Abstract 644: The Endothelin B Receptor Attenuates Endothelin Contraction Via An Endothelium Independent Mechanism In Mesenteric Arteries Of (mRen2)27 Rats

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Victor M Pulgar ◽  
Anne B Jeffers ◽  
Mark C Chappell ◽  
Azeez A Aileru
Keyword(s):  
Smooth Muscle ◽  
Isometric Force ◽  
Mesenteric Arteries ◽  
Maximal Response ◽  
Compensatory Mechanism ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Response Curves ◽  
Arterial Lumen ◽  
Endothelial Denudation

Endothelin-1 (ET-1) and Angiotensin II (Ang II) are important modulators of vascular tone. Contraction to ET-1 is dependent on the activation of ETA and ETB receptors. The contractile receptor ETA is localized in the smooth muscle cells whereas ETB receptors are predominantly found in the endothelium. We investigated the role of ETB receptors in ET-1 contraction in a model of Ang II-dependent hypertension, the (mRen2)27 rat. Third branch mesenteric arteries were isolated from 12 weeks old male Sprague-Dawley (SD) control and (mRen2)27 hypertensive rats and mounted on a wire Multi Myograph (Model 620, DMT) for determination of isometric force. Dose response curves to ET-1 (10 -11 -10 -7 M) were performed in arterial segments that were either intact, endothelium denuded or preincubated with the ETB specific antagonist BQ788 10 -6 M. Endothelial denudation was performed by passing a human hair through the arterial lumen and functional loss of the endothelium was confirmed by the absence of vasodilatation to acetylcholine. Maximal responses were expressed as percent of maximal response to 75mM KCl (%K MAX ) and the sensitivity as pD 2 (pD 2 = -Log[EC 50 ]). In SD control rats, addition of BQ788 significantly increased ET-1 sensitivity in intact arteries (8.9±0.1 vs 9.3±0.1, p<0.05) and the increase was abolished by endothelial denudation with no change in maximal response. However, the ETB blocker BQ788 increased the maximal tension in both intact (127±2 vs 154±13 %K MAX , p<0.05); and denuded (156±9 vs 188±12 %K MAX , p<0.05) arteries from (mRen2)27 rats with no change in sensitivity. In summary, the present results demonstrate that endothelial ETB receptors influence vasodilatory function in control SD rats, but apparently attenuate the contraction to ET-1 in the (mRen2)27 rats. We conclude that the expression of ETB receptors in the endothelium and smooth muscle of resistance vessels in the (mRen2)27 rats may function as a compensatory mechanism to the increased blood pressure or activated angiotensin system found in this model of hypertension.

Abstract P277: β-arrestin-2-mediated Vasodilatation In Mouse Mesenteric Arteries

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Victor M Pulgar ◽  
Krisztian Toth
Keyword(s):  
Vascular Function ◽  
Isometric Force ◽  
Mesenteric Arteries ◽  
Maximal Response ◽  
Lower Sensitivity ◽  
Dependent Manner ◽  
Resistance Arteries ◽  
Response Curves ◽  
Vascular Dilatation

As part of GPCRs-dependent signaling, β -arrestin-2 has been shown to stimulate eNOS activity and thus has the potential to modulate vascular function. We hypothesized that the absence of β -arrestin-2 would alter vascular dilatation and contraction in resistance arteries. We tested acetylcholine (ACh)-dependent relaxation and phenylephrine (PE)-dependent contraction in mouse mesenteric arteries isolated from 3-mo old male C57Bl6 (WT, n=5) and β -arrestin-2 KO ( βarr2 -/- , n=5) mice. Segments were mounted in a Wire Myograph (DMT) for determination of isometric force; vessels studied included intact, without endothelium, or pre-incubated with L-NAME (10 -4 M). Dose-response curves were performed for ACh (10 -10 -10 -4.5 M) and PE (10 -10 -10 -4.5 M). Data were acquired using a PowerLab (ADInstruments) system. Maximal response to ACh (ACh MAX ) was expressed as maximal relaxation after pre-constriction, maximal response to PE (PE MAX ) as % of contraction to 75mM KCl (%K MAX ), and sensitivity as pD 2 (-Log[EC 50 ]). Data were analyzed using Prism (GraphPad). After pre-constriction (PE, 3x10 -6 M), arteries from βarr2 -/- mice presented similar ACh MAX (79±6 vs. 82±6, p>0.05) and lower sensitivity to ACh compared to WT (6.66±0.2 vs. 7.12±0.1, p<0.05). The sensitivity of the contraction to PE was increased in βarr2 -/- arteries (6.4±0.2 vs. 6.04±0.1, p<0.05), with no changes in PE MAX . Differences in vasodilation and contraction were abolished in arteries without endothelium and in arteries pre-incubated with L-NAME. We conclude that the absence of β -arrestin-2 induces a pro-contractile phenotype in an endothelium- and nitric oxide-dependent manner in mouse resistance arteries.

