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1. A possible cerebroprotective effect of nicorandil was investigated in a canine model of 5 min global cerebral ischaemia, and compared with protective effects of nitroglycerin and nicardipine. 2. Cerebral ischaemia was produced by occlusion of the left subclavian and the brachiocephalic arteries with preceding ligation of the intercostal arteries. The decrease in baroreflex sensitivity (BRS), measured by phenylephrine-induced reflex bradycardia, was used to assess the cerebroprotective effect. 3. Nicorandil (10 or 30 micrograms kg-1 min-1, i.v.), nitroglycerin (3 micrograms kg-1 min-1, i.v.) or nicardipine (0.3 micrograms kg-1 min-1, i.v.) were infused for 60 min just before ischaemia. Nitroglycerin and nicardipine decreased mean arterial blood pressure to an extent similar to that induced by the lower dose of nicorandil. Blood flow in the dorsal medulla oblongata was increased by nicorandil and nicardipine, but not by nitroglycerin. 4. Nicorandil at both doses and nitroglycerin prevented the post-ischaemic decrease in BRS. In these cases, bilateral vagotomy during the reperfusion period decreased BRS, indicating that the vagal component of BRS was protected from ischaemia. On the other hand, nicardipine failed to exert a cerebroprotective effect. 5. The present study suggests that nicorandil may possess a direct cerebroprotective effect and that its property as a nitrate might, at least in part, be important for the observed cerebral protection.

In halothane-anesthetized dogs, a decrease in baroreflex sensitivity (BRS) of approximately 20% was observed during the reperfusion period following 5-min global cerebral ischemia. When compared with our previous study on animals under pentobarbital anesthesia, the extent of the decrease in BRS was smaller and apparently more severe ischemia was necessary to damage the vagal component of the baroreflex. Substitution of halothane with pentobarbital during the reperfusion period failed to affect either BRS or the ratio of the vagal component. In another group, pre- and post-ischemic measurements of BRS was performed under halothane anesthesia, but the ischemic insult was given under thiopental anesthesia. In these animals, the extent of decrease in BRS (about 50%) was greater than that in animals subjected to ischemia under halothane anesthesia. The present results suggest that the anesthetics used during the ischemic insult may affect the extent of post-ischemic dysfunction of the baroreflex. The vagal component of the baroreflex may be more resistant to ischemia under halothane anesthesia than under barbiturate anesthesia.

Baroreflex sensitivity assessed from the phenylephrine-induced reflex bradycardia was significantly decreased following 5 min global incomplete cerebral ischemia in pentobarbitalized dogs. Although bilateral vagotomy in the cervical region decreased baroreflex sensitivity by about 50% in sham-operated animals, it hardly affected the baroreflex in animals subjected to ischemia. The extent of the decrease in the influence of vagotomy on the baroreflex was dependent on the severity of ischemia in the dorsal medulla oblongata. In animals vagotomized before ischemia, no significant decrease in baroreflex sensitivity was observed following ischemia. Pretreatment with ifenprodil or flunarizine, 1 mg/kg i.v., 5 min prior to ischemia prevented the post-ischemic decrease in baroreflex sensitivity. Vagotomy decreased baroreflex sensitivity during the reperfusion period in these treated animals. These results suggest that the post-ischemic attenuation of reflex bradycardia may be due to a selective dysfunction of the vagal component of baroreflex, which can be prevented by the cerebroprotective agents.

1. A possible cerebroprotective effect of a chemically stable prostacyclin analogue, beraprost sodium, was investigated in a canine model of cerebral ischaemia. Cerebral ischaemia was produced by the combined occlusions of the left subclavian and the brachiocephalic arteries with preceding ligations of the intercostal arteries. 2. The decrease in baroreceptor reflex sensitivity (BRS), measured by phenylephrine-induced reflex bradycardia, following 5 min ischaemia was used to assess the cerebroprotective effect. 3. Beraprost (1 microgram kg-1 min-1 i.v., infused for 15 min just before ischaemia) completely prevented the decrease in BRS. Although the lower dose of beraprost (0.1 microgram kg-1 min-1 i.v.) failed to show such a protective effect, its inhibitory effect on ADP-induced platelet aggregation was as potent as that of the higher dose. 4. The extent of decrease in BRS was inversely correlated with the extent of the residual blood flow in the medulla oblongata during ischaemia. Since beraprost did not affect the extent of the residual blood flow during ischaemia, its cerebroprotective effect could not be ascribed to the reduction of the degree of ischaemia by increasing collateral blood flow to the brain. 5. Post-ischaemic reduction of the regional blood flow in the medulla and the cerebral cortex was completely prevented by the higher dose of beraprost. 6. The present study suggests that the cerebroprotective effect of beraprost may be independent of its anti-aggregatory and vasodilator effects. It is possible that the protection may be due to a prostacyclin-like cytoprotective effect through membrane stabilization.

Baroreflex sensitivity assessed by phenylephrine-induced reflex bradycardia was markedly decreased by 5- an 10-min global cerebral ischemia in anesthetized dogs. Flunarizine, 0.1 and 1 mg/kg i.v., administered 5 min prior to 5-min ischemia, completely inhibited the decrease in baroreflex sensitivity while such a protective effect of the latter dose was incomplete against 10-min ischemia. In contrast, papaverine, 0.5 mg/kg per min i.v., infused for 5 min prior to 5-min ischemia, failed to protect the decrease in baroreflex sensitivity. Flunarizine may possess a certain direct cerebroprotective effect in addition to its cerebrocirculatory effect.