Abstract P006: Purinergic Receptor Activation Protects Glomerular Microvasculature From Increased Mechanical Stress In Angiotensin Ii-induced Hypertension: A Modeling Study

Angiotensin II (Ang II)-induced hypertension increases afferent and efferent arteriole resistances via the actions of Ang II on the AT1 receptor. In addition to the increased interstitial levels of Ang II, the increased arterial pressure increases interstitial ATP concentrations which act on the purinergic receptors P2X1 and P2X7, to constrict the AA, preventing increases in plasma flow and single nephron GFR (SNGFR). Blockade of the P2 receptors also mitigates the effects of Ang II, thus increasing blood flow and SNGFR, but the resulting increases in mechanical stresses (shear stress and circumferential hoop stress) on the glomerular microvasculature have not been quantified. A mathematical microvascular hemodynamic glomerular model was developed to simulate blood flow and plasma filtration at each of 320 capillary segments in an anatomically-accurate rat glomerular capillary network topology. Afferent and efferent arteriole resistances and network hydraulic conductivity were adjusted to match glomerular hemodynamic data for control, Ang II-induced hypertension and P2X1-blocked conditions (Franco, Martha, et al. Amer. J. Physiology-Renal 313.1 (2017): F9-F19). Ang II infusion increased both afferent and efferent resistances, reducing blood flow while slightly raising glomerular pressure. Blockade of the purinergic receptors reduced both afferent and efferent resistances, maintaining glomerular pressure at hypertensive levels but increasing blood flow significantly, increasing shear stress from 24.9 dynes/cm 2 in hypertensive conditions to 71.3 dynes/cm 2 after purinergic blockade. Because glomerular pressure was maintained, hoop stress barely changed from 69.5 kPa in hypertensive conditions to 70.9 kPa after purinergic blockade. Purinergic blockade also increased hydraulic conductivity and filtering surface area, increasing SNGFR. In hypertension, purinergic stimulation does not prevent the transmission of increased arterial pressure to the glomerular capillaries to reduce capillary hoop stress. However, activation of the purinergic system protects the glomerular microvasculature from increases in shear stress caused by a marked increase in blood flow that would occur in the absence of purinergic stimulation.

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Abstract MP03: ROCK2 Specific Inhibition Attenuates Angiotensin II-induced Hypertension In Mice

Hypertension ◽

10.1161/hyp.78.suppl_1.mp03 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Daniel J Fehrenbach ◽

Meena S Madhur

Keyword(s):

Blood Pressure ◽

T Cell ◽

Angiotensin Ii ◽

Repeated Measures ◽

Flow Cytometric Analysis ◽

Coiled Coil ◽

Ang Ii ◽

Induced Hypertension

Hypertension, or an elevated blood pressure, is the primary modifiable risk factor for cardiovascular disease, the number one cause of mortality worldwide. We previously demonstrated that Th17 activation and interleukin 17A (IL-17A)/IL-21 production is integral for the full development of a hypertensive phenotype as well as the renal and vascular damage associated with hypertension. Rho-associated coiled-coil containing protein Kinase 2 (ROCK2) serves as a molecular switch upregulating Th17 and inhibiting regulatory T cell (Treg) differentiation. We hypothesize that hypertension is characterized by excessive T cell ROCK2 activation leading to increased Th17/Treg ratios and ultimately end-organ damage. We first showed in vitro that KD025, an experimental orally bioavailable ROCK2 inhibitor inhibits Th17 cell proliferation and IL-17A/IL-21 production. To determine if hypertensive stimuli such as endothelial stretch increases T cell ROCK2 expression, we cultured human aortic endothelial cells exposed to 5% (normotensive) or 10% (hypertensive) stretch with circulating human T cells and HLA-DR+ antigen presenting cells. Hypertensive stretch increased T cell ROCK2 expression 2-fold. We then tested the effect of ROCK2 inhibition with KD025 (50mg/kg i.p. daily) in vivo on angiotensin II (Ang II)-induced hypertension. Treatment with KD025 significantly attenuated the hypertensive response within 1 week of Ang II treatment (systolic blood pressure: 139± 8 vs 108±7mmHg) and this persisted for the duration of the 4 week study reaching blood pressures 20 mmHg lower (135±13mmHg) than vehicle treated mice (158±4mmHg p<0.05 effect of treatment 2-way Repeated Measures ANOVA). Flow cytometric analysis of tissue infiltrating leukocytes revealed that KD025 treatment increased Treg/Th17 ratios in the kidney (0.61±0.03 vs 0.79±0.08, p<0.05 student’s t-test). Thus, T cell ROCK2 may be a novel therapeutic target for the treatment of hypertension.

