A Comparative Study of the Effects of α1-Adrenoceptor Antagonists on Sympathetic Function in Rats

α₁-Adrenoceptor antagonists were comparatively evaluated in terms of their acute and long-term effects on sympathetic function in rats.In the first study, the effects of α₁-adrenoceptor antagonists on cardiovascular sympathetic nerve activity were electrophysiologically determined in anesthetized normotensive rats. Intravenous administration of four α₁-antagonists—prazosin, bunazosin, SM-2470, and YM-617—produced no changes or decreases in heart rate, in spite of the expected reflex tachycardia resulting from their marked hypotensive effect. Among the α₁-antagonists examined, some also produced a significant decrease in inferior cardiac nerve activity. All except prazosin decreased renal nerve activity, while prazosin showed an opposite tendency to increase the renal nerve activity. On the other hand, preganglionic adrenal nerve activity, an index of central sympathoinhibitory activity, underwent a significant decrease after SM-2470 and YM-617 administration, and a dose-dependent increase was observed in response to prazosin and bunazosin.In the second study, the long-term (4 weeks) effects of α₁-antagonists on plasma and urinary catecholamine levels and urinary electrolyte excretions were evaluated in stroke-prone spontaneously hypertensive rats (SHRSP). Prazosin and bunazosin did not exert any consistent changes on plasma and urinary catecholamine concentrations. SM-2470, however, significantly decreased both plasma and urinary epinephrine concentrations. In addition, bunazosin and SM-2470 produced increases in urinary sodium and potassium excretions. Urine volume tended to increase after bunazosin administration. Prazosin, on the other hand, produced decreases in urinary sodium and potassium excretions as well as in urine volume.These findings demonstrate that α₁-antagonists differentially affected cardiovascular sympathetic tone in anesthetized rats. These varied sympathoinhibitory profiles might be in part explainable as different effects on urinary electrolyte metabolism after long-term administration of α₁-antagonists in SHRSP. Am J Hypertens 1996;9:160S–169S     

Role of β-Adrenergic Receptor Subtypes in Lipolysis

In vitro lipolysis stimulated by low (-)-isopre-naline concentrations (30 nM) in epididymal white adipo-cytes from Sprague-Dawley rats was inhibited at least 60–80% by the specific ₁-antagonists LK 204-545 and CGP 20712A (1 M), suggesting that at these low (10 nM) concentrations of (-)-isoprenaline lipolysis was primarily (80%) but not solely mediated via ₁-adrenergic receptors. Low concentrations (100 nM) of (-)-noradrenaline and formoterol also confirmed a role for ₁-adrenergic receptors in mediating lipolysis at low concentrations of these agonists. At higher agonist concentrations, ₃-adrenergic receptors were fully activated and were the dominant -adrenergic receptor subtype mediating the maximum lipolytic response, and the maximum response was not affected by the ₁-antagonists, demonstrating that the ₃-receptor is capable of inducing maximum lipolysis on its own. Studies of lipolysis induced by the relatively ₂-selective agonist formoterol in the presence of ₁-blockade (1 M CGP 20712A) demonstrated the inability of the ₂-selective antagonist ICI 118-551 to inhibit the residual lipolysis at concentrations of ICI 118-551 1 M. Higher concentrations of ICI 118-551 inhibited the residual formoterol-induced lipolysis competetively, but with low affinity (500-fold lower than its ₂-adrenergic receptor pA ₂, 7.80 ± 0.21), suggesting that formoterol was not acting via ₂-adrenergic receptors. These data are consistent with ₁-adrenergic receptors playing an important role in lipolysis at physiological but not pharmacological concentrations of catecholamines and that ₂-adrenergic receptors play no obvious direct role in mediating -adrenergic receptor agonist-induced lipolysis in vitro. Finally, racemic-SR 59230A, unlike the pure (S, S)-isomer (a ₃-selective antagonist), was found to be a non-selective antagonist at the three -adrenergic receptor subtypes, showing that the other enantiomers have different selectivity.     

