Reduction of blood nitric oxide levels is associated with clinical improvement of the chronic pelvic pain related to endometriosis

The objective of this prospective study was to determine the plasma levels of nitric oxide (NO) in women with chronic pelvic pain secondary to endometriosis (n=24) and abdominal myofascial pain syndrome (n=16). NO levels were measured in plasma collected before and 1 month after treatment. Pretreatment NO levels (μM) were lower in healthy volunteers (47.0±12.7) than in women with myofascial pain (64.2±5.0, P=0.01) or endometriosis (99.5±12.9, P<0.0001). After treatment, plasma NO levels were reduced only in the endometriosis group (99.5±12.9 vs 61.6±5.9, P=0.002). A correlation between reduction of pain intensity and reduction of NO level was observed in the endometriosis group [correlation = 0.67 (95%CI = 0.35 to 0.85), P<0.0001]. Reduction of NO levels was associated with an increase of pain threshold in this group [correlation = -0.53 (-0.78 to -0.14), P<0.0001]. NO levels appeared elevated in women with chronic pelvic pain diagnosed as secondary to endometriosis, and were directly associated with reduction in pain intensity and increase in pain threshold after treatment. Further studies are needed to investigate the role of NO in the pathophysiology of pain in women with endometriosis and its eventual association with central sensitization.484363369CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQSem informaçã

Cardiovascular Pharmacogenetics [farmacogenética Cardiovascular]

The widely acknowledged variability in drug response is partiality due to differences in genetic background. Pharmacogenetics is a branch within the field of Clinical Pharmacology focused on the study of how genetic differences affect drug responses. Genetic variations (called polymorphisms) may change pharmacokinetic parameters (by altering enzymes involved in drug metabolism), and pharmacodynamic parameters (by altering receptor affinity by agonist and antagonist drugs). Presently, pharmacogenetics has been valued as a potentially useful tool in finding better therapeutics. This review is mostly concerned with cardiovascular pharmacogenetics. Clinical cases will be described and their possible pharmacogenetic implications will be briefly commented on.394535542Mooser, V., Waterworth, D.M., Isenhour, T., Middleton, L., Cardiovascular pharmacogenetics in the SNP era (2003) J Thromb Haemost, 1 (7), pp. 1398-1402Hingorani, A.D., Liang, C.F., Fatibene, J., Lyon, A., Monteith, S., Parsons, A., A common variant of the endothelial nitric oxide synthase (Glu298Asp) is a major risk factor for coronary artery disease in the UK (1999) Circulation, 100 (14), pp. 1515-1520Nakayama, M., Yasue, H., Yoshimura, M., Shimasaki, Y., Kugiyama, K., Ogawa, H., T-786-C mutation in the 5′-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm (1999) Circulation, 99 (22), pp. 2864-2870Ingelman-Sundberg, M., Pharmacogenetics of cytochrome P450 and its applications in drug therapy: The past, present and future (2004) Trends Pharmacol Sci, 25 (4), pp. 193-200Schaefer, B.M., Caracciolo, V., Frishman, W.H., Charney, P., Gender, ethnicity and genetics in cardiovascular disease: Part 1: Basic principles (2003) Heart Dis, 5 (2), pp. 129-143Sanderson, S., Emery, J., Higgins, J., CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: A HuGEnet systematic review and meta-analysis (2005) Genet Med, 7 (2), pp. 97-104Siffert, W., Cardiovascular pharmacogenetics: On the way toward individually tailored drug therapy (2003) Kidney Int, (SUPPL. 