Clinical and Experimental Pharmacology and Physiology
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Familial And Acquired Long QT Syndrome And The Cardiac Rapid Delayed Rectifier Potassium Current SUMMARY 1. Long QT syndrome (LQTS) is a cardiac disorder characterized by syncope, seizures and sudden death; it can be congenital, idiopathic, or iatrogenic. 2. Long QT syndrome is so‐named because of the connection observed between the distinctive polymorphic ventricular tachycardia torsade de pointes and prolongation of the QT interval of the electrocardiogram, reflecting abnormally slowed ventricular action potential (AP) repolarization. Acquired LQTS has many similar clinical features to congenital LQTS, but typically affects older individuals and is often associated with specific pharmacological agents. 3. A growing number of drugs associated with QT prolongation and its concomitant risks of arrhythmia and sudden death have been shown to block the ‘rapid’ cardiac delayed rectifier potassium current (IKr ) or cloned channels encoded by the human ether‐a‐go‐go ‐related gene (HERG; the gene believed to encode native IKr ). Because IKr plays an important role in ventricular AP repolarization, its inhibition would be expected to result in prolongation of both the AP and QT interval of the electrocardiogram. 4. The drugs that produce acquired LQTS are structurally heterogeneous, including anti‐arrhythmics, such as quinidine, non‐sedating antihistamines, such as terfenadine, and psychiatric drugs, such as haloperidol. In addition to heterogeneity in their structure, the electrophysiological characteristics of HERG/IKr inhibition differ between agents. 5. Here, clinical observations are associated with cellular data to correlate acquired LQTS with the IKr /HERG potassium (K+ Kr . Until such time, awareness of the QT‐prolongation risk of particular agents is important for the clinician.
Clinical and Experimental Pharmacology and Physiology - Tập 27 Số 10 - Trang 753-766 - 2000
STRUCTURE AND FUNCTION OF URIDINE DIPHOSPHATE GLUCURONOSYLTRANSFERASES SUMMARY 1. The uridine diphosphate (UDP)‐glucuronosyltransferases (UGT) are a family of enzymes that catalyse the covalent addition of glucuronic acid to a wide range of lipophilic chemicals. They play a major role in the detoxification of many exogenous and endogenous compounds by generating products that are more polar and, thus, more readily excreted in bile or urine. 2. Inherited deficiencies in UGT forms are deleterious, as exemplified by the debilitating effects of hyperbilirubinaemia and neurotoxicity in subjects with mutations in the enzyme that converts bilirubin to its more pola. glucuronide. 3. The UGT protein can be conceptually divided into two domains with the amino‐terminal half of the protein demonstrating greater sequence divergence between isoforms. This region apparently determines aglycone specificity. The aglycone binding site is presumed to be a ‘loose’ fit, as many structurally diverse substrates can be bound by the same UGT isoform. The carboxyl‐terminal half, which is more conserved in sequence between different isoforms, is believed to contain a binding site for the cosubstrate UDP glucuronic acid (UDPGA). 4. Uridine diphosphat. glucuronosyltransfera.se is localized to the endoplasmic reticulum (ER) and spans the membrane with a type I topology. The putative transmembrane domain is located near the carboxyl terminus of the protein such that only a small portion of the protein resides in the cytosol. This cytosolic tail is believed to contain an ER‐targeting signal. The major portion of the protein is located in the ER lumen, including the proposed substrate‐binding domains and the catalytic site. 5. The microsomal membrane impedes the access of UDPGA to the active site, resulting in latency of UGT activity in intact ER‐derived microsomes. Active transport of UDPGA is believed to occur in hepatocytes, but the transport system has not been fully characterized. Uridine diphosphate glucuronosyltransfer‐ase activity is also highly lipid dependent and the enzyme may contain regions of membrane association in addition to the transmembrane domain.
