Continuous determination of the cerebrovascular changes induced by bicuculline and kainic acid in unanaesthetized spontaneously breathing rats

Abstract

Cerebral blood flow was sequentially determined (every 2–3 min) with helium clearance in two “vulnerable” structures: the hippocampus and the frontoparietal cortex during bicuculline ( n = 11) and kainic acid ( n = 9)-induced seizures in unanaesthetized, spontaneously breathing rats. Tissue partial pressures of oxygen and carbon dioxide were continuously and simultaneously evaluated in the same brain areas. All these variables were measured by mass spectrometry with a single gas sampling cannula previously implanted in each structure. The systemic variables, arterial blood pressure, arterial partial pressures of oxygen and carbon dioxide, pH, and bicarbonate concentration were also determined. Arterial and venous catheters were chronically implanted several days prior to the definitive experiments. Bicuculline induced short (about 15 min), recurrent, generalized seizures, with an abrupt rise in arterial blood pressure, an arterial metabolic acidosis and comparable blood flow increases (4-fold) in the hippocampus and the neocortex. A marked increase in tissue partial pressure of oxygen was always preceded by an increase in tissue partial pressure of carbon dioxide. After the seizures, in the 5 rats that survived, cerebral blood flow was significantly lowered; tissue partial pressure of oxygen and partial pressure of carbon dioxide also decreased, but to a lesser extent. Histological examination revealed two types of lesions: predominantly selective chromatolysis but also ischaemic cell change. Kainic acid first induced a decrease in arterial pressure and then hypertension during status epilepticus, with a return of arterial pressure towards basal levels during the recovery period (4 h after the injection). Respiratory alkalosis occurred throughout the experiment. Cerebral blood flow increased progressively to become maximal during status epilepticus. This vasodilatation was greater in the hippocampus ( × 8) than in the neocortex (×4). During recovery, cerebral blood flow tended to decrease but remained significantly elevated. In both structures, tissue partial pressure of oxygen was first lowered while tissue partial pressure of carbon dioxide was elevated; with the occurrence of the wet dog shakes, tissue partial pressure of O 2 increased and tissue partial pressure of CO 2 decreased. The changes in tissue gases were maximal during status epilepticus and tended to return to their basal levels thereafter, but no decrease in tissue partial pressure of O 2 was observed, even 4 h after kainic acid administration. Histological analysis demonstrated ischaemic cell changes, particularly in the limbic system. This investigation provides direct evidence that, in unanaesthetized, spontaneously breathing rats, local hypoxia is not responsible for the neuronal damage induced by generalized or limbic seizures, even when they last for 4 h; in contrast, the present study reinforces the hypothesis of oxidative neuronal damage. Bicuculline and kainic acid induce different cerebrovascular events. The bicuculline-induced events are of the same amplitude in the two structures studied, whereas the kainic acid-induced events are greater in the hippocampus than in the neocortex. The results suggest that metabolism is primarily involved in the control of cerebral blood flow in the bicuculline model, whereas the mechanisms responsible for the vasodilatation due to kainic acid are different in nature.