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Angiotensin II induces insulin resistance independent of changes in interstitial insulin

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1999.277.5.e920 ◽

1999 ◽

Vol 277 (5) ◽

pp. E920-E926 ◽

Cited By ~ 24

Author(s):

Joyce M. Richey ◽

Marilyn Ader ◽

Donna Moore ◽

Richard N. Bergman

Keyword(s):

Insulin Resistance ◽

Heart Rate ◽

Blood Flow ◽

Angiotensin Ii ◽

Mean Arterial Pressure ◽

Arterial Pressure ◽

Glucose Uptake ◽

Peripheral Resistance ◽

Glucose Turnover ◽

Ang Ii

We set out to examine whether angiotensin-driven hypertension can alter insulin action and whether these changes are reflected as changes in interstitial insulin (the signal to which insulin-sensitive cells respond to increase glucose uptake). To this end, we measured hemodynamic parameters, glucose turnover, and insulin dynamics in both plasma and interstitial fluid (lymph) during hyperinsulinemic euglycemic clamps in anesthetized dogs, with or without simultaneous infusions of angiotensin II (ANG II). Hyperinsulinemia per se failed to alter mean arterial pressure, heart rate, or femoral blood flow. ANG II infusion resulted in increased mean arterial pressure (68 ± 16 to 94 ± 14 mmHg, P < 0.001) with a compensatory decrease in heart rate (110 ± 7 vs. 86 ± 4 mmHg, P < 0.05). Peripheral resistance was significantly increased by ANG II from 0.434 to 0.507 mmHg ⋅ ml−1⋅ min ( P < 0.05). ANG II infusion increased femoral artery blood flow (176 ± 4 to 187 ± 5 ml/min, P < 0.05) and resulted in additional increases in both plasma and lymph insulin (93 ± 20 to 122 ± 13 μU/ml and 30 ± 4 to 45 ± 8 μU/ml, P < 0.05). However, glucose uptake was not significantly altered and actually had a tendency to be lower (5.9 ± 1.2 vs. 5.4 ± 0.7 mg ⋅ kg−1⋅ min−1, P > 0.10). Mimicking of the ANG II-induced hyperinsulinemia resulted in an additional increase in glucose uptake. These data imply that ANG II induces insulin resistance by an effect independent of a reduction in interstitial insulin.

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Increased plasma angiotensin II in postural tachycardia syndrome (POTS) is related to reduced blood flow and blood volume

Clinical Science ◽

10.1042/cs20050254 ◽

2006 ◽

Vol 110 (2) ◽

pp. 255-263 ◽

Cited By ~ 44

Author(s):

Julian M. Stewart ◽

June L. Glover ◽

Marvin S. Medow

Keyword(s):