Comparison of Antihypertensive and β1-Adrenoceptor Antagonist Effect of Nebivolol and Atenolol in Essential Hypertension

dl-nebivolol is a new, chemically unique, selective β₁-adrenoceptor antagonist, without sympathomimetic activity. In the present study, the antihypertensive and negative chronotropic effects of 5 and 10 mg once-daily nebivolol were compared to those of 50 and 100 mg once-daily atenolol in 25 white, male subjects with essential hypertension, using a double-blind, crossover design, and a parallel placebo-treated group of subjects (N=7). 24 hours after dosing, sitting and standing diastolic and systolic blood pressures and heart rates (at rest and during submaximal exercise) were reduced to the same extent by nebivolol and atenolol. On a weight-for-weight basis, nebivolol is ten times more potent than atenolol. Nebivolol and atenolol also reduced 1-hour ambulatory plasma renin activity. Once-daily nebivolol is an effective antihypertensive β-adrenoceptor antagonist.     

Incidence and Risks of Congenital Anomalies of Kidney and Urinary Tract in Newborns: A Population-Based Case–Control Study in Taiwan

Congenital anomalies of the kidney and urinary tract (CAKUT) are 1 of the major factors in young adults needing renal replacement therapy, but there is little extensive assessment of their incidence and risk factors. This study aimed to evaluate trends in the incidence of and risk factors for CAKUT among all births in Taiwan.This population-based case–control study design was conducted using the Taiwan national births registry, which contains detailed information about maternal health and characteristics of newborns, supplied by health professionals. Of 1,603,794 newborns registered between 2004 and 2014, 668 infants were reported to have CAKUT. Newborns without congenital anomalies were matched with CAKUT cases by birth year, month, and Apgar score in a ratio of 5:1. Odds ratio (OR) and 95% confidence interval (CI) for developing CAKUT were calculated using a conditional multivariate logistic regression model.The incidence of CAKUT was approximately 4.2 per 10,000 births. The adjusted ORs for CAKUT in newborns associated with maternal age of 20 to 29 (OR, 2.18; 95% CI, 1.11–4.28), or 30 to 39 (OR, 2.29; 95% CI, 1.17–4.51), maternal gestational diabetes (OR, 2.22, 95% CI, 1.06–4.67), maternal thalassemia/hemochromatosis (OR, 2.67; 95% CI, 1.35–5.27), polyhydramnios or oligohydramnios (OR, 9.16; 95% CI, 5.46–15.37), birth parity >1 (OR, 0.27; 95% CI, 0.15–0.50), having a gestational age <37 weeks (OR, 1.48; 95% CI, 1.23–1.78), and being a boy (OR, 1.83; 95% CI, 1.53–2.19). Infants of mother with gestational diabetes were more likely to have congenital anomalies, small gestational age (<37 weeks) and low birth weight.CAKUT are associated with several maternal health risk factors. As Taiwan has the highest prevalence and incidence rates of end-stage renal disease in the world, these findings strongly support the need to develop professional guidelines for prenatal counseling and management of women at risk of adverse birth outcomes, to prevent kidney disease progression and reduce complications.     

Regional Distribution of Noradrenaline and Dopamine-β-Hydroxylase in the Brain of Spontaneously Hypertensive Rats

The catecholamine concentration and dopamine-β-hydroxylase activity were determined in several nuclei of the brain of spontaneously hypertensive rats (SHR) compared with Wistar Kyoto (WKY) controls. Catecholamines were measured by using liquid chromato-graphy coupled with electrochemical detection. The threshold of detection was 5 × 10^?14 mole. Dopamine-β-hydroxylase (DBH) was assayed by a sensitive radioenzymatic assay using tyramine as the substrate. The limit of detection was 5 pmoles of octopamine per sample.

