Pharmacological investigation into the involvement of nitric oxide in K⁺-induced cortical spreading depression

Abstract.

Cortical spreading depression (CSD) is a transient, local disruption of cellular ionic homeostasis that propagates slowly across the cerebral cortex. As previous data have suggested a possible link between nitric oxide (NO) formation and CSD, we have examined whether CSD is suppressed by local inhibition of NO synthesis with 7-nitroindazole (7-NINA), a compound which may have a greater selectivity for the neuronal NO synthase isoform.

Multifunctional microdialysis probes were implanted in the cortex of halothane-anaesthetised rats, and used for (1) elicitation of repetitive CSD by perfusion of 160 mM K⁺ through the probe, (2) recording of CSD as a negative shift of the extracellular direct current (DC) potential, and (3) perfusion of 7-NINA before and during CSD elicitation.

Elicitation of CSD was moderately inhibited by 1 mM 7-NINA in the perfusion medium, as shown in one treated group (n=8) by a significant reduction of both number (from 5.1±0.4 to 3.6±0.4; P<0.05) and cumulative DC negativity (from 16.4±0.7 mV.min to 13.3±0.9 mV.min; P<0.01). However, effective concentrations of 7-NINA were at least 100-fold higher than its K _i for the target enzyme in vitro, the moderate inhibition of CSD by 7-NINA was not reversed by the NO precursor, l-arginine, and the amplitude of the K⁺-induced sustained DC potential negative shift was also reduced significantly by 7-NINA (from 27.9±0.9 mV to 23.9±1.2 mV; P<0.05). These data do not support the hypothesis that NO formation contributes to the elicitation of CSD by high extracellular K⁺. The finding that 7-NINA reduced the intensity of K⁺-induced depolarisation may be relevant to previous investigations that used this drug to examine the role of NO in the modulation of K⁺-induced neurotransmitter release.