RESUMEN
OBJECTIVE: Our objective was to study the impact of the cytochrome P450 (CYP) 2D6 polymorphism on the tolerability of metoprolol in a real-life primary care setting. The adverse effects studied comprised effects related to the central nervous system, cardiovascular effects, and sexual dysfunction. METHODS: Patients in whom treatment with metoprolol was considered were enrolled into this prospective, 6-week multicenter study. The dosage of metoprolol was determined on an individual basis and could be freely adjusted on clinical grounds. The indication for treatment was hypertension in about 90% of cases. Systolic and diastolic blood pressure, resting heart rate, and plasma metoprolol and alpha-hydroxymetoprolol concentrations were measured. CYP2D6 genotyping covered alleles *3 to *10 and *41 and the duplications. Possible adverse effects of metoprolol were systematically assessed over a 6-week period by means of standardized rating scales and questionnaires. RESULTS: The final study population comprised 121 evaluable patients (all white patients); among them, there were 5 ultrarapid metabolizers (UMs) (4.1%), 91 extensive metabolizers (EMs) (75%), 21 intermediate metabolizers (IMs) (17%), and 4 poor metabolizers (PMs) (3.3%). Plasma metoprolol concentrations normalized for the daily dose and metoprolol/alpha-hydroxymetoprolol ratios at steady state were markedly influenced by CYP2D6 genotype and displayed a gene-dose effect. The median of the dose-normalized metoprolol concentration was 0.0088 ng/mL, 0.047 ng/mL, 0.34 ng/mL, and 1.34 ng/mL among UMs, EMs, IMs, and PMs, respectively (P<.0001). There was no significant association between CYP2D6 genotype-derived phenotype (EMs and UMs combined versus PMs and IMs combined) and adverse effects during treatment with metoprolol. There was a tendency toward a more frequent occurrence of cold extremities in the PM plus IM group as compared with the EM plus UM group (16.0% versus 4.2%, P=.056; relative risk, 3.8 [95% confidence interval, 1.03--14.3]). CONCLUSIONS: CYP2D6 genotype-derived phenotype was not significantly associated with a propensity for adverse effects to develop during treatment with metoprolol. However, the results concerning tolerability of metoprolol in PMs were inconclusive because of the small number of PMs enrolled.
Asunto(s)
Antagonistas de Receptores Adrenérgicos beta 1 , Citocromo P-450 CYP2D6/genética , Metoprolol/efectos adversos , Polimorfismo Genético , Citocromo P-450 CYP2D6/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Genotipo , Humanos , Hipertensión/tratamiento farmacológico , Masculino , Metoprolol/análogos & derivados , Metoprolol/sangre , Metoprolol/farmacocinética , Metoprolol/uso terapéutico , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
BACKGROUND: Adenosine is a vasoactive metabolite of ATP hydrolysis that is involved in the regulation of renal haemodynamics, tubular reabsorption and renin release. Elevated tissue levels are found under conditions of increased metabolic load, ischaemia or renal injury. Urinary adenosine excretion (EADO) may therefore provide a sensitive marker of renal functional impairment in allograft rejection and kidney disease. To provide a basis for evaluation of EADO in clinical settings, we investigated, in an intra-individual, crossover clinical trial the physiological variability and regulation of EADO in response to altered sodium and fluid balance. METHODS: Twelve healthy volunteers were randomized to normal (ad libitum), low (<5 g/day) or high (supplementation of 100 mg/kg/day) sodium chloride diets for 8 days prior to assessment of renal haemodynamics and tubular function in standard clearance investigations. Following baseline periods, fluid homeostasis was altered independently by acute oral water load. EADO was determined in 24 h urine collections and during clearance investigations. RESULTS: Mean EADO in humans was 3.2+/-0.2 micromol/ 24 h during euvolaemia and normal sodium intake. A weak correlation was found between sodium load and EADO. In clearance experiments, variation in EADO was <1.3-fold, despite profound alterations in sodium intake. EADO was independent of urinary flow rate. Renal haemodynamics were not significantly altered by dietary regimen or by acute volume load. CONCLUSION: In summary, the physiological variability of EADO is remarkably small in humans. We demonstrate that even profound alterations in sodium and fluid homeostasis do not significantly affect EADO. These data provide a basis for evaluation of elevated EADO as a marker of renal injury in various clinical settings.
