Aspirin and Ibuprofen groups could be discriminated accurately. Ultrastructural examination showed that the number of mitochondria was increased in both the Ibuprofen and Aspirin groups. Long-term administration of enteric-coated aspirin and ibuprofen induced the metabolic activity of the CYP450 enzyme. Aspirin had better tolerability than did ibuprofen, as reflected by pharmacokinetic data of probe drug metabolism.

Impact of Medication Adherence on Mortality and Cardiovascular Morbidity: Protocol for a Population-Based Cohort Study.

BackgroundCardiovascular disease (CVD) is a group of disorders of the heart and blood vessels, such as coronary heart disease (CHD), cerebrovascular disease, and peripheral artery disease. CVD is the leading threat to global health, whether measured by mortality, morbidity, or economic cost. Long-term administration of aspirin, statins, beta-blockers, and angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers improves survival in patients with stablished coronary heart disease. Nevertheless, adherence to prescribed medication is poor for long-term drug treatment.ObjectiveWe aim to assess the relationship between adherences to the four pharmacological groups recommended for secondary prevention and the clinical outcomes of cardiovascular morbidity and mortality in patients with established CHD according to the level of adherence to these drugs in a population of incident cases of acute coronary syndrome (ACS).MethodsPopulation-based cohort study of patients with a first episode of ACS during 2006-2015 in the Information System for Research in Primary Care (SIDIAP) database. We will estimate adherence to these drugs. The primary endpoint is a composite of all-cause mortality, ACS, and ischaemic stroke. Bivariate analyses will be performed estimating odds ratios for categorical variables and mean differences for continuous variables. Hazard ratios for adherences will be calculated for outcome events using Cox proportional hazard regression models, and proportionality of hazards assumption will be tested.ResultsWe expect to estimate adherence to all four study treatments, the incidence of MACE, and to analyze if this incidence is associated with the level of drug adherence.ConclusionsWe expect to find that adherent patients have a lower risk of the primary endpoints compared with nonadherent patients.Trial RegistrationThis study protocol was classified as EPA-OD by the AEMPS (IJG-EST-2017-01-2017-01, 07/04/2017) and registered in the EU PAS register (EUPAS19017, 09/05/2017).

Aspirin Reduces Cardiac Interstitial Fibrosis by Inhibiting Erk1/2-Serpine2 and P-Akt Signalling Pathways

Background/Aims: Cardiac interstitial fibrosis is an abnormality of various cardiovascular diseases, including myocardial infarction, hypertrophy, and atrial fibrillation, and it can ultimately lead to heart failure. However, there is a lack of practical therapeutic approaches to treat fibrosis and reverse the damage to the heart. The purpose of this study was to investigate the effect of long-term aspirin administration on pressure overload–induced cardiac fibrosis in mice and reveal the underlying mechanisms of aspirin treatment. Methods: C57BL/6 mice were subjected to transverse aortic constriction (TAC), and treated with 10 mg·kg^-1·day^-1 of aspirin for 4 weeks. Masson staining and a collagen content assay were used to detect the effects of aspirin on cardiac fibrosis in vivo and in vitro. Western blot and qRT-PCR were applied to examine the impact of aspirin on extracellular signal-regulated kinases (Erks), p-Akt/β-catenin, SerpinE2, collagen I, and collagen III levels in the mice heart. Results: Aspirin significantly suppressed the expression of α-smooth muscle actin (α-SMA; 1.19±0.19-fold) and collagen I (0.95±0.09-fold) in TAC mice. Aspirin, at doses of 100 and 1000 µM, also significantly suppressed angiotensin II-induced α-SMA and collagen I in cultured CFs. The enhanced phosphorylation of Erk1/2 caused by TAC (p-Erk1, 1.49±0.19-fold; p-Erk2, 1.96±0.68-fold) was suppressed by aspirin (p-Erk1, 1.04±0.15-fold; p-Erk2, 0.87±0.06-fold). SerpinE2 levels were suppressed via the Erk1/2 signalling pathway following treatment with aspirin (1.36±0.12-fold for TAC; 1.06±0.07-fold for aspirin+TAC). The p-Akt and β-catenin levels were also significantly inhibited in vivo and in vitro. Conclusions: Our study reveals a novel mechanism by which aspirin alleviates pressure overload-induced cardiac interstitial fibrosis in TAC mice by suppressing the p-Erk1/2 and p-Akt/β-catenin signalling pathways.

