Therapeutic resistance to angiotensin converting enzyme (ACE) inhibition is related to pharmacodynamic and -kinetic factors in 5/6 nephrectomized rats
| Autor: | Willemijn A.K.M. Windt, Dick de Zeeuw, Florian Hut, C. Alex Kluppel, Richard P. E. van Dokkum, Robert H. Henning, C. Margot Jeronimus-Stratingh |
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| Přispěvatelé: | Groningen University Institute for Drug Exploration (GUIDE), University of Groningen, Groningen Kidney Center (GKC), Vascular Ageing Programme (VAP), Groningen Institute for Organ Transplantation (GIOT) |
| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
Male
medicine.medical_specialty Urinary system Urology Drug Resistance Angiotensin-Converting Enzyme Inhibitors Blood Pressure Peptidyl-Dipeptidase A LISINOPRIL Nephrectomy End stage renal disease CARDIAC-FUNCTION Internal medicine Medicine Animals Rats Wistar renal ACE activity Antihypertensive Agents EXPERIMENTAL RENAL-FAILURE PREDICT SUSCEPTIBILITY Pharmacology DAMAGE Kidney Proteinuria biology business.industry 5/6 nephrectomy therapy response Lisinopril CONSCIOUS RATS Angiotensin-converting enzyme Rats MODEL Disease Models Animal Endocrinology medicine.anatomical_structure Blood pressure MYOCARDIAL-INFARCTION ACE inhibitor biology.protein ADRIAMYCIN NEPHROSIS medicine.symptom angiotensin converting enzyme inhibitor proteinuria SODIUM-INTAKE business medicine.drug |
| Zdroj: | European Journal of Pharmacology, 580(1-2), 231-240. ELSEVIER SCIENCE BV |
| ISSN: | 0014-2999 |
| Popis: | Proteinuria plays a pathogenic role in the development of end stage renal disease. Angiotensin converting enzyme (ACE) inhibitors lower proteinuria and are renoprotective. However, large inter-individual variation in antiproteinuric response to ACE inhibitors exists. In this study, we explored the mechanism of therapeutic resistance to an ACE inhibitor in the rat 5/6 nephrectomy model. At week 6 after 5/6 nephrectomy, treatment with lisinopril was initiated for 6 weeks. Proteinuria and blood pressure were evaluated weekly. At the end of the experiment, rats were divided into tertiles according to their antiproteinuric response: (1) responders (n=9), (2) intermediate responders (n=8) and (3) non-responders to ACE inhibitor therapy (n=9). At the start of treatment, proteinuria had progressively increased to 154 (95% confidence interval [Cl]: 123-185) mg/24 It in the entire cohort, with comparable proteinuria and blood pressure in all groups. Following treatment with ACE inhibitor, proteinuria was significantly lower in the responders (68, Cl: 46-89 mg/24 h) compared to the non-responders (25 1, CI: 83-420) mg/24 h). Similarly, blood pressure was reduced in the responders, but unaffected in the non-responders. At autopsy, renal ACE activity and renal ACE expression were significantly lower in the responders compared to the non-responders. Although lisinopril intake was comparable in all animals, urinary drug excretion was increased in the non-responders, demonstrating increased drug clearance. Average urinary lisinopril excretion was correlated with antiproteinuric response (R-2=0.32, P=0.003). In conclusion, both pharmacodynamic and -kinetic factors account for the non-response to lisinopril. Whether these can be overcome simply by increasing drug dosage in non-responders should be investigated. (c) 2007 Elsevier B.V All rights reserved. |
| Databáze: | OpenAIRE |
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