The development of proteinuria, and more rarely nephrotic syndrome, has been seen with the use of the first orally active converting-enzyme inhibitor captopril. Both of these side effects appear to occur more frequently when the drug is used at higher dose, particularly in the presence of renal impairment. We have used enalapril, a new orally active converting-enzyme inhibitor in the treatment of a patient with drug-resistant hypertension and renal impairment who previously developed nephrotic syndrome with captopril. Recurrence of the nephrotic syndrome was not seen in this patient during a period of 20 months on enalapril. On the contrary, urinary protein excretion over the same period was reduced to around 1 g in 24 hours. Our experience would suggest that enalapril may usefully be substituted for captopril in the treatment of hypertensive patients in whom the latter has caused proteinuria or nephrotic syndrome.
An investigation of restriction fragment length polymorphisms (RFLPs) and association with blood pressure was carried out for the candidate genes coding for renin (REN) and atrial natriuretic peptide (ANP). The relationship between blood pressure, REN and ANP gene RFLPs was tested in a population of black Afro-Caribbean and white European subjects sampled randomly from family practice registers. Upper and lower quintiles for diastolic blood pressure were selected for analysis. Digests of DNA were prepared from leucocytes and RFLPs were determined using Southern blotting analysis with REN and ANP gene probes. There were highly significant ethnic differences found for Bg/I, Bg/ll and Taql polymorphisms with 5'REN probe and for Bg/I polymorphism with an ANP probe. There was also an association between blood pressure and the Bg/I/REN polymorphism in Afro-Caribbeans but not with any other polymorphisms studied in either ethnic group. The findings show significant ethnic RFLP differences at the gene loci for both renin and ANP and provide evidence for a possible link between variations within or close to the renin gene and elevated blood pressure in Afro-Caribbeans.
Clinical pharmacologists in universities play major roles in research and teaching and provide important contributions to National Health Service (NHS) activities, such as work for research ethics, drug and therapeutics, and clinical governance committees. Their research extends from preclinical studies using drugs to understand physiology and the mechanisms of disease to large-scale clinical trials and population studies. This work is truly translational, with a focus on drugs and medicines and an emphasis on efficacy and safety. The lack of an organ base has allowed clinical pharmacologists to follow their interests wherever they lead, but their visibility has been hampered by successive earlier versions of the General Medical Council's Tomorrow's Doctors document, which undermined some of the necessary scientific underpinning of medical practice and reduced the time clinical pharmacologists had to interact with medical students and recently qualified doctors at the point of choosing their careers. Additional problems have arisen from the stifling effect of the European Union Clinical Trials Directive, and its UK interpretation, on clinical research. For future success, clinical pharmacologists need to embrace translational research, use recent changes to Tomorrow's Doctors, linked to the creation of safe prescribing skills, to spend more face-to-face time with their students, fight for a simplification and proportionate regulation of research, and persuade doctors, health service planners and the government of the importance of clinical pharmacology for UK clinical research, the NHS, patient safety and creation of health and wealth.
<div><b>Objective</b></div><div><b><br></b></div> <p>To assess the relationship between subclinical cardiac dysfunction and aerobic exercise capacity (peak VO<sub>2</sub>) in adults with type 2 diabetes (T2D), a group at high risk of developing heart failure.</p> <h3>Research design and methods</h3> <p>Cross-sectional study. We prospectively enrolled a multi-ethnic cohort of asymptomatic adults with T2D and no history, signs or symptoms of cardiovascular disease. Age-, sex-, and ethnicity-matched controls were recruited for comparison. Participants underwent bio-anthropometric profiling, cardiopulmonary exercise testing and cardiovascular magnetic resonance with adenosine stress perfusion imaging. Multivariable linear regression analysis was undertaken to identify independent associations between measures of cardiovascular structure and function and peak VO<sub>2</sub>.</p> <h3>Results</h3> <p>Two hundred and forty seven adults with T2D (age 51.8±11.9 years, 55% males, 37% black or south Asian ethnicity, HbA1c 7.4±1.1% (57±12 mmol/mol), duration of diabetes 61 (32 – 120) months and 78 controls were included. Subjects with T2D had increased concentric left ventricular (LV) remodelling, reduced myocardial perfusion reserve, and markedly lower aerobic exercise capacity (peak VO<sub>2 </sub>18.0±6.6 vs. 27.8±9.0mL/kg/min, p<0.001) compared with controls. In a multivariable linear regression model containing age, sex, ethnicity, smoking status and systolic blood pressure, only myocardial perfusion reserve (β=0.822, p=0.006) and E/e’ (β= -0.388, p=0.001) were independently associated with peak VO<sub>2</sub> in subjects with T2D.</p> <h3>Conclusions</h3> <p>In a multi-ethnic cohort of asymptomatic people with T2D, myocardial perfusion reserve and diastolic function are key determinants of aerobic exercise capacity, independent of age, sex, ethnicity, smoking status, or blood pressure. </p> <br>
Since its discovery in 1988, there has been an enormous amount of interest in endothelin-1 (ET-1) and its regulatory and growth-promoting role in cardiovascular physiology. Evidence from the Sixth International Conference on Endothelin, held in Montreal in October 1999, continued to demonstrate that the endothelin system is an important therapeutic target in cardiovascular disease, with promising results in animal studies now being confirmed by clinical trials in humans. In addition, many new and exciting roles for ET-1 were presented, suggesting that ET-1 antagonism may have a broader therapeutic potential than previously imagined.
PDE type 5 inhibitors (PDE5Is), such as sildenafil, tadalafil and vardenafil, are a class of drugs used to prolong the physiological effects of NO/cGMP signalling in tissues through the inhibition of cGMP degradation. Although these agents were originally developed for the treatment of hypertension and angina, unanticipated side effects led to advances in the treatment of erectile dysfunction and, later, pulmonary arterial hypertension. In the last decade, accumulating evidence suggests that PDE5Is may confer a wider range of clinical benefits than was previously recognised. This has led to a broader interest in the cardiovascular therapeutic potential of PDE5Is, in conditions such as hypertension, myocardial infarction, stroke, peripheral arterial disease, chronic kidney disease and diabetes mellitus. Here, we review the pharmacological properties and established licensed uses of this class of drug, along with emerging therapeutic developments and possible future indications.
We assessed forearm blood flow and plasma fibrinolytic factors in eight healthy males who received unilateral brachial artery infusions of the endothelium-dependent vasodilator, substance P, and the endothelium-independent vasodilator, sodium nitroprusside. These measurements, together with platelet aggregation studies, were performed on four occasions after double-blind randomized ingestion of placebo, methionine (0.1 mg/kg), vitamin C (2 g) and methionine plus vitamin C. Blood flow and platelet aggregation responses were unaffected by methionine loading. Substance P caused dose-dependent increases in plasma tissue plasminogen activator (t-PA) antigen (from 3.0+/-0.1 to 4.7+/-0.4 ng/ml; P<0.001) and activity (from 1.2+/-0.2 to 4.2+/-0.4 i.u./ml; P<0.001), which were augmented during acute methionine loading (4.7+/-0.4 to 5.6+/-0.5 ng/ml and 4.2+/-0.4 to 5.5+/-0.9 i.u./ml respectively; P
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