scholarly journals The angiotensin II type I receptor contributes to impaired cerebral blood flow autoregulation caused by placental ischemia in pregnant rats

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Junie P. Warrington ◽  
Fan Fan ◽  
Jeremy Duncan ◽  
Mark W. Cunningham ◽  
Babette B. LaMarca ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Angiotensin Ii ◽  
Renin Angiotensin System ◽  
At1 Receptor ◽  
Type I ◽  
Pregnant Rats ◽  
Doppler Flowmetry ◽  
Cerebrovascular Function ◽  
Placental Ischemia

Abstract Background Placental ischemia and hypertension, characteristic features of preeclampsia, are associated with impaired cerebral blood flow (CBF) autoregulation and cerebral edema. However, the factors that contribute to these cerebral abnormalities are not clear. Several lines of evidence suggest that angiotensin II can impact cerebrovascular function; however, the role of the renin angiotensin system in cerebrovascular function during placental ischemia has not been examined. We tested whether the angiotensin type 1 (AT1) receptor contributes to impaired CBF autoregulation in pregnant rats with placental ischemia caused by surgically reducing uterine perfusion pressure. Methods Placental ischemic or sham operated rats were treated with vehicle or losartan from gestational day (GD) 14 to 19 in the drinking water. On GD 19, we assessed CBF autoregulation in anesthetized rats using laser Doppler flowmetry. Results Placental ischemic rats had impaired CBF autoregulation that was attenuated by treatment with losartan. In addition, we examined whether an agonistic autoantibody to the AT1 receptor (AT1-AA), reported to be present in preeclamptic women, contributes to impaired CBF autoregulation. Purified rat AT1-AA or vehicle was infused into pregnant rats from GD 12 to 19 via mini-osmotic pumps after which CBF autoregulation was assessed. AT1-AA infusion impaired CBF autoregulation but did not affect brain water content. Conclusions These results suggest that the impaired CBF autoregulation associated with placental ischemia is due, at least in part, to activation of the AT1 receptor and that the RAS may interact with other placental factors to promote cerebrovascular changes common to preeclampsia.

scholarly journals The cerebrovascular dysfunction induced by slow pressor doses of angiotensin II precedes the development of hypertension

2011 ◽  
Vol 300 (1) ◽  
pp. H397-H407 ◽  
Author(s):  
Carmen Capone ◽  
Giuseppe Faraco ◽  
Laibaik Park ◽  
Xian Cao ◽  
Robin L. Davisson ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Angiotensin Ii ◽  
Time Course ◽  
Ang Ii ◽  
Doppler Flowmetry ◽  
Cranial Window ◽  
Cerebrovascular Function ◽  
Cerebrovascular Dysfunction ◽  
Blood Flow Increase

Hypertension alters cerebrovascular regulation and increases the brain's susceptibility to stroke and dementia. We investigated the temporal relationships between the arterial pressure (AP) elevation induced by “slow pressor” angiotensin II (ANG II) infusion, which recapitulates key features of human hypertension, and the resulting cerebrovascular dysfunction. Minipumps delivering saline or ANG II for 14 days were implanted subcutaneously in C57BL/6 mice ( n = 5/group). Cerebral blood flow was assessed by laser-Doppler flowmetry in anesthetized mice equipped with a cranial window. With ANG II (600 ng·kg−1·min−1), AP started to rise after 9 days ( P < 0.05 vs. saline), remained elevated at 11–17 days, and returned to baseline at 21 days ( P > 0.05). ANG II attenuated the cerebral blood flow increase induced by neural activity (whisker stimulation) or endothelium-dependent vasodilators, an effect observed before the AP elevation (7 days), as well as after the hypertension subsided (21 days). Nonpressor doses of ANG II (200 ng·kg−1·min−1) induced cerebrovascular dysfunction and oxidative stress without elevating AP ( P > 0.05 vs. saline), whereas phenylephrine elevated AP without inducing cerebrovascular effects. ANG II (600 ng·kg−1·min−1) augmented neocortical reactive oxygen species (ROS) with a time course similar to that of the cerebrovascular dysfunction. Neocortical application of the ROS scavenger manganic(I-II)meso-tetrakis(4-benzoic acid)porphyrin or the NADPH oxidase peptide inhibitor gp91ds-tat attenuated ROS and cerebrovascular dysfunction. We conclude that the alterations in neurovascular regulation induced by slow pressor ANG II develop before hypertension and persist beyond AP normalization but are not permanent. The findings unveil a striking susceptibility of cerebrovascular function to the deleterious effects of ANG II and raise the possibility that cerebrovascular dysregulation precedes the elevation in AP also in patients with ANG II-dependent hypertension.

