Xue, B., Zhang, Z., Beltz, T. G., Guo, F., Hay, M., & Johnson, A. K. (2014). Genetic knockdown of estrogen receptor alpha (ERα) in the subfornical organ augments angiotensin II-induced hypertension in female mice. American journal of physiology. Regulatory, integrative and comparative physiology, ajpregu.00406.2014.
The present study tested the hypotheses that 1) ERα in the brain plays a key role in the estrogen protective effects against angiotensin (ANG) II-induced hypertension, and 2) that the subfornical organ (SFO) is a key site where ERα mediates these protective actions. In this study, a "floxed" ERα transgenic mouse line (ERα(flox)) was used to create models in which ERα was knocked down in the brain or just in the SFO. Female mice with ERα ablated in the nervous system (Nestin-ERα(-) mice) showed greater increases in blood pressure (BP) in response to ANG II. Furthermore, females with ERα knockdown specifically in the SFO [SFO adenovirus-Cre (Ad-Cre) injected ERα(flox) mice] also showed an enhanced pressor response to ANG II. Immunohistochemical, RT-PCR and Western blot analyses revealed a marked reduction in the expression of ERα in nervous tissues and, in particular, in the SFO. These changes were not present in peripheral tissues in Nestin-ERα(-) mice or Ad-Cre injected ERα(flox) mice. mRNA expression of components of the renin-angiotensin system in the laminal terminalis were up-regulated in Nestin-ERα(-) mice. Moreover, ganglionic blockade on day 7 after ANG II infusions resulted in a greater reduction of BP in Nestin-ERα(-) mice or SFO Ad-Cre injected mice suggesting that knockdown of ERα in the nervous system or the SFO alone augments central ANG II-induced increase in sympathetic tone. The results indicate that interfering with the action of estrogen on SFO ERα is sufficient to abolish the protective effects of estrogen against ANG II-induced hypertension.
Xue, B., Pamidimukkala, J., Lubahn, D. B., & Hay, M. (2007). Estrogen receptor-alpha mediates estrogen protection from angiotensin II-induced hypertension in conscious female mice. American journal of physiology. Heart and circulatory physiology, 292(4), H1770-6.
It has been shown that the female sex hormones have a protective role in the development of angiotensin II (ANG II)-induced hypertension. The present study tested the hypotheses that 1) the estrogen receptor-alpha (ERalpha) is involved in the protective effects of estrogen against ANG II-induced hypertension and 2) central ERs are involved. Blood pressure (BP) was measured in female mice with the use of telemetry implants. ANG II (800 ng.kg(-1).min(-1)) was administered subcutaneously via an osmotic pump. Baseline BP in the intact, ovariectomized (OVX) wild-type (WT) and ERalpha knockout (ERalphaKO) mice was similar; however, the increase in BP induced by ANG II was greater in OVX WT (23.0 +/- 1.0 mmHg) and ERalphaKO mice (23.8 +/- 2.5 mmHg) than in intact WT mice (10.1 +/- 4.5 mmHg). In OVX WT mice, central infusion of 17beta-estradiol (E(2); 30 microg.kg(-1).day(-1)) attenuated the pressor effect of ANG II (7.0 +/- 0.4 mmHg), and this protective effect of E(2) was prevented by coadministration of ICI-182,780 (ICI; 1.5 microg.kg(-1).day(-1), 18.8 +/- 1.5 mmHg), a nonselective ER antagonist. Furthermore, central, but not peripheral, infusions of ICI augmented the pressor effects of ANG II in intact WT mice (17.8 +/- 4.2 mmHg). In contrast, the pressor effect of ANG II was unchanged in either central E(2)-treated OVX ERalphaKO mice (19.0 +/- 1.1 mmHg) or central ICI-treated intact ERalphaKO mice (19.6 +/- 1.6 mmHg). Lastly, ganglionic blockade on day 7 after ANG II infusions resulted in a greater reduction in BP in OVX WT, central ER antagonist-treated intact WT, central E(2) + ICI-treated OVX WT, ERalphaKO, and central E(2)- or ICI-treated ERalphaKO mice compared with that in intact WT mice given just ANG II. Together, these data indicate that ERalpha, especially central expression of the ER, mediates the protective effects of estrogen against ANG II-induced hypertension.