Clinical and Experimental Pharmacology and Physiology - Tập 24 Số 12 - Trang 907-915 - 1997
EFFECT OF PERIPHERAL SYMPATHETIC NERVE DYSFUNCTION ON SALT SENSITIVITY OF ARTERIAL PRESSURE SUMMARY
Dysregulation of peripheral sympathetic pathways contributes to some forms of salt‐dependent hypertension. However, at the present time it is not known whether salt‐induced activation of sympathetic nerves or loss of normal sympathoinhibitory responses to salt‐induced volume expansion contributes to neurogenic salt‐dependent hypertension. The present study was performed to the test the hypothesis that loss of peripheral sympathetic nerve function results in salt‐dependent hypertension. The effect of three pharmacological interventions of sympathetic nerve function on the long‐term salt‐sensitivity of mean arterial pressure (MAP) were measured: (i) blockade of ganglionic transmission with hexamethonium (HEX; n = 5); (ii) destruction of sympathetic nerve terminals with guanethidine (GUAN; n = 7); and (iii) a‐adrenoceptor blockade with two specific antagonists, namely prazosin (PRAZ; n = 7) and terazosin (TERAZ; n = 8). Mean arterial pressure and heart rate were measured 24 h/day by radiotelemetry in conscious rats during 5 days of normal and 7 days of high (HNa) dietary sodium intake. Despite marked increases in both sodium and water intake during 7 days of the HNa diet, no statistically significant changes in MAP were observed in HEX, GUAN, PRAZ or TERAZ groups. We conclude that loss of peripheral sympathetic neural pathways alone does not cause salt‐dependent hypertension in the rat.
Clinical and Experimental Pharmacology and Physiology - Tập 35 Số 3 - Trang 273-279 - 2008
Role Of Excitatory Amino Acid Inputs To The Rostral Ventrolateral Medulla In Cardiovascular Regulation SUMMARY 1. Excitatory amino acid (EAA)‐mediated neural transmission in the rostral ventrolateral medulla (RVLM) is important for many cardiovascular reflexes, although the receptor subtypes involved vary depending on the specific response. 2. Although injection of the EAA ionotropic receptor antagonist kynurenic acid into the RVLM has no effect on baseline arterial pressure, this lack of effect appears to result from EAA inputs to RVLM exciting both excitatory and inhibitory mechanisms within the RVLM. 3. The balance between EAA‐mediated excitation and inhibition of RVLM neurons may be shifted to excitation in experimental models of hypertension. 4. The excitatory influence that EAA inputs to the RVLM have on vasomotor neurons in the RVLM may involve a sarthran‐sensitive intermediary in the RVLM.
Clinical and Experimental Pharmacology and Physiology - Tập 29 Số 5-6 - Trang 503-506 - 2002
Microvascular Remodelling In Chronic Airway Inflammation In Mice SUMMARY 1. Chronic inflammation is associated with blood vessel remodelling, including vessel proliferation and enlargement, and changes in vessel phenotype. We sought to characterize these changes in chronic airway inflammation and to determine whether corticosteroids that inhibit inflammation, such as dexamethasone, can also reduce microvascular remodelling. 2. Chronic airway inflammation was induced in C3H mice by infection with Mycoplasma pulmonis and the tracheal vessels were examined in whole mounts after Lycopersicon esculentum lectin staining. 3. Neither the number nor the length of vessels changed in C3H mice after infection with M . pulmonis . Instead, vessel diameter and endothelial cell number doubled. 4. Immunoreactivity for P‐selectin, a marker of venular endothelial cells, also increased after infection, indicating that the proportion of venules doubled with a corresponding decrease in capillaries. 5. Whereas the average diameter of tracheal capillaries doubled in mice inoculated 10 days earlier (mean (± SEM) diameter in infected and pathogen‐free mice of 20.8± 1.6 and 9.0± 0.7 μm, respectively), dexamethasone treatment (0.2 mg/day, i.p.) for 7 days beginning 4 days after infection significantly decreased capillary diameter (13.0± 0.7 μm). The treatment also decreased the immunoreactivity for P‐selectin and the number of adherent leucocytes (595± 203 vs 2024± 393 cells/ mm
2 6. We conclude that microvascular enlargement and changes in vessel phenotype are features of some types of chronic inflammation and, furthermore, that dexamethasone reverses the microvascular enlargement, changes in vessel phenotype and leucocyte influx associated with chronic inflammatory airway disease.