scholarly journals The Angiotensin II Type 1—Receptor Blocker Candesartan Increases Cerebral Blood Flow, Reduces Infarct Size, and Improves Neurologic Outcome after Transient Cerebral Ischemia in Rats

2004 ◽  
Vol 24 (4) ◽  
pp. 467-474 ◽  
Author(s):  
Tobias Engelhorn ◽  
Sophia Goerike ◽  
Arnd Doerfler ◽  
Christine Okorn ◽  
Michael Forsting ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Angiotensin Ii ◽  
Cerebral Ischemia ◽  
Infarct Size ◽  
Laser Doppler Flowmetry ◽  
Transient Cerebral Ischemia ◽  
Doppler Flowmetry ◽  
Treatment Regimens

The goal of the present study was to test the impact of administration time of the angiotensin II type 1–receptor blocker candesartan on cerebral blood flow (CBF), infarct size, and neuroscore in transient cerebral ischemia. Therefore, 1-hour middle cerebral artery occlusion (MCAO) was followed by reperfusion. Rats received 0.5-mg/kg candesartan intravenously 2 hours before MCAO (pretreatment), 24 hours after MCAO, every 24 hours after MCAO, or 2 hours before and every 24 hours after MCAO. Infarct size (mm3) and a neuroscore at day 7 were compared with controls. CBF was quantified by radiolabeled microspheres and laser-Doppler flowmetry. Compared with controls (95 ± 8), infarct size in candesartan-treated groups was smaller (59 ± 5, 68 ± 10, 28 ± 3, and 15 ± 3, respectively; P < 0.05). Although there was no difference in neuroscore between pretreatment and controls (1.55 ± 0.18, 1.80 ± 0.13), other treatment regimens resulted in improved neuroscores (1.33 ± 0.16, 1.11 ± 0.11, 0.73 ± 0.15; P < 0.05). CBF in pretreated animals at 0.5 hours after MCAO was significantly higher than in controls (0.58 ± 0.09 mL · g−1 ·· min−1 and 44% ± 7% of baseline compared with 0.49 ± 0.06 mL · g−1 ·· min−1 and 37% ± 6%, microspheres and laser-Doppler flowmetry; P < 0.05). Thus, candesartan reduces infarct size even if administered only during reperfusion. Apart from pretreatment, other treatment regimens result in significantly improved neuroscores. In the acute phase of cerebral ischemia, candesartan increases CBF.

scholarly journals Tumor necrosis factor-α impairs cerebral blood flow in pregnant rats: role of vascular β-epithelial Na+ channel

2020 ◽  
Vol 318 (4) ◽  
pp. H1018-H1027 ◽  
Author(s):  
Jeremy W. Duncan ◽  
Subhi Talal Younes ◽  
Emily Hildebrandt ◽  
Michael J. Ryan ◽  
Joey P. Granger ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Vascular Function ◽  
Mapk Signaling ◽  
Pregnant Rats ◽  
Tnf Α ◽  
Factor Α ◽  
Placental Ischemia ◽  
Necrosis Factor