Modulation of uterine resistance artery lumen diameter by calcium and G protein activation during pregnancy

1994 ◽  
Vol 267 (3) ◽  
pp. H952-H961 ◽  
Author(s):  
G. D'Angelo ◽  
G. Osol
Keyword(s):  
Smooth Muscle ◽  
G Protein ◽  
G Proteins ◽  
Light Chain ◽  
Myosin Light Chain ◽  
Lumen Diameter ◽  
Maximal Response ◽  
Adrenergic Stimulation ◽  
Myosin Light Chain Phosphatase ◽  
Arterial Lumen

The purpose of this study was to determine whether the increased sensitivity of uterine resistance arteries from late pregnant (LP) rats to alpha-adrenergic stimulation is due to an alteration in the fundamental relationship between cytosolic calcium (Ca2+) and arterial lumen diameter. Uterine arcuate arteries were permeabilized with Staphylococcus aureus alpha-toxin under optimal conditions and constricted to varying degrees with discrete Ca2+ concentrations at a distending pressure of 50 mmHg. Arterial segments from nonpregnant (NP) and LP rats exhibited similar Ca2+/lumen diameter characteristics. Ca2+ (0.1 microM) produced appreciable constriction, and lumen diameter decreased steeply between 0.175 and 0.25 microM Ca2+; maximal responses were attained with 0.5 microM Ca2+. Activation of guanine nucleotide binding proteins (G proteins) with guanosine 5'-triphosphate (GTP; 1-100 microM), as reportedly occurs during alpha-adrenergic stimulation, potentiated the Ca(2+)-induced constriction by 121 and 79% in arteries from LP and NP rats, respectively. No significant differences between the two animal groups were noted. Guanosine 5'-O-(gamma-thiotriphosphate) (GTP gamma S; 0.1-10 microM), a nonhydrolyzable analogue of GTP, effected a larger potentiating effect over that maximal response caused by GTP in arteries from NP rats. Ca(2+)- and Ca2+/GTP-induced constrictions were more potently reversed by guanosine 5'-O-(beta-thiodiphosphate) (GDP beta S)., a competitive inhibitor of GTP, in arteries from NP rats. These data suggest that pregnancy-induced increases in sensitivity to alpha-adrenergic stimulation may be related to altered G protein cycling rates, such that G proteins in smooth muscle cells in arcuate arteries from NP rats are more susceptible to deactivation. Alternatively, consistent with the model of G protein-mediated inhibition of myosin light chain phosphatase, myosin light chain phosphatase activity may be enhanced in uterine vascular smooth muscle from NP rats relative to that from LP rats.

Smooth muscle mechanical responses in vitro to bethanechol after progesterone in male rat.