Short- Versus Long-Term Duration of Dual Antiplatelet Therapy in Patients Treated for In-Stent Restenosis: A PRODIGY Trial Substudy (Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia)

This study sought to investigate the clinical outcome of patients treated with percutaneous coronary intervention (PCI) for in-stent restenosis (ISR) randomized to short (6 months) versus long (24 months) dual antiplatelet therapy (DAPT) regimen. It is still unclear if patients treated for ISR may benefit from a long DAPT regimen. For the present purpose, we selected 224 patients undergoing the PCI procedure for ISR enrolled in the PRODIGY (Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia) trial and randomized to short (6 months) versus long (24 months) DAPT regimen. The primary objective was the cumulative incidence of death, nonfatal myocardial infarction (MI), or cerebrovascular accident at 24 months. Safety endpoints were moderate and major bleeding complications. Overall, 114 patients were allocated to short DAPT regimen, whereas 110 patients were allocated to long DAPT regimen. Twenty-seven patients reached the primary endpoint (19 in short DAPT regimen vs. 8 in long DAPT regimen; p= 0.02). The cumulative incidence of the primary endpoint at 24 months was 16.7% in the short DAPT regimen group compared with 7.3% in the long DAPT regimen group (p= 0.034). This is principally due to a lower occurrence of death and MI in the long DAPT regimen group as compared to the short DAPT regimen group (6.5%vs.15.5%; p= 0.03). There was no difference in the occurrence of bleeding complications between long and short DAPT regimen. Our study offers preliminary evidence that patients receiving a new PCI procedure for ISR may benefit from long-term administration of aspirin plus clopidogrel. (Synergy Between Stent and Drugs to Avoid Ischemic Recurrences After Percutaneous Coronary Intervention [PRODIGY]; NCT00611286).

Sa1023 A Prospective Evaluation of Multi-Factors on the Efficacy of Transjugular Intrahepatic Portosystemic Shunt in the Patients With Hepatitis B Virus Related Hepatic Cirrhosis

Background: Variceal bleeding is the third cause of deaths from cirrhosis. Numerous treatments for variceal bleeding are available. Treatment with a transjugular intrahepatic portosystemic shunt (TIPS) combined with adjunctive embolotherapy of gastroesophageal collateral vessels (AEGCV) is expected to further reduce the rate of rebleeding through embolization of persistent patent collaterals. In addition, it was reported that anticoagulation agents may partly reduce the shunt occlusion before the application of covered stent and the oral antiviral drugs could improve underlying liver function in decompensated patients. However, the long term survival of cirrhotic patients after TIPS creation is still not optimal due to the mortality may be determined by multi-factors. Objective: This prospective study was aimed to investigate the effects of TIPS combined with AEGCV, aspirin administration and antiviral drug on the shunt patency, rebleeding and survival. Methods: 114 eligible patients with hepatitis B virus (HBV) related-hepatic cirrhosis were included and were randomly assigned into the TIPS alone (n=57) and TIPS +AEGCV (n=57) groups. Aspirin was prescribed to all of them and adefovir dipivoxil was administrated by the patients with detectable HBV-DNA after TIPS creation. Then all the patients were prospectively followed up between May 2007 and July 2011. The primary outcomes included shunt occlusion, first variceal rebleeding and deaths related to the primary liver diseases, which were estimated by Kaplan-Meier method. The prognostic relevance of treatment and selected variables with respect to patency, rebleeding and survival were analyzed with Cox multivariate analysis. Results: Although the 3 years' cumulative rates of shunt patency, variceal rebleeding and survival of patients in TIPS+AEGCV or TIPS alone groups did not show the significant difference, p>0.05, the cumulative outcomes of shunt patency (90.8%) and variceal rebleeding (3.5%) in TIPS+AEGCV group was significantly better than those (80.7% and 10.1%) in TIPS alone group at half year, p<0.05. The risk ratio (RR) of aspirin administration ≥ 1 year for shunt patency was 0.434, p<0.05. The RRs of aspirin administration ≥ 1 year and shunt patency for variceal rebleeding were 0.487 and 0.301, p<0.05. The 3 years'overall survival rate was 85.1%. Both RRs of Child-Pugh score ≤ 9 (preor post-TIPS) and adefovir administration ≥ 0.5 year for survival were less than 0.3, p<0.05. Conclusion: TIPS combined with sufficient AEGCV and long term administration of aspirin at low dose after TIPS placement are helpful to prolong the survival through keeping shunt patency and controlling variceal rebleeding. For the patients with HBV infection, oral adefovir may further improve the survival.