Preeclampsia is a pregnancy-related disorder characterized by hypertension, vascular dysfunction and an increase in circulating inflammatory factors including the cytokine, tumor necrosis factor-α (TNF-α). Studies have shown that placental ischemia is associated with 1) increased circulating TNF-α, 2) attenuated pressure-induced cerebral vascular tone, and 3) suppression of β-epithelial Na+ channel (βENaC) protein in cerebral vessels. In addition to its role in epithelial Na+ and water transport, βENaC is an essential signaling element in transduction of pressure-induced (aka “myogenic”) constriction, a critical mechanism of blood flow autoregulation. While cytokines inhibit expression of certain ENaC proteins in epithelial tissue, it is unknown if the increased circulating TNF-α associated with placental ischemia mediates the loss of cerebrovascular βENaC and cerebral blood flow regulation. Therefore, the purpose of this study was to test the hypothesis that increasing plasma TNF-α in normal pregnant rats reduces cerebrovascular βENaC expression and impairs cerebral blood flow (CBF) regulation. In vivo TNF-α infusion (200 ng/day, 5 days) inhibited cerebrovascular expression of βENaC and impaired CBF regulation in pregnant rats. To determine the direct effects of TNF-α and underlying pathways mediating vascular smooth muscle cell βENaC reduction, we exposed cultured VSMCs (A10 cell line) to TNF-α (1–100 ng/mL) for 16–24 h. TNF-α reduced βENaC protein expression in a concentration-dependent fashion from 0.1 to 100 ng/mL, without affecting cell death. To assess the role of canonical MAPK signaling in this response, VSMCs were treated with p38MAPK or c-Jun kinase (JNK) inhibitors in the presence of TNF-α. We found that both p38MAPK and JNK blockade prevented TNF-α-mediated βENaC protein suppression. These data provide evidence that disorders associated with increased circulating TNF-α could lead to impaired cerebrovascular regulation, possibly due to reduced βENaC-mediated vascular function. NEW & NOTEWORTHY This manuscript identifies TNF-α as a possible placental-derived cytokine that could be involved in declining cerebrovascular health observed in preeclampsia. We found that infusion of TNF-α during pregnancy impaired cerebral blood flow control in rats at high arterial pressures. We further discovered that cerebrovascular β-epithelial sodium channel (βENaC) protein, a degenerin protein involved in mechanotransduction, was reduced by TNF-α in pregnant rats, indicating a potential link between impaired blood flow and this myogenic player. We next examined this effect in vitro using a rat vascular smooth muscle cell line. TNF-α reduced βENaC through canonical MAPK-signaling pathways and was not dependent on cell death. This study demonstrates the pejorative effects of TNF-α on cerebrovascular function during pregnancy and warrants future investigations to study the role of cytokines on vascular function during pregnancy.

Selective Blockade of AT1 Receptor Attenuates Impairment of Hypotensive Autoregulation and Improves Cerebral Blood Flow after Brain Injury in the Newborn Pig

2003 ◽  
Vol 99 (5) ◽  
pp. 1118-1124 ◽  
Author(s):  
Dimitry Baranov ◽  
William M. Armstead
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Angiotensin Ii ◽  
Receptor Activation ◽  
At1 Receptor ◽  
Sham Control ◽  
Fluid Percussion ◽  
Fluid Percussion Injury ◽  
At1 Antagonist ◽  
Severe Hypotension

