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Brain eicosanoids contribute to increased sympathetic activity and blood pressure in angiotensin II-salt hypertension in rats
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Abstracts / Autonomic Neuroscience: Basic and Clinical 163 (2011) 1–133
Kingdom), E. Colombari (UNESP — Fisiologia e Patologia, Brazil), R.R. Campos (Universidade Federal de São Paulo — Fisiologia, Brazil), J.F.R. Paton (University of Bristol — Physiology & Pharmacology, United Kingdom) Despite the extensive use of the Goldblatt model of hypertension (two kidney one clip, 2K1C), sympathetic mechanisms responsible for both the development and maintenance of the elevated blood pressure remain unclear. We tested the hypothesis that sympathetic nerve activity (SNA) is elevated before the onset of the hypertension. Using the in situ working heart brainstem preparation, male Wistar rats were divided into three groups: Sham (n = 7), and 2K1C (3 weeks) of which some were hypertensive (2K1C-H, n = 6) and others normotensive (2K1C-N, n = 9) as determined in vivo a priori. At comparable perfusion rates, arterial pressure was higher in both 2K1C groups (2K1C-H: 76 ± 1; 2K1C-N: 74 ± 3 vs Sham: 60 ± 2 mm Hg, p < 0.05). The respiratory modulation of SNA during inspiration and post-inspiration was significantly elevated in both 2 K-1 C groups (e.g. 2K1C-H: 47.7 ± 6.1; 2K1C-N: 32.8 ± 2.8 vs Sham: 20.5 ± 2.5 μ V, p < 0.05). Pre-collicular transection reduced SNA in all rat groups (2K1C-H: 32.5 ± 7.5, 2K1CNH: 48 ± 6.9 vs Sham: 13.2 ± 1%, p < 0.05). Subsequent transection at the medullary-spinal cord abolished SNA in Sham and 2K1C-N but only decreased it by 57 ± 5.5% in 2K1C-H. We conclude, SNA can be raised prior to onset of hypertension by the 3 rd week after renal artery clipping and this, in part, originates from enhanced respiratory modulation. Our data also support an elevation of activity within spinal sympathetic networks in the 2K1C-H rats. All told, ipsilateral renal ischemia engages multiple mechanisms to raise sympathetic activity that occur ahead of any detectable rise in arterial pressure. Keywords: Goldblatt model, hypertension, sympathetic nerve activity, respiratory modulation Financial support: Supported by CAPES and the British Heart Foundation. doi:10.1016/j.autneu.2011.05.122
P.108 Brain eicosanoids contribute to increased sympathetic activity and blood pressure in angiotensin II-salt hypertension in rats G.D. Fink, N.A. Jeyaraj (Michigan State University — Pharmacology and Toxicology, United States) Background/aims: Chronic subcutaneous infusion of angiotensin II into rats on high salt intake is an experimental model of hypertension caused in part by increased sympathetic activity. Our previous work suggests that increased production of a cyclooxgenase (COX) product is required for the elevated sympathetic activity and blood pressure. The aims of the current studies were to determine the specific COX isoform involved and its location. Methods: A standard model of angiotensin II-salt hypertension in male SD rats was used. Interventions included daily systemic dosing with either a selective COX-1 inhibitor (SC560) or COX-2 inhibitor (nimesulide), or chronic intracerebroventricular (icv) infusion of the non-selective COX inhibitor ketorolac. Eicosanoid-related gene expression analysis also was performed in key brain regions. Results: Systemic SC560 and icv ketorolac both attenuated hypertension development, but nimesulide had no effect. No differences in eicosanoid-related gene expression were observed in subfornical organ, paraventricular nucleus, nucleus of the solitary tract, or rostral ventrolateral medulla of hypertensive versus normotensive rats.
Conclusion: Full development of neurogenic hypertension caused by angiotensin II-salt treatment in rats requires a COX-1 product in the brain, but does not necessitate altered transcription of eicosanoidrelated genes in the brain regions studied. Keywords: hypertension, angiotensin, sympathetic, brain, eicosanoids Financial support: NIH RO1 HL076312.
