Pharmacological investigation into the involvement of nitric oxide in K+-induced cortical spreading depression.
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 x min to 13.3+/-0.9 mV x min; P<0.01). However, effective concentrations of 7-NINA were at least 100-fold higher than its Ki 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.
Urenjak
J
J
Pharmacology, School of Pharmacy, University of Bradford, UK. j.urenjak@bradford.ac.uk
Obrenovitch
T P
TP
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D013181:Cortical Spreading Depression / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D007191:Indazoles / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052248:Nitric Oxide Synthase Type I; D011188:Potassium / Q000494:pharmacology*; D051381:Rats
D004791:Enzyme Inhibitors; D007191:Indazoles; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D011188:Potassium; C080122:7-nitroindazole