84), pp. S168-S171Brookes, A.J., The essence of SNPs (1999) Gene, 234 (2), pp. 177-186Anderson, J.L., Carlquist, J.F., Horne, B.D., Muhlestein, J.B., Cardiovascular pharmacogenomics: Current status, future prospects (2003) J Cardiovasc Pharmacol Ther, 8 (1), pp. 71-83Endo, A., The discovery and development of HMG-CoA reductase inhibitors (1992) J Lipid Res, 33 (11), pp. 1569-1582Brown, M.S., Goldstein, J.L., A receptor-mediated pathway for cholesterol homeostasis (1986) Science, 232 (4746), pp. 34-47Gerdes, L.U., Gerdes, C., Kervinen, K., Savolainen, M., Klausen, I.C., Hansen, P.S., The apolipoprotein epsilon4 allele determines prognosis and the effect on prognosis of simvastatin in survivors of myocardial infarction : A substudy of the Scandinavian simvastatin survival study (2000) Circulation, 101 (12), pp. 1366-1371Bray, P.F., Cannon, C.P., Goldschmidt-Clermont, P., Moye, L.A., Pfeffer, M.A., Sacks, F.M., The platelet Pl(A2) and angiotensin-converting enzyme (ACE) D allele polymorphisms and the risk of recurrent events after acute myocardial infarction (2001) Am J Cardiol, 88 (4), pp. 347-352de Maat, M.P., Jukema, J.W., Ye, S., Zwinderman, A.H., Moghaddam, P.H., Beekman, M., Effect of the stromelysin-1 promoter on efficacy of pravastatin in coronary atherosclerosis and restenosis (1999) Am J Cardiol, 83 (6), pp. 852-856Bolego, C., Baetta, R., Bellosta, S., Corsini, A., Paoletti, R., Safety considerations for statins (2002) Curr Opin Lipidol, 13 (6), pp. 637-644Siest, G., Ferrari, L., Accaoui, M.J., Batt, A.M., Visvikis, S., Pharmacogenomics of drugs affecting the cardiovascular system (2003) Clin Chem Lab Med, 41 (4), pp. 590-599Kajinami, K., Brousseau, M.E., Ordovas, J.M., Schaefer, E.J., CYP3A4 genotypes and plasma lipoprotein levels before and after treatment with atorvastatin in primary hypercholesterolemia (2004) Am J Cardiol, 93 (1), pp. 104-107Kurland, L., Lind, L., Melhus, H., Using genotyping to predict responses to anti-hypertensive treatment (2005) Trends Pharmacol Sci, 26 (9), pp. 443-447Koopmans, R.P., Insel, P.A., Michel, M.C., Pharmacogenetics of hypertension treatment: A structured review (2003) Pharmacogenetics, 13 (12), pp. 705-713Bianchi, G., Ferrari, P., Staessen, J.A., Adducin polymorphism: Detection and impact on hypertension and related disorders (2005) Hypertension, 45 (3), pp. 331-340Mason, D.A., Moore, J.D., Green, S.A., Liggett, S.B., A gain-of-function polymorphism in a G-protein coupling domain of the human beta1-adrenergic receptor (1999) J Biol Chem, 274 (18), pp. 12670-12674Rigat, B., Hubert, C., Alhenc-Gelas, F., Cambien, F., Corvol, P., Soubrier, F., An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels (1990) J Clin Invest, 86 (4), pp. 1343-1346Splawski, I., Timothy, K.W., Tateyama, M., Clancy, C.E., Malhotra, A., Beggs, A.H., Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia (2002) Science, 297 (5585), pp. 1333-1336Tanus-Santos, J.E., Farmacogenetica em Cardiologia (2004) Rev SOCESP, 14 (3), pp. 530-538Sandrim, V.C., Tanus-Santos, J.E., Farmacogenomica em hipertensão: Aspectos fisiológicos (2006) Hipertensão, 9 (1), pp. 4-8Sandrim, V.C., Tanus-Santos, J.E., Farmacogenômica em hipertensão: Aspectos fisiopatológicos (2006) Hipertensão, 9 (1), pp. 9-1

Genetic Factors Modulate Lead Concentrations In The Organism [fatores Genéticos Que Modulam Concentrações De Chumbo No Organismo]

Lead (Pb) is a highly toxic heavy metal, even at low concentrations. There is no threshold considering "safe" for lead exposure. The toxic effects are due mainly to the enzymatic changes, such as inhibition of the enzyme delta aminolevulinic dehydratase (ALAD) and the ability to compete with calcium. The primary sites for lead absorption are gastrointestinal and respiratory tract. Once absorbed, lead is found in blood, soft tissues and mineralizing systems. Approximately 99% of the total body burden of lead is found in bones, body's major storage site. Around 1% of lead in blood is in plasma, representing the labile and biologically active lead fraction, able to pass the cells membranes and cause toxic effects. Despite the measures taken to reduce the concentrations of metal in nature, some individuals may be more susceptible to adverse effects caused by exposure to lead. Genetic factors has been studied and associated to differences among blood and plasma lead concentrations in subjects exposure. Subjects with different genotypes has proved lower or higher blood concentrations and plasma Pb. Recognize the individual or group of individuals more susceptible to high concentrations of lead can be a useful tool in preventing the toxic effects of metal. The gene coding for ALAD gene and of the Vitamin D Receptor (VDR), which are related to the toxicokinetics of lead have been outbreaks of this review.423331339Crawford, D.C., Akey, D.T., Nickerson, D.A., The patterns of natural variation in human genes (2005) Annu Rev Genomics Hum Genet, 6, pp. 287-312Onalaja, A.O., Claudio, L., Genetic susceptibility to lead poisoning (2000) Environ Health Perspect, 108 (SUPPL. 