L. Gentili

The tachykinin NH2-senktide, a selective neurokinin B receptor agonist, is a very potent inhibitor of salt appetite in the rat

The tachykinin peptide [Asp5.6, MePhe8]substance P(5-11) (NH2-senktide), a senktide analogue lacking the N-terminal succinyl group, is a selective and metabolically stable NK-3 receptor agonist. In the present study it potently inhibited salt appetite induced by sodium depletion in rats. Argo-neurokinin B, too, inhibited salt appetite, but was less potent than NH2-senktide. Neither peptide inhibited drinking behaviour induced by subcutaneous hypertonic NaCl. NH2-senktide slightly inhibited angiotensin-induced drinking, while Argo-neurokinin B was ineffective. On the other hand, eledoisin was a potent inhibitor in the 3 behavioural tests. Present results indicate that activation of NK-3 receptors is involved in the antinatriorexic action of tachykinins, and that different receptor subtypes might be involved in the different effects of tachykinins on the rat ingestive behaviour.

Tachykinin receptor subtypes involved in the central effects of tachykinins on water and salt intake

The present study was aimed at investigating which tachykinin receptor subtypes mediate the inhibitory effects of tachykinins a) on salt intake induced by sodium depletion, b) on water intake induced by subcutaneous hypertonic NaCl administration and c) on water intake induced by central angiotensin II injection. The study was carried out by evaluating the potency of action, following intracerebroventricular injection, of several peptides, including both naturally occurring tachykinins and synthetic peptides selective for a given receptor subtype. The results obtained show different rank orders of potency of the agonists in the different behavioral tests, thus suggesting that different receptor subtypes are involved in the effects of tachykinins on water and salt intake. NK-3 receptors appear to be involved in the inhibitory effect of tachykinins on depletion-induced salt appetite. NK-2 receptors apparently mediate the inhibitory effect of tachykinins on drinking induced by hyperosmotic NaCl administration, while NK-1 receptors are probably involved in the inhibition of angiotensin II-induced drinking.

The hypothalamic paraventricular nucleus is a site of action for the central effect of tachykinins on plasma vasopressin.

The intracerebroventricular injection of eledoisin (ELE), or of other tachykinins with potent agonist activity at neurokinin B (NK-3) receptors, increases plasma vasopressin in the rat. The effect is antagonized by saralasin pretreatment, thus suggesting that it is mediated by angiotensin receptor activation. Since the magnocellular part of the hypothalamic paraventricular nucleus (PVN) is very rich in NK-3 receptors, the present study was aimed at investigating the role of this nucleus in the effect of ELE on plasma vasopressin. Direct injection of ELE into the PVN increased plasma vasopressin levels more potently than the injection of the same doses into the lateral ventricle. Lesioning of the magnocellular part of the PVN completely abolished the increase in plasma vasopressin induced by the injection of ELE 100 ng/rat into the lateral ventricle. Pretreatment into the PVN either with saralasin or with captopril resulted in a marked suppression of the effect of ELE on plasma vasopressin. These findings indicate the PVN as a site of action for the central effect of tachykinins on plasma vasopressin and suggest that the angiotensin mediation of the effect might take place in the same nucleus.

Inhibition of salt appetite in the rat following injection of tachykinins into the medial amygdala.

The present study investigated the sensitivity of the medial region of the amygdala to the antinatriorexic action in the rat of the tachykinins eledoisin, substance P, neurokinin A and [Asp5,6, MePhe8] substance P(5-11) (also referred to as amino-senktide; NH2-SENK), which is a highly selective agonist for NK-3 receptors. The results obtained show that only the potent NK-3 agonists eledoisin and NH2-SENK inhibit salt appetite when injected into the medial region of the amygdala. Eledoisin and NH2-SENK inhibited salt appetite induced by sodium depletion, that has been proven to be governed by the synergism of angiotensin and aldosterone. They inhibited also salt appetite evoked by central renin injection, that is due to production of angiotensin II. On the other hand, eledoisin and NH2-SENK did not inhibit salt appetite evoked by subcutaneous deoxycorticosterone treatment. These findings suggest that the medial region of the amygdala is a site of action for the antinatriorexic effect of tachykinins and that their action at this site is mediated by NK-3 receptors. Moreover, our results show that in the medial amygdala, the antinatriorexic action of tachykinins appears to be directed toward the angiotensinergic component of the neural mechanism for salt appetite.

Effect of the 5-HT2 antagonist ketanserin on salt appetite in the rat

The 5-HT2 antagonist ketanserin inhibited salt appetite induced by subchronic deoxycorticosterone acetate (DOCA) treatment, as well as salt appetite induced by sodium depletion (which is governed by the synergy of aldosterone and angiotensin in the brain). The effect of ketanserin was more evident following intraperitoneal than intracerebroventricular injection. On the other hand, ketanserin did not inhibit either salt intake induced by intracranial renin injection, or the need-free salt intake of the multidepleted female rat, which is not dependent on the renin-angiotensin-aldosterone system. These findings suggest that the antinatriorexic action of ketanserin is selective for the mineralcorticoid mechanisms controlling salt appetite. Ritanserin, too, a potent 5-HT2 antagonist showing a different receptor selectivity profile from that of ketanserin, suppressed DOCA-induced salt appetite, thus supporting the involvement of 5-HT receptors in the antinatriorexic action. DOCA treatment alters serotonin metabolism in the central nervous system and it has been proposed that changes in 5-HT metabolism may be important in the genesis of DOCA-induced hypertension. The present results indicate that ketanserin inhibits DOCA-induced salt appetite and suggest that serotoninergic mechanisms might be involved in the elicitation of mineralocorticoid-induced salt appetite.

Central tachykinin injection potently suppresses the need-free salt intake of the female rat

Repeated sodium depletions produce a persistent, enhanced need-free salt intake in the rat, particularly in the female. The neurochemical mechanisms underlying the phenomenon are still unknown. The present studies evaluated the effect on the enhanced need-free salt intake of the female rat (1) of pharmacological interference with the natriorexigenic hormones angiotensin II and aldosterone and (2) of the central injection of the tachykinin peptides, which are endowed with antinatriorexic activity. The need-free salt intake of the female rat is not modified by treatment with the angiotensin-converting enzyme inhibitor captopril or by the aldosterone receptor antagonist RU-28318. On the other hand, the behavior is highly sensitive to the inhibitory effect of central tachykinins, suggesting the possibility that need-free salt intake might be linked to modification (down-regulation) of the inhibitory tachykininergic system.