Abstract P500: Activation of the Heterodimeric Erythropoietin /β-Common Receptor Impairs Acetylcholine Mediated Vasodilation in Mouse Mesenteric Arterioles

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Cody R Kilar ◽  
YanPeng Diao ◽  
Larysa Sautina ◽  
Sivakumar Sekharan ◽  
Shahar Keinan ◽  
...  
Keyword(s):  
Sodium Nitroprusside ◽  
Vascular Complications ◽  
Mesenteric Arteries ◽  
No Production ◽  
Resistance Arteries ◽  
Inhibitory Peptide ◽  
Receptor Complexes ◽  
Common Receptor ◽  
Potent Vasodilator ◽  
Selective Impairment

Erythropoietin (EPO) increases systemic vascular resistance and blood pressure. However, endothelial cells cultured in the presence of EPO demonstrate increased production of the potent vasodilator, nitric oxide (NO). The mechanism by which EPO causes vasoconstriction despite stimulating NO production may be dependent on its ability to differentially activate the two receptor complexes, the homodimeric EPO (EPOR 2 ) and the heterodimeric EPOR/β-common receptor (βCR). Objective: The purpose of this study was to investigate the contribution of the EPOR 2 and βCR receptor to the vasoactive properties of EPO. Methods: First order, mesenteric arteries isolated from 16-week old male C57BL/6 mice were cannulated and perfused using a pressure arteriography system. To determine the contribution of each receptor complex, arteries were incubated with EPO stimulating peptide (ESP) which binds and activates only the heterodimeric EPOR/βCR complex or EPO which activates both receptors, 20 min prior to evaluation of vasoconstrictor (phenylephrine and potassium chloride), endothelium-dependent (acetylcholine, bradykinin, A23187) and -independent (sodium nitroprusside) vasodilator responses. Additionally, we studied the effect of a novel βCR inhibitory peptide (βIP) which was developed in silico and validated by demonstrating that it selectively inhibits binding of ligands to the βCR. Results: Acetylcholine induced vasodilation was impaired in arteries pretreated with EPO or ESP by 100% and 60%, respectively. EPO and ESP did not affect endothelium-dependent vasodilation by Bradykinin or A23187, endothelium-independent vasodilation by sodium nitroprusside, or vasoconstriction by phenylephrine and KCl. The βIP prevented the impairment of acetylcholine-induced vasodilation by EPO and ESP. Conclusion: Together, our findings suggest that activation of the heterodimeric EPOR/βCR leads to selective impairment of ACh-mediated vasodilator response in mouse mesenteric resistance arteries. Thus the βCR might have a role in mediating hypertensive effects of EPO. Therapeutic inhibition of the βCR might prevent vascular complications of EPO without affecting erythropoiesis.

Selective Impairment of Acetylcholine-Mediated Endothelium-Dependent Relaxation in Isolated Resistance Arteries of the Streptozotocin-Induced Diabetic Rat

1995 ◽  
Vol 88 (5) ◽  
pp. 519-524 ◽  
Author(s):  
P. D. Taylor ◽  
J. E. Graves ◽  
L. Poston
Keyword(s):  
Nitric Oxide ◽  
Sodium Nitroprusside ◽  
Vascular Complications ◽  
Signal Transduction Pathway ◽  
Diabetic Rats ◽  
Mesenteric Arteries ◽  
Diabetic Rat ◽  
Resistance Arteries ◽  
Significant Difference ◽  
Endothelium Dependent Relaxation

1. There is growing evidence that an impairment in the function of nitric oxide synthase may play a role in the vascular complications of diabetes mellitus. The relaxation of resistance arteries from the mesenteric and hindlimb circulations of streptozotocin-induced diabetic rats and age-matched controls were investigated using two endothelium-dependent vasodilators, bradykinin and acetylcholine, and the endothelium-independent vasodilator sodium nitroprusside. The contractile responses to the α1-adrenergic agonist phenylephrine were also studied. 2. Endothelium-dependent relaxation to acetylcholine was impaired in the diabetic rats in arteries from both mesenteric and hindlimb circulations (hindlimb pEC50, 7.93 ± 0.08 in the control compared with 7.38 ± 0.10 in the diabetic rat; mesenteric pEC50, 7.47 ± 0.04 in the control compared with 6.65 ± 0.06 in the diabetic rat; unpaired t-test P < 0.0001). Bradykinin elicited relaxation in only the mesenteric arteries, and this was not attenuated in the diabetic rats compared with controls. 3. Endothelium-independent relaxation to sodium nitroprusside was similar in the two circulations and was not abnormal in the diabetic rats. There was no significant difference in constrictor responses to phenylephrine between diabetic rats and controls in either the hindlimb or mesenteric arteries, in contrast to an earlier study in which we showed increased sensitivity to noradrenaline. 4. The diabetic rats therefore demonstrated a specific impairment of receptor-mediated endothelium-dependent relaxation to acetylcholine. These results suggest that, in this diabetic model, the ability of the endothelium to relax arteries via nitric oxide may involve a defect of a specific signal transduction pathway, leading to reduced production of nitric oxide.