1978 ◽  
Vol 235 (4) ◽  
pp. E422 ◽  
Author(s):  
L A Bruce ◽  
F M Behsudi ◽  
I E Danhof
Keyword(s):  
Smooth Muscle ◽  
Contractile Activity ◽  
Circular Muscle ◽  
Male Rat ◽  
Equal Weight ◽  
Muscarinic Agonist ◽  
Sprague Dawley ◽  
Response Curves ◽  
Dose Levels

Male Sprague-Dawley rats were pretreated subcutaneously with either progesterone (3 mg/kg per day) in a vehicle or a vehicle only for 3 days. Antral and gastroduodenal junctional tissues (GJT) were excised from both groups of animals and prepared for in vitro mechanical measurements. Responses from the circular muscle axis of these tissues were recorded with strain gauge transducers over a 30-min period. Chemical stimulation of the tissue was achieved with a muscarinic agonist, bethanechol chloride. Log-dose response curves suggested that untreated antral tissue generated stronger contractile activity than untreated GJT on an equal weight basis at bethanechol dose levels of 6.4 X 10(-6) M to 1 X 10(-4) M (P less than 0.005). Antral tissue and GJT contractile activity from the progesterone pretreated animals was significantly reduced (P less than 0.01) compared to the corresponding tissues from untreated animals at bethanechol dose levels of 6.4 X 10(-6) M and 1.28 X 10(-5) M. Progesterone pretreatment appeared to have little effect on the contractile frequency of either tissue. These results suggest possible progesteronic influences on contractile force in gastrointestinal smooth muscle.

Abstract 637: Hydrogen Sulfide Acts on Endothelial Cells to Elicit Dilation.

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Nancy L Kanagy ◽  
Jessica M Osmond ◽  
Olan Jackson-Weaver ◽  
Benjimen R Walker
Keyword(s):  
Endothelial Cells ◽  
Smooth Muscle ◽  
Hydrogen Sulfide ◽  
Mesenteric Arteries ◽  
Direct Effects ◽  
Sprague Dawley ◽  
Imaging Studies ◽  
Knock Out ◽  
Event Frequency ◽  
Sprague Dawley Rats

Hydrogen sulfide (H 2 S), produced by the enzyme cystathionine-γ lyase (CSE), dilates arteries by hyperpolarizing and relaxing vascular smooth muscle cells (VSMC) and CSE knock-out causes hypertension and endothelial dysfunction showing the importance of this system. However, it is not clear if H 2 S-induced VSMC depolarization and relaxation is mediated by direct effects on VSMC or indirectly through actions on endothelial cells (EC). We reported previously that disrupting EC prevents H 2 S-induced vasodilation suggesting H 2 S might act directly on EC. Because inhibiting large-conductance Ca 2+ -activated K + (BK Ca ) channels also inhibits H 2 S-induced dilation, we hypothesized that H 2 S activates EC BK Ca channels to hyperpolarize EC and increase EC Ca 2+ which stimulates release of a secondary hyperpolarizing factor. Small mesenteric arteries from male Sprague-Dawley rats were used for all experiments. We found that EC disruption prevented H 2 S-induced VSMC membrane potential ( E m ) hyperpolarization. Blocking EC BK Ca channels with luminal application of the BK Ca inhibitor, iberiotoxin (IbTx, 100 nM), also prevented NaHS-induced dilation and VSMC hyperpolarization but did not affect resting VSMC E m showing EC specific actions. Sharp electrode recordings in arteries cut open to expose EC demonstrated H 2 S-induced hyperpolarization of EC while Ca 2+ imaging studies in fluor-4 loaded EC showed that H 2 S increases EC Ca 2+ event frequency. Thus H 2 S can act directly on EC. Inhibiting the EC enzyme cytochrome P 450 2C (Cyp2C) with sulfaphenazole also prevented VSMC depolarization and vasodilation. Finally, inhibiting TRPV4 channels to block the target of the Cyp2C product 11,12-EET inhibited NaHS-induced dilation. Combined with our previous report that CSE inhibition decreases BK Ca currents in EC, these results suggest that H 2 S stimulates EC BK Ca channels and activates Cyp2C upstream of VSMC hyperpolarization and vasodilation.

