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SUMMARY1. Isolated rat neurohypophyses were studied in vitro and the hormones released on electrical stimulation of the pituitary stalk or on exposure to excess potassium were estimated by a milk-ejection assay.2. The stalk was stimulated with trains of 500 stimuli, or multiples thereof, applied at different frequencies. Below frequencies of ca. 35 c/s, hormone release was found to depend on the total number of stimuli applied as well as on the frequency of stimulation. Above ca. 35 c/s, identical numbers of stimuli were progressively less effective as the frequency of stimulation was increased, and the dependence of the hormone output on the total number of stimuli was less apparent.3. The amplitude of the compound action potential recorded from the neurohypophysis following electrical stimulation of the stalk was found to decrease as a function of the frequency of stimulation. Stimulation at 50 c/s reduced its amplitude about sevenfold within 30 sec.4. The addition oftetrodotoxin (TTX) to the incubation media abolished the compound action potential recorded from the neural lobe as well as the release of hormones evoked by electrical stimulation. Resting release, however, was unaffected by TTX.5. In TTX-treated neural lobes, excess potassium was still effective in eliciting graded secretary responses. This indicates the independence of the release process from the action potential generating mechanism and suggests that TTX-paralysed preparations represent a useful model for the study of hormone release in the absence of conducted action potentials.6. The release of hormones from the neurohypophysis and the release of neurotransmitters at chemical synapses both depend on the entry of calcium into the nerve terminals following their depolarization by invading

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We report on the pharmacological properties of a potent and selective linear vasopressin (AVP) V_1a receptor antagonist HO-Phenylacetyl¹-D-Tyr(Me)²-Phe³-Gln⁴-Asn⁵-Arg⁶-Pro⁷-Arg⁸-NH₂ (HO-LVA). Iodinated on the phenolic substituent at position 1, [¹²⁵I]-HO-LVA displayed the highest affinity for rat liver V_1a receptors (8 pM) ever reported. Furthermore, affinities of HO-LVA and I-HO-LVA for V_1b, V₂ and oxytocin (OT) receptors was 400- to 1,000-fold lower than for V_1a receptors, rendering it a highly selective ligand. Both HO-LVA and its iodinated derivative are V_1a antagonists, they potently inhibited AVP-induced inositol-phosphate accumulation in WRK₁ cells, and also, although with a much lower potency, the AVP-induced ACTH release from freshly prepared pituitary cells. Using autoradiography [¹²⁵I]-HO-LVA appeared to be the first radioligand to successfully identify and localize the presence of V_1a receptors in rat liver and blood vessel walls. Moreover, several new brain regions expressing V_1a receptors could be identified, in addition to those brain regions that were previously identified with other radiolabelled AVP analogues.