Blood Flow ◽

Angiotensin Ii ◽

Blood Volume ◽

High Flow ◽

The Other ◽

Low Flow ◽

Postural Tachycardia Syndrome ◽

Peripheral Blood Flow ◽

Ang Ii ◽

Postural Tachycardia

POTS (postural tachycardia syndrome) is associated with low blood volume and reduced renin and aldosterone; however, the role of Ang (angiotensin) II has not been investigated. Previous studies have suggested that a subset of POTS patients with increased vasoconstriction related to decreased bioavailable NO (nitric oxide) have decreased blood volume. Ang II reduces bioavailable NO and is integral to the renin–Ang system. Thus, in the present study, we investigated the relationship between blood volume, Ang II, renin, aldosterone and peripheral blood flow in POTS patients. POTS was diagnosed by 70° upright tilt, and supine calf blood flow, measured by venous occlusion plethysmography, was used to subgroup POTS patients. A total of 23 POTS patients were partitioned; ten with low blood flow, eight with normal flow and five with high flow. There were ten healthy volunteers. Blood volume was measured by dye dilution. All biochemical measurements were performed whilst supine. Blood volume was decreased in low-flow POTS (2.14±0.12 litres/m2) compared with controls (2.76±0.20 litres/m2), but not in the other subgroups. PRA (plasma renin activity) was decreased in low-flow POTS compared with controls (0.49±0.12 compared with 0.90±0.18 ng of Ang I·ml−1·h−1 respectively), whereas plasma Ang II was increased (89±20 compared with 32±4 ng/l), but not in the other subgroups. PRA correlated with aldosterone (r=+0.71) in all subjects. PRA correlated negatively with blood volume (r=−0.72) in normal- and high-flow POTS, but positively (r=+0.65) in low-flow POTS. PRA correlated positively with Ang II (r=+0.76) in normal- and high-flow POTS, but negatively (r=−0.83) in low-flow POTS. Blood volume was negatively correlated with Ang II (r=−0.66) in normal- and high-flow POTS and in five low-flow POTS patients. The remaining five low-flow POTS patients had reduced blood volume and increased Ang II which was not correlated with blood volume. The data suggest that plasma Ang II is increased in low-flow POTS patients with hypovolaemia, which may contribute to local blood flow dysregulation and reduced NO bioavailability.

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Proximal Tubule-Specific Deletion of Angiotensin II Type 1a Receptors in the Kidney Attenuates Circulating and Intratubular Angiotensin II–Induced Hypertension in PT- Agtr1a −/− Mice

Hypertension ◽

10.1161/hypertensionaha.120.16336 ◽

2021 ◽

Author(s):

Xiao Chun Li ◽

Ana Paula Oliveira Leite ◽

Xiaowen Zheng ◽

Chunling Zhao ◽

Xu Chen ◽

...

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Fusion Protein ◽

Proximal Tubule ◽

Proximal Tubules ◽

Normal Blood ◽

Ang Ii ◽

Normal Blood Pressure ◽

Wild Type ◽

Induced Hypertension

The present study used a novel mouse model with proximal tubule-specific knockout of AT 1a receptors in the kidney, PT- Agtr1a −/− , to test the hypothesis that intratubular Ang II (angiotensin II) and AT 1a receptors in the proximal tubules are required for maintaining normal blood pressure and the development of Ang II–induced hypertension. Twenty-six groups (n=6–15 per group) of adult male wild-type, global Agtr1a −/− , and PT- Agtr1a −/− mice were infused with Ang II (1.5 mg/kg per day, IP), or overexpressed an intracellular Ang II fusion protein in the proximal tubules for 2 weeks. Basal telemetry blood pressure were ≈15±3 mm Hg lower in PT- Agtr1a −/− than wild-type mice and ≈13±3 mm Hg higher than Agtr1a −/− mice ( P <0.01). Basal glomerular filtration was ≈23.9% higher ( P <0.01), whereas fractional proximal tubule Na + reabsorption was lower in PT- Agtr1a −/− mice ( P <0.01). Deletion of AT 1a receptors in the proximal tubules augmented the pressure-natriuresis response ( P <0.01) and natriuretic responses to salt loading or Ang III infusion ( P <0.01). Ang II induced hypertension in wild-type, PT- Agtr1a −/− and PT- Nhe3 −/− mice, but the pressor response was ≈16±2 mm Hg lower in PT- Agtr1a −/− and PT- Nhe3 −/− mice ( P <0.01). Deletion of AT 1a receptors or NHE3 (Na + /H + exchanger 3) in the proximal tubules attenuated ≈50% of Ang II–induced hypertension in wild-type mice ( P <0.01), but blocked intracellular Ang II fusion protein-induced hypertension in PT- Agtr1a −/− mice ( P <0.01). Taken together, the results of the present study provide new insights into the critical role of intratubular Ang II/AT 1 (AT 1a )/NHE3 pathways in the proximal tubules in normal blood pressure control and the development of Ang II–induced hypertension.

