Abstract P435: Differential Responses of Cerebral Cortical and Renal Cortical Microvessels to Perfusion Pressure and Angiotensin II: Effect of Angiotensin II or DOCA/salt Hypertension

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Lingli Li ◽  
En Yin Lai ◽  
William J Welch ◽  
Christopher S Wilcox
Keyword(s):  
Blood Flow ◽  
Angiotensin Ii ◽  
Perfusion Pressure ◽  
High Salt ◽  
Ang Ii ◽  
Cerebral Microvessels ◽  
Salt Hypertension ◽  
Afferent Arterioles ◽  
Myogenic Responses ◽  
The Brain

Background: The brain and kidney autoregulate their blood flow well yet both suffer from hypertensive damage. We found that a pressor infusion of angiotensin II (Ang II) reduced renal blood flow yet did not change cerebral blood flow. Therefore, we tested the hypothesis that their myogenic and Ang II responses differed. Methods: Cerebral cortical microvessels (cerebral) and renal afferent arterioles (afferent) were isolated and perfused from mice after 4 weeks of hypertension from Ang II infusion /high salt/uninephrectomy (Ang II hypertension) or DOCA/high salt/uninephrectomy (DOCA/salt hypertension) or normotensive controls without Ang II or DOCA (n=4-6 per group). Results: Normal cerebral and afferents had similar myogenic responses (Δ diameter: cerebral -21±3 versus afferent-19±2%, NS), but bath addition of Ang II or norepinephrine contracted afferents strongly (Ang II: -48±5%, P<0.001, NE: -95±2%, P<0.001), yet cerebrals were entirely unresponsive. Myogenic responses in Ang II hypertension were reduced selectively by 40% in cerebral microvessels compared to controls (-13±3 versus -21±3%, P<0.001) yet maintained in afferents (-17±3 versus -19±2%, NS). However, myogenic responses in DOCA/salt hypertension were maintained in both groups. Contractions to Ang II in cerebral microvessels were increased in Ang II hypertension (-5±2 versus 0±1%, P<0.01) and increased in DOCA/salt hypertension (-18±8 versus -2±2%, P<0.01). In contrast, contractions to Ang II in afferent arterioles were reduced 50% in Ang II hypertension (-23±5 versus -48±5%, P<0.001) and reduced 25% in DOCA/salt hypertension (-38±6 versus -50±10%, P=0.05). Conclusions: The kidney is well protected from hypertension and excessive Ang II vasoconstriction. However, the breakdown of myogenic responses in the cerebral microvessels during Ang II hypertension and the enhanced Ang II responses in the cerebral microvessels during Ang II and DOCA/salt hypertension make the brain especially vulnerable to hypertensive ischemia or damage.

Abstract P266: Thromboxane-prostanoid Receptors (tp-rs) Mediate Hypertension, H2o2 Generation and Impaired Renal Afferent Arteriolar Myogenic Responses Leading to Nephropathy in Doca/salt Mice

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Christopher S Wilcox ◽  
Lingli Li ◽  
En Yin Lai ◽  
Adam Hosszu ◽  
William J Welch
Keyword(s):  
Blood Pressure ◽  
Perfusion Pressure ◽  
High Salt ◽  
Myogenic Tone ◽  
Prostanoid Receptors ◽  
Hypertensive Nephropathy ◽  
Sham Treatment ◽  
H2o2 Generation ◽  
Afferent Arterioles ◽  
Myogenic Responses

Background: DOCA/uninephrectomy/high salt (DOCA) is a model of hypertensive nephropathy. Afferent arteriolar myogenic responses prevent hypertensive renal barotrauma but myogenic tone is blocked by vascular generation of H 2 O 2 . Since thromboxane-prostanoid receptors (TP-Rs) generate H 2 O 2 , we tested the hypothesis that they mediate hypertensive nephropathy. Methods: DOCA and Sham TP-R +/+ and -/- mice (n=6/group) were studied at 2 weeks and myogenic responses recorded from the diameter of perfused single afferent arterioles studied in a bath preparation during increased perfusion pressure (40 to 80 mmHg). Results: DOCA treatment in TP-R +/+ mice increased (p<0.001) 24-hour excretion of H 2 O 2 (45 ± 3 vs 220 + 15 nmol) , TxB 2 (4 ± 2 vs 29 ± 4 pmol) and albumin (20 ± 5 vs 270 ± 20 mg) and increased MAP by 35 ± 5 mmHg. However, all effects of DOCA were prevented in TP-R -/- mice. Sham treatment had no effect in TPR +/+ or -/- mice. Myogenic responses were severely impaired in DOCA vs sham WT mice (Δ diameter: -4 ± 1 vs -8 ± 1%; p< 0.005). Myogenic responses also were reduced by incubation of arterioles with 10 -10 mol·l -1 of the TP-R mimetic, U-46,619 vs vehicle added to the bath for 10 minutes (Δ diameter: -7 ± 1 vs -10 ± 1%; p<0.01) and in WT mice infused for 3 days with U-46,619 (500 ng·kg -1 ·d -1 x 3) vs vehicle (Δ diameter: -3 ± 1 vs -10 ± 1%; p<0.005). Conclusion: Hypertensive nephropathy is dependent on TP-Rs that mediate the increase in H 2 O 2 and blood pressure and likely the impaired myogenic responses that expose the kidney to barotrauma

