The hypothalamic arcuate nucleus: a new site of cardiovascular action of angiotensin-(1–12) and angiotensin II

Abstract

Arakawa H, Chitravanshi VC, Sapru HN. The hypothalamic arcuate nucleus: a new site of cardiovascular action of angiotensin-(1-12) and angiotensin II. Am J Physiol Heart Circ Physiol 300: H951-H960, 2011. First published December 24, 2010 doi:10.1152/ajpheart.01144.2010.-The hypothalamic arcuate nucleus (ARCN) has been reported to play a significant role in cardiovascular regulation. It has been hypothesized that the ARCN may be one of the sites of cardiovascular actions of angiotensins (ANGs). Experiments were carried out in urethaneanesthetized, artificially ventilated, adult male Wistar rats. The ARCN was identified by microinjections of N-methyl-D-aspartic acid (NMDA; 10 mM). Microinjections (50 nl) of ANG-(1-12) (1 mM) into the ARCN elicited increases in mean arterial pressure (MAP), heart rate (HR), and greater splanchnic nerve activity (GSNA). The tachycardic responses to ANG-(1-12) were attenuated by bilateral vagotomy. The cardiovascular responses elicited by ANG-(1-12) were attenuated by microinjections of ANG II type 1 receptor (AT1R) antagonists but not ANG type 2 receptor (AT2R) antagonist. Combined inhibition of ANG-converting enzyme (ACE) and chymase in the ARCN abolished ANG-(1-12)-induced responses. Microinjections of ANG II (1 mM) into the ARCN also increased MAP and HR. Inhibition of ARCN by microinjections of muscimol (1 mM) attenuated the pressor and tachycardic responses to intravenously administered ANG-(1-12) and ANG II (300 pmol/kg each). These results indicated that 1) microinjections of ANG-(1-12) into the ARCN elicited increases in MAP, HR, and GSNA; 2) HR responses were mediated via both sympathetic and vagus nerves; 3) AT1Rs, but not AT2Rs, in the ARCN mediated ANG-(1-12)-induced responses; 4) both ACE and chymase were needed to convert ANG-(1-12) to ANG II in the ARCN; and 5) ARCN plays a role in mediating the cardiovascular responses to circulating ANGs. blood pressure; heart rate; microinjection; N-methyl-D-aspartic acid; sympathetic nerve activity THE HYPOTHALAMIC ARCUATE NUCLEUS (ARCN) may play a significant role in cardiovascular regulation (10, 38). Consistent with this notion, we (31) have recently reported that chemical stimulation of the ARCN elicited increases in mean arterial pressure (MAP), heart rate (HR), and sympathetic nerve activity (SNA). These reports have provided a basis for investigations on different neurotransmitters and neuromodulators in the ARCN that may play a role in the regulation of cardiovascular function in normal and pathological states.A new endogenous angiotensin (ANG), ANG-(1-12), has recently been identified (30,44). Intravenous administration of this peptide has been reported to elicit an immediate pressor response in the rat, and this effect was blocked by prior administration of an ANG-converting enzyme (ACE) inhibitor or an ANG II type 1 receptor (AT 1 R) antagonist (30). These data indicated that in the periphery, ANG-(1-12) exerts its actions via a rapid conversion to ANG II (30). High concentrations of ANG-(1-12) have been reported in th...

Cardiovascular effect of angiotensin-(1–12) in the caudal ventrolateral medullary depressor area of the rat

“…In a previous study (10), microinjections of ANG-(1-12) into the nucleus tractus solitarius (NTS) elicited decreases in mean arterial pressure (MAP), heart rate (HR), and sympathetic nerve activity (SNA). In the rostral ventrolateral medullary pressor area (RVLM) and hypothalamic paraventricular and arcuate nuclei, microinjections of ANG-(1-12) elicited increases in MAP, HR, and SNA (4,5,11).This laboratory was the first to report the critical role that the caudal ventrolateral medullary depressor area (CVLM) plays as a relay nucleus in medullary baroreflex pathways (28,(43)(44)(45)(46). Peripheral baroreceptor, chemoreceptor, and cardiopulmonary afferents are known to make their first synapse in the NTS.…”

“…In a previous study (10), microinjections of ANG-(1-12) into the nucleus tractus solitarius (NTS) elicited decreases in mean arterial pressure (MAP), heart rate (HR), and sympathetic nerve activity (SNA). In the rostral ventrolateral medullary pressor area (RVLM) and hypothalamic paraventricular and arcuate nuclei, microinjections of ANG-(1-12) elicited increases in MAP, HR, and SNA (4,5,11).…”

“…Unlike ANG II, renin is not involved in the formation of ANG-(1-12) (15,40), prompting the suggestion that ANG-(1-12) may act as a renin-independent alternative substrate for the formation of ANG II in several organs (40). In the periphery, ANG-(1-12) may exert its actions via a rapid conversion to ANG II because pressor responses elicited by intravenous injections of ANG- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) in the rat were blocked by prior injections of an ANG type 1 receptor (AT 1 R) antagonist (29). Because it is known that ANG I and ANG II can be converted into ANG-(1-7) (41), there is a possibility that ANG-(1-7) may be formed from ANG- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) in the brain.…”

“…In the periphery, ANG-(1-12) may exert its actions via a rapid conversion to ANG II because pressor responses elicited by intravenous injections of ANG- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) in the rat were blocked by prior injections of an ANG type 1 receptor (AT 1 R) antagonist (29). Because it is known that ANG I and ANG II can be converted into ANG-(1-7) (41), there is a possibility that ANG-(1-7) may be formed from ANG- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) in the brain. The receptors via which ANG- (1)(2)(3)(4)(5)(6)(7) exerts its actions [Mas receptors (MasRs)] have been identified in medullary brain tissue (14).…”

“…Because it is known that ANG I and ANG II can be converted into ANG-(1-7) (41), there is a possibility that ANG-(1-7) may be formed from ANG- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) in the brain. The receptors via which ANG- (1)(2)(3)(4)(5)(6)(7) exerts its actions [Mas receptors (MasRs)] have been identified in medullary brain tissue (14).…”