Significantly lower noradrenaline content was observed in 4 week-old SHR in some medullary and hypothalamic areas which are involved in cardiovascular regulation. This abnormality was no longer detectable in 12 week-old rats. The changes in catecholamine levels observed in young rats were not observed during the development of deoxycorticosterone-salt hypertension and therefore probably do not represent a compensatory mechanism tending to limit the progressive rise blood pressure. No significant difference in DBH activity was observed between the young SHR and WKY in any brain region measured. The altered relationship between noradrenaline content and DBH activity observed in young SHR when compared to WKY suggests a change in noradrenergic neu-rones activity and/or structure which could correspond to a genetically transmitted neurochemical abnormality associated with the intitiation of hypertension in the SHR     

Taurine Ameliorates Water Avoidance Stress–Induced Degenerations of Gastrointestinal Tract and Liver

We investigated the role of taurine, is a potent free radical scavenger, on water avoidance stress (WAS)-induced degeneration of the gastric, ileal, and colonic mucosa and liver parenchyma. Wistar albino rats were exposed to chronic WAS (WAS group) 2 hr daily for 5 days. After exposing animals to chronic WAS (WAS + taurine group), 50 mg/kg taurine was injected IP for 3 days. Control animals received vehicle solution only. The stomach, ileum, colon, and liver samples were investigated under light microscope for histopathologic changes. To demonstrate the topography of the luminal mucosa of the stomach, ileum, and colon, scanning electron microscope was used and for hepatocyte ultastructure transmission electron microscope was used. Malondialdehyde (MDA, a biomarker of oxidative damage) and glutathione (GSH, a biomarker of protective oxidative injury) levels were also determined in all tissues. In the WAS group, the stomach epithelium showed ulceration in some areas, dilatations of the gastric glands, and degeneration of gastric glandular cells; prominent congestion of the capillaries was apparent. In the WAS group, severe vascular congestion was observed along with degeneration of ileal and colonic epithelium. Prominent vascular congestion and dilated sinusoids, activated Kupffer cells, dilated granular endoplasmic reticulum membranes, and focal pyknotic nuclei were observed in liver parenchyma. MDA levels (stomach, P < 0.01; ileum, colon, and liver P < 0.05) were increased and GSH levels (P < 0.01) were decreased in all tissues in the WAS group compared with the control group. The morphology of gastric, ileal, and colonic mucosa and liver parenchyma in the WAS + taurine group (stomach and ileum, P < 0.05; colon and liver, P < 0.01) showed a significant amelioration when compared to the WAS group. Increased MDA and decreased GSH levels in the WAS group were ameliorated with taurine treatment. Based on the results, taurine supplementation effectively attenuates the oxidative damage of gastrointestinal mucosa and liver because of WAS induction possibly by its antioxidant effects.     

Impact of Opium on the Serum Levels of TGF-β in Diabetic,Addicted and Addicted-Diabetic Rats

Background: Several cells of immune system such as regulatory T cells and macrophages secrete transforming growth factor-β (TGF-β) in response to different stimuli. This cytokine has inhibitory effect on immune system and diminished production of this cytokine is associated with autoimmune disorders. Objective: The aim of this study was to evaluate the influence of opium addiction on serum level of TGF-β in male and female diabetic and non-diabetic Wistar rats. Methods: This experimental study was performed on normal, opium addicted, diabetic and addicted-diabetic male and female rats. Serum level of TGF-β was measured by ELISA. Results: The results of our study indicated that the mean serum level of TGF-β in female addicted rats was significantly increased compared to control group (p<0.004). Conversely, in male addicted rats the mean serum level of TGF-β was lower compared with control (p<0.065). Conclusion: Our results suggest that opium and its derivatives have differential inductive effects on the cytokine expression in male and female rats.     

Gender and Estradiol as Major Factors in the Expression and Dimerization of nNOSα in Rats with Experimental Diabetic Gastroparesis

Background

The molecular mechanisms of cellular changes responsible for diabetic gastroparesis, primarily seen in middle-aged women, still remain incompletely defined. We hypothesized that a decrease in the expression, dimerization, and post-translational modification of neuronal nitric oxide synthase alpha (nNOSα) is estrogen mediated and responsible for the gender-specific prevalence of this malady.

Methods

We induced diabetes by injecting male and female rats with streptozotocin. Male diabetic rats without gastroparesis were then injected with estrogen for 3?weeks and evaluated for gastroparesis development. Gastric tissues were analyzed for the elucidation of biochemical events associated with diabetes and gastroparetic dysfunction.

