Acute renal failure in 2K2C Goldblatt hypertensive rats during antihypertensive therapy: comparison of an angiotensin AT1 receptor antagonist and clonidine analogues.
1. This study compared the effect of a non-peptide angiotensin II receptor antagonist and a series of clonidine analogues on blood pressure and renal function in a two-kidney two-clip Goldblatt rat model of hypertension subjected to 2 weeks of dietary sodium deprivation. 2. Animals received either vehicle, the angiotensin II antagonist, ZD7155 or structural analogues derived from clonidine (AL-11, AL-12 and CN-10) at 10 mg kg-1 day-1 for 4 days. 3. All groups of rats had systolic blood pressure in the hypertensive range (160-180 mmHg). ZD7155 caused a 33-mmHg fall in blood pressure (P < 0.05) and raised plasma urea and creatinine four- to six-fold. 4. AL-12 decreased blood pressure by 30 mmHg (P < 0.05), but had no effect on water intake, urine flow or plasma urea and creatinine. AL-11 and CN-10 had minimal effects on blood pressure and water intake and while CN-10 decreased urine flow on the third treatment day, AL-11 markedly reduced urine flow by some 70%. 5. These data show that in this sodium deficient renovascular model of hypertension, blockade of angiotensin II receptors normalizes blood pressure but causes renal failure, whereas the vasodepressor action of the clonidine analogue AL-12 occurs without detriment to renal function. These findings imply that angiotensin II receptor antagonists could lead to renal failure if used as antihypertensive agents in renovascular hypertension whereas this would be avoided with the use of clonidine-like analogues.
Sattar
M A
MA
School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia.
Yusof
A P
AP
Gan
E K
EK
Sam
T W
TW
Johns
E J
EJ
D058186:Acute Kidney Injury / Q000209:etiology* / Q000503:physiopathology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D003000:Clonidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D003404:Creatinine / Q000097:blood; D004039:Diet, Sodium-Restricted; D006978:Hypertension, Renovascular / Q000150:complications* / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D009287:Naphthyridines / Q000009:adverse effects / Q000627:therapeutic use; D011188:Potassium / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D012964:Sodium / Q000097:blood; D014508:Urea / Q000097:blood
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D009287:Naphthyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; C095905:ZD 7155; D014508:Urea; D012964:Sodium; D003404:Creatinine; D003000:Clonidine; D011188:Potassium