Changes in Vsmc Phenotypes in Ang Ii-Dependent Hypertension of TGR (mREN2) 27 (Tgr) Transgenic Rats

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 688-688
Author(s):  
Gian Paolo P Rossi ◽  
Saverio Sartore ◽  
Stefania Colonna ◽  
Alfredo Sacchetto ◽  
Damiano Rizzoni ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Iliac Artery ◽  
Structural Changes ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Selective Antagonist ◽  
Heavy Chains ◽  
Group I ◽  
Group B

57 Arterial hypertension is associated with vascular smooth muscle cells (VSMC) phenotypic differentiation, but the role of Ang II and ET-1 is still unclear. Thus, we investigated the changes of VSMC phenotypes in Ang II-dependent hypertension and the role of ET-1 and its A receptor (ET A ). Four-week old heterozygote male TGR rats (n=24) were body weight (BW)- and blood pressure (BP)-matched and randomly allocated to receive orally a placebo (Group P), the mixed ET A /ET B antagonist Bosentan (100 mg/Kg, Group B) the Ang II AT-1 specific receptor antagonist Irbesartan (50 mg/Kg BW, Group I) or the ET A selective antagonist BMS-182874 (52 mg/Kg BW, Group BMS). After 4-wk of treatments, during which BW and BP were measured weekly, animals were euthanized; the iliac artery and mesenteric arterioles were collected. In the latter the structural changes were assessed with a myograph. Immunohistochemistry with a panel of different antibodies specific for ET-1, ET A , smooth muscle (SM) myosin, SM actin, SM 22, myosin heavy chains Apla 22 and fibronectin EIIIA was carried out. The fetal, neonatal and adult aorta from normotensive Sprague-Dawley rats were studied as control. Compared to all other groups, Group I rats showed significantly (p<0.001) lower systolic BP (161±8 mmHg, vs 269±23 Group P; vs 254±21 Group BMS), LV weight (2.28±0.15 mg/g BW vs 3.71±0.26, 3.38±0.27 and 3.96±0.51), and normalized media thickness of the mesenteric arterioles (22.3±0.6 μm vs 25.3±0.5, 25.5±0.7 and 24.1±1.5). Hypertension, LVH and medial arterioles hypertrophy in group P TGR were paralleled by a shift of VSMC toward a fetal phenotype in the iliac artery, despite no change in the expression of both irET-1 and ET A . The VSMC phenotypic shift was prevented by both irbesartan and Bosentan, but not by the ET A -selective antagonist BM 182874. Thus, Ang II-dependent hypertension of TGR is associated with both vascular hypertrophy and a shift of VSMC toward a fetal phenotype, which occurs through AT-1- and ET B - but not ET A -mediated mechanisms.

Time course of airway hyperresponsiveness and remodeling induced by hyperoxia in rats

1995 ◽  
Vol 269 (2) ◽  
pp. L227-L233 ◽  
Author(s):  
J. L. Szarek ◽  
H. L. Ramsay ◽  
A. Andringa ◽  
M. L. Miller
Keyword(s):  
Smooth Muscle ◽  
Airway Hyperresponsiveness ◽  
Time Course ◽  
Electrical Field Stimulation ◽  
Maximal Response ◽  
Sprague Dawley ◽  
Electrical Field ◽  
Muscle Area ◽  
Sprague Dawley Rats ◽  
The Relationship

The purpose of this study was to answer two questions concerning hyperoxia-induced airway hyperresponsiveness: 1) What is the time course of the development of airway hyperresponsiveness? 2) What is the relationship between the increase in responsiveness and smooth muscle area? Segments of intrapulmonary bronchi were isolated from male Sprague-Dawley rats that had been exposed to 80-85% O2 for a period of 1, 3, 5, or 7 days and from aged-matched control animals that breathed room air. Hyperoxia increased the sensitivity (log concentration or frequency that elicited a half-maximal response) and reactivity (maximum tension developed) of the airways to electrical field stimulation (EFS) after 3, 5, and 7 days; sensitivity to acetylcholine was not affected, but reactivity was increased after 7 days. Hyperoxia increased smooth muscle area beginning 5 days after commencing the exposure. After normalizing tension responses to smooth muscle area, reactivity of the airways to the stimuli was not different between the two groups, but sensitivity to EFS was still increased. The increase in reactivity observed after 5 and 7 days of exposure can be explained by an increase in smooth muscle area that occurred at these time points. The fact that the sensitivity of the airways to EFS remained increased after normalization, together with the fact that the increase in airway responsiveness after 3 days of exposure occurred at a time when smooth muscle area was not different from control, suggests that mechanisms other than increased smooth muscle area contribute to the development of hyperoxia-induced airway hyperresponsiveness.