Results

Although male diabetic, gastroparetic (either streptozotocin- or estrogen-induced) rats exhibited similarity in disease pathology to that of females, the molecular mechanisms of development were different. Our results indicate that slow gastric emptying in both male diabetic, gastroparetic rat groups was not associated with the level of expression of nNOSα in gastric tissues. However, nNOSα dimerization, which reflects nNOSα activation, did decline slightly in the antrum of diabetic males with estrogen-induced gastroparesis, suggesting a possible estrogen role. Females with diabetic gastroparesis, in contrast, demonstrated significantly impaired levels and dimerization of nNOSα in the antrum and pylorus. Although the precise mechanism remains unknown, nNOSα dimerization impairment in female antrum is apparently associated with reduced phosphorylation of Ser¹⁴¹⁶ in the activation loop of nNOSα.

Conclusion

Taken together, these results demonstrate that gender and estrogens may be leading factors, through molecular changes involved in nitric oxide synthesis down-regulation, within the antrum and pylorus of female diabetic, gastroparetic rats.     

Distribution of β-Thalassemia Mutations in the Northern Provinces of Iran

β-Thalassemia (thal) is one of the most common autosomal recessive disorders in Iran. There are more than two million carriers of β-thal and over 15,000 people affected with β-thal major who live in Iran. Prevalent mutations were identified by examining genomic DNAs isolated from 392 blood samples of β-thal carriers from three northern provinces of Iran. Furthermore, 172 pregnant women were analyzed from the 196 couples who requested pregnant diagnosis for β-thal. Allele identification was carried out using routine reverse dot-blot, amplification refractory mutation system (ARMS), and genomic sequencing. The most common mutation, IVS-II-1 (G→A), is followed, in order of frequency, by codon 30 (G→C), frameshift codons (FSC) 8,9 (+G), FSC 22/23/24 (?AAGTTGG), IVS-I-110 (G→A), IVS-I-5 (G→C), IVS-II-745 (C→G), IVS-I-2 (T→C), FSC 8 (?AA), IVS-I,3′-end (?25 bp), IVS-I-1 (G→A), FSC 36/37 (?T), IVS-I-6 (T→C), FSC 5 (?CT), ?28 (A→C), codon 37 (G→A), IVS-II-2,3 (+11/?2), ?30 (T→A), and ?88 (C→A). We have also revealed the existence of five new mutations from northern Iran, one of which (codon 37) is the first reported for Iran. Furthermore, the rate of unknown mutations is significantly reduced in our study (about 6%). These results could help with establishing a center for prenatal diagnosis, prevention, and control of thalassemia in the northern provinces of Iran.     

Quality of Life and Depression in Turkish Patients with β-Thalassemia Major: A Cross-Sectional Study

Abstract

Thalassemias are the most common monogenic disorders worldwide. Thalassemia patients experience difficulties in their schooling, finding jobs and/or marriage because of functional and physical limitations caused by this disease. It is expected that the quality of life (QoL) of patients with thalassemia will be lower than those without this disease. The aim of this study was to benefit worldwide thalassemia patients in terms of QoL and mental health. This cross-sectional study was performed in Turkey. The study population consisted of of 57 β-thalassemia major (β-TM) patients and the control group. The short form-36 (SF-36) questionnaire and Beck depression inventory (BDI) were used. The mean age of the patients was 21.6?±?6.6 (age range 15-39) and the male-to-female ratio was 0.7. The mean SF-36 scores of the patient and the control groups were 59.2?±?12.4 and 75.7?±?11.8, and the mean BDI scores of the patients and controls were 13.5?±?6.4 and 6.1?±?3.7, respectively. There was a statistically significant difference between the total SF-36 and BDI scores of patients and controls. We aimed to investigate the effects of the decrease in morbidity and mortality of β-thalassemia (β-thal) due to regular transfusions and chelation therapy on the QoL and mental health of patients. The β-TM patients have a comparatively worse QoL score than the normal population. Improving QoL should be the target of clinicians who are monitoring adolescent or young adult β-TM patients.     