Long-term administration of aspirin inhibits tumour formation and triggers anti-neoplastic molecular changes in a pre-clinical model of colon carcinogenesis

Despite numerous studies aimed at verifying the anti-tumour activity of aspirin on colon carcinogenesis little is known on the molecular targets involved in the anti-carcinogenic properties of this drug. We investigated the long-term administration of low dose of aspirin in a model of experimental colon carcinogenesis in rats. Adult Wistar rats received an intraperitoneal injection of azoxymethane (AOM) once a week for two weeks in order to initiate colon carcinogenesis. One week after AOM injection, rats received daily 0.01% aspirin (6 mg/kg body weight) in drinking water for 10 months. Compared to AOM control rats, aspirin treatment for 10 months caused a 50% reduction of the number of aberrant crypt foci associated with a 50% reduction of prostaglandin E2 (PGE2) concentration and suppressed by 80% tumour formation in the colon. RT-PCR quantitative analysis showed that aspirin treatment reduced significantly (P<0.01) the AOM-triggered increase in mRNA levels of soluble inflammatory mediators (TNFalpha and IL-1beta) and metalloproteinases (MMP3 and MMP7). Conversely, we detected an increased expression level of alpha-defensin-5 (Rd-5, 2 fold) and lipocalin-2 (LCN2, 4 fold), two markers of the innate immunity system. The expression of apoptosis-related genes such as death receptors and their ligands were reduced by aspirin and the Bcl-2/Bax transcript ratio droped, Bcl-2 expression being reduced to the level found in saline control rats. The present study identifies new molecular targets triggered by aspirin in the colonic mucosa and may support the use of non-toxic low dose of aspirin in long-term treatments as a prophylactic approach against colon carcinogenesis.

Effects of low-dose aspirin on endothelial function in hypertensive patients.

It has been reported that administration of low-dose aspirin significantly reduces the frequency of major cardiovascular events in patients with hypertension and coronary artery disease. It is generally considered that the preventative effects of long-term aspirin administration on major cardiovascular events are due to the inhibition of platelet aggregation. It is not known whether administration of low-dose aspirin restores endothelium-dependent vasodilatation, and this study was undertaken to prove or disprove this question in patients with hypertension. Flow-mediated endothelium-dependent dilatation and glyceryl trinitrate-induced endothelium-independent dilatation were investigated in 18 hypertensive patients and 10 normotensive control subjects. In the hypertensive patients, flow-mediated dilatation was investigated and cyclic guanosine monophosphate plasma (cGMP) was measured before and at 8 weeks after the administration of 162 mg of aspirin. Flow-mediated dilatation before aspirin administration was more reduced in the hypertensive patients than in the control subjects (6.4+/-2.0% vs. 11.3+/-2.3%, p <0.0001). Glyceryl trinitrate-induced dilatation before aspirin administration was similar in hypertensive patients and control subjects. Flow-mediated dilatation after aspirin administration was improved compared with that before aspirin administration (10.4+/-3.5% vs. 6.4+/-2.0%, p<0.0004). The cGMP product after aspirin administration was significantly higher than that before aspirin administration. Administration of low-dose aspirin may restore the endothelium-dependent vasodilatation in hypertensive patients. Furthermore, increased nitric oxide production may play a partial role in the improvement in endothelial function induced by administration of low-dose aspirin.

Association of 72-kDa heat shock protein expression with adaptation to aspirin in rat gastric mucosa.