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Abstract 476: Renal AT2 Receptor Activation Prevents Sodium Retention And Lowers Blood Pressure In Angiotensin II-Dependent Hypertension

Hypertension ◽

10.1161/hyp.64.suppl_1.476 ◽

2014 ◽

Vol 64 (suppl_1) ◽

Author(s):

Shetal H Padia ◽

Nancy L Howell ◽

Brandon A Kemp ◽

John J Gildea ◽

Susanna R Keller ◽

...

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Receptor Activation ◽

Pressure Probe ◽

Ang Ii ◽

Induced Hypertension ◽

Group 5 ◽

Group 2 ◽

Angiotensin Type

A major proposed mechanism for the initiation of hypertension involves a primary increase in renal tubular sodium (Na+) reabsorption. Activation of intrarenal angiotensin type-2 receptors (AT2R) increases Na+ excretion; however, the role of intrarenal angiotensin type-2 receptors (AT2R) in the development of hypertension is unknown. Sprague-Dawley rats (N=36) underwent uninephrectomy and telemetric blood pressure probe implantation. Following a 72h recovery, two osmotic minipumps were inserted in each rat, one for chronic systemic delivery of 5% dextrose in water (D5W) or angiotensin II (Ang II, 200 ng/kg/min), and one for chronic intrarenal delivery of D5W (0.25 μL/h x 7d), highly selective AT2R agonist Compound 21 (C-21; 60 ng/kg/min x 7d), or specific AT2R antagonist PD-1223319 (PD; 10 ng/kg/min x 7d). Five groups of rats were studied: Group 1 (Control; N=10): systemic D5W + intrarenal D5W; Group 2 (Ang II-induced hypertension; N=8): systemic Ang II + intrarenal D5W; Group 3 (N=6): systemic Ang II + intrarenal C-21; Group 4 (N=6): systemic Ang II + 48h lead-in intrarenal C-21; Group 5 (N=6): systemic Ang II + intrarenal PD. Systemic Ang II infusion increased mean systolic blood pressure from 126±5 to 190±3 mm Hg over a 7d period in Group 2 (ANOVA F=73; P<1 X 10-6). Intrarenal administration of AT2R agonist C-21 (Groups 3 and 4) markedly inhibited the pressor effect of systemic Ang II (P<0.0001). Intrarenal AT2R antagonist PD (Group 5) augmented the pressor action of Ang II (P<0.0001). Consecutive 24h urinary Na+ excretion (UNaV) was reduced from 0.95±0.04 to 0.34±0.07 μmol/min (P<0.0001) on day 1 of Ang II infusion; Ang II-induced antinatriuresis was inhibited by intrarenal C-21 (P<0.0001) and augmented by intrarenal PD (P<0.0001) during the entire 7d infusion, demonstrating that one of the mechanisms to prevent Ang II-induced hypertension during intrarenal AT2R activation is the abolition of the initial increase in Na+ reabsorption that triggers the hypertensive cascade in this model. Thus, renal AT2Rs represent a novel therapeutic target for the prevention of hypertension.

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Abstract P363: Annexin-A1 Deficiency Exaggerates Cardiac Remodeling In Angiotensin II-induced Hypertension

Circulation Research ◽

10.1161/res.129.suppl_1.p363 ◽

2021 ◽

Vol 129 (Suppl_1) ◽

Author(s):

Kristy Jackson ◽

Jaideep Singh ◽

Yen Zhi Ng ◽

Cheng Peng ◽

Anida Velagic ◽

...

