Inhibitors of
angiotensin converting enzyme (ACE) have been developed recently for therapeutic purposes in
hypertension and ischemic
cardiovascular diseases. Ogiku et al. reported that one such inhibitor,
imidapril, significantly prolonged survival in
stroke-prone spontaneously hypertensive rats (SHRSP). The present study was designed to investigate the effect of
imidapril on cerebral blood vessels in SHRSP to clarify role of the
ACE inhibitor in mechanisms of
cerebral thrombosis and
stroke.
Imidapril was administered orally at 1.0 and 5.0 mg/kg/day for 3 weeks from the age of 7 weeks, and was shown to prevent the usual increase in blood pressure seen in these animals. It also delayed He-Ne
laser-induced
cerebral thrombosis and increased significantly the plasma concentration of
nitric oxide metabolites (NO2/NO3). To confirm the association between
nitric oxide (NO) and these effects of
imidapril, an inhibitor of
nitric oxide synthase,
N(G)-nitro-L-arginine methyl ester hydrochloride (
L-NAME) was dissolved in
drinking water and administered to the animals for 3 weeks. Four of six rats died from
stroke when
L-NAME was given alone. When
imidapril (5.0 mg/kg/day) was administered with
L-NAME, however, the animals showed no signs or symptoms of
stroke. In these instances, therefore, the concurrent administration of
L-NAME with
imidapril reversed significantly the effects of
imidapril.
Intravenous injection of
imidaprilat (100 microg/kg), an active metabolite of
imidapril, also decreased blood pressure significantly and increased the plasma levels of NO2/NO3 after 5 min. Moreover,
imidaprilat enlarged arteriolar diameters and caused an increase in red cell velocity and mean blood flow in pial arterioles after 15 min. The results strongly suggested that
imidapril protects cerebral vessels in SHRSP by elevating the release of NO, thereby improving the cerebral circulation and reducing the tendency to
thrombosis and
stroke.