It is well documented that gastric mucosa can increase its resistance to mucosal damage caused by aspirin during repeated long-term administration of aspirin. However, the underlying mechanism of this adaptation is not well established. In the present study, we investigated the effect of long-term (chronic) administration of aspirin on expression of heat shock proteins (HSPs), which are known as endogenous cytoprotectants, in rat gastric mucosa. Rats were administered aspirin (100 mg/kg) daily for up to 20 days. After various periods of aspirin administration, a high dose of aspirin (250 mg/kg) was administered, and the mucosal damage was assessed. Expression of heat shock proteins (HSPs) in gastric mucosa was evaluated by Western blot. Intracellular localization of each HSP was studied immunohistochemically. Prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) levels were also investigated. Long-term aspirin administration resulted in development of resistance to aspirin-induced mucosal damage, and the increase of HSP72 expression correlated with mucosal resistance to aspirin. No significant increase was observed in HSP60 and HSP90 levels. Immunohistochemical study showed an increase of HSP72 in the cytoplasm of mucosal surface cells. The PGE2 level was suppressed and no change in the level of LTB4 was observed. It is possible that HSP72 could play important roles in gastric mucosal adaptation when the PGE2 level is suppressed by NSAIDs.

Increased gastroduodenal concentrations of transforming growth factor alpha in adaptation to aspirin in monkeys and rats

BACKGROUND & AIMS: The mechanism by which gastric mucosa becomes more resistant to damage by repeated aspirin administration is not known. Transforming growth factor alpha (TGF-alpha) and epidermal growth factor (EGF) prevent drug-induced gastric injury. The aim of this study was to determine whether gastroduodenal tissue levels of TGF-alpha and EGF protein were altered during adaptation to aspirin-induced injury in monkeys and rats in vivo. METHODS: Animals were given aspirin daily for up to 28 days. Gross mucosal injury was assessed by computerized image analysis in rats and by endoscopy in monkeys. Mucosal concentrations of TGF-alpha and EGF were quantitated by radioimmunoassays from endoscopic biopsy samples in monkeys and from scraped mucosa in rats. RESULTS: Long-term administration of aspirin caused a significant increase in gastric and duodenal tissue levels of TGF-alpha in monkeys and rats; the increased levels of TGF-alpha significantly correlated with the decrease in aspirin-induced injury. No change in the gastroduodenal tissue levels of EGF was observed. Adaptation was not associated with any significant change in basal gastric acid secretion in monkeys and occurred despite a significant decrease in gastric mucin in rats. CONCLUSIONS: Adaptation of the gastric mucosa to the damaging effect of aspirin is associated with a significant and specific increase in TGF- alpha protein in the gastroduodenum. (Gastroenterology 1996 May;110(5):1448-55)

Prostaglandins modulate the responsiveness of the gastric microcirculation of sodium nitroprusside in cirrhotic rats

Cirrhotic rats have an increased susceptibility to ethanol-induced gastric injury, related to an inability to mount a defensive gastric hyperemic response to luminal irritants, and associated with an impaired reactivity of the gastric microcirculation to nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)-dependent vasodilators. Whether this hyporesponsiveness is in some way related to depressed prostaglandin synthesis by the stomach of cirrhotic rats is not clear. The aims of this study were to evaluate the role of NO and prostaglandins in the regulation of the gastric microcirculation under resting conditions and in response to administration of sodium nitroprusside, as well as to investigate the mechanisms of the hyporesponsiveness of the gastric microcirculation to nitrovasodilators. Cirrhosis was induced in rats by bile duct ligation, and controls had sham-operation. NG-nitro-L-arginine-methyl-ester (L-NAME) and indomethacin administration produced a greater reduction in gastric blood flow in cirrhotic rats than controls. Indomethacin pretreatment almost completely abolished the responsiveness to sodium nitroprusside (NaNP) in cirrhotic rats, while not affecting controls. Long-term administration of misoprostol to cirrhotic rats restored to normal the responsiveness to NaNP, whereas long-term administration of aspirin to healthy rats resulted in a hyporesponsiveness of the gastric microcirculation to NaNP similar to that seen in cirrhotic rats. We conclude that there are interactions between NO and prostaglandins in regulating gastric blood flow in both healthy and cirrhotic rats. The hyporesponsiveness of the gastric microcirculation of cirrhotic rats to a nitrovasodilator may occur as a consequence of prolonged depression of gastric prostaglandin synthesis.