Clinical and Experimental Pharmacology and Physiology - Tập 27 Số 10 - Trang 836-841 - 2000
Linear regression analysis for comparing two measurers or methods of measurement: But which regression? Summary 1. There are two reasons for wanting to compare measurers or methods of measurement. One is to calibrate one method or measurer against another; the other is to detect bias. Fixed bias is present when one method gives higher (or lower) values across the whole range of measurement. Proportional bias is present when one method gives values that diverge progressively from those of the other. 2. Linear regression analysis is a popular method for comparing methods of measurement, but the familiar ordinary least squares (OLS) method is rarely acceptable. The OLS method requires that the x values are fixed by the design of the study, whereas it is usual that both y and x values are free to vary and are subject to error. In this case, special regression techniques must be used. 3. Clinical chemists favour techniques such as major axis regression (‘Deming’s method’), the Passing–Bablok method or the bivariate least median squares method. Other disciplines, such as allometry, astronomy, biology, econometrics, fisheries research, genetics, geology, physics and sports science, have their own preferences. 4. Many Monte Carlo simulations have been performed to try to decide which technique is best, but the results are almost uninterpretable. 5. I suggest that pharmacologists and physiologists should use ordinary least products regression analysis (geometric mean regression, reduced major axis regression): it is versatile, can be used for calibration or to detect bias and can be executed by hand‐held calculator or by using the loss function in popular, general‐purpose, statistical software.
Clinical and Experimental Pharmacology and Physiology - Tập 37 Số 7 - Trang 692-699 - 2010
SEQUENTIAL ACTIVATION OF THE REACTIVE OXYGEN SPECIES/ANGIOTENSINOGEN/RENIN–ANGIOTENSIN SYSTEM AXIS IN RENAL INJURY OF TYPE 2 DIABETIC RATS SUMMARY
The present study was performed to test the hypothesis that the reactive oxygen species (ROS)–angiotensinogen (AGT)–renin angiotensin system (RAS) axis is sequentially activated in the development of diabetic nephropathy in Zucker diabetic fatty (ZDF) obese rats. Genetic pairs of male ZDF obese and control ZDF lean rats (n = 12 of each species) were killed every 3 weeks from 12 to 21 weeks of age (n = 6 at each time point). The ZDF obese rats developed diabetes mellitus at 12 weeks. At that time, urinary excretion rates of 8‐isoprostane were similar between the groups; however, urinary 8‐isoprostane levels were significantly increased at 15 weeks in ZDF obese rats compared with controls (36 ± 6 vs 15 ± 2 ng/day, respectively). At 15 weeks, protein levels of cortical angiotensinogen were similar between groups; however, cortical angiotensinogen levels were significantly increased at 18 weeks in ZDF obese rats compared with controls (relative ratio of 2.32 ± 0.21 vs 1.00 ± 0.20, respectively). At 12 weeks, angiotensin (Ang) II‐like immunoreactivity was similar between groups in both the glomeruli and tubules; however, AngII‐like immunoreactivity was increased significantly at 21 weeks in ZDF obese rats compared with controls (relative ratios of 1.98 ± 0.55 vs 1.00 ± 0.03, respectively, for glomeruli and 1.58 ± 0.16 vs 1.00 ± 0.13, respectively, for tubules). Moreover, at 21 weeks, the desmin‐positive area in the glomeruli (0.63 ± 0.08 vs 0.22 ± 0.05%) and Masson's trichrome stain‐positive area in the interstitium (4.97 ± 0.05 vs 3.18 ± 0.41%) were significantly increased in ZDF obese rats compared with controls, even though these differences had not been observed earlier. These data suggest that the sequential activation of the ROS–AGT–RAS axis plays an important role in the development of diabetic nephropathy in ZDF obese rats.