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Cardiac Remodeling ◽

Physiological Role ◽

Preclinical Model ◽

Annexin A1 ◽

Ang Ii ◽

Cardiac Damage ◽

Induced Hypertension ◽

Deficient Mice

Introduction: We have previously demonstrated that the naturally-occurring anti-inflammatory and pro-resolving protein Annexin-A1 (Anx-A1) limits the acute inflammatory response post myocardial infarction, but its impact on chronic inflammation, such as hypertension, has not been explored. This study aims to investigate the role of Anx-A1 in a preclinical model of hypertension, induced by angiotensin-II (Ang-II). Methods: 15-week-old male C57BL/6 or ANXA1 -/- were anesthetized (isoflurane, 2-4% v/v) and implanted with an osmotic minipump randomly assigned to receive Ang-II (0.7mg/kg/day) or vehicle (saline). Radiotelemetry recordings of blood pressure were taken at 10 intermittent timepoints from baseline to the end of the 29-day infusion period. Animals were euthanized with pentobarbitone (100mg/kg; i.p.) at endpoint and organ weights recorded and normalized to bodyweight. Left ventricle (LV) samples were stained with picrosirius red to assess total LV collagen deposition. Results: Ang II-induced mice at the end of the study had elevated mean arterial pressure (MAP), cardiac hypertrophy and fibrosis compared to normotensive mice (Table). Anx-A1 deficient mice given Ang II had an even greater increase in MAP and cardiac remodeling compared to WT. Interestingly, MAP of Anx-A1 deficient mice at baseline is significantly higher compare to C57BL/6 counterparts (Table). Conclusion: This is the first study to demonstrate that deficiency of Anx-A1 exaggerates cardiac remodeling in AngII-induced hypertension, suggesting that endogenous Anx-A1 might play previously unappreciated physiological role in regulating blood pressure. This supports the development of Anx-A1 based pharmacotherapy against hypertension-induced cardiac damage.

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Abstract P041: Proximal Tubule-specific Deletion Of Angiotensin Ii Type 1a Receptors In The Kidney Lowers Basal Blood Pressure And Attenuates Angiotensin Ii-induced Hypertension By Increasing Glomerular Filtration And The Pressure-natriuresis Response

Hypertension ◽

10.1161/hyp.76.suppl_1.p041 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

