In Female Rats, the Sympathoexcitatory and Pressor Actions of Arcuate Nucleus Angiotensin II Vary During the Estrus Cycle and are Mediated by Inhibition of Neuropeptide Y, and Excitation of α‐Melanocyte Stimulating Hormone, Projections to the Hypothalamic Paraventricular Nucleus

Abstract

In male rats, nanoinjections of Angiotensin II (AngII) into the arcuate nucleus (ArcN) increases sympathetic nerve activity (SNA) by suppressing tonic sympathoinhibitory Neuropeptide Y (NPY) inputs, and activating excitatory pro‐opiomelanocortin (POMC) inputs that release alpha melanocyte stimulating hormone (α‐MSH), into the hypothalamic paraventricular nucleus (PVN). In female rats, ArcN AngII AT1a receptor (AT1aR) expression is generally higher than in males, but varies with the estrus cycle (highest during estrus; lowest during proestrus). However, whether ArcN AngII increases SNA in females, or if the response varies during the cycle, is unknown. Therefore, we tested bilateral ArcN AngII injections (30 pmol in 30 nL) in α‐chloralose anesthetized female rats throughout the reproductive cycle, and found that 90 min after ArcN AngII injections, LSNA increased (P<0.05) in rats during estrus (by 72±12 %; n=6) and diestrus (by 40±9 %; n=4), but not proestrus (−1±8 %; n=5). ArcN AngII also induced an initial rapid rise (P<0.05) in mean arterial pressure (MAP) in all groups (estrus: 13±2 mmHg; diestrus: 11±3 mmHg; proestrus: 13±3 mmHg), but the increase was sustained only in estrus rats (by 12±2 mmHg; P<0.05). We next tested if ArcN AngII suppresses inhibitory NPY inputs by determining if blockade of PVN NPY Y1 receptors (Y1R) with bilateral nanoinjections of BIBO3304 (60 pmol/60nL) elicits smaller increases in MAP and LSNA 60 min after nanoinjection of AngII into the ArcN. As previously reported, PVN injections of BIBO3304 (without ArcN AngII; n=3) increased (P<0.05) LSNA (by 34±6 %) and MAP (by 10±1 mmHg). However, the increases (P<0.05) in LSNA (to 93±16 %) and MAP (by 19±1 mmHg) (n=4) following ArcN AngII and PVN BIBO3304 were the same as ArcN AngII followed by PVN artificial cerebrospinal fluid (n=3; LSNA by 107±30 % and MAP by 17±4 mmHg). Thus, ArcN AngII markedly attenuated the pressor and sympathoexcitatory effects of blockade of PVN Y1R, indicating that AngII increases LSNA and MAP in part by inhibition of NPY projections to the PVN. Finally, because suppression of tonic NPY inhibition of PVN presympathetic neurons permits increased activation of PVN α‐MSH receptors (MC4R), we tested if blockade of PVN MC4R with SHU9119 decreases LSNA and MAP 90 min after ArcN AngII (n=4). Indeed, bilateral PVN SHU9119 decreased (P<0.05) LSNA (by 30±10 %) and MAP (by 10±1 mmHg). In conclusion, in females as in males, ArcN AngII increases SNA and MAP by inhibiting NPY inputs and increasing α‐MSH inputs into the PVN. However, these effects vary during the estrus cycle in parallel to AngII AT1aR expression: highest during estrus and undetectable during proestrus.Support or Funding InformationHL128181