Intrinsic properties of the nonpeptide angiotensin II antagonist losartan in glomeruli and mesangial cells at high concentrations.
Intrinsic activities of the nonpeptide angiotensin II antagonist losartan were examined in a number of in vitro assays. Losartan produced contraction of rat isolated glomeruli at 100 mumol/l and of human mesangial cells at 1 to 100 mumol/l. Cell surface reduction was associated with disorganization of the alpha actin microfilament bundles. Losartan also stimulated cytosolic calcium concentration in cultured human mesangial cells at high concentrations (10-100 mumol/l). Losartan-dependent cytosolic free calcium concentration increase was not affected by nicardipine or 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxy-benzoate hydrochloride, whereas it was abolished in a calcium-free medium. There was a marked homologous desensitization response to losartan which was also obtained after pretreatment by EXP 3174 (2-n-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl) biphenyl-4-yl)methyl]imidazole-5-carboxylic acid), the metabolite of losartan. The search for other agonistic effects of losartan in human mesangial cells including inositoltriphosphate formation, prostaglandin E2 production, [3H]leucine or [3H]thymidine incorporation was negative. Losartan and EXP 3174 were not toxic for human mesangial cells at the concentrations studied as judged by the absence of release of lactate dehydrogenase and the normal uptake of neutral red. These studies demonstrate that losartan exhibits glomerular effects in vitro only at high concentrations. Their relevance to in vivo situations is still questionable.
I.N.S.E.R.M. 64, Hôpital Tenon, Paris, France.
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D
Chansel
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L
Badre
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Czekalski
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Vandermeersch
J
J
Cambar
R
R
Ardaillou
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007678:Kidney Glomerulus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D019808:Losartan; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C066026:losartan carboxylic acid; D019808:Losartan; D002118:Calcium