Effects of losartan on cerebral arteries in stroke-prone spontaneously hypertensive rats.
OBJECTIVE
To investigate in young salt-loaded stroke-prone spontaneously hypertensive rats (SHR-SP) the effects of a long-term administration of the angiotensin II AT1 receptor antagonist losartan [1 mg/kg (L1) and 10 mg/kg (L10) per day, from 5 to 20 weeks of age] on the structural and functional characteristics of the middle cerebral artery.


METHODS
Morphological measurements and isometric tension recordings (myograph, contractile responses to potassium chloride and serotonin, relaxant responses to bradykinin and sodium nitroprusside) were performed on isolated vessels from randomly selected control and losartan-treated SHR-SP and age-matched Wistar-Kyoto (WKY) rats killed at ages 6-7, 10-11 and 16-17 weeks.


RESULTS
Whereas all control SHR-SP had died within 18 weeks of being born, losartan at both doses afforded full protection against stroke and mortality. Losartan limited malignant hypertension development dose-dependently. Age-related increases in cerebral arterial wall thickness and wall:lumen ratio were not affected (L1) or limited slightly (L10) by losartan. In control SHR-SP, contractile responses of cerebral arteries to agonists decreased with ageing and stroke occurrence and were significantly smaller than those of age-matched WKY rat arteries. Losartan limited the cerebrovascular contractility impairment dose-dependently in SHR-SP but did not affect the WKY rat cerebral artery contractility. In addition, losartan limited the age-related alteration of the endothelium-dependent relaxation of cerebral arteries observed in control SHR-SP dose-dependently.


CONCLUSIONS
In SHR-SP, losartan prevented stroke and improved the cerebral artery's smooth muscle and endothelial cell functions, which are altered during ageing and impaired even more dramatically by stroke occurrence.
Vacher
E
E
Département de Pharmacologie, Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France.
Richer
C
C
Giudicelli
J F
JF
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D002536:Cerebral Arteries / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D002561:Cerebrovascular Disorders / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control; D004730:Endothelium, Vascular / Q000502:physiology; D006973:Hypertension / Q000150:complications* / Q000188:drug therapy / Q000503:physiopathology; D007093:Imidazoles / Q000627:therapeutic use*; D019808:Losartan; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D013777:Tetrazoles / Q000627:therapeutic use*
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D019808:Losartan