Minidose Aspirin and Gastrointestinal Bleeding—A Retrospective,Case–Control Study in Hospitalized Patients

Low or minimal doses of aspirin are widely used for prevention of cardiovascular diseases. Aspirin is known to produce severe adverse gastrointestinal effects, such as bleeding and perforation. Less is known about the risk associated with minidose aspirin. Our aim was to assess the possible association of upper gastrointestinal tract bleeding with minidose aspirin therapy. A retrospective controlled design was used. Patients hospitalized for melena or hematemesis between January 1, 2000, and December 31, 2001, were identified by ICD-9 codes, and their clinical findings were compared to these of patients without upper gastrointestinal bleeding hospitalized during the same period and matched for age and sex. Bleeding was attributed to therapy if patients used a nonsteroidal anti-inflammatory drug or aspirin therapy within 30 days before hospitalization. The study group included 318 patients (59% male), and the control group 141 (65% male). Mean ages were 67 ± 19 and 64 ± 19 years, respectively. Study patients had more accompanying diseases, used more medications, and required more blood transfusions than controls (37%, vs. 2% of controls; P < 0.001). Minidose aspirin was used by 28% of the study group and 18% of the controls (P = 0.03). The average dose was 40 ± 86 and 21 ± 55 mg/day, respectively (P = 0.012). Only 26% of the study patients received a gastric protective agent. On multivariate analysis, aspirin consumption was the only independent risk factor for upper gastrointestinal tract bleeding. There appears to be an association between minidose aspirin treatment and hospitalization for upper gastrointestinal tract bleeding. Despite the advanced age of the patients, only one-quarter were treated with gastric protective agent.     

Effect of 5-Fluorouracil on Gastrointestinal Carcinogenesis Induced by N-Methyl-N′-Nitro-N-Nitrosoguanidine in Rats

This study was undertaken to determine theeffect of 5-fluorouracil on gastrointestinalcarcinogenesis. Sixty rats were divided into threegroups of 20 rats each. All rats were exposed toN-methyl-N-nitro-N-nitrosoguanidine for the first20 weeks. Group 1 rats received intraperitonealinjections of 5-fluorouracil for the first 20 weeks andwere then observed for the second 20 weeks. Group 2 ratsalso received 5-fluorouracil injections, but for the second20 weeks. Group 3 rats received no 5-fluorouraciltreatment. Four of 20 rats in group 1 developed aninvasive adenocarcinoma. In group 3, invasive squamous cell carcinoma and adenocarcinoma developed inone rat each. None of the group 2 rats had malignantlesions. These results suggested that 5-fluorouracil isnot effective in suppressing the initial stage of gastrointestinal carcinogenesis with acoexisting carcinogen. Rather, the therapeutic effect isexerted in later stages of tumor progression.     

Tolerability Profiles of Leukotriene Receptor Antagonists and Long-Acting β2-Adrenoceptor Agonists in Combination with Inhaled Corticosteroids for Treatment of Asthma: A Review

Inhaled corticosteroids, long-acting β₂-adrenoceptor agonists, and leukotriene receptor antagonists are widely used for treatment of asthma. Inhaled corticosteroids are recommended as first-line therapy, whereas long-acting β₂-adrenoceptor agonists and leukotriene receptor antagonists are indicated as add-on therapy in patients not adequately controlled with corticosteroids alone. A number of studies have investigated the efficacy of combinations of these drugs in asthma, but several issues concerning the safety of these treatments are highly debated. This review provides a critical appraisal of the tolerability profiles of long-acting β₂-agonists and leukotriene receptor antagonists used in combination with inhaled corticosteroids for the treatment of asthma.     

Telmisartan in the Treatment of Cohen-Rosenthal Diabetic Hypertensive Rats: The Benefit of PPAR-γ Agonism

The antihypertensive and hypoglycemic effects of telmisartan, which has dual angiotensin II antagonist-PPAR-γ agonist properties, was studied in Cohen-Rosenthal Diabetic Hypertensive rats (CRDH), a model in which hypertension, insulin resistance, and diabetes co-exist. CRDH, Cohen-diabetic rats (CDR), and SHR received telmisartan (3 mg/kg/day in drinking water) for five months. Telmisartan significantly lowered systolic and diastolic BP in SHR and CRDH, independent of body weight, and remained fairly constant in controls throughout the experiment. Blood glucose levels fell rapidly in the treated animals and remained steady in controls. Results indicate that telmisartan is a prototype of a new approach to treating coexisting diabetes and hypertension.     

