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 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 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 Mechanisms of Stroke in Sickle Cell Disease: Sickle Erythrocytes Decrease Cerebral Blood Flow in Rats After Nitric Oxide Synthase Inhibition

Blood ◽  
1997 ◽  
Vol 89 (12) ◽  
pp. 4591-4599 ◽  
Author(s):  
James A. French ◽  
Dermot Kenny ◽  
J. Paul Scott ◽  
Raymond G. Hoffmann ◽  
James D. Wood ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Vascular Endothelium ◽  
Cell Disease ◽  
Cerebral Microvessels ◽  
Doppler Flowmetry ◽  
Cranial Window

Abstract The etiology of stroke in sickle cell disease is unclear, but may involve abnormal red blood cell (RBC) adhesion to the vascular endothelium and altered vasomotor tone regulation. Therefore, we examined both the adhesion of sickle (SS)-RBCs to cerebral microvessels and the effect of SS-RBCs on cerebral blood flow when the nitric oxide (NO) pathway was inhibited. The effect of SS-RBCs was studied in the rat cerebral microcirculation using either a cranial window for direct visualization of infused RBCs or laser Doppler flowmetry (LDF ) to measure RBC flow. When fluorescently labeled human RBCs were infused into rats, SS-RBCs had increased adhesion to rat cerebral microvessels compared with control AA-RBCs (P = .01). Next, washed SS-RBCs or AA-RBCs were infused into rats prepared with LDF probes after pretreatment (40 mg/kg intravenously) with the NO synthase inhibitor, N-ω-nitro-L-arginine methyl ester (L-NAME), or the control isomer, D-NAME. In 9 rats treated with systemic L-NAME and SS-RBCs, 5 of 9 experienced a significant decrease in LDF and died within 30 minutes after the RBC infusion (P = .0012). In contrast, all control groups completed the experiment with stable LDF and hemodynamics. Four rats received a localized superfusion of L-NAME (1 mmol/L) through the cranial window followed by infusion of SS-RBCs. Total cessation of flow in all observed cerebral microvessels occurred in 3 of 4 rats within 15 minutes after infusion of SS-RBCs. We conclude that the NO pathway is critical in maintaining cerebral blood flow in the presence of SS-RBCs in this rat model. In addition, the enhanced adhesion of SS-RBCs to rat brain microvessels may contribute to cerebral vaso-occlusion either directly, by disrupting blood flow, or indirectly, by disturbing the vascular endothelium.

scholarly journals NITRIC OXIDE SYNTHASE DYSFUNCTION UNDERLIES CEREBROVASCULAR DEFICITS IN A MOUSE MODEL OF TAUOPATHY

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S91-S91
Author(s):  
Candice E Van Skike ◽  
Stacy A Hussong ◽  
Andy Banh ◽  
Veronica Galvan
Keyword(s):  
Nitric Oxide ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Nitric Oxide Synthase ◽  
Mouse Model ◽  
Doppler Flowmetry ◽  
Cerebrovascular Dysfunction ◽  
Oxide Synthase

Abstract We recently identified pathogenic soluble aggregated tau (tau oligomers) in the cerebral microvasculature of human patients with tauopathies, including Alzheimer’s disease (AD). The functional consequences of cerebrovascular tau accumulation are not yet understood. The aim of the present study was to determine whether pathogenic tau accumulation leads to cerebrovascular dysfunction. To this end, we measured neurovascular coupling (NVC), a highly regulated process that synchronizes cerebral blood flow to neuronal activation, using the PS19(P301S) mouse model of tauopathy. The change in cerebral blood flow evoked by whisker stimulation was measured using Laser Doppler flowmetry in PS19 and wildtype control mice and the functional contribution of neuronal and endothelial nitric oxide synthase (nNOS and eNOS, respectively) was calculated. Vascular reactivity was assessed using topical acetylcholine to evoke endothelium-dependent vasodilation. To assess the direct impact of pathogenic tau on cell-specific NOS function, we treated N2a neuroblastoma cells or mouse brain vascular endothelial cells with soluble tau aggregates and measured activity of nNOS and eNOS. Our data indicate isolated overexpression of mutant tau impairs NVC responses, and this deficit is mediated by a reduction in nNOS activity in vivo. Further, our studies suggest tauopathy also impairs endothelium-dependent vasoreactivity in the cortex. Additionally, soluble tau aggregates inhibit the phosphorylation of NOS in primary cultured cells. Therefore, inhibition of NOS phosphorylation by pathogenic soluble tau aggregates may underlie cerebrovascular dysfunction in tauopathies. Thus, therapeutic modulation of pathogenic tau may mitigate brain microvascular deficits, which occur prior to clinical onset in Alzheimer’s disease and potentially other tauopathies.

