Relaxin increases sympathetic nerve activity and activates spinally projecting neurons in the paraventricular nucleus of nonpregnant, but not pregnant, rats

Abstract

Coldren KM, Brown R, Hasser EM, Heesch CM. Relaxin increases sympathetic nerve activity and activates spinally projecting neurons in the paraventricular nucleus of nonpregnant, but not pregnant, rats. Am J Physiol Regul Integr Comp Physiol 309: R1553-R1568, 2015. First published September 23, 2015; doi:10.1152/ajpregu.00186.2015.-Pregnancy is characterized by increased blood volume and baseline sympathetic nerve activity (SNA), vasodilation, and tachycardia. Relaxin (RLX), an ovarian hormone elevated in pregnancy, activates forebrain sites involved in control of blood volume and SNA through ANG II-dependent mechanisms and contributes to adaptations during pregnancy. In anesthetized, arterial baroreceptordenervated nonpregnant (NP) rats, RLX microinjected into the subfornical organ (SFO; 0.77 pmol in 50 nl) produced sustained increases in lumbar SNA (8 Ϯ 3%) and mean arterial pressure (MAP; 26 Ϯ 4 mmHg). Low-dose intracarotid artery infusion of RLX (155 pmol·ml Ϫ1 ·h Ϫ1 ; 1.5 h) had minor transient effects on AP and activated neurons [increased Fos-immunoreactivity (IR)] in the SFO and in spinally projecting (19 Ϯ 2%) and arginine-vasopressin (AVP)-IR (21 Ϯ 5%) cells in the paraventricular nucleus of the hypothalamus of NP, but not pregnant (P), rats. However, mRNA for RLX and ANG II type 1a receptors in the SFO was preserved in pregnancy. RLX receptor-IR is present in the region of the SFO in NP and P rats and is localized in astrocytes, the major source of angiotensinogen in the SFO. These data provide an anatomical substrate for a role of RLX in the resetting of AVP secretion and increased baseline SNA in pregnancy. Since RLX and ANG II receptor expression was preserved in the SFO of P rats, we speculate that the lack of response to exogenous RLX may be due to maximal activation by elevated endogenous levels of RLX in near-term pregnancy.Fos; paraventricular nucleus; subfornical organ; circumventricular organs; ANG II; arginine-vasopressin WITH ITS HIGHEST CIRCULATING levels achieved during pregnancy, relaxin (RLX) is a 6-kDa peptide hormone secreted primarily by the corpus luteum of the ovary. RLX-2 in humans is functionally equivalent to RLX-1 in all other mammals, and often both are called simply "relaxin" (2, 4, 21). Although best known for its role in growth and remodeling of the female reproductive tract during pregnancy, RLX peptide and RLX binding sites are present in male reproductive tissue and the heart, vasculature, kidney, and brain of both males and females. In regards to the cardiovascular system, in both male and female humans and rats, chronic administration of RLX causes vascular remodeling, angiogenesis, and systemic vasodilation (8). Endogenous RLX is a major contributor to peripheral vasodilation and augmented renal function seen in pregnancy, and recent clinical trials suggest that exogenously administered RLX may have therapeutic value in treating heart-failure patients (2,8,14).In addition to peripheral vascular effects, circulating RLX plays an important role in the central nervous sys...

Muscle sympathetic nerve activity and volume-regulating factors in healthy pregnant and nonpregnant women

“…In rats, pregnancy causes striking changes in the central control of sympathetic outflow (22,23), including alterations in ANG II and vasopressin signaling in the paraventricular nucleus (6). In humans, recent data point to reductions in sympathetic vascular transduction (20,35) and baroreflex responsiveness (34), both of which may contribute to the maintenance of normal blood pressure in the face of markedly higher SNA.…”

A reversal of fate : unravelling the role of central 5-HT in cardiorespiratory control in neonatal and adult rodents

“…Further, we noticed that following blockade of V1A receptors with Manning Compound, these rats still exhibited a small but significant response to AVP (Supplemental Figure 4.13); suggesting blockade of AVP was not complete. We note, however, that the doses we used in our experiments were consistent with previous reports where blockade of V1A receptors was complete [330]. Considering the low "n", additional animals are needed to verify the contribution of AVP to resting MAP in our model.…”

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“…Combined α- and β-adrenergic blockade with carvedilol completely abrogated the inotropic effects of NE [ 10 ]. In non-pregnant rats, RLX administration has been shown to increase sympathetic nerve activity [ 17 ]. Thus, enhanced sympathetic activation and its differential effects on the cardiac ventricles might be an explanation for the differences in the RV and LV inotropic responses to RLX.…”