1), pp. 23-28Rezende, V.B., Barbosa Jr., F., Montenegro, M.F., Sandrim, V.C., Gerlach, R.F., Tanus-Santos, J.E., Haplotypes of vitamin D receptor modulate the circulating levels of lead in exposed subjects (2008) Arch Toxicol, 82, pp. 29-36Montenegro, M.F., Barbosa Jr., F., Sandrim, V.C., Gerlach, R.F., Tanus-Santos, J.E., A polymorphism in the delta-aminolevulinic acid dehydratase gene modifies plasma/whole blood lead ratio (2006) Arch Toxicol, 80, pp. 394-398Weaver, V.M., Lee, B.K., Todd, A.C., Ahn, K.D., Shi, W., Jaar, B.G., Effect modification by delta-aminolevulinic acid dehydratase, vitamin D receptor, and nitric oxide synthase gene polymorphisms on associations between patella lead and renal function in lead workers (2006) Environ Res, 102, pp. 61-69Weaver, V.M., Schwartz, B.S., Ahn, K.D., Stewart, W.F., Kelsey, K.T., Todd, A.C., Associations of renal function with polymorphisms in the delta-aminolevulinic acid dehydratase, vitamin D receptor, and nitric oxide synthase genes in Korean lead workers (2003) Environ Health Perspect, 111, pp. 1613-1619Wetmur, J.G., Influence of the common human deltaaminolevulinate dehydratase polymorphism on lead body burden (1994) Environ Health Perspect, 102 (SUPPL. 3), pp. 215-219Wetmur, J.G., Lehnert, G., Desnick, R.J., The delta-aminolevulinate dehydratase polymorphism: Higher blood lead levels in lead workers and environmentally exposed children with the 1-2 and 2-2 isozymes (1991) Environ Res, 56, pp. 109-119Schwartz, B.S., Stewart, W.F., Kelsey, K.T., Simon, D., Park, S., Links, J.M., Associations of tibial lead levels with BsmI polymorphisms in the vitamin D receptor in former organolead manufacturing workers (2000) Environ Health Perspect, 108, pp. 199-203Goyer, R.A., Lead toxicity: Current concerns (1993) Environ Health Perspect, 100, pp. 177-187(1999) Agency for Toxic Substances and Disease Registry Toxicological profile for lead, pp. 68-196. , ATSDR, U.S. Department of Health and Human Services, Public Health ServiceGilbert, S.G., Weiss, B., A rationale for lowering the blood lead action level from 10 to 2 microg/dL (2006) Neurotoxicology, 27, pp. 693-701Braun, J.M., Kahn, R.S., Froehlich, T., Auinger, P., Lanphear, B.P., Exposures to environmental toxicants and attention deficit hyperactivity disorder in U.S. children (2006) Environ Health Perspect, 114, pp. 1904-1909Bellinger, D., Fau - Leviton, A., Leviton, A., Fau - Waternaux, C., Waternaux, C., Fau - Needleman, H., Needleman, H., Rabinowitz, M., Low-level lead exposure, social class, and infant development (1988) Neurotoxicol Teratol, 10, pp. 497-503Mudipalli, A., Lead hepatotoxicity & potential health effects (2007) Indian J Med Res, 126, pp. 518-527Gidlow, D.A., Lead toxicity (2004) Occup Med (Lond), 54, pp. 76-81Selevan, S.G., Landrigan, P.J., Stern, F.B., Jones, J.H., Mortality of lead smelter workers (1985) Am J Epidemiol, 122, pp. 673-683Selevan, S.G., Landrigan, P.J., Stern, F.B., Jones, J.H., Lead and hypertension in a mortality study of lead smelter workers (1988) Environ Health Perspect, 78, pp. 65-66Rothenberg, S.J., Kondrashov, V., Manalo, M., Jiang, J., Cuellar, R., Garcia, M., Increases in hypertension and blood pressure during pregnancy with increased bone lead levels (2002) Am J Epidemiol, 156, pp. 1079-1087Cooper, W.C., Wong, O., Kheifets, L., Mortality among employees of lead battery plants and lead-producing plants, 1947-1980 (1985) Scand J Work Environ Health, 11, pp. 331-345Patrick, L., Lead toxicity, a review of the literature. Part 1: Exposure, evaluation, and treatment (2006) Altern Med Rev, 11, pp. 2-22Kopp, S.J., Barron, J.T., Tow, J.P., Cardiovascular actions of lead and relationship to hypertension: A review (1988) Environ Health Perspect, 78, pp. 91-99Loghman-Adham, M., Renal effects of environmental and occupational lead exposure (1997) Environ Health Perspect, 105, pp. 928-939Aviv, A., John, E., Bernstein, J., Goldsmith, D.I., Spitzer, A., Lead intoxication during development: Its late effects on kidney function and blood pressure (1980) Kidney Int, 17, pp. 430-437Fleischer, N., Mouw, R., Vander, A.J., Chronic effects of lead on renin and renal sodium excretion (1980) J Lab Clin Med, 95, pp. 759-770Schwartz, B.S., Lee, B.K., Stewart, W., Ahn, K.D., Kelsey, K., Bressler, J., Associations of subtypes of hemoglobin with deltaaminolevulinic acid dehydratase genotype and dimercaptosuccinic acid-chelatable lead levels (1997) Arch Environ Health, 52, pp. 97-103Schwartz, B.S., Lee, B.K., Stewart, W., Sithisarankul, P., Strickland, P.T., Ahn, K.D., delta-Aminolevulinic acid dehydratase genotype modifies four hour urinary lead excretion after oral administration of dimercaptosuccinic acid (1997) Occup Environ Med, 54, pp. 241-246Schwartz, B.S., Lee, B.K., Lee, G.S., Stewart, W.F., Simon, D., Kelsey, K., Associations of blood lead, dimercaptosuccinic acidchelatable lead, and tibia lead with polymorphisms in the vitamin D receptor and [delta-aminolevulinic acid dehydratase genes (2000) Environ Health Perspect, 108, pp. 949-954Rabinowitz, M.B., Toxicokinetics of bone lead (1991) Environ Health Perspect, 91, pp. 33-37Bergdahl, I.A., Gerhardsson, L., Liljelind, I.E., Nilsson, L., Skerfving, S., Plasma-lead concentration: Investigations into its usefulness for biological monitoring of occupational lead exposure (2006) Am J Ind Med, 49, pp. 93-101Moreira FR, Moreira JC. [Effects of lead exposure on the human body and health implications. Rev Panam Salud Publica. 2004;15:119-29Berglund, M., Akesson, A., Bjellerup, P., Vahter, M., Metal-bone interactions (2000) Toxicol Lett, pp. 112-113,219-225Silbergeld, E.K., Schwartz, J., Mahaffey, K., Lead and osteoporosis: Mobilization of lead from bone in postmenopausal women (1988) Environ Res, 47, pp. 79-94Silbergeld, E.K., Patrick, T.E., Environmental exposures, toxicologic mechanisms, and adverse pregnancy outcomes (2005) Am J Obstet Gynecol, 192 (SUPPL. 5), pp. S11-S21Astrin, K.H., Bishop, D.F., Wetmur, J.G., Kaul, B., Davidow, B., Desnick, R.J., delta-Aminolevulinic acid dehydratase isozymes and lead toxicity (1987) Ann N Y Acad Sci, 514, pp. 23-29Barbosa Jr., F., Tanus-Santos, J.E., Gerlach, R.F., Parsons, P.J., A critical review of biomarkers used for monitoring human exposure to lead: Advantages, limitations, and future needs (2005) Environ Health Perspect, 113, pp. 1669-1674Wetmur, J.G., Kaya, A.H., Plewinska, M., Desnick, R.J., Molecular characterization of the human delta-aminolevulinate dehydratase 2 (ALAD2) allele: Implications for molecular screening of individuals for genetic susceptibility to lead poisoning (1991) Am J Hum Genet, 49, pp. 757-763Montenegro, M.F., Barbosa Jr., F., Sandrim, V.C., Gerlach, R.F., Tanus-Santos, J.E., Ethnicity affects the distribution of delta-aminolevulinic acid dehydratase (ALAD) genetic variants (2006) Clin Chim Acta, 367, pp. 192-195Ziemsen, B., Angerer, J., Lehnert, G., Benkmann, H.G., Goedde, H.W., Polymorphism of delta-aminolevulinic acid dehydratase in lead-exposed workers (1986) Int Arch Occup Environ Health, 58, pp. 245-247Lee, S.S., Lee, B.K., Lee, G.S., Stewart, W.F., Simon, D., Kelsey, K., Associations of lead biomarkers and delta-aminolevulinic acid dehydratase and vitamin D receptor genotypes with hematopoietic outcomes in Korean lead workers (2001) Scand J Work Environ Health, 27, pp. 402-411Bergdahl, I., Fau - Grubb, A., Grubb, A., Fau - Schutz, A., Schutz, A., Fau - Desnick, R.J., Desnick, R., Fau - Skerfving, S., Lead binding to delta-aminolevulinic acid dehydratase (ALAD) in human (1997) Pharmacol Toxicol, 81, pp. 153-158Fleming, D.E., Chettle, D.R., Wetmur, J.G., Desnick, R.J., Robin, J.P., Boulay, D., Effect of the delta-aminolevulinate dehydratase polymorphism on the accumulation of lead in bone and blood in lead smelter workers (1998) Environ Res, 77, pp. 49-61Montenegro, M.F., Barbosa Jr., F., Sandrim, V.C., Gerlach, R.F., Tanus-Santos, J.E., A polymorphism in the delta-aminolevulinic acid dehydratase gene modifies plasma/whole blood lead ratio (2005) Arch Toxicol. 