Prostaglandins modulate the responsiveness of the gastric microcirculation of sodium nitroprusside in cirrhotic rats

Cirrhotic rats have an increased susceptibility to ethanol-induced gastric injury, related to an inability to mount a defensive gastric hyperemic response to luminal irritants, and associated with an impaired reactivity of the gastric microcirculation to nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)-dependent vasodilators. Whether this hyporesponsiveness is in some way related to depressed prostaglandin synthesis by the stomach of cirrhotic rats is not clear. The aims of this study were to evaluate the role of NO and prostaglandins in the regulation of the gastric microcirculation under resting conditions and in response to administration of sodium nitroprusside, as well as to investigate the mechanisms of the hyporesponsiveness of the gastric microcirculation to nitrovasodilators. Cirrhosis was induced in rats by bile duct ligation, and controls had sham-operation. NG-nitro-L-arginine-methyl-ester (L- NAME) and indomethacin administration produced a greater reduction in gastric blood flow in cirrhotic rats than controls. Indomethacin pretreatment almost completely abolished the responsiveness to sodium nitroprusside (NaNP) in cirrhotic rats, while not affecting controls. Long-term administration of misoprostol to cirrhotic rats restored to normal the responsiveness to NaNP, whereas long-term administration of aspirin to healthy rats resulted in a hyporesponsiveness of the gastric microcirculation to NaNP similar to that seen in cirrhotic rats. We conclude that there are interactions between NO and prostaglandins in regulating gastric blood flow in both healthy and cirrhotic rats. The hyporesponsiveness of the gastric microcirculation of cirrhotic rats to a nitrovasodilator may occur as a consequence of prolonged depression of gastric prostaglandin synthesis. (Hepatology 1996 Jan;23(1):123-9)

The effect of long-term administration of aspirin and sodium saccharin on the rat kidney

In a study primarily designed to evaluate the inhibitory effects of aspirin on N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT)-initiated and saccharin-promoted bladder carcinogenesis, significant renal lesions were observed. Thus, administration in the diet of aspirin and sodium saccharin to F344 male rats for 68 weeks resulted in significant lesions of the renal papilla. In contrast to the bladder, aspirin enhanced the frequency and severity of the proliferative action of sodium saccharin on the epithelium of the renal papilla ( p < 0.05 compared to rats treated with either compound alone). The majority of rats administered the two chemicals together demonstrated moderate to severe urothelial hyperplasia of the renal papilla. Columnar metaplasia of the papillary epithelium also occurred frequently in rats fed the combination of chemicals. The rats treated with a combination of sodium saccharin and aspirin had a high incidence of renal papillary necrosis which was also present to a lesser extent among rats treated with aspirin only. Papillary calcification was also frequently observed in the rats fed the combination of aspirin and sodium saccharin. Sodium saccharin or aspirin alone reduced the light microscopic incidence and severity of rat nephropathy, a common finding in aging rats. It would appear that the hyperplastic and renal papillary toxic effects of aspirin and sodium saccharin are independent responses, and that the administration of the two chemicals together greatly accentuates these responses.

Aspirin intolerance and asthmal induction of a tolerance and long‐term monitoring

Acetylsalicylic-acid (ASA) intolerance is well recognized as a possible cause for exacerbating asthma. It has been postulated that if this could be overcome, long-term aspirin administration could improve asthma symptoms and enable reduction of the use of other anti-asthmatic drugs. We succeeded in inducing an ASA tolerance in nine corticosteroid-dependent asthmatics, and this tolerance lasted at least 1 month and at most 1 year. Progressive deterioration in lung function was seen, however, in all patients taking ASA for more than 1 month, unless the corticosteroid intake was increased. These results suggest that ASA long-term treatment is of no help to severe corticosteroid-dependent, ASA-sensitive asthmatics. This conclusion differs from other reports on ASA intolerance in asthma.