ON THE ROLE OF ARACHIDONIC-ACID IN M-CURRENT MODULATION BY MUSCARINE IN BULLFROG SYMPATHETIC NEURONS

The modulation by muscarine or LHRH of the potassium M-current (I-M) i n whole-cell voltage-clamped bullfrog sympathetic neurons presents an initial phase of current reduction, followed, after agonist removal, b y a transient enhancement or ''overrecovery.'' Employing a fast soluti on exchange system, an inhibitory process and an enhancing process wer e distinguished kinetically. The extent of overrecovery increased with the extent of the preceding inhibition. The rate and degree of inhibi tion increased with the concentration of agonist. In contrast, the rat e of recovery and the extent of overrecovery were independent. The hal f-lives of the inhibitory and enhancing processes were 21 and 53 sec, respectively. Several observations suggest that arachidonic acid (AA) may be involved in overrecovery: (1) AA enhanced I-M in a dose-depende nt and reversible manner, with an IC50 of 2.8 mu M. (2) Muscarine inhi bited the A-current (I-A), a potassium current that is blocked by AA. (3) Phospholipase A(2) inhibitors (quinacrine and bromophenacyl bromid e) and a lipoxygenase inhibitor (nordihydroguaiaretic acid) prevented overrecovery, without affecting the rate or extent of I-M inhibition s ignificantly. However, kinetic analysis indicates that these drugs wer e preventing overrecovery by prolonging the half-life of the inhibitor y process to >80 sec (e.g., not necessarily by blocking the enhancing pathway). In addition, the extent of I-A inhibition was less than expe cted if AA was mediating both I-M enhancement and I-A inhibition. The observed relation between extent and rate of overrecovery, and the act ion of arachidonic acid metabolism inhibitors can be accounted for by a model proposing that the agonist alters the equilibrium between thre e pools of M-channels.