Length-dependent sensitivity in vascular smooth muscle

1981 ◽  
Vol 241 (4) ◽  
pp. H557-H563 ◽  
Author(s):  
J. M. Price ◽  
D. L. Davis ◽  
E. B. Knauss
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Dose Response ◽  
Length Change ◽  
Maximal Response ◽  
Anterior Tibial Artery ◽  
Response Curves ◽  
Anterior Tibial ◽  
Dose Response Curves ◽  
Best Fit

Dose-response curves were obtained from dog anterior tibial artery rings at various lengths (L) to determine whether sensitivity to norepinephrine (NE) and potassium (K+) depends on arterial circumference. The dose for half maximal response (ED50) was determined by graphical estimation and by calculation from a best fit curve. For both NE and K+: 1) ED50 was lowest (most sensitive) at L for maximum active force (Lmax) and increased significantly as L decreased from Lmax; 2) ED50 at 1.0 and 1.15 Lmax was not significantly different; 3) ED50 of repeated dose-response curves at Lmax was not significantly different; and 4) when the direction of length change was reversed (from decreasing to increasing), the direction of change in ED50 was also reversed (from increasing to decreasing). Change in the dose for 10% maximal response was the same as ED50. The results did not depend on the method of determining ED50 or on whether responses were expressed as absolute values or as relative values. The results show that sensitivity of vascular smooth muscle depends on L and that the length-sensitivity relation is similar to the length-active tension relation. Similarity of results for NE and K+ indicate that length-dependent sensitivity does not depend on the method of stimulation.

Interactions of adenosine A1 receptor-mediated renal vasoconstriction with endogenous nitric oxide and ANG II

1993 ◽  
Vol 265 (5) ◽  
pp. F651-F659 ◽  
Author(s):  
R. J. Barrett ◽  
D. A. Droppleman
Keyword(s):  
Nitric Oxide ◽  
Dose Response ◽  
Rat Kidney ◽  
Maximal Response ◽  
Ang Ii ◽  
Response Curves ◽  
Renal Vasoconstriction ◽  
Adenosine A1 ◽  
A1 Receptor ◽  
Synthase Inhibitor

Renal vasoconstrictor responses to the adenosine A1 agonist N6-cyclopentyladenosine (CPA) were compared in the in situ autoperfused rat kidney to responses evoked by angiotensin II (ANG II), endothelin-1 (ET-1), arginine vasopressin (AVP), carbocyclic thromboxane A2 (CTxA2), phenylephrine (PE), and 5-hydroxytryptamine (5-HT). On the basis of their ED50 values (dose of agonist, in mass units, that produced 50% of maximal response to that agonist), the order of vasoconstrictor potency was ANG II > or = AVP > ET-1 > CPA > 5-HT > or = PE > CTxA2. Dose-response curves to CPA were shallower and maximal responses were weaker than those produced by the other agonists. Maximal responses, the log ED50, and the slope of the dose-response curve to CPA were markedly potentiated in the presence of the nitric oxide (NO) synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME). Selective antagonism of A1 receptors increased renal blood flow and markedly attenuated CPA-induced renal vasoconstriction in the absence or presence of L-NAME but had no effect on the maximal responses to ANG II. Conversely, AT1 receptor antagonism attenuated renal vasoconstriction produced by ANG II but had little effect on the produced by CPA. These results suggest that endogenous NO modulates renal vasoconstriction produced by A1 receptor stimulation and provide evidence against an interaction between renovascular adenosine A1 and angiotensin AT1 receptors.

scholarly journals Relaxin deficiency attenuates pregnancy-induced adaptation of the mesenteric artery to angiotensin II in mice

2016 ◽  
Vol 310 (9) ◽  
pp. R847-R857 ◽  
Author(s):  
Sarah A. Marshall ◽  
Chen Huei Leo ◽  
Sevvandi N. Senadheera ◽  
Jane E. Girling ◽  
Marianne Tare ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Reactive Oxygen Species Generation ◽  
Normal Pregnancy ◽  
Functional Adaptation ◽  
Mesenteric Arteries ◽  
Ang Ii ◽  
Renal Vasculature ◽  
Altered Expression ◽  
Endothelin 1 ◽  
Uterine Arteries

