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 (Δ22.1 mm Hg males versus Δ18 mm : Hg females). After adoptive transfer of male T cells, Ang II significantly increased systolic blood pressure in males (Δ37.7 mm : Hg; P
Intrinsic membrane properties, voltage-dependent sodium and voltage-dependent potassium currents of area postrema neurons in culture have been characterized with respect to their voltage dependence, time dependence and sensitivity to specific blocking agents. The area postrema is a hindbrain circumventricular organ which is known to have an important role in the central regulation of cardiovascular function. This study is the first to describe the biophysical properties of ion channels present in rat area postrema neurons. Recordings in current-clamp mode revealed a mean resting membrane potential of -55.0 +/- 1.6 (n = 24) mV and an input resistance of 213.6 +/- 23 M omega. For the 24 neurons tested, the evoked action potential had a mean threshold of 38.8 +/- 2 mV and a mean amplitude of 107.3 +/- 15 mV. Our results show that the area postrema possesses only one principle sodium current which is completely abolished by 5 microM tetrodotoxin (TTX) (n = 28). This current activated near -50 mV and reached peak amplitude at -30 mV. The area postrema does not possess a TTX insensitive sodium current. The area postrema has at least two types of potassium currents. All area postrema neurons studied with tetraethylamonium (TEA) (n = 40) showed the presence of a slowly activating outward current which was present at voltages greater than -40 mV and was blocked by 10 mM TEA. In addition, 75% of the neurons studied (n = 30/40) also showed a rapidly inactivating, 4-AP sensitive IA type current which activated near -30 mV. Angiotensin II attenuated both the peak and the steady-state potassium currents, suggesting that angiotensin II may modulate area postrema activity by inhibiting voltage-gated potassium channels.
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.
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.