Reliability of Lightguide Spectrophotometry (O2C?) for the Investigation of Skin Tissue Microvascular Blood Flow and Tissue Oxygen Supply in Diabetic and Nondiabetic Subjects

Background and Aims

Skin microvascular assessment has progressed to an important evaluation in patients with diabetes mellitus. This study was done to evaluate a new device using micro-lightguide spectrophotometry in the assessment of skin microvascular function.

Material and Methods

Twenty nondiabetic subjects (age 46.6 ± 14.8 years; mean ± SD) and 20 diabetic patients (age 59.4 ± 8.4 years) participated in repeated microvascular measurements using micro-lightguide spectrophotometry. This technique allows simultaneous, noninvasive measurement of microvascular blood flow and hemoglobin oxygenation (SO₂) at the same anatomical area in different tissue layers. A skin probe was placed on nonhairy skin at the thenar eminence of the left hand for the measurement of SO₂, and the postischemic reactive hyperemia response (PRH) was measured in skin and underlying muscle tissue.

Results

Repeated measurements in PRH revealed a good correlation at the superficial skin layer (r = 0.97, p < 0.0001) with a coefficient of variation at 9.2 ± 1.7% and at the superficial muscle layer (r = 0.80, p < 0.0002) with a coefficient of variation at 9.7 ± 1.5%. A slightly weaker correlation was observed for the SO₂ measurement at the skin layer (r = 0.69 ± p < 0.0001) with a coefficient of variation at 17.5 ± 3.8% and at the muscle layer (r = 0.48; p = 0.0016) with a coefficient of variation at 18.1 ± 10.5%.

Conclusions

Lightguide spectrophotometry is an easy, noninvasive, and reliable method for simultaneous measurement of superficial microvascular blood flow by laser Doppler fluxmetry and skin oxygenation by spectrophotometry. Further studies are required to clarify the validity of these measures in special patient populations such as diabetes mellitus with specified microvascular complications.     

Chronic Effects of Inhaled Albuterol on β-Adrenoceptor System Function in Human Respiratory Cells

The in vivo effects of β-adrenergic receptor (βAR) agonists given chronically by metered-dose inhaler (MDI) on the molecular components of the β-adreno-ceptor system expressed by human respiratory cells are poorly understood. This study examined the effects of inhaled albuterol (180 μg four times daily for 7 days) on βAR function of airway epithelial cells (AECs) and alveolar macrophages (AMs) freshly isolated from 10 normal subjects. Responses were related to β₂AR genotype in codons 16 and 27, regions which affect chronic responses to β₂-agonists. In AEC, βAR density and adenosine cyclic 3′,5′-phosphate (cAMP) production in response to isoproterenol (ISO) were significantly lower in the albuterol versus placebo treatment arm (p < 0.01 for both). Moreover, in AEC, albuterol treatment increased βAR-kinase (βARK) protein immunoreactivity. In contrast, in AM, albuterol tended to decrease βAR density and cAMP production but changes did not achieve statistical significance (p > 0.20 for both) and had no effect on βARK immunoreactivity. Changes in (JAR density occurred in all subjects but tended to be greater in subjects with the glycine 16 genotype. In cultured cells exposed to equal concentrations of β-agonist in vitro, the magnitude of βAR down-regulation (p < 0.05) and cAMP densensiti-zation (p < 0.05) was greater in AEC than AM. These results indicate that albuterol taken by inhalation in a therapeutically relevant dose for 1 week produces pAR down-regulation, densensitizes the cAMP response of airway epithelial cells to a β₂-adrenergic agonist, and increases PARK immunoreactivity. Greater densensitization of AEC than AM in response to chronic albuterol inhalation likely reflects cell type-specific responses.