Production, transport, storage and release of antidiuretic hormone (ADH) in the hypothalamo-neurohypophysial system were investigated. ADH produced by nerve cells in the paraventricular and supraoptic nuclei of the hypothalamus is present in a form bound to the speicfic protein neurophysin, in the neurosecretary granula. Electric and chemical stimulation of these nuclei results in evoked release of ADH in ionic association with neurophysin from the neural lobes. Acetylcholine, norepinephrine, histamine, angiotensin II, gammaaminobutyric acid and L-glutamic acid have been regarded as candidates of chemical transmitters for the release of ADH in the hypothalamus. Prostaglandin (PG) E
2 may be another important compound for central regulation of water metabolism. The possibility that PGE
2 may be the transmitter or a modulator in the nuclei has to be considered. Serotonin, dopamine and taurine, however, may not be involved in the ADH releasing mechanisms in the hypothalamus. It appears that norepinephrine, histamine, angiotensin II, PGE
2 and bradykinin stimulate directly the neural lobe to release ADH. The ADH release is regulated by intracellular Ca
++. The existence of a “readily-releasable pool” of ADH can be ruled out and any limitation in the amount of ADH released under experimental conditions may be due to insufficient activation of the neural lobe. A physiological significance other than a carrier was proposed for neurophysin.
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