Effects of angiotensin-converting-enzyme inhibitors in combination with diuretics on blood pressure and renal injury in nitric oxide-deficiency-induced hypertension in rats.
The present study investigates the effects of chronic administration of ACEIs (angiotensin-converting-enzyme inhibitors; either zofenopril or enalapril) in combination with a diruetic (hydrochlorothiazide) on BP (blood pressure) increase and renal injury induced by L-NAME (NG-nitro-L-arginine methyl ester), an inhibitor of NO (nitric oxide) synthesis. Rats were untreated or received L-NAME alone, L-NAME+zofenopril+hydrochlorothiazide or L-NAME+enalapril+hydrochlorothiazide for 8 weeks. L-NAME treatment resulted in marked elevation in BP and mortality. Treatment with either ACEI and diuretic prevented the increase in BP induced by L-NAME, reduced the death rate and improved excretory parameters. Renal injury in the L-NAME group was severe, but, in the groups treated with either ACEI and diuretic, glomerular and tubulointerstitial lesions were not observed and the intensity, number and size of vessels affected was reduced. However, the efficacy of zofenopril+diuretic was superior to that of enalapril+diuretic in reducing vascular alterations. Oxidative stress indices and the expression of NO synthase and nitrotyrosine were normalized by the treatments. In conclusion, the combined treatment of zofenopril or enalapril with hydrochlorothiazide completely prevented the development of arterial hypertension induced by L-NAME. Renal morphological and functional alterations in the hypertensive animals were also almost completely normalized, but the treatment with zofenopril+diuretic produced a more complete organ protection. The protective effect is related to an activation of endothelial NO synthase expression and to a normalization of the oxidative stress parameters due to the inhibition of angiotensin II.
García-Estañ
Joaquín
J
Department of Physiology, Faculty of Medicine, University of Murcia, 30100 Murcia, Spain. jgestan@um.es
Ortiz
M Clara
MC
O'Valle
Francisco
F
Alcaraz
Antonia
A
Navarro
Esther G
EG
Vargas
Félix
F
Evangelista
Stefano
S
Atucha
Noemí M
NM
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004232:Diuretics / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D004656:Enalapril / Q000627:therapeutic use*; D006852:Hydrochlorothiazide / Q000627:therapeutic use*; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000378:metabolism / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D004232:Diuretics; D006852:Hydrochlorothiazide; C044958:zofenopril; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D004656:Enalapril; D002216:Captopril; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester