Mibefradil, a selective calcium T-channel blocker, in stroke-prone spontaneously hypertensive rats.
Several types of antihypertensive agents, including calcium antagonists, have been reported to prevent stroke and prolong survival in stroke-prone spontaneously hypertensive rats (SHR-SP). We investigated whether mibefradil, a new calcium antagonist acting selectively at the level of T-type calcium channels, would be able to (a) limit or prevent the structural and functional alterations that develop in the cerebral arteries of SHR-SP before stroke and (b) suppress stroke and prolong survival. Mibefradil (30 mg/kg/day) was given orally to young salt-loaded SHR-SP from age 5 weeks to age 20 weeks. Blood pressure (BP) (in conscious animals), diuresis, and proteinuria were determined weekly. After 1012 weeks of treatment, middle cerebral arteries and aortas were removed from randomly selected control and treated SHR-SP. Aortic media thickness and collagen density were evaluated by histomorphometry. Middle cerebral arteries were mounted in a myograph for wall thickness determination and isometric tension recordings. Mibefradil completely prevented stroke and mortality, significantly limited the increase in BP, and opposed the increases in diuresis and proteinuria observed in controls. Simultaneously, mibefradil abolished vascular fibrinoid necrosis formation in the brain and reduced arterial thickening in the cerebral artery as well as in the aorta. The maximal contractile responses of the cerebral arteries to potassium chloride and serotonin were greater in mibefradil-treated animals than in controls, as were the endothelium-dependent relaxant responses. Mibefradil, chronically administered to young SHRSP in a dose that limits the development of hypertension not only prevents stroke and mortality but also affords protection against the vascular structural alterations which develop with age in these animals and preserves or improves the cerebral artery's smooth muscle and endothelial cell functions.
Vacher
E
E
Département de Pharmacologie, Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France.
Richer
C
C
Fornes
P
P
Clozel
J P
JP
Giudicelli
D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D002536:Cerebral Arteries / Q000187:drug effects / Q000502:physiology; D002561:Cerebrovascular Disorders / Q000517:prevention & control; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy* / Q000473:pathology; D066298:In Vitro Techniques; D008297:Male; D020748:Mibefradil; D051381:Rats; D011918:Rats, Inbred SHR; D013764:Tetrahydronaphthalenes / Q000627:therapeutic use*
D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D013764:Tetrahydronaphthalenes; D020748:Mibefradil