2006, 80, pp. 394-398. , Epub Dec 9Schwartz, B.S., Lee, B.K., Lee, G.S., Stewart, W.F., Simon, D., Kelsey, K., Associations of blood lead, dimercaptosuccinic acidchelatable lead, and tibia lead with polymorphisms in the vitamin D receptor and [delta-aminolevulinic acid dehydratase genes (2000) Environ Health Perspect, 108, pp. 949-954Bellinger, D., Hu, H., Titlebaum, L., Needleman, H.L., Attentional correlates of dentin and bone lead levels in adolescents (1994) Arch Environ Health, 49, pp. 98-105Lips, P., Vitamin D physiology (2006) Prog Biophys Mol Biol. 2006, 92, pp. 4-8. , Epub Feb 28Wasserman, R.H., Fullmer, C.S., Vitamin D and intestinal calcium transport: Facts, speculations and hypotheses (1995) J Nutr, 125 (SUPPL. 7), pp. 1971S-1979SSix, K.M., Goyer, R.A., Experimental enhancement of lead toxicity by low dietary calcium (1970) J Lab Clin Med, 76, pp. 933-942Mykkanen, H.M., Wasserman, R.H., Gastrointestinal absorption of lead (203Pb) in chicks: Influence of lead, calcium, and age (1981) J Nutr, 111, pp. 1757-1765Fullmer, C.S., Dietary calcium levels and treatment interval determine the effects of lead ingestion on plasma 1,25-dihydroxyvitamin D concentration in chicks (1995) J Nutr, 125, pp. 1328-1333Holick, M.F., Vitamin D deficiency (2007) N Engl J Med, 357, pp. 266-281McDonnell, D.P., Mangelsdorf, D.J., Pike, J.W., Haussler, M.R., O'Malley, B.W., Molecular cloning of complementary DNA encoding the avian receptor for vitamin D (1987) Science, 235, pp. 1214-1217Morrison, N.A., Qi, J.C., Tokita, A., Kelly, P.J., Crofts, L., Nguyen, T.V., Prediction of bone density from vitamin D receptor alleles (1994) Nature, 367, pp. 284-287Uitterlinden, A.G., Fang, Y., Van Meurs, J.B., Pols, H.A., Van Leeuwen, J.P., Genetics and biology of vitamin D receptor polymorphisms (2004) Gene, 338, pp. 143-156Miyamoto, K., Kesterson, R.A., Yamamoto, H., Taketani, Y., Nishiwaki, E., Tatsumi, S., Structural organization of the human vitamin D receptor chromosomal gene and its promoter (1997) Mol Endocrinol, 11, pp. 1165-1179Crofts, L.A., Hancock, M.S., Morrison, N.A., Eisman, J.A., Multiple promoters direct the tissue-specific expression of novel Nterminal variant human vitamin D receptor gene transcripts (1998) Proc Natl Acad Sci U S A, 95, pp. 10529-10534Uitterlinden, A.G., Fang, Y., Van Meurs, J.B., Pols, H.A., Van Leeuwen, J.P., Genetics and biology of vitamin D receptor polymorphisms (2004) Gene, 338, pp. 143-156Cooper, G.S., Umbach, D.M., Are vitamin D receptor polymorphisms associated with bone mineral density? A meta-analysis (1996) J Bone Miner Res, 11, pp. 1841-1849Need, A.G., Horowitz, M., Stiliano, A., Scopacasa, F., Morris, H.A., Chatterton, B.E., Vitamin D receptor genotypes are related to bone size and bone density in men (1996) Eur J Clin Invest, 26, pp. 793-796Haynes, E.N., Kalkwarf, H.J., Hornung, R., Wenstrup, R., Dietrich, K., Lanphear, B.P., Vitamin D receptor Fok1 polymorphism and blood lead concentration in children (2003) Environ Health Perspect, 111, pp. 1665-1669Crawford, D.C., Nickerson, D.A., Definition and clinical importance of haplotypes (2005) Annu Rev Med, 56, pp. 303-320Montpetit A, Chagnon F. [The Haplotype Map of the human genome: a revolution in the genetics of complex diseases. Med Sci (Paris). 2006;22:1061-

Pharmacogenetic Implications Of The Enos Polymorphisms For Cardiovascular Action Drugs

The pharmacogenetics is one of the most promising fields of medicine. The conclusion of the Genome Project allowed this field to start discovering complex factors modulating the response to drugs, and new technologies are close a great expansion of the area. The cardiovascular diseases are currently among the major causes of hospitalizations and death, and have been the target of a large part of genetic studies of complex diseases. Parallel to the susceptibility to disease markers identification, it is necessary to investigate how different genetic profiles can change the responses to the currently used drugs. The biological system that controls the endothelial production of the nitric oxide has been one of the greatest targets in the pharmacological responses to the drugs used in the cardiovascular diseases therapy. 