scholarly journals Central and peripheral slow-pressor mechanisms contributing to Angiotensin II-salt hypertension in rats

2017 ◽  
Vol 114 (2) ◽  
pp. 233-246 ◽  
Author(s):  
Jiao Lu ◽  
Hong-Wei Wang ◽  
Monir Ahmad ◽  
Marzieh Keshtkar-Jahromi ◽  
Mordecai P Blaustein ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Adrenal Cortex ◽  
Salt Intake ◽  
Plasma Corticosterone ◽  
High Salt ◽  
Ang Ii ◽  
Intracerebroventricular Infusion ◽  
High Salt Intake ◽  
Endogenous Ouabain ◽  
Salt Hypertension

AbstractAimsHigh salt intake markedly enhances hypertension induced by angiotensin II (Ang II). We explored central and peripheral slow-pressor mechanisms which may be activated by Ang II and salt.Methods and resultsIn protocol I, Wistar rats were infused subcutaneously with low-dose Ang II (150 ng/kg/min) and fed regular (0.4%) or high salt (2%) diet for 14 days. In protocol II, Ang II-high salt was combined with intracerebroventricular infusion of mineralocorticoid receptor (MR) blockers (eplerenone, spironolactone), epithelial sodium channel (ENaC) blocker (benzamil), angiotensin II type 1 receptor (AT1R) blocker (losartan) or vehicles. Ang II alone raised mean arterial pressure (MAP) ∼10 mmHg, but Ang II-high salt increased MAP ∼50 mmHg. Ang II-high salt elevated plasma corticosterone, aldosterone and endogenous ouabain but not Ang II alone. Both Ang II alone and Ang II-high salt increased mRNA and protein expression of CYP11B2 (aldosterone synthase gene) in the adrenal cortex but not of CYP11B1 (11-β-hydroxylase gene). In the aorta, Ang II-high salt increased sodium-calcium exchanger-1 (NCX1) protein. The Ang II-high salt induced increase in MAP was largely prevented by central infusion of MR blockers, benzamil or losartan. Central blockades significantly lowered plasma aldosterone and endogenous ouabain and markedly decreased Ang II-high salt induced CYP11B2 mRNA expression in the adrenal cortex and NCX1 protein in the aorta.ConclusionThese results suggest that in Ang II-high salt hypertension, MR-ENaC-AT1R signalling in the brain increases circulating aldosterone and endogenous ouabain, and arterial NCX1. These factors can amplify blood pressure responses to centrally-induced sympatho-excitation and thereby contribute to severe hypertension.

scholarly journals Purinergic P2X1 receptor, purinergic P2X7 receptor, and angiotensin II type 1 receptor interactions in the regulation of renal afferent arterioles in angiotensin II-dependent hypertension

2020 ◽  
Vol 318 (6) ◽  
pp. F1400-F1408 ◽  
Author(s):  
Supaporn Kulthinee ◽  
Weijian Shao ◽  
Martha Franco ◽  
L. Gabriel Navar
Keyword(s):  
Angiotensin Ii ◽  
Perfusion Pressure ◽  
Renal Perfusion ◽  
Ang Ii ◽  
Renal Perfusion Pressure ◽  
Arteriolar Resistance ◽  
Purinergic P2x7 Receptor ◽  
Afferent Arterioles ◽  
Purinergic P2x Receptors