Pregnancy is associated with reduced peripheral vascular resistance, underpinned by changes in endothelial and smooth muscle function. Failure of the maternal vasculature to adapt correctly leads to serious pregnancy complications, such as preeclampsia. The peptide hormone relaxin regulates the maternal renal vasculature during pregnancy; however, little is known about its effects in other vascular beds. This study tested the hypothesis that functional adaptation of the mesenteric and uterine arteries during pregnancy will be compromised in relaxin-deficient ( Rln−/−) mice. Smooth muscle and endothelial reactivity were examined in small mesenteric and uterine arteries of nonpregnant (estrus) and late-pregnant ( day 17.5) wild-type ( Rln+/+) and Rln−/− mice using wire myography. Pregnancy per se was associated with significant reductions in contraction to phenylephrine, endothelin-1, and ANG II in small mesenteric arteries, while sensitivity to endothelin-1 was reduced in uterine arteries of Rln+/+ mice. The normal pregnancy-associated attenuation of ANG II-mediated vasoconstriction in mesenteric arteries did not occur in Rln−/− mice. This adaptive failure was endothelium-independent and did not result from altered expression of ANG II receptors or regulator of G protein signaling 5 ( Rgs5) or increases in reactive oxygen species generation. Inhibition of nitric oxide synthase with l-NAME enhanced ANG II-mediated contraction in mesenteric arteries of both genotypes, whereas blockade of prostanoid production with indomethacin only increased ANG II-induced contraction in arteries of pregnant Rln+/+ mice. In conclusion, relaxin deficiency prevents the normal pregnancy-induced attenuation of ANG II-mediated vasoconstriction in small mesenteric arteries. This is associated with reduced smooth muscle-derived vasodilator prostanoids.

scholarly journals Vascular function in rats with adenine-induced chronic renal failure

2012 ◽  
Vol 302 (12) ◽  
pp. R1426-R1435 ◽  
Author(s):  
Lisa Nguy ◽  
Holger Nilsson ◽  
Jaana Lundgren ◽  
Maria E. Johansson ◽  
Tom Teerlink ◽  
...  
Keyword(s):  
Renal Failure ◽  
Chronic Renal Failure ◽  
Vascular Function ◽  
Ex Vivo ◽  
Mesenteric Arteries ◽  
Maximal Response ◽  
Sprague Dawley ◽  
Resistance Arteries ◽  
Severe Renal Failure ◽  
Stress Markers

The aim of the present study was to characterize the function of resistance arteries, and the aorta, in rats with adenine-induced chronic renal failure (A-CRF). Sprague-Dawley rats were randomized to chow with or without adenine supplementation. After 6–10 wk, mesenteric arteries and thoracic aortas were analyzed ex vivo by wire myography. Plasma creatinine concentrations were elevated twofold at 2 wk, and eight-fold at the time of death in A-CRF animals. Ambulatory systolic and diastolic blood pressures measured by radiotelemetry were significantly elevated in A-CRF animals from week 3 and onward. At death, A-CRF animals had anemia, hyperphosphatemia, hyperparathyroidism, and elevated plasma levels of asymmetric dimethylarginine and oxidative stress markers. There were no significant differences between groups in the sensitivity, or maximal response, to ACh, sodium nitroprusside (SNP), norepinephrine, or phenylephrine in either mesenteric arteries or aortas. However, in A-CRF animals, the rate of aortic relaxation was significantly reduced following washout of KCl (both in intact and endothelium-denuded aorta) and in response to ACh and SNP. Also the rate of contraction in response to KCl was significantly reduced in A-CRF animals both in mesenteric arteries and aortas. The media of A-CRF aortas was thickened and showed focal areas of fragmented elastic lamellae and disorganized smooth muscle cells. No vascular calcifications could be detected. These results indicate that severe renal failure for a duration of less than 10 wk in this model primarily affects the aorta and mainly slows the rate of relaxation.

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