Clinical and Experimental Pharmacology and Physiology - Tập 35 Số 8 - Trang 922-927 - 2008
Discovery of curcumin, a component of golden spice, and its miraculous biological activities Summary 1. Curcumin is the active ingredient of the dietary spice turmeric and has been consumed for medicinal purposes for thousands of years. Modern science has shown that curcumin modulates various signalling molecules, including inflammatory molecules, transcription factors, enzymes, protein kinases, protein reductases, carrier proteins, cell survival proteins, drug resistance proteins, adhesion molecules, growth factors, receptors, cell cycle regulatory proteins, chemokines, DNA, RNA and metal ions. 2. Because of this polyphenol’s potential to modulate multiple signalling molecules, it has been reported to possess pleiotropic activities. First demonstrated to have antibacterial activity in 1949, curcumin has since been shown to have anti‐inflammatory, anti‐oxidant, pro‐apoptotic, chemopreventive, chemotherapeutic, antiproliferative, wound healing, antinociceptive, antiparasitic and antimalarial properties as well. Animal studies have suggested that curcumin may be active against a wide range of human diseases, including diabetes, obesity, neurological and psychiatric disorders and cancer, as well as chronic illnesses affecting the eyes, lungs, liver, kidneys and gastrointestinal and cardiovascular systems. 3. Although many clinical trials evaluating the safety and efficacy of curcumin against human ailments have already been completed, others are still ongoing. Moreover, curcumin is used as a supplement in several countries, including India, Japan, the US, Thailand, China, Korea, Turkey, South Africa, Nepal and Pakistan. Although inexpensive, apparently well tolerated and potentially active, curcumin has not been approved for the treatment of any human disease. 4. In the present article, we discuss the discovery and key biological activities of curcumin, with a particular emphasis on its activities at the molecular and cellular levels, as well as in animals and humans.
Clinical and Experimental Pharmacology and Physiology - Tập 39 Số 3 - Trang 283-299 - 2012
Ginsenoside Rd prevents glutamate‐induced apoptosis in rat cortical neurons Summary 1. The role of voltage‐independent Ca2+ entry in cell apoptosis has recently received considerable attention. It has been found that ginsenoside Rd significantly inhibits voltage‐independent Ca2+ entry. The aim of the present study was to investigate the protective effects of ginsenoside Rd against glutamate‐induced apoptosis of rat cortical neurons. 2. Ginsenoside Rd significantly reduced glutamate‐induced apoptotic morphological changes and DNA laddering. In comparison, nimodipine only had a weak effect. 3. Ginsenoside Rd (1, 3 and 10 μmol/L) concentration‐dependently inhibited caspase 3 activation and expression of the p20 subunit of active caspase 3 (by 30 ± 10%, 41 ± 9% and 62 ± 19%, respectively, compared with glutamate alone; P < 0.05), whereas 1 μmol/L nimodipine had no effect. 4. Glutamate decreased cell viability to 37.4 ± 4.7 (n = 8) and evoked cell apoptosis. Ginsenoside Rd (1, 3, 10 and 30 μmol/L) concentration‐dependently inhibited glutamate‐induced cell death, increased cell viability and reduced apoptotic percentage (from 47.5 ± 4.9% to 37.4 ± 6.9%, 28.3 ± 5.2% and 22.5 ± 5.6%, respectively; P < 0.05). At 1 μmol/L, nimodipine had no effect on cell viability. Furthermore, although 1, 3, 10, 30 and 60 μmol/L ginsenoside Rd concentration‐dependently inhibited glutamate‐induced Ca2+ entry by 8 ± 2%, 24 ± 4%, 40 ± 7%, 49 ± 8% and 50 ± 8% (P < 0.05), respectively, nimodipine had no effect. 5. In conclusion, the results indicate that ginsenoside Rd prevents glutamate‐induced apoptosis in rat cortical neurons and provide further evidence of the potential of voltage‐independent Ca2+ channel blockers as new neuroprotective drugs for the prevention of neuronal apoptosis and death induced by cerebral ischaemia.
Clinical and Experimental Pharmacology and Physiology - Tập 37 Số 2 - Trang 199-204 - 2010
HOW DO FISH OILS AFFECT VASCULAR FUNCTION? SUMMARY 1. This is a review on the mechanisms by which fish oils affect vascular function and how such changes contribute to their documented cardioprotective effects. 2. Evidence that fish oils depress vascular responses to contractile agents will be examined. It is concluded that this effect of fish oils is mediated predominantly by alterations in prostanoid profile. 3. Effects of fish oils on arterial relaxation are discussed with particular emphasis on endothelium dependent relaxation. It is suggested that the functional impairment of endothelium dependent relaxation documented in a number of cardiovascular disease states can be reversed by dietary fish oils. 4. In addition, possible effects of fish oils on growth factors, inositol trisphosphate and lipid metabolism, the sympathetic nervous system, rheological and membrane properties and inducible nitric oxide are reviewed.
Clinical and Experimental Pharmacology and Physiology - Tập 22 Số 2 - Trang 71-81 - 1995
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