In ANG II-dependent hypertension, ANG II activates ANG II type 1 receptors (AT1Rs), elevating blood pressure and increasing renal afferent arteriolar resistance (AAR). The increased arterial pressure augments interstitial ATP concentrations activating purinergic P2X receptors (P2XRs) also increasing AAR. Interestingly, P2X1R and P2X7R inhibition reduces AAR to the normal range, raising the conundrum regarding the apparent disappearance of AT1R influence. To evaluate the interactions between P2XRs and AT1Rs in mediating the increased AAR elicited by chronic ANG II infusions, experiments using the isolated blood perfused juxtamedullary nephron preparation allowed visualization of afferent arteriolar diameters (AAD). Normotensive and ANG II-infused hypertensive rats showed AAD responses to increases in renal perfusion pressure from 100 to 140 mmHg by decreasing AAD by 26 ± 10% and 19 ± 4%. Superfusion with the inhibitor P2X1Ri (NF4490; 1 μM) increased AAD. In normotensive kidneys, superfusion with ANG II (1 nM) decreased AAD by 16 ± 4% and decreased further by 19 ± 5% with an increase in renal perfusion pressure. Treatment with P2X1Ri increased AAD by 30 ± 6% to values higher than those at 100 mmHg plus ANG II. In hypertensive kidneys, the inhibitor AT1Ri (SML1394; 1 μM) increased AAD by 10 ± 7%. In contrast, treatment with P2X1Ri increased AAD by 21 ± 14%; combination with P2X1Ri plus P2X7Ri (A438079; 1 μM) increased AAD further by 25 ± 8%. The results indicate that P2X1R, P2X7R, and AT1R actions converge at receptor or postreceptor signaling pathways, but P2XR exerts a dominant influence abrogating the actions of AT1Rs on AAR in ANG II-dependent hypertension.

Abstract 376: Prolonged Excess of Superoxide in Mouse Afferent Arterioles Causes Remodeling and Enhances Myogenic and Angiotensin II Contractions

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
En Yin Lai ◽  
Lingli Li ◽  
Di Feng ◽  
William J Welch ◽  
Christopher S Wilcox
Keyword(s):  
Angiotensin Ii ◽  
Vascular Remodeling ◽  
Perfusion Pressure ◽  
Area Ratio ◽  
Superoxide Dismutases ◽  
Strongly Correlated ◽  
Ang Ii ◽  
Wall Tension ◽  
Sod Isoforms ◽  
Afferent Arterioles

Background: Superoxide (O 2 .- ) is associated with cardiovascular disease (CVD) and inactivating SNIPs of the EC-SOD gene increased CVD, but the mechanisms are unclear. Superoxide dismutases (SODs) have three isoforms: cytoplasmic Cu/ZnSOD (SOD1), mitochondrial MnSOD (SOD2) and extracellular Cu/ZnSOD (SOD3). Complete SOD2-/- was lethal. We tested the hypothesis that these isoforms of SOD modulate angiotensin II (Ang II), myogenic responses (MRs) and remodeling of afferent arterioles (Affs). Methods and Results: MRs were assessed from the slope of the regression of active wall tension on perfusion pressure (PP) and Ang II contractions from incubation with 10 -6 M Ang II. O 2 .- was assessed from PEG-SOD inhibitable ethidium:dihydroethidium fluorescence and remodeling from media:lumen area ratio (M:L). Results: 1. Compared to +/+, increasing PP from 40 to 80 mmHg or applying 10 -6 M Ang II in Affs increased O 2 .- more in SOD1-/- (PP, 8 ± 1% vs 5 ± 1% , P<0.05; Ang II, 29 ± 7 vs 10 ± 2%, P<0.05), in SOD2+/- (PP, 15 ± 2% vs 7 ± 1%, P<0.01; Ang II, 32 ± 5 % vs 7 ± 1%, P<0.01), and in SOD3-/- ( PP, 20 ± 4% vs 7 ± 1%, P<0.05; Ang II, 32 ± 5% vs 12 ± 3%, P<0.05). However, O 2 .- did not increase in SOD1+/- and SOD3+/-. 2. Compared to +/+, MRs (dynes.cm -1 .mmHg -1 ) were significantly increased in SOD1-/- (3.49 ± 0.30 vs 2.30 ± 0.27, P<0.05), in SOD2+/- (3.85 ± 0.48 vs 1.80 ± 0.34, P<0.05), and in SOD3-/- (3.51 ± 0.20 vs 2.43 ± 0.15, P<0.01), with no increase in SOD1+/- and SOD3+/-. 3. Compared to +/+, Ang II contractions were stronger in SOD1-/- (-68 ± 2% vs -33 ± 3%, P<0.0001), in SOD2+/- (-66 ± 6% vs -42 ± 3%, P<0.01), and in SOD3-/- (-75 ± 3% vs -34 ± 3%, P<0.0001) 4. Compared to +/+, M:L ratio of Affs were greater in SOD1-/- (4.0 ± 0.2 vs 1.8 ± 0.2, P<0.0001), in SOD2+/- (3.7 ± 0.4 vs 1.8 ± 0.4, P<0.001), and in SOD3-/- (4.5 ± 0.2 vs 1.9 ± 0.1, P<0.0001), but were unchanged in SOD1+/- and SOD3+/-. M:L ratio was strongly correlated to MR (r 2 =0.32, P<0.005) and Ang II contractions (r 2 = 0.56, P<0.005) across genotypes. 5. There were no compensatory changes in expression of other SOD isoforms. Conclusions: Lifetime increases in cytosolic, mitochondrial or extracellular O 2 .- enhanced afferent arteriolar myogenic and Ang II contractions that were closely related to vascular remodeling.

