INHIBITION OF NEURONAL NITRIC OXIDE SYNTHASE CAUSES ATTENUATION OF CEREBROVASCULAR DYSFUNCTION IN EXPERIMENTAL HEATSTROKE

Abstract

The present study was performed to assess the prophylactic effect of 7-nitroindazole (7-NI), an inhibitor of neuronal nitric oxide synthase (nNOS), in an animal model of heatstroke. Anesthetized rats, immediately before the start of heat stress, were divided into two major groups and given the following: vehicle solution (1mL per kg body weight)or 7-NI (5-20 mg/mL per kg body weight) intraperitoneally. They were exposed to ambient temperature of 43□ to induce heatstroke. Another group of rats was exposed to room temperature (24□) and was as normothermic controls. Their physiologic and biochemical parameters were continuously monitored. When the vehicle-pretreated rats underwent heat stress, their survival time values were found to be 21-25 min. pretreatment with intraperitoneal doses of 7-NI significantly improved survival during heatstroke (55-174 min). As compared to those of normothermic controls, all vehicle-pretreated heatstroke animals displayed higher levels of core temperature, intracranial pressure, nitric oxide (NO), glutamate, glycerol, lactate/pyruvate ratio, neuronal damage score and nNOS expression in the hypothalamus, and tumor necrosis factor-α (TNF-α) in the plasma. In contrast, all vehicle-pretreated heatstroke animal had lower levels of mean arterial pressure, cerebral perfusion pressure, cerebral blood flow, and brain PO2. Immediately after the start of heat exposure, prior administration of 7-NI significantly reduced the hyperthermia, intracranial hypertension, nNOS-dependent NO, glutamate, glycerol, lactate/pyruvate ratio, and neuronal damage in the hypothalamus, as well as overproduction of TNF-α with plasma that occurred during heatstroke. The data indicate that inhibition of nNOS causes attenuation of cerebrovascular dysfunction in experimental heatstroke.