Meredith Hay

Central interactions of aldosterone and angiotensin II in aldosterone- and angiotensin II-induced hypertension.

Many studies have implicated both angiotensin II (ANG II) and aldosterone (Aldo) in the pathogenesis of hypertension, the progression of renal injury, and cardiac remodeling after myocardial infarction. In several cases, ANG II and Aldo have been shown to have synergistic interactions in the periphery. In the present studies, we tested the hypothesis that ANG II and Aldo interact centrally in Aldo- and ANG II-induced hypertension in male rats. In rats with blood pressure (BP) and heart rate (HR) measured by DSI telemetry, intracerebroventricular (icv) infusions of the mineralocorticoid receptor (MR) antagonists spironolactone and RU28318 or the angiotensin type 1 receptor (AT1R) antagonist irbesartan significantly inhibited Aldo-induced hypertension. In ANG II-induced hypertension, icv infusion of RU28318 significantly reduced the increase in BP. Moreover, icv infusions of the reactive oxygen species (ROS) scavenger tempol or the NADPH oxidase inhibitor apocynin attenuated Aldo-induced hypertension. To confirm these effects of pharmacological antagonists, icv injections of either recombinant adeno-associated virus carrying siRNA silencers of AT1aR (AT1aR-siRNA) or MR (MR-siRNA) significantly attenuated the development of Aldo-induced hypertension. The immunohistochemical and Western blot analyses of AT1aR-siRNA- or MR-siRNA-injected rats showed a marked reduction in the expression of AT1R or MR in the paraventricular nucleus compared with scrambled siRNA rats. When animals from all studies underwent ganglionic blockade with hexamethonium, there was a smaller reduction in the fall of BP in animals receiving icv AT1R or MR antagonists. These results suggest that ANG II and Aldo interact in the brain in a mutually cooperative manner such that the functional integrity of both brain AT1R and MR are necessary for hypertension to be induced by either systemic ANG II or Aldo. The pressor effects produced by systemic ANG II or Aldo involve increased central ROS and sympathetic outflow.

INTERACTIONS BETWEEN VASOPRESSIN AND BAROREFLEX CONTROL OF THE SYMPATHETIC NERVOUS SYSTEM

1. In addition to its effects at the renal tubules to influence water retention and at vascular smooth muscle to cause vasoconstriction, the hormone arginine vasopressin also appears to modulate cardiovascular reflex control of the sympathetic nervous system. Infusion or endogenous release of vasopressin results in enhanced baroreflex sympatho‐inhibitory responses compared with other pressor agents. In addition, when changes in arterial pressure are imposed on an elevated background level of circulating vasopressin, due either to infusion or endogenous release, the arterial baroreflex response is shifted to lower pressures, and the maximum sympatho‐excitation to a decrease in pressure is reduced.

Involvement of the area postrema in the regulation of sympathetic outflow to the cardiovascular system.

The circumventricular organs of the brain have been implicated in the central regulation of the cardiovascular system. The area postrema, which is the only circumventricular organ in the hindbrain, has received less attention than the others, but recent studies suggest that it may play an important role in the regulation of the cardiovascular system. Studies in rats and rabbits indicate that angiotensin II (Ang II)-dependent hypertension is abolished by lesioning of the area postrema. Additional studies indicate that the hypertension associated with Ang II involves a resetting of the arterial baroreflex to a higher pressure. This upward resetting requires an interaction of neurons in the area postrema with barosensitive neurons terminating in the medial nucleus tractus solitarius (mNTS). Another peptide, arginine vasopressin (AVP), has been shown to enhance the sympathoinhibitory influence of the arterial baroreflex via an action at the area postrema. Studies in rabbits suggest that the sympathoinhibitory response is due to resetting of the baroreflex to a lower pressure. Electrophysiological studies, using an in vitro brain slice preparation, have shown that activation of area postrema neurons projecting to the mNTS alters the responsiveness of mNTS neurons to afferent inputs. It is postulated that alpha-adrenergic mechanisms are involved in these interactions.

