Angiotensin selectively activates a subpopulation of postganglionic sympathetic neurons in mice.
Angiotensin II (Ang II) increases renal sympathetic nerve activity in anesthetized mice before and after ganglionic blockade, suggesting that Ang II may directly activate postganglionic sympathetic neurons. The present study directly tested this hypothesis in vitro. Neurons were dissociated from aortic-renal and celiac ganglia of C57BL/6J mice. Cytosolic Ca(2+) concentration ([Ca(2+)](i)) was measured with ratio imaging using fura 2. Ang II increased [Ca(2+)](i) in a subpopulation of sympathetic neurons. At a concentration of 200 nmol/L, 14 (67%) of 21 neurons responded with a rise in [Ca(2+)](i). The Ang II type 1 (AT(1)) receptor blocker (losartan, 2 micromol/L) but not the Ang II type 2 (AT(2)) receptor blocker (PD123,319, 4 micromol/L) blocked this effect. The Ang II-induced [Ca(2+)](i) increase was abolished by removal of extracellular Ca(2+) but not altered by depletion of intracellular Ca(2+) stores with thapsigargin. Ang II no longer elicited a [Ca(2+)](i) increase in the presence of lanthanum (25 micromol/L). The specific N-type and L-type Ca(2+) channel blockers, omega-conotoxin GVIA and nifedipine, respectively, significantly inhibited the Ang II-induced [Ca(2+)](i) increase. The protein kinase C inhibitor H7 but not the protein kinase A inhibitor H89 blocked the response to Ang II. These results demonstrate that Ang II selectively activates a subpopulation of postganglionic sympathetic neurons in aortic-renal and celiac ganglia, triggering Ca(2+) influx through voltage-gated Ca(2+) channels. This effect is mediated through AT(1) receptors and requires the activation of protein kinase C. The activation of a subgroup of sympathetic neurons by Ang II may exert unique effects on kidney function in pathological states associated with elevated Ang II.
Ma
X
X
Department of Internal Medicine, The Cardiovascular Center, University of Iowa College of Medicine, Iowa City, Iowa, USA. xiuying-ma@uiowa.edu
Chapleau
M W
MW
Whiteis
C A
CA
Abboud
F M
FM
Bielefeldt
K
K
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001683:Biological Clocks / Q000187:drug effects; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005456:Fluorescent Dyes; D005728:Ganglia, Sympathetic / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007424:Intracellular Fluid / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism; D017779:Sympathetic Fibers, Postganglionic / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D011189:Potassium Chloride; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D002118:Calcium