Variability in the Magnitude of the Cerebral Blood Flow Response and the Shape of the Cerebral Blood Flow: Pressure Autoregulation Curve during Hypotension in Normal Rats

2002 ◽  
Vol 97 (2) ◽  
pp. 488-496 ◽  
Author(s):  
Stephen C. Jones ◽  
Carol R. Radinsky ◽  
Anthony J. Furlan ◽  
Douglas Chyatte ◽  
Yinsheng Qu ◽  
...  
Keyword(s):  
Carbon Dioxide ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Lower Limit ◽  
Vascular Reactivity ◽  
Surgical Trauma ◽  
Sprague Dawley ◽  
Doppler Flowmetry ◽  
Cranial Window ◽  
Pressure Autoregulation

Background The maintenance of constant cerebral blood flow (CBF) as mean cerebral perfusion pressure (CPP) varies is commonly referred to as CBF-pressure autoregulation. The lower limit of autoregulation is the CPP at which the vasodilatory capacity is exhausted and flow falls with pressure. We evaluated variability in the magnitude of percent change in CBF during the hypotensive portion of the autoregulatory curve. We hypothesize that this variability, in normal animals, obeys a Gaussian distribution and characterizes a vasodilatory mechanism that is inherently different from that described by the lower limit. Methods Sixty-five male Sprague-Dawley rats were anesthetized with 0.5-1% halothane and 70% nitrous oxide in oxygen. Body temperature was maintained at 37 degrees C. Using a closed, superfused cranial window, CBF (as % of control) was determined using laser Doppler flowmetry (LDF) through the window with the intracranial pressure set at 10 mmHg. Animals with low vascular reactivity to inhaled carbon dioxide and superfused adenosine diphosphate (ADP) or acetylcholine were excluded. MABP was sequentially lowered by exsanguination to 100, 85, 70, 55, and 40 mmHg. Using the %CBF versus CPP plots for each curve (1) the lower limit of autoregulation was identified; (2) the pattern of autoregulation was classified as "peak" (a rise in LDF flow of at least 15% as arterial pressure was dropped), "classic" (plateau with a fall), or "none" (a fall in LDF flow of greater than 15%); (3) the area under the autoregulatory curve between CPPs of 30 and 90 mmHg was calculated; and (4) the magnitude of the %CBF response to hypotension was assessed by determining the %CBF at a CPP of 60 mmHg (%CBFCPP60). Results Of the 65 curves, 21 had the peak pattern, 33 the classic pattern, and 11 the none pattern. The %CBFCPP60 and autoregulatory area displayed Gaussian distributions, consistent with normal variability. Although %CBFCPP60, autoregulatory area, and pattern were significantly correlated (r or rho &gt; 0.84, P &lt; 0.001), the lower limit correlated weakly with autoregulatory area (r = 0.34, P = 0.012), and not at all with autoregulatory pattern or %CBFCPP60. Conclusions The %CBFCPP60 measures an aspect of the autoregulatory curve that is distinct from the lower limit. The peak autoregulatory pattern indicates that vessels are dilating more than is necessary to maintain a plateau in response to the pressure decrease, whereas the none pattern existed in spite of acceptable vascular responses to inhaled carbon dioxide and superfused ADP or ACh and the lack of surgical trauma. These results provide a different view of autoregulation during hypotension, are most likely dependent on the highly regional CBF method used, and could have implications concerning potential cerebral ischemia and hypotension during anesthesia.