doi:10.1016/j.autneu.2011.05.123
P.109 Differential role of central insulin action and the autonomic nervous system on the hepatic production of glucose (HPG) in Wistar and SHR I.M.R. Ribeiro (USP — Fisiologia e Biofísica, Brazil), V.R. Antunes (Universidade de São Paulo — Fisiologia, Brazil) Central action of insulin and the autonomic nervous system play a key role on the control of the HPG in normotensive rats. In the present study we aimed to investigate the role of insulin injected in the lateral ventricle (LV) and the autonomic outflow on the HPG of conscious Wistar e SHR. Animals received a guide-cannula into the LV for microinjection of insulin (100 nU/mL, 1 mL). Five days later hepatic vein and femoral artery were catheterized in order to monitor the HPG and blood pressure (BP), respectively. In the Wistar group we observed that the injection of insulin in the LV elicited a maximum decrease in HPG at 10′ (81.4 mg/dL, n = 5, p < 0.05) when compared to the control group (denatured insulin), at the same time course (1170.5 mg/dL, n = 5). In the SHR group, injection of insulin in the LV did not produced significant changes in the HPG at any time evaluated. In a second group of SHR we have shown that intravenous injection of alpha and betaadrenoceptors antagonists (phentolamine, 3 mg/kg, and propranolol, 0.5 mg/kg, respectively) induced a significant decreasing in the HPG 40′ later (92.8 mg/dL n = 5, p < 0.05) when compared to the control (saline) group (113.6 mg/dL, n = 5); however any change in the HPG was observed in the Wistar group at the same time course. In a third group of SHR intravenous injection of methylatropine (2 mg/kg, iv) caused an increase of the HPG (129.5 mg/dL, n = 2) at 40′ when compared to the control group at the same time course (118 mg/dL, n = 2). In conclusion, these findings suggest that HPG is differently controlled in Wistar and SHR by central action of insulin and peripheral blockade of autonomic nervous system, which could be related to the autonomic imbalance, specifically to the liver, of these two rats' strains. Keywords: Hepatic glucose production, insulin, autonomic nervous system, SHR Financial support: FAPESP and CAPES. doi:10.1016/j.autneu.2011.05.124
P.110 Mesenchymal stem cells decrease AT1 receptor in the RVLM and the hypertension in 2K-1C Wistar rats E.B. Oliveira-Sales (Universidade Federal de São Paulo — Physiology, Brazil), E. Maquigussa, P. Semedo, L.P. Guilhermino, N.O.S. Câmara (Universidade Federal de São Paulo — Nephrology Department, Brazil), C.T. Bergamaschi (Universidade Federal de São Paulo — Physiology, Brazil), M. Boim (Universidade Federal de São Paulo —
Abstracts / Autonomic Neuroscience: Basic and Clinical 163 (2011) 1–133
Kingdom), E. Colombari (UNESP — Fisiologia e Patologia, Brazil), R.R. Campos (Universidade Federal de São Paulo — Fisiologia, Brazil), J.F.R. Paton (University of Bristol — Physiology & Pharmacology, United Kingdom) Despite the extensive use of the Goldblatt model of hypertension (two kidney one clip, 2K1C), sympathetic mechanisms responsible for both the development and maintenance of the elevated blood pressure remain unclear. We tested the hypothesis that sympathetic nerve activity (SNA) is elevated before the onset of the hypertension. Using the in situ working heart brainstem preparation, male Wistar rats were divided into three groups: Sham (n = 7), and 2K1C (3 weeks) of which some were hypertensive (2K1C-H, n = 6) and others normotensive (2K1C-N, n = 9) as determined in vivo a priori. At comparable perfusion rates, arterial pressure was higher in both 2K1C groups (2K1C-H: 76 ± 1; 2K1C-N: 74 ± 3 vs Sham: 60 ± 2 mm Hg, p < 0.05). The respiratory modulation of SNA during inspiration and post-inspiration was significantly elevated in both 2 K-1 C groups (e.g. 2K1C-H: 47.7 ± 6.1; 2K1C-N: 32.8 ± 2.8 vs Sham: 20.5 ± 2.5 μ V, p < 0.05). Pre-collicular transection reduced SNA in all rat groups (2K1C-H: 32.5 ± 7.5, 2K1CNH: 48 ± 6.9 vs Sham: 13.2 ± 1%, p < 0.05). Subsequent transection at the medullary-spinal cord abolished SNA in Sham and 2K1C-N but only decreased it by 57 ± 5.5% in 2K1C-H. We conclude, SNA can be raised prior to onset of hypertension by the 3 rd week after renal artery clipping and this, in part, originates from enhanced respiratory modulation. Our data also support an elevation of activity within spinal sympathetic networks in the 2K1C-H rats. All told, ipsilateral renal ischemia engages multiple mechanisms to raise sympathetic activity that occur ahead of any detectable rise in arterial pressure. Keywords: Goldblatt model, hypertension, sympathetic nerve activity, respiratory modulation Financial support: Supported by CAPES and the British Heart Foundation. doi:10.1016/j.autneu.2011.05.122
