Effects of icatibant on the ramipril-induced decreased in renal lithium clearance in the rat.
The interaction between an inhibitor of angiotensin I converting enzyme (ramipril) and renal lithium handling was analysed in conscious, normotensive Wistar rats in the absence or the presence of a specific bradykinin B2 receptor antagonist, icatibant. The rats were treated for 5 days with ramipril (1 mg/kg/day p.o.) or its vehicle, alone or together with icatibant (0.1 mg/kg/day, s.c. infusion). Lithium chloride (8.3 mg/kg i.p.) was given as a single dose on day 5. Systolic blood pressure and heart rate were measured by tail plethysmography on day 3 (3, 9 and 15 h after ramipril administration) and renal function on day 4 (0-6 and 6-24 h urine sampling) and day 5 (0-6 h urine sampling). In another group of rats, 24 h sodium excretion was assessed during the first 4 days of ramipril treatment. Ramipril decreased renal lithium clearance (90+/-8 vs. 142+/-10 microl/min/100 g, P<0.001, n=24) and increased the fractional lithium reabsorption (74.3+/-1.9 vs. 66.7+/-1.7%, P<0.05) and plasma lithium concentration (0.108+/-0.006 vs. 0.085+/-0.004 mM, P<0.01). Alteration of renal lithium handling by ramipril was associated with a decrease in systolic blood pressure (-15% 3 h after ramipril administration) and sodium excretion (0-6 h after ramipril). The 24-h sodium excretion, however, tended to increase. Icatibant had no effect per se on renal function but attenuated the ramipril-induced decrease in renal lithium clearance (118+/-16 vs. 90+/-8 microl/min/100 g, n=12 and 24 respectively, P<0.05 one-tailed test) and systolic blood pressure. These results suggest that endogenous bradykinin contributes to the ramipril-associated alteration in renal lithium handling. Bradykinin B2 receptor-mediated vasodilation seems to be involved.
Institut de Pharmacologie, Faculté de Médecine, Université Louis Pasteur, Strasbourg, France.
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Bagaté
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Grima
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De Jong
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Barthelmebs
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000502:physiology; D065168:Bradykinin Receptor Antagonists; D003864:Depression, Chemical; D004347:Drug Interactions; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008094:Lithium / Q000493:pharmacokinetics* / Q000652:urine; D018021:Lithium Chloride / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D017257:Ramipril / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D043782:Receptor, Bradykinin B2; D012964:Sodium / Q000378:metabolism / Q000652:urine
D000806:Angiotensin-Converting Enzyme Inhibitors; D065168:Bradykinin Receptor Antagonists; D043782:Receptor, Bradykinin B2; C065679:icatibant; D008094:Lithium; D012964:Sodium; D018021:Lithium Chloride; D017257:Ramipril; D001920:Bradykinin