Expression of angiotensin II type 1 (AT1) receptor in the rostral ventrolateral medulla in rats. J Appl Physiol 92: 2153–2161, 2002. First published January 11, 2002; 0.1152/japplphysiol.00261.2001.-In the present study, the changes of amino acids release in the spinal cord after the application of angiotensin II (ANG II) in the rostral ventrolateral medulla (RVLM) and the distribution of ANG receptors on neurons of the RVLM were investigated. A microdialysis experiment showed that microinjection of angiotensin II into the RVLM significantly (P＜0.01) increased the release of aspartate and glutamate in the intermediolateral column of the spinal cord. Immunofluorescence technique combined with confocal microscopy demonstrated that most of the glutamatergic and GABAergic neurons in the RVLM of both Wistar and spontaneously hypertensive rats (SHR) were double labeled with ANG type 1 (AT1) receptor. Immunocytochemical studies demonstrated that the mean optic density of AT1 receptor of the cell surface as well as the whole cell was higher (P＜0.05) in SHR than that in Wistar rats, indicating that the higher expression of AT1 receptors in the RVLM may contribute to the higher responsiveness of SHR to ANG II stimulation. Immunogold staining and electronmicroscopic study demonstrated that AT1 receptor in the RVLM was distributed on the rough endoplasmic reticulum, cell membrane, and nerve processes. The results suggest that effects evoked by ANG II in the RVLM are closely related to glutamatergic and GABAergic pathways. These results indirectly support the hypothesis that ANG II in the RVLM may activate vasomotor sympathetic glutamatergic neurons, leading to an increase in sympathetic nerve activity and arterial blood pressure.

Effects of all-trans retinoic acid on angiotensin II-induced myocyte hypertrophy. J Appl Physiol 92: 2162–2168, 2002. First published January 4, 2002; 10.1152/japplphysiol.01192.2001.-We used cultured neonatal rat cardiac myocytes to test the hypothesis that all-trans retinoic acid (atRA) may act to modulate ANG II actions in inducing myocyte hypertrophy. Our observations were as follows. 1) atRA (10-7 to～10-5M) inhibited ANG II-induced hyperplasia of fibroblasts in a dose-dependent manner. 2) Treatment of atRA attenuated the ANG II-induced increase in total cell protein content. 3) Treated with ANG II (10-7M) for 5 days, the cultured neonatal rat cardiac myocytes demonstrated an apparent accumulation of sarcomeric fiber proteins and Golgi's complex, as well as reorganization of the sarcomeric unit within individual myocytes. atRA (10-6M) treatment reduced the accumulation of contractile proteins and Golgi's complex without affecting the ANG II-induced reorganization of the sarcomeric unit. 4) atRA attenuated the ANG II-induced increase in intracellular Ca2+. Our results show that atRA inhibits some effects of ANG II on neonatal rat cardiac myocytes and suggest that atRA may be a therapeutic candidate for the prevention and therapy of cardiac hypertrophy and remodeling.

There are in vitro data linking all-trans retinoic acid (atRA) with inhibition of hypertrophy and hyperplasia in cardiomyocytes, vascular smooth muscle cells, and fibroblasts. In the present study, we tested the hypothesis that chronic treatment with atRA may blunt the process of myocardial remodeling in spontaneously hypertensive rats (SHR). Four-week-old male SHR were treated with atRA (5 or 10mg

Increasing lines of evidence indicate that estrogen acts as a neuroprotective agent through a nongenomic mechanism. We tested the hypothesis that 17h-estradiol could rapidly attenuate glutamate-induced calcium (Ca2+) overload in rat primary hippocampal neurons via a membrane receptor-dependent mechanism. The bulk cytosolic intracellular Ca2+ level was measured in neurons with fluorescent Ca2+ probe fluo3. Preexposure of primary cultured hippocampal neurons to 17h-estradiol for 3 min attenuated intracellular Ca2+ increase induced by glutamate in a concentration-dependent manner. The action of 17h-estradiol was reversible after washout. Administration of membraneimpermeable 17h-estradiol conjugated to bovine serum albumin (E2–BSA) produced the same effect, suggesting possible involvement of cell membrane receptors. ICI 182,780, a specific estrogen receptor (ER) antagonist, blocked the neuronal response to 17h-estradiol and estradiol BSA, indicating a role of specific ERs. The present study demonstrates that 17h-estradiol acutely reduces glutamate-stimulated intracellular Ca2+ increase via ERs probably on the cell surface of the hippocampal neurons.

Aim: To investigate the mechanism of the action of estrogen, which stimulates the release of secreted amyloid precursor protein a (sAPPa) and decreases the generation of amyloid-β protein (Aβ), a dominant component in senile plaques in the brains of Alzheimer's disease patients. Metheds: Experiments were carried out in primary rat cortical neurons, and Western blot was used to detect sAPPa in a culture m edium and the total am ount of cellular amyloid precursor protein (APP) in neurons. Results: 17β-Estradiol (but not 17a-estradiol) andβ-estradiol 6-(0-carboxym ethyl) oxim e: B SA increased the secretion of sAPPa and this effect was blocked by protein kinase C (PKC) inhibitor calphostin C, but not by the classical estrogen receptor antagonist ICI 182, 780. Meanwhile, 17β-estradiol did not alter the synthesis ofcellularAPR Conclusion: The effect of 17β-estradiol unsAPPa secretion is likely mediated through the membrane binding sites, and needs molecular configuration specificity of the ligand. Furthermore, the action of the PKC-dependent pathway might be involved in estrogen-induced sAPPa secretion.