Yu, R., Hay, M., & Ticku, M. K. (1996). Chronic neurosteroid treatment attenuates single cell GABAA response and its potentiation by modulators in cortical neurons. Brain research, 706(1), 160-2.
In previous studies we have observed that chronic neurosteroid 5 alpha-pregnan-3 alpha-ol-20-one (5 alpha 3 alpha) treatment produced downregulation of the GABAA receptors, heterologous uncoupling, and decreased heterologous efficacy at the GABAA receptor complex in cultured mammalian cortical neurons. In this study, using whole cell recording, we examined the consequence of chronic 5 alpha 3 alpha (1 microM; 5 days) treatment on GABA-induced currents in isolated cortical neurons. We observed that the GABA current was decreased by 78% after 5 days treatment of cortical cells with 1 microM 5 alpha 3 alpha. We also observed decreased pentobarbital, and 5 alpha 3 alpha potentiation of GABA currents after chronic 5 alpha 3 alpha treatment. These findings support the notion that GABA response, and its potentiation by pentobarbital, and neurosteroid, 5 alpha 3 alpha, are attenuated after chronic 5 alpha 3 alpha treatment.
Hay, M. (2015). The Good and the Bad: Immune Cells and Hypertension. Clin Sci (Lond)., 117(10), 830-1.
Schild, J. H., Clark, J. W., Hay, M., Mendelowitz, D., Andresen, M. C., & Kunze, D. L. (1994). A- and C-type rat nodose sensory neurons: model interpretations of dynamic discharge characteristics. Journal of neurophysiology, 71(6), 2338-58.
1. Neurons of the nodose ganglia provide the sole connection between many types of visceral sensory inputs and the central nervous system. Electrophysiological studies of isolated nodose neurons provide a practical means of measuring individual cell membrane currents and assessing their putative contributions to the overall response properties of the neuron and its terminations. Here, we present a comprehensive mathematical model of an isolated nodose sensory neuron that is based upon numerical fits to quantitative voltage- and current-clamp data recorded in our laboratory. Model development was accomplished using an iterative process of electrophysiological recordings, nonlinear parameter estimation, and computer simulation. This work is part of an integrative effort aimed at identifying and characterizing the fundamental ionic mechanisms participating in the afferent neuronal limb of the baroreceptor reflex. 2. The neuronal model consists of two parts: a Hodgkin-Huxley-type membrane model coupled to a lumped fluid compartment model that describes Ca2+ ion concentration dynamics within the intracellular and external perineuronal media. Calcium buffering via a calmodulin-type buffer is provided within the intracellular compartment. 3. The complete model accurately reproduces whole-cell voltage-clamp recordings of the major ion channel currents observed in enzymatically dispersed nodose sensory neurons. Specifically, two Na+ currents exhibiting fast (INaf) and slow tetrodotoxin (TTX)-insensitive (INas) kinetics; low- and high-threshold Ca2+ currents exhibiting transient (ICa,t) and long-lasting (ICa,n) dynamics, respectively; and outward K+ currents consisting of a delayed-rectifier current (IK), a transient outward current (I(t)) and a Ca(2+)-activated K+ current (IK,Ca). 4. Whole-cell current-clamp recordings of somatic action-potential dynamics were performed on enzymatically dispersed nodose neurons using the perforated patch-clamp technique. Stimulus protocols consisted of both short ( or = 2.0 ms) and long (> or = 200 ms) duration current pulses over a wide range of membrane holding potentials. These studies clearly revealed two populations of nodose neurons, often termed A- and C-type cells, which exhibit markedly different action-potential signatures and stimulus response properties. 5. Using a single set of equations, the model accurately reproduces the electrical behavior of both A- and C-type nodose neurons in response to a wide variety of stimulus conditions and membrane holding potentials. The structure of the model, as well as the majority of its parameters are the same for both A- and C-type implementations.(ABSTRACT TRUNCATED AT 400 WORDS)