Brain-derived adrenomedullin controls blood volume through the regulation of arginine vasopressin production and release

Abstract

tral nervous system-derived adrenomedullin (AM) has been shown to be a physiological regulator of thirst. Administration of AM into the lateral ventricle of the brain attenuated water intake, whereas a decrease in endogenous AM, induced by an AM-specific ribozyme, led to exaggerated water intake. We hypothesized that central AM may control fluid homeostasis, in part by regulating plasma arginine vasopressin (AVP) levels. To test this hypothesis, AM or a ribozyme specific to AM was administered intracerebroventricularly, and alterations in plasma AVP concentrations were examined under basal and stimulated (hypovolemic) conditions. Additionally, we examined changes in blood volume, kidney function, and plasma electrolyte and protein levels, as well as changes in plasma aldosterone concentrations. Intracerebroventricular administration of AM increased plasma AVP levels, whereas AM ribozyme treatment led to decreased plasma AVP levels under stimulated conditions. During hypovolemic challenges, AM ribozyme treatment led to an increased loss of plasma volume compared with control animals. Although overall plasma osmolality did not differ between treatment groups during hypovolemia, aldosterone levels were significantly higher and, consequently, plasma potassium concentrations were lower in AM ribozyme-treated rats than in controls. These data suggest that brain-derived AM is a physiological regulator of vasopressin secretion and, thereby, fluid homeostasis.ribozyme; proadrenomedullin amino-terminal 20 peptide; aldosterone POSTTRANSLATIONAL PROCESSING of the adrenomedullin (AM) gene product results in two biologically active proteins, proadrenomedullin NH 2 -terminal 20 peptide (PAMP) and AM. AM, a member of the calcitonin peptide family, is a vasoactive peptide that is produced in many peripheral tissues as well as in the central nervous system. The AM receptor calcitonin receptor-like receptor, in association with receptor activitymodifying protein 2 or 3 (1, 17), is also present in the central nervous system (23, 33) and is particularly abundant in the hypothalamus (41). Additionally, there are several reports that intracerebroventricular administration of AM increased c-fos mRNA and Fos protein in many areas of the hypothalamus, including the paraventricular nucleus (PVN) and supraoptic nucleus (SON) (32, 42). The PVN and SON contain neuronal cell bodies that produce arginine vasopressin (AVP) and/or oxytocin (OT) and project to the neural lobe of the pituitary.There is a great deal of evidence suggesting that central and peripheral AM regulates fluid and electrolyte balance. Centrally, AM has been proven to be a physiological regulator of thirst and sodium appetite. Central AM administration decreased water intake to a variety of classical drinking paradigms (19), whereas decreased endogenous AM (by an AMspecific ribozyme) (40) led to exaggerated water intake under these same paradigms. Similarly, central administration of AM decreased salt appetite (31), whereas compromise of central AM (through passive immunoneu...

A possible relationship between brain-derived adrenomedullin and oxytocin in the regulation of sodium balance

“…While AVP is well known to control fluid balance by its antidiuretic action, OT, particularly when acting as a neurotransmitter, has been implicated as an important regulator of sodium balance (Balment et al 1980, Van Tol et al 1987, Blackburn et al 1992a,b, 1993, Verbalis et al 1995, Amico et al 2001, Fitts et al 2003, Rigatto et al 2003. We have previously demonstrated that brain-derived AM is a physiologic regulator of AVP secretion (Taylor et al 2005). i.c.v.…”

“…Two treatment groups were employed: one treated with the control scrambled ribozyme (2 mg in 2 ml saline) and another administered the AM-specific ribozyme (2 mg in 2 ml saline; Taylor & Samson 2002). Eighteen hours following ribozyme administration, when hypothalamic AM protein levels were decreased by w30% (Taylor & Samson 2002), rats were killed by decapitation and trunk blood was collected as before (Taylor et al 2005). Because decreased plasma levels of OT were predicted following central AM ribozyme treatment, OT levels were elevated in rats by i.p.…”

“…administration of AM inhibited water intake in rats stimulated by overnight fluid restriction (Murphy & Samson 1995). Selective compromise of brain-derived AM production with a ribozyme, a catalytic RNA, led to exaggerated water consumption in both the euvolemic and driven states (Taylor & Samson 2002, Taylor et al 2005. Similarly, i.c.v.…”

“…Central administration of AM also inhibited food intake, although larger doses were needed to see the food inhibition than were used to study water and salt intake (Taylor et al 1996). Nevertheless, ribozyme compromise of endogenous AM led to increased food intake in ad libitum fed rats (Taylor et al 2005). These results led us to hypothesize that endogenous, brain-derived AM is a physiologic regulator of fluid and electrolyte balance.…”

“…i.c.v. administration of AM stimulated AVP release, while ribozyme compromise of brain-derived AM prevented an appropriate AVP response to dehydration challenges (Taylor et al 2005). Here, we examine the effects of AM within brain to regulate OT release and discuss the possible implications this has on mechanisms controlling sodium ingestion.…”