Xiao C Li ◽

Ana P Leite ◽

Liang Zhang ◽

Jia L Zhuo

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Proximal Tubule ◽

Pressor Response ◽

Control Group ◽

Ang Ii ◽

Induced Hypertension ◽

Basal Blood Pressure ◽

Pressure Natriuresis ◽

Specific Deletion

The present study tested the hypothesis that intratubular angiotensin II (Ang II) and AT 1a receptors in the proximal tubules of the kidney plays an important role in basal blood pressure control and in the development of Ang II-induced hypertension. Mutant mice with proximal tubule-specific deletion of AT 1a receptors in the kidney, PT- Agtr1a -/- , were generated to test the hypothesis. Eight groups (n=7-12 per group) of adult male wild-type (WT) and PT- Agtr1a -/- mice were infused with or without Ang II for 2 weeks (1.5 mg/kg, i.p.). Basal systolic, diastolic, and mean arterial pressures were ~13 ± 3 mmHg lower in PT- Agtr1a -/- than WT mice ( P <0.01). Basal glomerular filtration rate (GFR), as measured using transdermal FITC-sinistrin, was significantly higher in PT- Agtr1a -/- mice (WT: 160.4 ± 7.0 μl/min vs. PT- Agtr1a -/- : 186.0 ± 6.0 μl/min, P <0.05). Basal 24 h urinary Na + excretion (U Na V) was significantly higher in PT- Agtr1a -/- than WT mice ( P <0.01). In response to Ang II infusion, both WT and PT- Agtr1a -/- mice developed hypertension, and the magnitude of the pressor response to Ang II was similar in WT (Δ43 ± 3 mmHg, P <0.01) and PT- Agtr1a -/- mice (Δ39 ± 5 mmHg, P <0.01). However, the absolute blood pressure level was still 16 ± 3 mmHg lower in PT- Agtr1a -/- mice ( P <0.01). Ang II significantly decreased GFR to 132.2 ± 7.0 μl/min in WT mice ( P <0.01), and to 129.4 ± 18.6 μl/min in PT- Agtr1a -/- mice ( P <0.01), respectively. In WT mice, U Na V increased from 139.3 ± 22.3 μmol/24 h in the control group to 196.4 ± 29.6 μmol/24 h in the Ang II-infused group ( P <0.01). In PT- Agtr1a -/- mice, U Na V increased from 172.0 ± 10.2 μmol/24 h in the control group to 264.7 ± 35.4 μmol/24 h in the Ang II-infused group ( P <0.01). The pressor response to Ang II was attenuated, while the natriuretic response was augmented by losartan in WT and PT- Agtr1a -/- mice ( P <0.01). Finally, proximal tubule-specific deletion of AT 1a receptors significantly augmented the pressure-natriuresis response and natriuretic responses to acute saline infusion ( P <0.01) or a 2% high salt diet ( P <0.01). We concluded that deletion of AT 1a receptors selectively in the proximal tubules lowers basal blood pressure and attenuates Ang II-induced hypertension by increasing GFR and promoting the natriuretic response in PT- Agtr1a -/- mice.

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Site-1 Protease-Derived Soluble (Pro)Renin Receptor Contributes to Angiotensin II–Induced Hypertension in Mice

Hypertension ◽

10.1161/hypertensionaha.120.15100 ◽

2020 ◽

Author(s):

Ye Feng ◽

Kexin Peng ◽

Renfei Luo ◽

Fei Wang ◽

Tianxin Yang

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Collecting Duct ◽

Short Circuit ◽

Ussing Chamber ◽

Short Circuit Current ◽

Duct Cell ◽

Ang Ii ◽

Cortical Collecting Duct ◽

Induced Hypertension

Activation of PRR ([pro]renin receptor) contributes to enhancement of intrarenal RAS and renal medullary α-ENaC and thus elevated blood pressure during Ang II (angiotensin II) infusion. The goal of the present study was to test whether such action of PRR was mediated by sPRR (soluble PRR), generated by S1P (site-1 protease), a newly identified PRR cleavage protease. F1 B6129SF1/J mice were infused for 6 days with control or Ang II at 300 ng/kg per day alone or in combination with S1P inhibitor PF-429242 (PF), and blood pressure was monitored by radiotelemetry. S1P inhibition significantly attenuated Ang II–induced hypertension accompanied with suppressed urinary and renal medullary renin levels and expression of renal medullary but not renal cortical α-ENaC expression. The effects of S1P inhibition were all reversed by supplement with histidine-tagged sPRR termed as sPRR-His. Ussing chamber technique was performed to determine amiloride-sensitive short-circuit current, an index of ENaC activity in confluent mouse cortical collecting duct cell line cells exposed for 24 hours to Ang II, Ang II + PF, or Ang II + PF + sPRR-His. Ang II–induced ENaC activity was blocked by PF, which was reversed by sPRR-His. Together, these results support that S1P-derived sPRR mediates Ang II–induced hypertension through enhancement of intrarenal renin level and activation of ENaC.