Angiotensin II and cardiovascular regulation in a freshwater teleost, Anguilla rostrata LeSueur

1995 ◽  
Vol 269 (3) ◽  
pp. R726-R735 ◽  
Author(s):  
G. Y. Oudit ◽  
D. G. Butler
Keyword(s):  
Blood Flow ◽  
Angiotensin Ii ◽  
Pressor Response ◽  
Aortic Blood Flow ◽  
Adrenergic Blockade ◽  
Ang Ii ◽  
Passive Response ◽  
Similar Dose ◽  
Vagal Innervation ◽  
Blood Flow Increase

Cardiac output (CO), dorsal aortic blood flow (BFDA) and blood pressure (PDA), and heart rate (HR) were recorded simultaneously in conscious freshwater eels. Physiological doses of [Asn1,Val5]angiotensin II (ANG II; 25-150 ng/kg iv) were used to investigate its effects on the blood flow [CO, BFDA, and estimated branchial shunting (BS)] and systemic vascular resistance (RSys) components of the pressor response and possible mechanism(s) of action. CO was increased mainly by an elevated stroke volume (SV) due to positive inotropy and/or Frank-Starling principle in a dose-related manner. An intact baroreceptor reflex attenuated the blood flow increase by 25% via the inhibitory cardiac vagal innervation. The elevation in estimated BS was a passive response to the increased CO, since the proportion of CO perfusing the pathway remained constant. PDA showed a similar dose-dependent increase in response to ANG II but the peak PDA preceded the peak CO responses at all doses; RSys was only transiently elevated at peak PDA. The increase in blood flow was an important contributor to the vasopressor responses. Alpha-Adrenergic blockade partially inhibited the pressor effect of ANG II (100 ng/kg) primarily by attenuating the increase in blood flow (50-70%). The data provide evidence for an ANG II-mediated cardiovascular control in teleosts directly and indirectly via catecholamine release.

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.

Cortical cerebral blood flow cycling: anesthesia and arterial blood pressure

1995 ◽  
Vol 268 (2) ◽  
pp. H569-H575 ◽  
Author(s):  
S. C. Jones ◽  
J. L. Williams ◽  
M. Shea ◽  
K. A. Easley ◽  
D. Wei
Keyword(s):  
Blood Pressure ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Pressure Change ◽  
Sprague Dawley ◽  
Doppler Flowmetry ◽  
Blood Withdrawal ◽  
Cranial Window ◽  
Arterial Blood ◽  
Mean Pressure

Cycling of various cerebral metabolic substances, arterial vascular diameter, and flow has been noted by many workers at a frequency near 0.1 Hz. Suspicion that this phenomenon is dependent on the type of anesthesia led us to investigate the occurrence of cerebral blood flow (CBF) cycling with different anesthetics. Fifteen Sprague-Dawley rats were anesthetized with either pentobarbital (n = 5, 40–50 mg/kg), alpha-chloralose (n = 5, 60 mg/kg), or halothane (n = 5, 1–0.5%). Body temperature was maintained at 37 degrees C. Femoral arterial and venous catheters were placed, and a tracheotomy was performed, permitting artificial ventilation with 30% O2–70% N2. A closed cranial window was formed over a 3-mm diameter craniotomy. Mean arterial pressure (MABP), arterial partial pressures of CO2 and O2 (PaCO2 and PaO2), and pH were controlled and stabilized at normal values. CBF was determined using laser Doppler flowmetry. To induce cycling, MABP was transiently and repeatedly lowered by exsanguination. Fast Fourier analysis of selected 64-s flow recordings (n = 38) was performed. CBF cycling was observed, independent of the type of anesthesia, in all animals. In 36 epochs, cycling was induced when MABP was reduced to a mean pressure of 65 +/- 1.5 mmHg. The mean frequency and amplitude were 0.094 +/- 0.003 Hz and 6.6 +/- 0.5%, respectively. Cycling occurred without blood withdrawal in two epochs. With the use of the blood-withdrawal epochs (n = 36), all three anesthetics shared a common linear slope between amplitude and blood pressure (P < 0.02) and blood pressure change (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

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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