Electrical depolarisation-(2 Hz, 1 ms)-induced [3H]noradrenaline ([3H]NA) release was measured from the isolated min pulmonary artery of the rabbit in the presence of uptake blockers (cocaine, 3×10 -5M; corticosterone, 5×10-5M) and after blocking the MAO-enzyme by pargyline (1,2×10-4M). Substitution of most of the external Na+ by Li+ (113 mM; [Na+] o:25 mM) slightly otentiated the stimulation-induced release of [3H]NA in a tetrodotoxin (TTX, 10-7M) sensitive manner. The reverse Na+/Ca2+-exchange inhibitor KB-R7943 (3×10-5M) failed to inhibit the stimulation-evoked release of [3H]NA, but increased the resting outflow of neurotransmitter. The 'N-type' voltage-sensitive Ca2+-channel (VSCC) blocker w-conotoxin (ω-CgTx)·GVIA (10-8M) significantly and irreversibly inhibited the release of [3H]NA on stimulation (∼60-70%). The 'residual release' of NA was abolished either by TTX or by reducing external Ca2+ from 2,5 to 0,25 mM. The 'residual release' of NA was also blocked by the non-.selective VSCC-blocker neomycin (3±10-3M). Direct correlation was obtained between the extent of VSCC-inhibition and the transmitter release enhancing-effect of presynaptic α2-receptor blacker yohimbine (3×10-7M). When the release of [ 3H]NA was blocked by ω-CgTx GVIA plus neomycin, yohimbine was ineffective. Inhibition of the Na+-pump by removal of K +from the external medium increased both the resting and the stimulation-evoked release of [3H]NA in the absence of functioning VSCCs (i.e. in the presence of neomycin and after ω-CgTx treatment). Under these conditions the stimulation-evoked release of NA was abolished either by TTX or by external Ca2+-removal (+1 mM EGTA). Similarly, external Li+ (113 mM) or the reverse Na+/Ca2+ exchange blocker KB-R7943 (3×10-5M) significantly inhibited the nerve-evoked release of NA in 'K+-free' solution. KB-R7943 decreased the resting outflow of NA as well. Under conditions, in which the Na +-pump was inhibited in the absence of functioning VSCCs, yohimbine (3×10-7M) further enhanced the release of neurotransmitter, while l-noradrenaline (l-NA, 10-6M), an agonist of presynaptic α2-receptors, inhibited it. The yohimbine-induced enhancement of NA-release was abolished by Li+-substitution and significantly inhibited by KB-R7943 application. It is concluded that after blockade of VSCCs, brief depolarising pulses may reverse Na+/Ca2+-exchange and release neurotransmitter in Na+-loaded sympathetic nerves. Further, similar to that of VSCCs, the reverse Na+/Ca 2+-exchange may also be inhibited by presynaptic α2- receptor activation.
|Translated title of the contribution||Electrogenic Na+/Ca2+-exchange regulation by α2-receptor in peripheral sympathetic nerve|
|Number of pages||14|
|Journal||Acta pharmaceutica Hungarica|
|Publication status||Published - Apr 12 2005|
ASJC Scopus subject areas
- Pharmaceutical Science