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Functional role of angiotensin II type 1 and 2 receptors in regulation of uterine blood flow in nonpregnant sheep

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2000.278.2.h353 ◽

2000 ◽

Vol 278 (2) ◽

pp. H353-H359 ◽

Cited By ~ 5

Author(s):

Donna S. Lambers ◽

Suzanne G. Greenberg ◽

Kenneth E. Clark

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Angiotensin Ii ◽

Uterine Artery ◽

Receptor Subtype ◽

Ang Ii ◽

Uterine Blood Flow ◽

Response Curves ◽

Vascular Responses

The objective was to determine the receptor subtype of angiotensin II (ANG II) that is responsible for vasoconstriction in the nonpregnant ovine uterine and systemic vasculatures. Seven nonpregnant estrogenized ewes with indwelling uterine artery catheters and flow probes received bolus injections (0.1, 0.3 and 1 μg) of ANG II locally into the uterine artery followed by a systemic infusion of ANG II at 100 ng ⋅ kg−1 ⋅ min−1for 10 min to determine uterine vasoconstrictor responses. Uterine ANG II dose-response curves were repeated following administration of the ANG II type 2 receptor (AT2) antagonist PD-123319 and then repeated again in the presence of an ANG II type 1 receptor (AT1) antagonist L-158809. In a second experiment, designed to investigate the mechanism of ANG II potentiation that occurred in the presence of AT2 blockade, nonestrogenized sheep received a uterine artery infusion of L-158809 (3 mg/min for 5 min) prior to the infusion of 0.03 μg/min of ANG II for 10 min. ANG II produced dose-dependent decreases in uterine blood flow ( P < 0.03), which were potentiated in the presence of the AT2 antagonist ( P < 0.02). Addition of the AT1 antagonist abolished the uterine vascular responses and blocked ANG II-induced increases in systemic arterial pressure ( P < 0.01). Significant uterine vasodilation ( P < 0.01) was noted with AT1 blockade in the second experiment, which was reversed by administration of the AT2 antagonist or by the nitric oxide synthetase inhibitor N ω-nitro-l-arginine methyl ester. We conclude that the AT1- receptors mediate the systemic and uterine vasoconstrictor responses to ANG II in the nonpregnant ewe. AT2-receptor blockade resulted in a potentiation of the uterine vasoconstrictor response to ANG II, suggesting that the AT2-receptor subtype may modulate uterine vascular responses to ANG II potentially by release of nitric oxide.

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Median preoptic nucleus ablation does not affect angiotensin II-induced hypertension

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1986.251.1.h148 ◽

1986 ◽

Vol 251 (1) ◽

pp. H148-H152

Author(s):

G. D. Fink ◽

C. A. Bruner ◽

M. L. Mangiapane

Keyword(s):

Angiotensin Ii ◽

Mean Arterial Pressure ◽

Arterial Pressure ◽

Cardiovascular Responses ◽

Base Line ◽

Ang Ii ◽

Preoptic Nucleus ◽

Water Excretion ◽

Median Preoptic Nucleus ◽

Induced Hypertension

Previous studies implicated the ventral median preoptic nucleus (MNPOv) in cardiovascular responses to circulating and intracerebroventricular angiotensin II (ANG II) and in normal cardiovascular and fluid homoeostasis. In the present experiments, chronically catheterized rats received continuous (24 h/day) intravenous infusions of ANG II (10 ng/min) for 5 days, and changes in mean arterial pressure, heart rate, water intake and urinary electrolyte and water excretion were determined daily. Three groups of rats were compared as follows: 1) sham-operated control rats (n = 12), 2) rats with 20-70% of the MNPOv ablated electrolytically (n = 6), and 3) rats with over 90% of the MNPOv ablated (n = 5). The organum vasculosum of the lamina terminalis was intact in all three groups. Base-line values of all measured variables were identical in the three groups on two control days preceding ANG II infusion and on two recovery days after infusion. During the administration of ANG II for 5 days, mean arterial pressure rose significantly (and similarly) in all three groups of rats; no other variable was significantly affected by ANG II infusion. These results suggest that neural pathways originating in, or passing through, the MNPOv region are not critical in the pathogenesis of ANG II-induced hypertension in the rat.

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