Heterogeneity of metabotropic glutamate receptors in autonomic cell groups of the medulla oblongata of the rat

Metabotropic glutamate receptors (mGluRs) in the medulla oblongata have been suggested to be involved in the regulation of autonomic function. The aim of the present study was to examine the localization and expression of four types of mGluRs: mGluR1a, mGluR2/3, mGluR5, and mGluR7 in the dorsal and ventral autonomic nuclei of the medulla of the rat. The four mGluR subtypes studied were differentially distributed in distinct subnuclei in the nucleus of the solitary tract (NTS). mGluR1a immunoreactivity was identified in cell bodies, dendrites, and axonal processes in the intermediate, dorsal lateral, and interstitial subnuclei of the NTS. No mGluR1a immunoreactivity was observed in the commissural or medial NTS subnuclei. Immunoreactivity for mGluR2/3 and mGluR5 as observed in fibers and putative axonal processes in the interstitial, intermediate, and dorsolateral subnuclei of the NTS. In contrast, mGluR7 was expressed primarily in fibers and terminals in the central and commissural NTS subnuclei. Expression of mGluR2/3 was clearly evident in cell bodies, dendrites, and axonal processes within the area postrema. The vagal outflow nuclei were also studied. The dorsal motor nucleus of the vagus (DMN) contained mGluR1a cell bodies, dendrites, and axonal fibers and light mGluR2/3 processes. Throughout the rostral‐caudal extent of the compact and semicompact formation nucleus ambiguus, mGluR1a was found in cell bodies and fibers. Within the caudal and rostral regions of the ventral lateral medulla, mGluR1a was observed in cell bodies and fibers. Cell bodies containing mGluR1a were found adjacent to cells staining positive for tyrosine hydroxylase (TH) in these regions but were not colocalized with the TH staining. However, mGluR1a‐expressing neurons in the ventral lateral medulla did appear to receive innervation from TH‐containing fibers. These results suggest that the mGluR1a‐expressing neurons within the ventral lateral medulla are predominantly not catecholaminergic but may be innervated by catecholamine‐containing fibers. These data are the first to provide a mapping of the different mGluR subtypes within the medulla and may facilitate predictions regarding the function of L‐glutamate neurotransmission in these regions. J. Comp. Neurol. 403:486–501, 1999.

Sex differences in angiotensin II- and aldosterone-induced hypertension: the central protective effects of estrogen

Premenopausal women have lower blood pressure and a reduced incidence of cardiovascular disease compared with age-matched men. Similar sex differences have been seen across species and in multiple animal models of hypertension. While important progress over the last decade has been made in elucidating some of the mechanisms underlying these differences, there are still significant gaps in our knowledge. Understanding the cellular and molecular mechanisms responsible for sex differences in hypertension will be important for developing sex-specific therapies targeted toward the prevention and treatment of hypertension. Female sex hormones, especially estrogen, have been demonstrated to modulate the renin-angiotensin-aldosterone system (RAAS) and to have beneficial effects on cardiovascular function through actions not only on the kidney, heart, and vasculature, but also on the central nervous system (CNS). This review primarily focuses on the central regulatory actions of estrogen on brain nuclei involved in blood pressure regulation and the interactions between estrogen and the RAAS in the CNS by which estrogen plays an important protective role against the development of hypertension.

Area Postrema And Sympathetic Nervous System Effects Of Vasopressin And Angiotensin II

1. Precise control over the cardiovascular system requires the integration of both neural and humoral signals related to blood volume and blood pressure. Humoral signals interact with neural systems, modulating their control over the efferent mechanisms that ultimately determine the level of pressure and volume.

Sex Differences in T-Lymphocyte Tissue Infiltration and Development of Angiotensin II Hypertension

There is extensive evidence that activation of the immune system is both necessary and required for the development of angiotensin II (Ang II)–induced hypertension in males. The purpose of this study was to determine whether sex differences exist in the ability of the adaptive immune system to induce Ang II–dependent hypertension and whether central and renal T-cell infiltration during Ang II–induced hypertension is sex dependent. Recombinant activating gene-1 (Rag-1)–/– mice, lacking both T and B cells, were used. Male and female Rag-1–/– mice received adoptive transfer of male CD3+ T cells 3 weeks before 14-day Ang II infusion (490 ng/kg per minute). Blood pressure was monitored via tail cuff. In the absence of T cells, systolic blood pressure responses to Ang II were similar between sexes (&Dgr;22.1 mm Hg males versus &Dgr;18 mm Hg females). After adoptive transfer of male T cells, Ang II significantly increased systolic blood pressure in males (&Dgr;37.7 mm Hg; P<0.05) when compared with females (&Dgr;13.7 mm Hg). Flow cytometric analysis of total T cells and CD4+, CD8+, and regulatory Foxp3+-CD4+ T-cell subsets identified that renal lymphocyte infiltration was significantly increased in males versus females in both control and Ang II–infused animals (P<0.05). Immunohistochemical staining for CD3+-positive T cells in the subfornical organ region of the brain was increased in males when compared with that in females. These results suggest that female Rag-1–/– mice are protected from male T-cell–mediated increases in Ang II–induced hypertension when compared with their male counterparts, and this protection may involve sex differences in the magnitude of T-cell infiltration of the kidney and brain.