Role of angiotensin II and prostaglandins in the regulation of uteroplacental blood flow

1993 ◽  
Vol 264 (3) ◽  
pp. R584-R590 ◽  
Author(s):  
L. L. Woods
Keyword(s):  
Blood Flow ◽  
Angiotensin Ii ◽  
Arterial Pressure ◽  
Perfusion Pressure ◽  
Moderate Degree ◽  
Ang Ii ◽  
Response Curves ◽  
Uteroplacental Blood Flow ◽  
Uterine Perfusion

This study was designed to determine the importance of the renin-angiotensin (RAS) and prostaglandin (PG) systems in regulating uteroplacental blood flow (UBF). Our objectives were to determine: 1) whether angiotensin II (ANG II) acts as a vasodilator or purely as a vasoconstrictor in the uteroplacental circulation, and 2) whether this circulation is capable of autoregulation. In chronically instrumented pregnant dogs (41-54 days gestation), ANG II was infused intravenously at increasing doses (8, 16, and 24 ng.kg-1 x min-1). Arterial pressure rose from 108 +/- 6 to 146 +/- 4 mmHg and UBF did not change but uterine vascular resistance (UVR) progressively increased. When the experiment was repeated while servo-controlling uterine arterial pressure, UBF fell at all doses, reaching 62 +/- 7% of control at the highest dose, and UVR increased as before. Meclofenamate (6 mg/kg i.v.) did not alter the dose-response curves. In separate experiments, uterine perfusion pressure was reduced in steps to 55 mmHg. UBF was well autoregulated down to approximately 85 mmHg, and neither captopril (14 micrograms.kg-1 x min-1) nor meclofenamate altered UBF autoregulation. Thus ANG II appears to act as a vasoconstrictor in the uteroplacental circulation and any preservation of UBF during ANG II appears to be due to the increased arterial pressure. Also, in the dog the uteroplacental circulation possesses a mild to moderate degree of autoregulatory capability, which does not appear to be dependent on the RAS or PGs.

Microvascular features that suggest effectors of blood-flow regulation in the brain: Evidence by SEM of corrosion casts of intracerebral vessels

1990 ◽  
Vol 48 (3) ◽  
pp. 274-275
Author(s):  
Enrico D.F. Motti ◽  
Hans-Georg Imhof ◽  
Gazi M. Yasargil
Keyword(s):  
Blood Flow ◽  
Perfusion Pressure ◽  
Corrosion Casts ◽  
Cerebral Microcirculation ◽  
Pial Arteries ◽  
Random Occurrence ◽  
Brain Arteries ◽  
Homogeneous Network ◽  
The Brain

Physiologists have devoted most attention in the cerebrovascular tree to the arterial side of the circulation which has been subdivided in three levels: 1) major brain arteries which keep microcirculation constant despite changes in perfusion pressure; 2) pial arteries supposed to be effectors regulating microcirculation; 3) intracerebral arteries supposed to be deprived of active cerebral blood flow regulating devices.The morphological search for microvascular effectors in the cerebrovascular bed has been elusive. The opaque substance of the brain confines in vivo investigation to the superficial pial arteries. Most morphologists had to limit their observation to the random occurrence of a favorable site in the practically two-dimensional thickness of diaphanized histological sections. It is then not surprising most investigators of the cerebral microcirculation refer to an homogeneous network of microvessels interposed between arterioles and venules.We have taken advantage of the excellent depth of focus afforded by the scanning electron microscope (SEM) to investigate corrosion casts obtained injecting a range of experimental animals with a modified Batson's acrylic mixture.

