Early and late haemodynamic and morphological effects of angiotensin II subtype 1 receptor blockade during genetic hypertension development.
OBJECTIVE
To investigate the haemodynamic and morphological effects resulting from the chronic administration to young spontaneously hypertensive rats (SHR) of a new selective angiotensin II subtype 1 (AT1) receptor antagonist, SR 47436/BMS-186295 (SR/BMS) both during and after the treatment period.


METHODS
SR/BMS (60 mg/kg per day, orally) or distilled water was chronically (from 4 to 20 weeks of age) administered to SHR. At age 8, 14, 20 and 28 weeks the effects of SR/BMS on the systemic and regional haemodynamic (radioactive microsphere technique) and the cardiac and vascular morphological parameters (automatic image analysis) were investigated.


RESULTS
SR/BMS limited genetic hypertension development and opposed the age-related rises in total peripheral and regional vascular resistances. Simultaneously, it limited the age-related increases in heart weight, left ventricular cross-sectional area and collagen content. Age-related increases in aortic media thickness and amount of collagen were also significantly reduced, whereas aortic compliance was increased. Eight weeks after withdrawal of treatment the antihypertensive effect of SR/BMS, although attenuated, and the limitation of cardiac and vascular remodelling, persisted.


CONCLUSIONS
Early AT1 receptor blockade in SHR opposes genetic hypertension development during the treatment period and persistently after its interruption. Prevention of genetic hypertension development during the treatment period can be accounted for by the limitation of the age-related development of the haemodynamic and morphological abnormalities, whereas the persistence of the antihypertensive effect observed after drug withdrawal is due mainly to a maintained prevention of the development of the cardiovascular morphological alterations.
Vacher
E
E
Département de Pharmacologie, Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France.
Fornes
P
P
Richer
C
C
Bruneval
P
P
Nisato
D
D
Giudicelli
J F
JF
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001011:Aorta / Q000473:pathology; D001713:Biphenyl Compounds / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects*; D006973:Hypertension / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D000077405:Irbesartan; D008297:Male; D009206:Myocardium / Q000473:pathology; D051381:Rats; D011918:Rats, Inbred SHR; D013777:Tetrazoles / Q000494:pharmacology*; D013997:Time Factors
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D013777:Tetrazoles; D000077405:Irbesartan