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Scott, A.K., Walley, T.J., Adverse drug reactions as cause of admission to hospital: Prospective analysis of 18 820 patients (2004) BMJ, 329 (7456), pp. 15-19Peters, E.J., McLeod, H.L., Ability of whole-genome SNP arrays to capture 'must have' pharmacogenomic variants (2008) Pharmacogenomics, 9 (11), pp. 1573-1577Bader, J.S., Systems approaches for pharmacogenetics and pharmacogenomics (2008) Pharmacogenomics, 9 (3), pp. 257-262Topol, E.J., Frazer, K.A., The resequencing imperative (2007) Nat Genet, 39 (4), pp. 439-440Dorn, G.W., Cresci, S., The mechanistic imperative for pharmacogenomics (2008) Pharmacogenomics, 9 (7), pp. 801-803Marsh, S., Pharmacogenetics: Global clinical markers (2008) Pharmacogenomics, 9 (4), pp. 371-373Lacchini, R., Sabha, M., Coeli, F.B., Favero, F.F., Yugar-Toledo, J., Izidoro-Toledo, T.C., T allele of -344C/T polymorphism in aldosterone synthase gene is not associated with resistant hypertension (2009) Hypertens Res, 32 (2), pp. 159-162Sandrim, V.C., Palei, A.C., Cavalli, R.C., Araujo, F.M., Ramos, E.S., Duarte, G., eNOS Haplotypes associated with gestational hypertension or preeclampsia (2008) Pharmacogenomics, 9 (10), pp. 1467-1473Moncada, S., Higgs, A., The L-arginine-nitric oxide pathway (1993) N Engl J Med, 329 (27), pp. 2002-2012Kiechle, F.L., Malinski, T., Nitric oxide: Biochemistry, pathophysiology, and detection (1993) Am J Clin Pathol, 100 (5), pp. 567-575Cooke, J.P., Dzau, V.J., Nitric oxide synthase: Role in the genesis of vascular disease (1997) Annu Rev Med, 48, pp. 489-509Dudzinski, D.M., Igarashi, J., Greif, D., Michel, T., The regulation and pharmacology of endothelial nitric oxide synthase (2006) Annu Rev Pharmacol Toxicol, 46, pp. 235-276Perticone, F., Ceravolo, R., Pujia, A., Ventura, G., Iacopino, S., Scozzafava, A., Prognostic significance of endothelial dysfunction in hypertensive patients (2001) Circulation, 104 (2), pp. 191-196Sandrim, V.C., Palei, A.C., Metzger, I.F., Gomes, V.A., Cavalli, R.C., Tanus-Santos, J.E., Nitric oxide formation is inversely related to serum levels of antiangiogenic factors soluble fms-like tyrosine kinase-1 and soluble endogline in preeclampsia (2008) Hypertension, 52 (2), pp. 402-407Gomes, V.A., Casella-Filho, A., Chagas, A.C., Tanus-Santos, J.E., Enhanced concentrations of relevant markers of nitric oxide formation after exercise training in patients with metabolic syndrome (2008) Nitric Oxide, 19 (4), pp. 345-350Gryglewski, R.J., Palmer, R.M., Moncada, S., Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor (1986) Nature, 320 (6061), pp. 454-456Vasquez-Vivar, J., Kalyanaraman, B., Martasek, P., Hogg, N., Masters, B.S., Karoui, H., Superoxide generation by endothelial nitric oxide synthase: The influence of cofactors (1998) Proc Natl Acad Sci U S A, 95 (16), pp. 9220-9225Mason, R.P., Cockcroft, J.R., Targeting nitric oxide with drug therapy (2006) J Clin Hypertens (Greenwich), 8 (12 suppl 4), pp. 40-52Liao, J.K., Laufs, 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Original Contributions: Cardiovascular Effects Of Transdermal Nicotine In Mildly Hypertensive Smokers

Smoking potentiates the enhanced cardiovascular risk of hypertensive patients. Although nicotine replacement therapy is safe when used by healthy individuals to quit smoking, there is no evidence that nicotine replacement therapy is safe in hypertensive smokers. In this crossover, single-blinded, placebo-controlled study, we compared for 4 h the acute effects of transdermal nicotine on the mean arterial pressure (MAP) and heart rate (HR) of mildly hypertensive smokers treated with hydrochlorothiazide with the responses in normotensive smokers and nonsmokers monitored with Finapres and ambulatory blood pressure systems. The plasma concentrations of thromboxane B2 (TXB2, the stable breakdown product of TXA2) were also measured by ELISA to assess whether transdermal nicotine acutely affects TXA2 production. The use of 21-mg nicotine patches increased the MAP and HR in nonsmokers (from 94 ± 4 mm Hg and 69 ± 3 beats/min to 117 ± 7 mm Hg and 83 ± 3 beats/min, respectively; P &lt; .05) as well as the MAP in normotensive smokers (from 83 ± 4 to 106 ± 7 mm Hg; P &lt; .05). However, MAP and HR remained unaltered in hypertensive smokers after transdermal nicotine. Higher basal TXB2 levels were observed in hypertensive smokers compared with normotensive smokers and nonsmokers (2019 ± 402 v 670 ± 167 and 556 ± 68 pg/mL, respectively; P &lt; .05). Transdermal nicotine increased the TXB2 levels only in nonsmokers (P &lt; .05). These data indicate that the use of transdermal nicotine in mildly hypertensive smokers is probably safe. Further studies involving other classes of hypertensive patients are warranted. © 2001 American Journal of Hypertension, Ltd.147 I610614Lakier, J.B., Smoking and cardiovascular disease (1992) Am J Med, 93, pp. 8S-12SMoreno H., Jr., Chalon, S., Urae, A., Tangphao, O., Abiose, A.K., Hoffman, B.B., Blaschke, T.F., Endothelial dysfunction in human hand veins is rapidly reversible after smoking cessation (1998) Am J Physiol, 275, pp. H1040-H1045Powell, J.T., Vascular damage from smoking: Disease mechanisms at the arterial wall (1998) Vasc Med, 3, pp. 21-28Fiore, M.C., Smith, S.S., Jorenby, D.E., Baker, T.B., The effectiveness of the nicotine patch in smoking cessation: A meta-analysis (1994) JAMA, 271, pp. 1940-1947Tang, J.L., Law, M., Wald, N., How effective is nicotine replacement therapy in helping people to stop smoking? (1994) Br Med J, 308, pp. 21-26Jorenby, D.E., Smith, S.S., Fiore, M.C., Hurt, R.D., Offord, K.P., Croghan, I.T., Hays, J.T., Baker, T.B., Varying nicotine patch dose and type of smoking cessation counseling (1995) JAMA, 274, pp. 1347-1352Benowitz, N.L., Zevin, S., Jacob III, P., Suppression of nicotine intake during ad libitum cigarette smoking by high-dose transdermal nicotine (1998) J Pharmacol Exp Ther, 287, pp. 958-962Jorenby, D.E., Leischow, S.J., Nides, M.A., Rennard, S.I., Johnston, J.A., Hughes, A.R., Smith, S.S., Baker, T.B., A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation (1999) N Engl J Med, 340, pp. 685-691Benowitz, N.L., Treating tobacco addiction - Nicotine or no nicotine? 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L-name-induced Hypertension Does Not Completely Reproduce The Hemodynamic Pattern Of The Hypertensive-diabetic Cardiomyopathy In Rats

Renovascular hypertension (2K1C) + type 1 diabetes mimics the morphological abnormalities described in the cardiomyopathy induced by L-NAME in rats, but their hemodynamic patterns are still controversial. The present study investigated the cardiovascular function in these two models of cardiomyopathy in rats after 8 weeks of treatment. Wistar rats were divided into the following groups: Control (C); L-NAME (L)-60 mg/kg/ day; 2K1C+DM (R+D)-streptozotocin (60 mg/kg) and one renal artery clipped. The following parameters were measured: mean arterial pressure (MAP), heart rate, cardiac output (CO) and total peripheral vascular resistance (TPVR). dP/dt+ and dP/dt- were also evaluated in an isolated heart setup. L and R+D groups had increased MAP (175.4±29.7 and 158.7±16.7 mmHg, respectively) and reduced CO after the 8th week. TPVR was increased in both groups. A decrease in dP/dt+ was found in the R+D (1895±98 mmHg/s, p<0.05) vs. C group (2534±120 mmHg/ s, p< 0.05). dP/dt- was diminished in the L and R+D groups vs. C group (1490±104 and 1460±94 mmHg/s, respectively vs. 2080±92 mmHg/s, p<0.05). 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Mdr-1 C3435t Polymorphism May Affect Blood Pressure In Resistant Hypertensive Patients Independently Of Its Effects On Aldosterone Release

