Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.15.1 (ACE)
 18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The blood pressure (BP) response to any single antihypertensive drug is characterized by marked interindividual variation, and the known predictors of response are of limited value in identifying the optimum drug for an individual patient. Analysis of genetic variation has the potential to improve our understanding of determinants of antihypertensive drug response in order to individualize drug selection. Genetic variation can influence both pharmacokinetic and pharmacodynamic mechanisms underlying variation in drug response. Classic pharmacogenetic investigations have identified variations in single genes that have a large effect on antihypertensive drug metabolism and are inherited in a Mendelian fashion. These include a polymorphism in the CYP2D6 gene, encoding a cytochrome p450 family member involved in phase I drug metabolism, and polymorphisms in genes encoding enzymes involved in phase II drug metabolism, including N-acetyltransferase (NAT2), catechol-O-methyltransferase (COMT), and phenol sulfotransferase (P-PST, SULT1A1). Although these polymorphisms have major effects on the pharmacokinetic profiles of both commonly used antihypertensive drugs such as metoprolol (CYP2D6), and lesser used drugs such as hydralazine (NAT2), methyldopa (COMT), and minoxidil (SULT1A1), they have not been shown to influence variation in the antihypertensive effect of these drugs at conventional doses. Interest is now focused on identifying genetic polymorphisms that influence the pharmacodynamic determinants of antihypertensive response. Using a candidate gene approach, such polymorphisms have been identified in genes encoding alpha-adducin (ADD1), subunits of G-proteins (GNB3 and GNAS1), the beta(1)-adrenergic receptor (ADRB1), endothelial nitric oxide synthase (NOS3), and components of the renin-angiotensin-aldosterone system (angiotensinogen [AGT], angiotensin converting enzyme [ACE], the angiotensin type I receptor [AGTR1], and aldosterone synthase [CYP11B2]). These polymorphisms have been shown to influence the BP response to diuretics (ADD1, GNB3, NOS3, and ACE), beta-blockers (GNAS1 and ADRB1), ACE inhibitors (AGT, ACE, and AGTR1), angiotensin receptor blockers (ACE and CYP11B2), and clonidine (GNB3).An emerging consensus from these studies is that single gene effects on antihypertensive drug responses are small, and even the combined effects of all presently known polymorphisms do not account for enough variation in response to be clinically useful. New genome-wide scanning techniques may lead to the identification of genes previously unsuspected of influencing drug response. Additional requirements for pharmacogenetic approaches to become clinically useful are the characterization of the effects of haplotypes and multi-locus genotypes on drug response, and consideration of gene-by-environment interactions. Such studies will require huge sample sizes and novel statistical methods, but the theoretical and technical framework is in place to make this possible.
 ...
PMID:Pharmacogenetics of antihypertensive drug responses. 1517 96

The 31st Annual Meeting of the American Society of Nephrology, held in Philadelphia, Pennsylvania, USA, October 25-28, 1998, presented the newest advances in basic and clinical nephrology science. Several presentations discussed the results of studies with the newer immunosuppressants such as tacrolimus, sirolimus, mycophenolate mofetil and the anti-CD25 monoclonal antibodies, with the conclusion that studies on long-term use of these agents are needed. A number of other issues on immunosuppression protocols in renal transplantation were addressed during the meeting, including the subjects of steroid withdrawal and the role of TGF-beta in the development of chronic allograft nephropathy. The use of NESP in the treatment of renal anemia, the use of sildenafil to treat erectile dysfunction in hemodialysis patients, and the use of ACE inhibitors in nondiabetic renal patients were other important issues discussed at this meeting. Newer approaches to the treatment of hypertension discussed at the meeting highlighted the potential role of angiotensin II receptor antagonists in renal disease patients. Researchers also presented the promising results of a trial of a new, hybrid cell vaccine approach to the treatment of renal cell carcinoma.
 ...
PMID:Recent advances in nephrology. 1561 34

Renin angiotensin system (RAS) worsens diabetic nephropathy (DN) by increasing oxidative stress. We compared the effect of three different RAS inhibitors: the angiotensin converting enzyme inhibitor Ramipril, the vasopeptidase inhibitor AVE7688 and the angiotensin receptor (AT1) antagonist Losartan on the formation of oxidative and carbonyl stress derived protein modifications in kidney from Zucker obese hyperglycemic rats (ZDFn Gm-fa/fa). Gas chromatography-mass spectrometry was used to measure representative markers of several protein oxidative pathways: direct oxidation [dinitrophenylhydrazine reactive carbonyls (DNP), glutamic (GSA), and aminoadipic (AASA) semialdehydes], mixed glyco- and lipoxidation [N(epsilon)-carboxyethyl-lysine (CEL) and N(epsilon)-(carboxymethyl)-lysine (CML)] and lipoxidation-[N(epsilon)-(malondialdehyde)-lysine-(MDAL)], as well as renal fatty acid composition. Urinary albumin (a marker of DN), DNP, GSA, and MDAL levels, were increased in all obese rats and were dose dependently decreased by AVE7688 whereas Ramipril and Losartan were less efficient. These results show that RAS inhibition improves DN at several levels, independently of its effects on blood pressure and glycemic control, via mechanisms depending of renal oxidative stress.
 ...
PMID:Inhibition of renin angiotensin system decreases renal protein oxidative damage in diabetic rats. 1824 27

Prenatal development of the epididymis was studied in bovine fetuses ranging from 10 to 90cm crown-rump length (CRL) (75-285 pcd). The studies aimed to apply both glycohistochemistry and immunohistochemistry for the detection of the differentiation of the developing prenatal epididymis. Both conventional histological and histochemical techniques were applied on paraffin sections of the epididymis from different fetal stages. Establishment of the urogenital junction between the extra-testicular rete testis and the mesonephric duct, via the growing efferent ductules (ductuli efferentes) was first evident in fetuses with 10cm CRL. At the fetal age of 110 pcd (24cm CRL), the mesonephric duct began to lengthen and coil forming three distinct regions (caput, corpus and cauda). In addition to the macroscopical modifications in the extra-testicular excurrent duct system, histological differentiation involved both the tubular epithelial and the peritubular mesenchymal cells. The epithelium lining the efferent ductules was differentiated into ciliated and non-ciliated columnar cells. The simple epithelium of the epididymal duct increased in height and developed stereocilia on the apical surface. Additionally, some basal cells first appeared at 185 pcd (56cm CRL), within the epithelium lining the cauda only. Lectin histochemistry (WGA, PNA, GSA-I) showed early immunostaining in epithelium of the efferent ductules and in peritubular mesenchymal structures. Immunoreactivity for different proteins (S-100, fibroblast growth factor-1 and factor-2, angiotensin converting enzyme, laminin, alpha-smooth muscle actin) was evident, both in the epithelial and in the peritubular mesenchymal cells as early as at 75 pcd. On the basis of our histochemical observations, we conclude that both glycohistochemistry and immunohistochemistry are useful tools to demonstrate that the differentiation in the peritubular structures and efferent ductular epithelium begins earlier than other components.
 ...
PMID:Prenatal development of the bovine epididymis: light microscopical, glycohistochemical and immunohistochemical studies. 2220 23