Membrane potential measurements in renal afferent and efferent arterioles: actions of angiotensin II

1997 ◽  
Vol 273 (2) ◽  
pp. F307-F314 ◽  
Author(s):  
R. Loutzenhiser ◽  
L. Chilton ◽  
G. Trottier
Keyword(s):  
Angiotensin Ii ◽  
Perfusion Pressure ◽  
Rat Kidney ◽  
Renal Perfusion ◽  
Membrane Potentials ◽  
Ang Ii ◽  
Ca Channels ◽  
Renal Perfusion Pressure

An adaptation of the in vitro perfused hydronephrotic rat kidney model allowing in situ measurement of arteriolar membrane potentials is described. At a renal perfusion pressure of 80 mmHg, resting membrane potentials of interlobular arteries (22 +/- 2 microns) and afferent (14 +/- 1 microns) and efferent arterioles (12 +/- 1 microns) were -40 +/- 2 (n = 8), -40 +/- 1 (n = 45), and -38 +/- 2 mV (n = 22), respectively (P = 0.75). Using a dual-pipette system to stabilize the impalement site, we measured afferent and efferent arteriolar membrane potentials during angiotensin II (ANG II)-induced vasoconstriction. ANG II (0.1 nM) reduced afferent arteriolar diameters from 13 +/- 1 to 8 +/- 1 microns (n = 8, P = 0.005) and membrane potentials from -40 +/- 2 to -29 +/- mV (P = 0.012). ANG II elicited a similar vasoconstriction in efferent arterioles, decreasing diameters from 13 +/- 1 to 8 +/- 1 microns (n = 8, P = 0.004), but failed to elicit a significant depolarization (-39 +/- 2 for control; -36 +/- 3 mV for ANG II; P = 0.27). Our findings thus indicate that resting membrane potentials of pre- and postglomerular arterioles are similar and lie near the threshold activation potential for L-type Ca channels. ANG II-induced vasoconstriction appears to be closely coupled to membrane depolarization in the afferent arteriole, whereas mechanical and electrical responses appear to be dissociated in the efferent arteriole.

Angiotensin II induces insulin resistance independent of changes in interstitial insulin

1999 ◽  
Vol 277 (5) ◽  
pp. E920-E926 ◽  
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.

Angiotensin II effects on microvascular diameters of in vitro blood-perfused juxtamedullary nephrons

1986 ◽  
Vol 251 (4) ◽  
pp. F610-F618 ◽  
Author(s):  
P. K. Carmines ◽  
T. K. Morrison ◽  
L. G. Navar
Keyword(s):  
Angiotensin Ii ◽  
Constant Pressure ◽  
Ang Ii ◽  
Experimental Conditions ◽  
Vasoactive Hormones ◽  
Juxtamedullary Nephron ◽  
Single Nephron ◽  
Afferent Arterioles ◽  
Dose Dependent

The purpose of this study was to determine the specific renal microvascular segments that are functionally responsive to angiotensin II (ANG II) and other vasoactive hormones. Experiments were performed on juxtamedullary tissue from captopril-treated rats during perfusion with blood at a constant pressure of 110 mmHg. Epifluorescence videomicroscopy was utilized to measure diameters of arcuate and interlobular arteries (ART), mid- (MA) and late- (LA) afferent arterioles, and efferent arterioles (EA). Norepinephrine (700 nM) significantly decreased, and sodium nitroprusside (380 nM) increased, inside diameters of all segments. Topical application of ANG II (0.01 to 1 nM) induced significant reductions in diameters of all vessel segments: ART, 17.5 +/- 2.0%; MA, 19.6 +/- 2.5%; LA, 13.5 +/- 1.5%; and EA, 16.9 +/- 2.7%. The preglomerular response to ANG II was blocked by saralasin (10 microM) and, in most cases, was dose dependent; however, an initial hypersensitivity to low ANG II doses (30% decrease in diameter) was exhibited by 38% of the preglomerular vessels studied. Under these experimental conditions, single-nephron glomerular filtration rate decreased significantly in response to 0.01 nM ANG II exposure. These observations demonstrate that physiological concentrations of ANG II can elicit receptor-dependent and reversible vasoconstriction of the juxtamedullary nephron microvasculature at both pre- and postglomerular sites.

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