Sex-Specific T-Cell Regulation of Angiotensin II–Dependent Hypertension

Studies suggest T cells modulate arterial pressure. Because robust sex differences exist in the immune system and in hypertension, we investigated sex differences in T-cell modulation of angiotensin II–induced increases in mean arterial pressure in male (M) and female (F) wild-type and recombination-activating-gene-1–deficient (Rag1−/−) mice. Sex differences in peak mean arterial pressure in wild-type were lost in Rag1−/− mice (mm Hg: wild-type-F, 136±4.9 versus wild-type-M, 153±1.7; P<0.02; Rag1−/−-F, 135±2.1 versus Rag1−/−-M, 141±3.8). Peak mean arterial pressure was 13 mm Hg higher after adoptive transfer of male (CD3M→Rag1−/−-M) versus female (CD3F→Rag1−/−-M) T cells. CD3M→Rag1−/−-M mice exhibited higher splenic frequencies of proinflammatory interleukin-17A (2.4-fold) and tumor necrosis factor-&agr; (2.2-fold)–producing T cells and lower plasma levels (13-fold) and renal mRNA expression (2.4-fold) of interleukin-10, whereas CD3F→Rag1−/−-M mice displayed a higher activation state in general and T-helper-1–biased renal inflammation. Greater T-cell infiltration into perivascular adipose tissue and kidney associated with increased pressor responses to angiotensin II if the T cell donor was male but not female and these sex differences in T-cell subset expansion and tissue infiltration were maintained for 7 to 8 weeks within the male host. Thus, the adaptive immune response and role of pro- and anti-inflammatory cytokine signaling in hypertension are distinct between the sexes and need to be understood to improve therapeutics for hypertension-associated disease in both men and women.

Glutamate in the nucleus of the solitary tract activates both ionotropic and metabotropic glutamate receptors

Glutamate is the proposed neurotransmitter of baroreceptor afferents at the level of the nucleus of the solitary tract (NTS). Blockade of ionotropic glutamate receptors with kynurenic acid blocks the arterial baroreflex but, paradoxically, does not abolish the response to exogenous glutamate. This study tested the hypothesis that exogenous glutamate in the NTS activates both ionotropic and metabotropic glutamate receptors (mGluRs). In urethan-anesthetized rats, unilateral microinjections of glutamate into the NTS decreased mean arterial pressure, heart rate, and lumbar sympathetic nerve activity. The cardiovascular response to injection of glutamate was not altered by NTS blockade of mGluRs with α-methyl-4-carboxyphenylglycine (MCPG). Blockade of ionotropic glutamate receptors with kynurenic acid attenuated the response to glutamate injection. After combined NTS injection of MCPG and kynurenic acid, the response to glutamate was blocked. These data suggest that exogenous glutamate microinjected into the NTS acts at both ionotropic glutamate receptors and mGluRs. In addition, blockade of both classes of glutamate receptors is required to block the cardiovascular response to microinjection of glutamate in the NTS.

Central estrogen inhibition of angiotensin II-induced hypertension in male mice and the role of reactive oxygen species

It has been shown that reactive oxygen species (ROS) contribute to the central effect of ANG II on blood pressure (BP). Recent studies have implicated an antihypertensive action of estrogen in ANG II-infused female mice. The present study used in vivo telemetry recording and in vitro living mouse brain slices to test the hypothesis that the central activation of estrogen receptors in male mice inhibits ANG II-induced hypertension via the modulation of the central ROS production. In male wild-type mice, the systemic infusion of ANG II induced a significant increase in BP (Delta30.1 +/- 2.5 mmHg). Either central infusion of Tempol or 17beta-estradiol (E2) attenuated the pressor effect of ANG II (Delta10.9 +/- 2.3 and Delta4.5 +/- 1.4 mmHg), and the protective effect of E2 was prevented by the coadministration of an estrogen receptor, antagonist ICI-182780 (Delta23.6 +/- 3.1 mmHg). Moreover, the ganglionic blockade on day 7 after the start of ANG II infusions resulted in a smaller reduction of BP in central Tempol- and in central E2-treated males, suggesting that estrogen inhibits the central ANG II-induced increases in sympathetic outflow. In subfornical organ slices, the application of ANG II resulted in a 21.5 +/- 2.5% increase in ROS production. The coadministration of irbesartan, an ANG II type 1 receptor antagonist, or the preincubation of brain slices with Tempol blocked ANG II-induced increases in ROS production (-1.8 +/- 1.6% and -1.0 +/- 1.8%). The ROS response to ANG II was also blocked by E2 (-3.2 +/- 2.4%). The results suggest that the central actions of E2 are involved in the protection from ANG II-induced hypertension and that estrogen modulation of the ANG II-induced effects may involve interactions with ROS production.