Tacrolimus-induced hypertension and nephrotoxicity in Fawn-Hooded rats are attenuated by dual inhibition of renin-angiotensin system.
Chronic immunosuppressive therapy is often complicated by the development of both arterial hypertension and renal dysfunction. The principal aim of this study was to assess the effects of dual inhibition of renin-angiotensin system (RAS) and other antihypertensive treatment on blood pressure and renal function in normotensive and hypertensive Fawn-Hooded (FH) strains during chronic calcineurin inhibitor (CNI) administration. Combinations of perindopril (5 mg kg(-1) per day) and losartan (50 mg kg(-1) per day) or amlodipine (6 mg kg(-1) per day) and metoprolol (80 mg kg(-1) per day) were administered to normotensive (FHL) and hypertensive (FHH) rats, fed with diet containing tacrolimus (Tac; 12 mg kg(-1) per day). Tac-induced arterial hypertension in both animal strains (FHL: 151±4; FHH: 198±6 mm Hg) was prevented by dual RAS inhibition (FHL: 132±3 mm Hg, P<0.05; FHH: 153±3 mm Hg, P<0.05) as well as by a combination of amlodipine and metoprolol (FHL: 136±3 mm Hg, P<0.05; FHH: 166±4 mm Hg, P<0.05). However, significant nephroprotection was observed only in animals on dual RAS inhibition where albuminuria was reduced in both FHL (51.1±3.9 vs. 68.3±4.5 μg per day; P<0.05) and FHH rats (13.1±0.3 vs. 18.8±0.7 mg per day; P<0.05). We also found Tac-induced enhancement in renal angiotensin II activity that was significantly reduced by dual RAS inhibition in both FHL (63.5±3.2 vs. 23.1±3.0 fmol g(-1)) and FHH (79.8±8.5 vs. 32.2±5.8 fmol g(-1)). In addition, histological analysis revealed that RAS inhibition noticeably diminished glomerulosclerosis and tubulo-interstitial injury. This study indicates that dual blockade of RAS significantly attenuates Tac-induced arterial hypertension and nephrotoxicity in FH rats and further supports the notion that RAS inhibitors display efficient renoprotective properties during CNI treatment.
Department of Cardiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
Lenka
L
Hošková
Department of Cardiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
Ivan
I
Málek
Department of Cardiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
Josef
J
Kautzner
Department of Clinical and Transplant Pathology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
Eva
E
Honsová
Department of Clinical Pharmacology, University Medical Center Groningen, Groningen, The Netherlands.
Richard P E
RP
van Dokkum
Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
Zuzana
Z
Husková
Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
Alžbeta
A
Vojtíšková
Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
Sárka
S
Varcabová
Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
Luděk
L
Cervenka
Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
Libor
L
Kopkan
D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000517:prevention & control*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D019703:Calcineurin / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004032:Diet; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D008297:Male; D051381:Rats; D012084:Renin-Angiotensin System / Q000187:drug effects*; D016559:Tacrolimus / Q000037:antagonists & inhibitors* / Q000633:toxicity*
D000319:Adrenergic beta-Antagonists; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D002121:Calcium Channel Blockers; D007166:Immunosuppressive Agents; D019703:Calcineurin; D016559:Tacrolimus