beraprost and Cerebrovascular-Disorders

Beraprost sodium is a stable analog of the vasodilator, platelet antiaggregatory eicosanoid, prostacyclin. Experiments were performed to determine whether long-term therapy with beraprost produces vascular protective effects in saline-drinking stroke-prone spontaneously hypertensive rats (SHRSPs). Oral beraprost at 30, 100, or 300 micrograms/kg/day starting at 8.4 weeks of age did not affect the progressive increase of systolic blood pressure (measured by tail-cuff plethysmography) in these rats. Additional experiments in SHRSPs, prepared for continuous monitoring of blood pressure by radiotelemetry, revealed that oral beraprost administration reduced mean arterial pressure but that these hypotensive responses were not sustained (< 4 h). In all SHRSPs receiving oral beraprost, proteinuria and cerebrovascular lesions developed. In contrast, continuous subcutaneous infusion of beraprost at 2.8 mg/kg/day from age 8.3-12.3 weeks reduced systolic blood pressure and markedly diminished the development of renal lesions and the occurrence of stroke in saline-drinking SHRSPs. Beraprost at 0.9 mg/kg/day reduced blood pressure less than did 2.8 mg/kg/day and provided partial protection against cerebral and renal lesions after a 4-week infusion period. These results indicate that long-term subcutaneous infusion of beraprost can protect saline-drinking SHRSPs against stroke and renal damage. This effect is not readily dissociated from the ability of beraprost to reduce blood pressure in SHRSPs.

Topics: Administration, Oral; Animals; Blood Pressure; Cerebrovascular Disorders; Drug Evaluation, Preclinical; Epoprostenol; Heart; Heart Rate; Hypertension; Injections, Subcutaneous; Kidney; Male; Organ Size; Rats; Rats, Inbred SHR; Vasodilator Agents

We evaluated the effects of beraprost Na (Sodium (+-)-(1R*,2R*, 3aS*,8bS*)-2,3,3a,8b-tetrahydro-2-hydroxy-1-[(E)-(3S*)-3- hyd roxy-4-methyl-1- octen-6-ynyl]-1H-cyclopenta[b]benzofuran-5-butylate, beraprost), a stable and orally active prostacyclin (PGI2) analog with potent antiplatelet and vasodilating properties, on two stroke models, namely sudden death induced by arachidonate (AA) in rabbits and spontaneous stroke in stroke-prone spontaneously hypertensive rats (SHRSP). In the AA-induced sudden death model, 30 min after beraprost administration (1 or 3 mg/kg, po), AA was injected into the rabbit internal carotid artery, and incidence of convulsion and sudden death were assessed. Beraprost decreased both incidence of convulsion and mortality of rabbits. In SHRSP, orally administered beraprost (100 micrograms/kg, twice a day from 56-385 d of age) improved survival rate and decreased incidence of stroke. Preventive effects of beraprost on the two stroke models may have been caused mainly by the improvement of cerebral circulation. These results indicate that beraprost may have potential in the treatment and/or prevention of the cerebral circulatory disorders.

Topics: Animals; Arachidonic Acid; Blood Pressure; Body Weight; Cerebrovascular Circulation; Cerebrovascular Disorders; Death, Sudden; Diltiazem; Epoprostenol; Male; Platelet Aggregation Inhibitors; Rabbits; Rats; Rats, Inbred SHR; Ticlopidine