SPONTANEOUS [³H]NORADRENALINE RELEASE FROM THE MAIN PULMONARY ARTERY OF THE RABBIT INDUCED BY SODIUM-PUMP INHIBITION

¹ Department of Pharmacodynamics, Semmelweis University of Medicine, H-1089 Budapest, Nagyvárad tér 4, P.O. Box 370, Hungary

Inhibition of Na pump either by ouabain (10^-4 M) or by K removal increased the [³H]noradrenaline ([³H]NA) release from the isolated main pulmonary artery of the rabbit in the presence of neuronal (cocaine, 3 x 10^-5 M) and extraneuronal (corticosterone, 5 x 1O^-5 M) uptake blockers. The ouabain-evoked [³H]NA release began after a delay of about 30 min and peaked after 66 min of ouabain application. Both times were shortened by omission of K from the external medium. About 90% of ouabain-evoked [³H]NA release proved to be external Ca concentration ([Ca]_o) dependent and the peak effect was delayed by about 80 min in Ca-free (+1 mM EGTA) solution. In the presence of external Ca (2·5 mM) the [³H]NA-releasing effect of ‘K-free’ treatment was much less pronounced than that of 10^-4 M ouabain, the initial delay in transmitter release was shorter (10-15 min) and the peak effect developed earlier (at 42 min). On readmission of K the [³H]NA release recovered quickly to the original value. Ca removal did not antagonize the transmitter release observed in K-free solution, but the peak release was delayed by about 90 min. A low concentration of ouabain (10-5 M) failed to produce transmitter release in the presence of normal external K, but markedly increased the release in K-free solution. The release was much bigger than the sum of their separate effects, and the rate of rise was faster than when 10-4 M ouabain was applied in normal solution. Excess Ca (7·5; 15 mM) inhibited the [³H]NA release observed in K-free solution. 7·5 mM-Ca also delayed the transmitter-releasing action of 10^-4 M ouabain, an effect antagonized by omission of K from the external medium. The mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP, 10^-5 M) significantly increased the [³H]NA release in Ca-free, 1 mM EGTA-containing solution, and enhanced the effects of ouabain (10^-4 M). The Ca ionophore A23187 (10^-5 M) also significantly increased the [³H]NA release in the absence of external Ca and in the presence of 1 mM EGTA. Again, in the presence of A23187 the effects of 10^-4 M ouabain in releasing neurotransmitter were enhanced. When CCCP and A23187 were applied together in Ca-free, EGTA solution the [³H]NA releasing action of ouabain was still apparent. Veratridine (10^-4 M) enhanced the transmitter release in the absence of external Ca in a tetrodotoxin (TTX)-sensitive manner. After veratridine treatment the action of ouabain was totally abolished. However, in the presence of TTX (10^-7 and 3 x 10^-7 M) which by itself significantly inhibited the veratridine-evoked transmitter release the action of ouabain persisted. It is suggested that excess Ca, like external K, inhibits the transmitter-releasing effect of Na-pump inhibition, furthermore that in the absence of external Ca the ouabain-evoked transmitter release is the result of Ca release from internal stores rather than Na-pump inhibition per se.

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