Eprosartan reduces cardiac hypertrophy, protects heart and kidney, and prevents early mortality in severely hypertensive stroke-prone rats.
OBJECTIVE
Eprosartan is a selective angiotensin II type I receptor antagonist approved for the treatment of hypertension. In the present studies, eprosartan's ability to provide end-organ protection was evaluated in a model of cardiomyopathy and renal failure in stroke-prone rats (SP).


METHODS
SP were fed a high fat (24.5% in food) and high salt (1% in water) diet (SFD). Eprosartan (60 mg/kg/day) or vehicle (saline control) (n = 25/group) was administered by intraperitoneally-implanted minipumps to these SP on the SFD for 12 weeks. Normal diet fed SP and WKY rats (n = 25/group) were also included for comparison (i.e. served as normal controls). Mortality, hemodynamics, and both renal and cardiac function and histopathology were monitored in all treatment groups.


RESULTS
Eprosartan decreased the severely elevated arterial pressure (-12%; P < 0.05) produced by SFD but did not affect heart rate. Vehicle-treated SP-SFD control rats exhibited significant weight loss (-13%; P < 0.05) and marked mortality (50% by week 6 and 95% by week 9; P < 0.01). Eprosartan-treated SP-SFD rats maintained normal weight, and exhibited zero mortality at week 12 and beyond. Eprosartan prevented the increased urinary protein excretion (P < 0.05) that was observed in vehicle-treated SP-SFD rats. Echocardiographic (i.e. 2-D guided M-mode) evaluation indicated that SP-SFD vehicle control rats exhibited increased septal (+22.2%) and posterior left ventricular wall (+30.0%) thickness, and decreased left ventricular chamber diameter (-15.9%), chamber volume (-32.7%), stroke volume (-48.7%) and ejection fraction (-22.3%), and a remarkable decrease in cardiac output (-59.3%) compared to controls (all P < 0.05). These same parameters in eprosartan-treated SP-SFD rats were normal and differed markedly and consistently from vehicle-treated SP-SFD rats (i.e. treatment prevented pathology; all P < 0.05). Cardiac-gated MRI data confirmed the ability of eprosartan to prevent cardiac pathology/remodeling (P < 0.05). Histopathological analysis of hearts and kidneys indicated that eprosartan treatment significantly reduced end-organ damage (P < 0.01) and provided corroborative evidence that eprosartan reduced remodeling of these organs. Vehicle-treated SP-SFD rats exhibited a 40% increase in the plasma level of pro-atrial natiuretic factor that was reduced to normal by eprosartan (P < 0.05).


CONCLUSIONS
These data demonstrate that eprosartan, at a clinically relevant dose, provides significant end-organ protection in the severely hypertensive stroke-prone rat. It preserves cardiac and renal structural integrity, reduces cardiac hypertrophy and indices of heart failure, maintains normal function of the heart and kidneys, and eliminates premature mortality due to hypertension-induced end-organ failure.
Barone
F C
FC
Department of Cardiovascular Pharmacology, UW2521 709 Swedeland Road, P.O. Box 1539, King of Prussia, PA 19406, USA. frank c barone@sbphrd.com
Coatney
R W
RW
Chandra
S
S
Sarkar
S K
SK
Nelson
A H
AH
Contino
L C
LC
Brooks
D P
DP
Campbell
W G
WG
Ohlstein
E H
EH
Willette
R N
RN
D000179:Acrylates / Q000627:therapeutic use*; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D009320:Atrial Natriuretic Factor / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D006332:Cardiomegaly / Q000188:drug therapy*; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy*; D007093:Imidazoles / Q000627:therapeutic use*; D007668:Kidney / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D009206:Myocardium / Q000473:pathology; D009318:Natriuresis / Q000502:physiology; D009929:Organ Size / Q000187:drug effects; D010446:Peptide Fragments / Q000097:blood; D011498:Protein Precursors / Q000097:blood; D011507:Proteinuria / Q000517:prevention & control; D051381:Rats; D011918:Rats, Inbred SHR; D020521:Stroke / Q000517:prevention & control; D015996:Survival Rate; D013876:Thiophenes; D020257:Ventricular Remodeling / Q000187:drug effects
D000179:Acrylates; D000959:Antihypertensive Agents; D007093:Imidazoles; D010446:Peptide Fragments; D011498:Protein Precursors; D013876:Thiophenes; C054548:atrial natriuretic factor prohormone (31-67); C068373:eprosartan; D009320:Atrial Natriuretic Factor