Release of vasopressin from the rat hypothalamo-neurohypophysial system by angiotensin-(1-7) heptapeptide.

Abstract

We have recently shown that hydrolysis of labeled angiotensin I in canine brainstem homogenate causes a rapid accumulation of the heptapeptide aniotensin-l-7) [Ang-(1-7)]. Although this angiotensin fragment has no vasopressor activity its consistent generation in brain homogenate led us to study its potential neirosecretory effects in the rat hypothalamo-neurohypophysial system (INS) in vitro. Ang-(1-7) or angiotensin U (Ang II) was added to HNS perifusate in concentrations of 0.04, 0.4, and 4 pLM, and release of arginire vasopressin (AVP) during each treatment was quantified as a percentage of the AVP release detected in the preceding collection period. Base-line release of AVP averaged 281' ±47 pg per 15 min (mean SEM) in HNS explants (five experiments, five explants per chamber) perifused in Krebs solution at 37C, after a 1-hr equilibration period. At 0.04 pM, Ang'II-or Ang-(1-7) did-not stimulate AVP release. Ang II increased AVP release over the control value by 172% ± 44% and 268% ± 66% at 0.4 and 4 pM, respectively; the same concentrations of Ang-(1-7) increased AVP release by 134% ± 12% and 216% ± 45%. The responses to Ang I and Ang-(1-7) at the highest concentration were both s cant (P < 0.05), and comparison by two-way analysis of variance indicated that Ang II and Ang-(1-7) were equipotent in stimulating AVP release over the range of concentrations studied. In the presence of the competitive Aug II antagonist [Sar',Thr'JAng 11 (20 pzM), the release of AVP increased '2-fold. Neither Ang U nor Ang-(1-7) (4 pAM) caused a further enhancement of AVP release in the presence of [Sarl,ThrJAng UI. These d.ata suggest that a hydrophobic residue in position 8 of the angiotensin peptide is not essential for activation of angiotensin receptors in the rat HNS. Moreover, the equipotence of Ang U and Ang-(1-7) indicates that Ang-(1-7) may participate in the control of AVP release.Angiotensin II (Ang II) plays an important role in the control ofcardiovascular function and body fluid regulation by acting on blood vessels, renal hemodynamics, and the endocrine system. There is also evidence that Ang II may function as a paracrine hormone, since a number of studies showed that this peptide may be synthesized and released by a variety of tissues, including the brain (1). In the central nervous system, Ang II may participate in the central regulation of blood pressure by augmenting sympathetic and parasympathetic efferent discharges (2,3), by the release of arginine vasopressin (AVP) (4, 5) and corticotropin releasing factor (6), and by stimulating thirst (7,8 (17). Since this heptapeptide fragment was generated even in the presence of the angiotensin-converting enzyme inhibitor MK-422, the results suggested that a direct pathway may exist for endogenous generation of Ang-(1-7) in the brain. Although Ang-(1-7) has been shown to possess minimal pressor activity when administered into the peripheral circulation (18,19) and may have no dipsogenic effects when administered intracerebroventricularly (20), the consist...

Hemodynamic effects of vasorelaxant compounds in mice lacking one, two or all three angiotensin II receptors

“…28 In pharmacological approaches using the specific Ang-(1-7) antagonist A779, 21,29,30 and in genetically modified animals lacking the G protein-coupled receptor Mas, 21,31 it has been …”

Renal actions of angiotensin-(1-7)

“…Ang-(1-7) can be formed by an angiotensin converting enzyme (ACE)-independent pathway (4), and exerts important biological effects. In vitro this peptide is a potent vasopressin secretagogue (5) and possesses a potent prostaglandin-releasing activity in several cell lines (6,7). Microinjection of this angiotensin into the dorsomedial or ventrolateral medulla produces significant changes in mean arterial pressure and heart rate, comparable to those produced by Ang II (8)(9)(10)(11).…”

“…As documented above, in the past few years a large body of evidence has been accumulated suggesting a role for Ang- (1)(2)(3)(4)(5)(6)(7) in the control of hydroelectrolyte balance. However, due to several factors discussed below there is no consensus regarding the major action of Ang-(1-7) in the kidney.…”

Angiotensin‐(1‐7): Pharmacology and New Perspectives in Cardiovascular Treatments

“…More recently, the discovery of angiotensin-(1-7) [Ang-(1-7), Fig. 1] by our laboratory in 1988 (Schiavone et al 1988) and the cloning of ACE2 in 2000 (Donoghue et al 2000;Tipuis et al 2000) have led to a new perception of the intrinsic mechanisms through which the RAS regulates homeostasis. Ang-(1-7) is a downstream heptapeptide product of the system that can regulate blood pressure (Benter et al 1995b;Ferrario et al 2005), cardiac function (Ferreira et al 2002;Loot et al 2002;De Mello et al 2004), and cell growth (Tallant et al 2005).…”

“…The heptapeptide Ang-(1-7) may very well in the near future join those few such drugs in that quest, and it emanates from our own bodies. First discovered by our laboratory in 1988 (Schiavone et al 1988), Ang-(1-7) has been the focus of much current research in the cardiovascular field.…”