Background Fluid percussion injury (FPI) in piglets produces vasoconstriction of pial arteries (PAs), decreases in cerebral blood flow (CBF), and impairment of hypotensive autoregulation. Two types of angiotensin II receptors, AT1 and AT2, have been identified in the brain. This study characterized the effect of pretreatment with AT1- and AT2-selective antagonists on CBF and hypotensive autoregulation after FPI. Methods Fluid percussion injury was induced in chloralose-anesthetized newborn pigs equipped with closed cranial windows. CBF was determined by the radiolabeled microsphere technique. Results Moderate and severe hypotension (71 +/- 3, 53 +/- 2, and 40 +/- 1 mmHg for normotension, moderate hypotension, and severe hypotension, respectively) elicited PA dilation without changes in CBF in sham control piglets. The AT1 antagonist ZD 7155 partially restored impaired hypotension-induced PA dilation after FPI (19 +/- 1 and 34 +/- 1 vs. 5 +/- 1 and 7 +/- 1 vs. 12 +/- 1 and 20 +/- 3% for PA dilation during moderate and severe hypotension in sham control, FPI, and FPI + ZD 7155 animals, respectively). ZD 7155 also blunted the reductions in CBF during normotension and hypotension observed in untreated animals (43 +/- 4, 38 +/- 5, and 55 +/- 3 vs. 32 +/- 4, 19 +/- 2, and 27 +/- 5% CBF reductions during normotension, moderate hypotension, and severe hypotension in untreated and pretreated animals, respectively). The AT2 selective antagonist PD 123,319 did not restore hypotension-induced PA dilation and did not prevent decreases in CBF observed during normotension and moderate and severe hypotension after FPI. Conclusion These data indicate that blockade of the AT1 and not the AT2 receptor diminished the reduction in hypotensive PA dilation after FPI. AT1 blockade also blunted the decrease in CBF during normotension as well as the further decrease in CBF observed during hypotension after FPI. These data suggest that AT1 receptor activation by angiotensin II contributes to cerebrovascular dysregulation during hypotension after FPI.

Abstract 127: Agonistic Autoantibodies to Angiotensin II Type I Receptor Contributes Partly to Placental Ischemia-induced Cerebrovascular Abnormalities

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Junie P Warrington ◽  
Fan Fan ◽  
Babbette B LaMarca ◽  
Ralf Dechend ◽  
Gerd Wallukat ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Water Content ◽  
Type I ◽  
Brain Water Content ◽  
Pregnant Rats ◽  
Blood Pressures ◽  
Bbb Permeability ◽  
Agonistic Autoantibodies ◽  
Placental Ischemia ◽  
Brain Water

Placental ischemia, a characteristic feature of preeclampsia, leads to impaired cerebral blood flow (CBF) autoregulation, cerebral edema, and increased blood-brain barrier (BBB) permeability; however, the placental factors that contribute to these cerebral abnormalities are not clear. Agonistic autoantibodies to the angiotensin II type 1 receptor (AT1-AA) are increased in preeclamptic patients as well as in a rat model of preeclampsia induced by placental ischemia. In this study, we tested the hypothesis that AT1-AA mediates placental ischemia-induced cerebrovascular abnormalities. To determine whether the AT1-AA contributes to impaired CBF autoregulation, we infused purified rat AT1-AA into normal pregnant rats from gestational day (GD) 12 to 19 via mini-osmotic pumps and measured CBF using laser Doppler flowmetry on GD 19. Autoregulatory index increased from 0.7 to 1.0±0.2 in the AT1-AA infused group over the range of 120 to 160 mmHg compared to pregnant controls (0.3 to 0.5±0.1 over the same range of pressures, p<0.05) suggesting impaired CBF autoregulation. However, AT1-AA infusion did not affect brain water content at baseline blood pressures (104±2 mmHg in normal pregnant rats vs. 113±2 mmHg in AT1-AA infused rats, p<0.01). To determine the role of endogenous AT1-AA in mediating placental ischemia-induced cerebrovascular abnormalities, losartan (5 mg/kg/day), an AT1 receptor antagonist, was administered in the drinking water from GD 14 to 19. Losartan reduced anterior brain water content from 79.6±0.2% in placental ischemic rats to 79.2±0.1% (compared to 79.1±0.1% in normal pregnant untreated rats) and BBB permeability from 0.06±0.01 in placental ischemic rats to 0.03±0.03 (compared to 0.03±0.004 in normal pregnant untreated rats). These results indicate that impaired CBF autoregulation in response to placental ischemia is due, at least in part, to increases in circulating AT1-AA. While AT1-AA infusion, by itself, did not alter brain water content at baseline blood pressures, the beneficial effects of losartan in placental ischemic rats suggests that the renin-angiotensin system may interact with other placental factors to promote cerebral vascular changes common to preeclampsia.

