title: K+ and Ca2+ channel blockers may enhance or depress sympathetic transmitter release via a Ca(2+)-dependent mechanism "upstream" of the release site.
abstract: Extracellular recording of the pre- and postjunctional electrical activity in guinea-pig or mouse vas deferens or rat tail artery was employed to study the mechanisms by which the K+ channel blockers, tetraethylammonium and 4-aminopyridine and the Ca2+ channel blockers, Cd2+, Mn2+ or nifedipine influence the nerve stimulation-induced release of adenosine 5'-triphosphate as a sympathetic co-transmitter. The K+ and Ca2+ channel blocking agents examined had no effect on the spontaneous quantal release of adenosine 5'-triphosphate. However, addition of tetraethylammonium and 4-aminopyridine inside the recording electrode broadened the nerve terminal action potential and caused it to become more resistant to local application of tetrodotoxin, and dramatically increased the magnitude and tetrodotoxin resistance of adenosine 5'-triphosphate release within the patch. Surprisingly, tetraethylammonium and 4-aminopyridine were equally effective when added outside the recording electrode; now they did not increase the duration of the nerve terminal action potential inside the patch but increased its resistance to locally applied tetrodotoxin and dramatically increased the magnitude as well as the tetrodotoxin resistance of adenosine 5'-triphosphate release from sites inside the patch. Both tetraethylammonium and 4-aminopyridine contributed to these effects, with a strong potentiating interaction. Nifedipine was without effect, but application of 1-100 microM Cd2+ or 1-5 mM Mn2+ either inside or outside the recording electrode blocked adenosine 5'-triphosphate release inside the patch. The results indicate: (i) that the nerve terminal action potential is generated by activation of voltage-gated, regenerative Na+ channels but also has a small component carried by influx of Ca2+ and that it is "normally" terminated by activation of voltage- as well as Ca(2+)-dependent K+ channels; (ii) that the release probability is tonically depressed by the resting K+ efflux, and promoted by the resting Ca2+ influx, "upstream" of the release sites; and (iii) that the upstream control of the release probability may involve both changes in properties of ionic channels in the nerve terminal membrane, and effects on the cytoskeleton leading to changes in the availability of releasable quanta in varicosities within the patch.
authors.affiliation: Department of Physiology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Stjärne
authors.forename: E
authors.initials: E
authors.lastname: Stjärne
authors.forename: M
authors.initials: M
authors.lastname: Msghina
authors.forename: J X
authors.initials: JX
authors.lastname: Bao
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology*; D000200:Action Potentials / Q000187:drug effects*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002104:Cadmium / Q000494:pharmacology; D002118:Calcium / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D006168:Guinea Pigs; D015640:Ion Channel Gating / Q000187:drug effects*; D008297:Male; D008345:Manganese / Q000494:pharmacology; D051379:Mice; D008839:Microelectrodes; D008959:Models, Neurological; D009638:Norepinephrine / Q000378:metabolism*; D011188:Potassium / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology; D019789:Tetraethylammonium; D013757:Tetraethylammonium Compounds / Q000494:pharmacology*; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D015221:Potassium Channels; D015222:Sodium Channels; D013757:Tetraethylammonium Compounds; D002104:Cadmium; D008345:Manganese; D013779:Tetrodotoxin; D019789:Tetraethylammonium; D000255:Adenosine Triphosphate; D015761:4-Aminopyridine; D011188:Potassium; D002118:Calcium; D009638:Norepinephrine