Aldosterone increases plasma volume and may be involved with resistant hypertension. P-glycoprotein is a transporter involved in the distribution and disposition of aldosterone, and is encoded by the MDR-1 gene. MDR-1 has functional polymorphisms that may affect P-glycoprotein expression. We hypothesized that the C3435T polymorphism in MDR-1 could be associated with resistant hypertension and with changes in hypertension-related parameters. We studied 105 healthy volunteers, 137 hypertensive patients responsive to treatment, and 83 resistant hypertensive patients. While we found no association of C3435T genotypes with resistance to treatment (p = 0.31), C allele was associated with hypertension (p = 0.03). Furthermore, the CC genotype was associated with higher systolic blood pressure (p T affects mRNA stability (2005) Pharmacogenet Genomics, 15, pp. 693-704Sissung, T.M., Gardner, E.R., Piekarz, R.L., Impact of ABCB1 allelic variants on QTc interval prolongation (2011) Clin Cancer Res, 17, pp. 937-946Bochud, M., Eap, C.B., Maillard, M., Association of ABCB1 genetic variants with renal function in Africans and in Caucasians (2008) BMC Med Genomics, 1, p. 21Cascorbi, I., Paul, M., Kroemer, H.K., Pharmacogenomics of heart failure - Focus on drug disposition and action (2004) Cardiovasc Res, 64, pp. 32-39Eap, C.B., Bochud, M., Elston, R.C., CYP3A5 and ABCB1 genes influence blood pressure and response to treatment, and their effect is modified by salt (2007) Hypertension, 49, pp. 1007-1014VI Brazilian Guidelines on Hypertension [in Portuguese] (2010) Arq Bras Cardiol, 95, pp. 1-51Taylor, D.W., Sackett, D.L., Haynes, R.B., Compliance with antihypertensive drug therapy (1978) Ann N y Acad Sci, 304, pp. 390-403Morisky, D.E., Green, L.W., Levine, D.M., Concurrent and predictive validity of a self-reported measure of medication adherence (1986) Med Care, 24, pp. 67-74De Souza, W.A., Yugar-Toledo, J.C., Bergsten-Mendes, G., Effect of pharmaceutical care on blood pressure control and health-related quality of life in patients with resistant hypertension (2007) Am J Health Syst Pharm, 64, pp. 1955-1961Zolk, O., Jacobi, J., Pahl, A., MDR1 genotype-dependent regulation of the aldosterone system in humans (2007) Pharmacogenet Genomics, 17, pp. 137-144Manunta, P., Ferrandi, M., Bianchi, G., Endogenous ouabain in cardiovascular function and disease (2009) J Hypertens, 27, pp. 9-18Tripodi, G., Citterio, L., Kouznetsova, T., Steroid biosynthesis and renal excretion in human essential hypertension: Association with blood pressure and endogenous ouabain (2009) Am J Hypertens, 22, pp. 357-363Fromm, M.F., Importance of P-glycoprotein at blood-tissue barriers (2004) Trends Pharmacol Sci, 25, pp. 423-42

Common matrix metalloproteinase 2 gene haplotypes may modulate left ventricular remodelling in hypertensive patients

Matrix metalloproteinases (MMPs) are involved in cardiac remodelling. We examined whether MMP-2 genetic polymorphisms are associated with hypertension and left ventricular (LV) remodelling in hypertensive patients. We studied 160 hypertensive patients and 123 healthy controls. Echocardiography was performed in all patients and the C-1306T (rs243865) and C-735T (rs 2285053) MMP-2 polymorphisms were analysed. Haplo.stats analysis was used to evaluate whether MMP-2 haplotypes are associated with hypertension and with extremes in LV mass index (LVMI). Multiple linear regression analysis was performed to assess whether MMP-2 genotypes or haplotypes affect LVMI and other echocardiography parameters. The C-1306T 'CC' genotype was associated with reduced LVMI and LV end-diastolic diameter (EDD) (P=0.0365 and P=0.0438, respectively). The haplotype 'C, C' was associated with reduced LVMI and EDD (P=0.0278 and P=0.0322, respectively). The comparison of upper and lower extremes of the LVMI phenotype showed that the 'C, C' haplotype was more common in the lower LVMI group (P=0.0060), whereas the 'T, C' haplotype was more common in the higher quartile of LVMI (P=0.0187), and this haplotype was associated with increased risk of higher LVMI values (odds ratio=3.5121, 95% confidence interval 1.3193-9.3494). The findings suggest that MMP-2 polymorphisms affect hypertension-induced LV remodelling. Journal of Human Hypertension (2012) 26, 171-177; doi:10.1038/jhh.2011.8; published online 10 February 2011Fundacao de Amparo a Pesquisa do Estado de Sao PauloFundacao de Amparo a Pesquisa do Estado de Sao PauloConselho Nacional de Desenvolvimento Cientifico e TecnologicoConselho Nacional de Desenvolvimento Cientifico e TecnologicoCoordenadoria de Aperfeicoamento de Pessoal de Nivel SuperiorCoordenadoria de Aperfeicoamento de Pessoal de Nivel Superio