Regional cerebral blood flow response to vibrissal stimulation in mice lacking type I NOS gene expression

1996 ◽  
Vol 270 (3) ◽  
pp. H1085-H1090 ◽  
Author(s):  
J. Ma ◽  
C. Ayata ◽  
P. L. Huang ◽  
M. C. Fishman ◽  
M. A. Moskowitz
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Regional Cerebral Blood Flow ◽  
No Production ◽  
Type I ◽  
Regional Cerebral Blood ◽  
Doppler Flowmetry ◽  
Cranial Window ◽  
Whisker Stimulation ◽  
Neuronal Nos

The role of nitric oxide (NO) in cerebral blood flow-metabolism coupling was assessed in SV-129 wild-type (WT) and neuronal (type I) NO synthase (NOS) knockout mice (Kn). Regional cerebral blood flow (rCBF; laser-Doppler flowmetry) was measured over the contralateral cortical barrel field during unilateral mechanical vibrissal deflection (2-3 Hz, 60 s) under urethan anesthesia. The rCBF response was similar in WT and Kn and did not differ when recorded over the intact skull or closed cranial window preparations. Whisker stimulation increased rCBF by 41 +/- 8% (maximum) and 27 +/- 6% (mean) in WT (n = 6) and 41 +/- 7% (maximum) and 26 +/- 6% (mean) in Kn (n = 6) when recorded through a closed cranial window. After superfusion with topical N omega-nitro-L-arginine (L-NNA; 1 mM), the rCBF response was inhibited by approximately 45% in WT mice (P < 0.05), whereas there was no inhibition in Kn. Endothelium-dependent relaxation, assessed by pial vessel dilation in response to topical acetylcholine (100 microM) and inhibition by L-NNA (1 mM), was the same in both groups. Our results suggest that 1) endothelial NO production does not mediate the rCBF coupling to neuronal activity in Kn, 2) the inhibitory effect of L-NNA on the rCBF response to whisker stimulation in WT is a consequence of type I (neuronal) NOS inhibition, and 3) NO-independent mechanisms couple rCBF and metabolism during whisker stimulation in mice lacking expression of neuronal NOS.

L-NNA-sensitive regional cerebral blood flow augmentation during hypercapnia in type III NOS mutant mice

1996 ◽  
Vol 271 (4) ◽  
pp. H1717-H1719 ◽  
Author(s):  
J. Ma ◽  
W. Meng ◽  
C. Ayata ◽  
P. L. Huang ◽  
M. C. Fishman ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Regional Cerebral Blood Flow ◽  
Mutant Mice ◽  
Type I ◽  
Wild Type ◽  
Regional Cerebral Blood ◽  
Doppler Flowmetry ◽  
Type Iii ◽  
Cranial Window

The effect of NG-nitro-L-arginine (L-NNA) on regional cerebral blood flow (rCBF) response to hypercapnia (5% CO2 inhalation) was studied in urethan-anesthetized wild-type (SV-129) and type III nitric oxide (NO) synthase (NOS)-deficient mice, using laser-Doppler flowmetry and the closed cranial window technique. Resting rCBF during normocapnia decreased by approximately 25% after L-NNA superfusion in wild-type mice only (n = 18), suggesting a role for type III NOS in baseline blood flow. Hypercapnia augmented rCBF approximately 50% in both wild-type and type III NOS mutant mice. L-NNA superfusion (1 mM) inhibited this increase by approximately 60% in both strains. Hence, synthesis of NO by the constitutively expressed type I NOS contributes to blood flow augmentation during hypercapnia.

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