Asunto(s)
Adenosina/orina , Riñón/metabolismo , Natriuresis/fisiología , Adulto , Estudios Cruzados , Femenino , Hemodinámica , Homeostasis , Humanos , Inulina/metabolismo , Túbulos Renales Proximales/metabolismo , Masculino , Cloruro de Sodio/administración & dosificación , Cloruro de Sodio/metabolismo , Sodio en la Dieta/administración & dosificación , Sodio en la Dieta/metabolismo , Ácido p-Aminohipúrico/metabolismoRESUMEN
The main aim of the present study was to investigate the direct inotropic effects of stimulation of the endothelin (ET) receptor ETA under in vivo conditions. It is well known that ETA receptor stimulation causes pronounced vasoconstriction. The ET-1-induced coronary vasoconstriction may lead to myocardial ischaemia and, consequently, to cardiodepressor effects that may mask the direct positive inotropic effect of ETA receptor stimulation. Thus, in the present study, steps were taken to avoid this possibility. In anaesthetized open-chest rats the haemodynamic and inotropic effects of ETA receptor stimulation were studied by monitoring responses evoked by ET-1 (1 nmol/kg of body weight) after ETB receptor blockade with BQ 788 (0.5 micromol/kg of body weight); these responses were compared with saline controls (after ETB receptor blockade). To avoid vasoconstrictor effects induced by ETA receptor stimulation, additional experiments were performed in the presence of the vasodilator adenosine (2.0 mg.kg(-1) of body weight.min(-1)). Myocardial function was also examined during aortic clamping so as to circumvent the effect of changes in afterload. We studied further the effect of ETA receptor stimulation on myocardial energy metabolism. ETA receptor stimulation reduced cardiac output (-49% compared with control), raised total peripheral resistance (+173%) and reduced myocardial ATP content (-23%). Aortic clamping did not reveal a positive inotropic effect of ETA receptor stimulation. Furthermore, even though adenosine attenuated the decrease in cardiac output (-21%), the increase of total peripheral resistance (+48%) and prevented the fall of myocardial ATP content (+6%), this did not unmask a positive inotropic effect of ETA receptor stimulation. Thus we conclude that ETA receptor stimulation causes vasoconstriction and myocardial ischaemia, but has no positive inotropic effects in rats.
Asunto(s)
Endotelina-1/farmacología , Hemodinámica/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Receptor de Endotelina A/fisiología , Animales , Antihipertensivos/farmacología , Gasto Cardíaco/efectos de los fármacos , Hemodinámica/fisiología , Masculino , Contracción Miocárdica/fisiología , Oligopéptidos/farmacología , Piperidinas/farmacología , Ratas , Ratas Wistar , Vasoconstricción/efectos de los fármacos , Vasoconstricción/fisiologíaRESUMEN
Most S-adenosylmethionine (AdoMet)-dependent methyltransferases are regulated in vivo by the AdoMet/S-adenosylhomocysteine (AdoHcy) ratio, also termed as "methylation potential." Since adenosine inhibits in vitro AdoHcy hydrolysis and since adenosine tissue levels increase during hypoxia, it can be predicted that AdoHcy levels may increase in the rat kidney in parallel of those of adenosine. Therefore, the present investigation was performed to assess changes of renal AdoHcy and AdoMet tissue contents during ischemia and after administration of adenosine and homocysteine or both in the ischemic rat kidney. In anesthetized rats ischemia of the kidney was induced by renal artery occlusion for various time intervals. Adenosine and homocysteine were infused into the renal artery of the ischemic kidney. To induce a hyperhomocysteinemia homocysteine was continuously infused. The kidneys were removed and immediately snap-frozen. Tissue contents of AdoHcy, AdoMet, adenosine and adenine nucleotides were analyzed by means of HPLC. Under normoxic condition the tissue contents of AdoHcy, AdoMet and adenosine were 0.7+/-0.05, 44.1+/-1.0 and 3.8+/-0.1nmol/g wet weight, respectively. Renal ischemia for 30min resulted in an increase of AdoHcy levels from 0.7+/-0.05 to 9.1+/-0.6nmol/g wet weight and in a dramatic decrease of the AdoMet/AdoHcy ratio and energy charge from 65.1+/-5.6 to 2.8+/-0.2 and from 0.87+/-0.01 to 0.25+/-0.01, respectively. Application of exogenous adenosine into the ischemic kidney did not result in further AdoHcy accumulation. However, when homocysteine was infused into the ischemic kidney, AdoHcy increased five-fold above control levels, during 5min ischemia. Systemic infusion of homocysteine leads to a reduction of the methylation potential also in the normoxic kidney. We conclude that (i) the methylation potential in the kidney is markedly reduced during ischemia, mainly due to accumulation of AdoHcy; (ii) elevation of AdoHcy tissue content during ischemia is the result of the inhibition of AdoHcy hydrolysis; (iii) homocysteine is rate limiting for AdoHcy synthesis in the ischemic kidney; (iv) under normoxic conditions hyperhomocysteinemia can affect the methylation potential in the renal tissue.