TY - JOUR
T1 - Activation of central angiotensin type 2 receptors suppresses norepinephrine excretion and blood pressure in conscious rats
AU - Gao, Juan
AU - Zhang, Hao
AU - Le, Khang D.
AU - Chao, Jie
AU - Gao, Lie
N1 - Funding Information:
Acknowledgments:We acknowledge the expert technical assistance of Li Yu, Phyllis Anding, johnnie F. Hackley, and Pamela Curry.We also thank Drs Mingqi Zheng and George j. Rozanski for their help with the patch-clamp experiments.We appreciate the suggestions from Dr Irving H. Zucker regarding the experiments, and his valuable inputs for the revision of the manuscript.The authors thankVicore Pharma AB for their generous donation of Compound 21.This study was supported by a Scientist Development Grant from the American Heart Association 0635007n and nIH grants RO1HL093028 and P30HL101296.
PY - 2011/6
Y1 - 2011/6
N2 - Background We have previously documented the finding that central angiotensin type 2 receptors (AT2R) negatively modulate sympathetic outflow and arterial blood pressure (BP). In this study, we investigated the effects of intracerebroventricular (icv) infusion of Compound 21 (C21), the first selective nonpeptide AT2R agonist, on norepinephrine (NE) excretion and BP in rats. Methods C21 was infused icv for 7 days, using a micro-osmotic pump. Urinary NE concentration was measured using the NE enzyme immunoassay kit. BP was recorded by radiotelemetry. After 7 days, the rats were killed and three relevant samples from sympathetic brain regions and the cerebral cortex were obtained by micro-punching to measure neuronal nitric oxide synthase (nNOS) protein expression by western blot. In addition, the influence of C21 on neuronal potassium current (IKv) was determined by whole-cell patch-clamp in a neuron cell line, CATH.a. Results (i) Icv treatment with C21 significantly decreased both the concentration and the amount of NE in night time urine, but had no effect on daytime urine. (ii) C21-treated rats exhibited a slight but significant decrease in BP. (iii) The effects of C21 on NE excretion and BP were abolished by use of the AT2R antagonist, PD123319, and nitric oxide synthase (NOS) inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME). (iv) C21 treatment significantly upregulated nNOS expression in the paraventricular nucleus of the hypothalamus (PVN) and rostral ventrolateral medulla (RVLM), but not in the nucleus of the solitary tract (NTS) and cerebral cortex. (v) In CATH.a neurons, C21 treatment significantly increased IKv, and this increase was completely abolished by PD123319 and L-NAME. Conclusions These Results demonstrate a central inhibitory influence of C21 on sympathetic outflow by means of a nNOS-dependent mechanism that might be mediated by facilitating the neuronal potassium channel.
AB - Background We have previously documented the finding that central angiotensin type 2 receptors (AT2R) negatively modulate sympathetic outflow and arterial blood pressure (BP). In this study, we investigated the effects of intracerebroventricular (icv) infusion of Compound 21 (C21), the first selective nonpeptide AT2R agonist, on norepinephrine (NE) excretion and BP in rats. Methods C21 was infused icv for 7 days, using a micro-osmotic pump. Urinary NE concentration was measured using the NE enzyme immunoassay kit. BP was recorded by radiotelemetry. After 7 days, the rats were killed and three relevant samples from sympathetic brain regions and the cerebral cortex were obtained by micro-punching to measure neuronal nitric oxide synthase (nNOS) protein expression by western blot. In addition, the influence of C21 on neuronal potassium current (IKv) was determined by whole-cell patch-clamp in a neuron cell line, CATH.a. Results (i) Icv treatment with C21 significantly decreased both the concentration and the amount of NE in night time urine, but had no effect on daytime urine. (ii) C21-treated rats exhibited a slight but significant decrease in BP. (iii) The effects of C21 on NE excretion and BP were abolished by use of the AT2R antagonist, PD123319, and nitric oxide synthase (NOS) inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME). (iv) C21 treatment significantly upregulated nNOS expression in the paraventricular nucleus of the hypothalamus (PVN) and rostral ventrolateral medulla (RVLM), but not in the nucleus of the solitary tract (NTS) and cerebral cortex. (v) In CATH.a neurons, C21 treatment significantly increased IKv, and this increase was completely abolished by PD123319 and L-NAME. Conclusions These Results demonstrate a central inhibitory influence of C21 on sympathetic outflow by means of a nNOS-dependent mechanism that might be mediated by facilitating the neuronal potassium channel.
KW - angiotensin type 2 receptor
KW - blood pressure
KW - central nervous system
KW - hypertension; norepinephrine
KW - potassium current
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U2 - 10.1038/ajh.2011.33
DO - 10.1038/ajh.2011.33
M3 - Article
C2 - 21394088
AN - SCOPUS:79956120211
SN - 0895-7061
VL - 24
SP - 724
EP - 730
JO - American Journal of Hypertension
JF - American Journal of Hypertension
IS - 6
ER -