P.108 Brain eicosanoids contribute to increased sympathetic activity and blood pressure in angiotensin II-salt hypertension in rats G.D. Fink, N.A. Jeyaraj (Michigan State University — Pharmacology and Toxicology, United States) Background/aims: Chronic subcutaneous infusion of angiotensin II into rats on high salt intake is an experimental model of hypertension caused in part by increased sympathetic activity. Our previous work suggests that increased production of a cyclooxgenase (COX) product is required for the elevated sympathetic activity and blood pressure. The aims of the current studies were to determine the specific COX isoform involved and its location. Methods: A standard model of angiotensin II-salt hypertension in male SD rats was used. Interventions included daily systemic dosing with either a selective COX-1 inhibitor (SC560) or COX-2 inhibitor (nimesulide), or chronic intracerebroventricular (icv) infusion of the non-selective COX inhibitor ketorolac. Eicosanoid-related gene expression analysis also was performed in key brain regions. Results: Systemic SC560 and icv ketorolac both attenuated hypertension development, but nimesulide had no effect. No differences in eicosanoid-related gene expression were observed in subfornical organ, paraventricular nucleus, nucleus of the solitary tract, or rostral ventrolateral medulla of hypertensive versus normotensive rats.
Conclusion: Full development of neurogenic hypertension caused by angiotensin II-salt treatment in rats requires a COX-1 product in the brain, but does not necessitate altered transcription of eicosanoidrelated genes in the brain regions studied. Keywords: hypertension, angiotensin, sympathetic, brain, eicosanoids Financial support: NIH RO1 HL076312.
doi:10.1016/j.autneu.2011.05.123
P.109 Differential role of central insulin action and the autonomic nervous system on the hepatic production of glucose (HPG) in Wistar and SHR I.M.R. Ribeiro (USP — Fisiologia e Biofísica, Brazil), V.R. Antunes (Universidade de São Paulo — Fisiologia, Brazil) Central action of insulin and the autonomic nervous system play a key role on the control of the HPG in normotensive rats. In the present study we aimed to investigate the role of insulin injected in the lateral ventricle (LV) and the autonomic outflow on the HPG of conscious Wistar e SHR. Animals received a guide-cannula into the LV for microinjection of insulin (100 nU/mL, 1 mL). Five days later hepatic vein and femoral artery were catheterized in order to monitor the HPG and blood pressure (BP), respectively. In the Wistar group we observed that the injection of insulin in the LV elicited a maximum decrease in HPG at 10′ (81.4 mg/dL, n = 5, p < 0.05) when compared to the control group (denatured insulin), at the same time course (1170.5 mg/dL, n = 5). In the SHR group, injection of insulin in the LV did not produced significant changes in the HPG at any time evaluated. In a second group of SHR we have shown that intravenous injection of alpha and betaadrenoceptors antagonists (phentolamine, 3 mg/kg, and propranolol, 0.5 mg/kg, respectively) induced a significant decreasing in the HPG 40′ later (92.8 mg/dL n = 5, p < 0.05) when compared to the control (saline) group (113.6 mg/dL, n = 5); however any change in the HPG was observed in the Wistar group at the same time course. In a third group of SHR intravenous injection of methylatropine (2 mg/kg, iv) caused an increase of the HPG (129.5 mg/dL, n = 2) at 40′ when compared to the control group at the same time course (118 mg/dL, n = 2). In conclusion, these findings suggest that HPG is differently controlled in Wistar and SHR by central action of insulin and peripheral blockade of autonomic nervous system, which could be related to the autonomic imbalance, specifically to the liver, of these two rats' strains. Keywords: Hepatic glucose production, insulin, autonomic nervous system, SHR Financial support: FAPESP and CAPES. doi:10.1016/j.autneu.2011.05.124
P.110 Mesenchymal stem cells decrease AT1 receptor in the RVLM and the hypertension in 2K-1C Wistar rats E.B. Oliveira-Sales (Universidade Federal de São Paulo — Physiology, Brazil), E. Maquigussa, P. Semedo, L.P. Guilhermino, N.O.S. Câmara (Universidade Federal de São Paulo — Nephrology Department, Brazil), C.T. Bergamaschi (Universidade Federal de São Paulo — Physiology, Brazil), M. Boim (Universidade Federal de São Paulo —