Potent vasodilator responses to human urotensin-II in human pulmonary and abdominal resistance arteries

2001 ◽  
Vol 280 (2) ◽  
pp. H925-H928 ◽  
Author(s):  
Alison Stirrat ◽  
Marie Gallagher ◽  
Stephen A. Douglas ◽  
Eliot H. Ohlstein ◽  
Colin Berry ◽  
...  
Keyword(s):  
Sodium Nitroprusside ◽  
Vascular Function ◽  
Pulmonary Arteries ◽  
Systemic Resistance ◽  
Internal Diameter ◽  
Urotensin Ii ◽  
Resistance Arteries ◽  
Pulmonary Vessels ◽  
Potent Vasodilator ◽  
Abdominal Arteries

The peptide human urotensin-II (hUT-II) and its receptor have recently been cloned. The vascular function of this peptide in humans, however, has yet to be determined. Vasoconstrictor and vasodilator responses to hUT-II were investigated in human small muscular pulmonary arteries [∼170 μm internal diameter (ID)] and human abdominal resistance arteries (∼200 μm ID). Vasodilator responses were investigated in endothelin-1 (3 nM) precontracted vessels and, in the small pulmonary vessels, compared with the known vasodilators adrenomedullin, sodium nitroprusside, and acetylcholine. In human small pulmonary arteries, hUT-II did not induce vasoconstriction but was a potent vasodilator [−log M concentration causing 50% of the maximum vasodilator effect (pIC50) 10.4 ± 0.5; percentage of reduction in tone ( E max) 81 ± 8% (vs. 23 ± 11% in time controls), n = 5]. The order of potency for vasodilation was human urotensin-II = adrenomedullin (pIC50 10.1 ± 0.4, n = 6) > sodium nitroprusside (pIC50 7.4 ± 0.2, n = 6) = acetylcholine (pIC50 6.8 ± 0.3, n = 6). In human abdominal arteries, hUT-II did not induce vasoconstriction but was a potent vasodilator [pIC50 10.3 ± 0.7; E max96 ± 8% (vs. 43 ± 16% in time controls), n = 4]. This is the first report that hUT-II is a potent vasodilator but not a vasoconstrictor of human small pulmonary arteries and systemic resistance arteries.

Abstract MP10: Early Functional and Structural Alterations of Resistance Arteries in Mice Treated with an Inhibitor of the Vascular Endothelial Growth Factor Receptor

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
CARMINE SAVOIA ◽  
Emanuele Arrabito ◽  
Augusto C Montezano ◽  
Carmine Nicoletti ◽  
Heather Y Small ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Vascular Remodeling ◽  
Growth Factor Receptor ◽  
Mesenteric Arteries ◽  
No Production ◽  
Vascular Endothelial ◽  
Resistance Arteries ◽  
Structural Alterations ◽  
Endothelial Growth Factor

Background: Inhibition of tyrosine kinases receptors such as vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) improves outcomes in patients with cancers. Only VEGFR inhibitors, however, induce severe hypertension whose mechanisms remain unclear. We hypothesized that VEGFR inhibitors may induce early vascular functional and structural alterations, that may precede the development of hypertension. Methods and results: Normotensive SV-129 mice (8 weeks old, 5 for each group) were treated or not with the VEGFR inhibitor Vatalanib (VAT, 100 mg/Kg/day) or the EGFR inhibitor Gefitinib (GEF, 100 mg/Kg/day). Vehicle-treated control mice were also studied. Blood pressure (BP) was measured by tail-cuff method. Endothelium-dependent and -independent relaxations were assessed by concentration-response curves to acetylcholine (1 nM to 100 μM) ± L-NAME (100 μM) and sodium nitroprusside (10 nM to 1 mM) respectively, in mesenteric arteries pre-contracted with norepinephrine (10 μM). Media-to-lumen ratio (M/L, an index of early vascular remodeling), and cross sectional area (CSA) were evaluated on pressurized preparations. After two weeks, BP was similarly preserved in both VAT- and GEF-treated mice as compared to vehicle-treated mice (89.8±1.5 mmHg and 87.2±2.8 mmHg vs 92.2±2.2 mmHg, respectively, NS). Endothelium-dependent relaxation was similarly preserved in vehicle-treated and GEF-treated mice, whereas it was reduced in VAT-treated mice (-17% vs vehicle-treated mice, P<0.05). L-NAME blunted acetylcholine-induced relaxation in all groups except in VAT-treated mice, suggesting an impairment of NO production only in this group. Endothelium-independent relaxation was similar in all groups. Only VAT-treated mice presented increased M/L as compared to vehicle-treated mice (6.3±0.1% vs 5.4±0.1%, P<0.05). M/L resulted similar in GEF-treated and vehicle-treated mice. CSA was similar in all groups. Conclusion: In normotensive mice, only VAT promoted early vascular alterations such as endothelial dysfunction and vascular remodeling in resistance arteries. Those changes in the vasculature are distinctive of hypertension and might precede and sustain the development of the hypertensive disease.

scholarly journals Secondhand smoke exposure impairs ion channel function and contractility of mesenteric arteries

Function ◽  
2021 ◽  
Author(s):  
Thanhmai Le ◽  
Miguel Martín-Aragón Baudel ◽  
Arsalan Syed ◽  
Navid Singhrao ◽  
Shiyue Pan ◽  
...  
Keyword(s):  
Cigarette Smoke ◽  
Secondhand Smoke ◽  
Vascular Complications ◽  
Mesenteric Arteries ◽  
Myogenic Tone ◽  
Resistance Arteries ◽  
Vascular Effects ◽  
Shs Exposure ◽  
Underlying Mechanisms ◽  
Myocyte Contractility

Abstract Cigarette smoke, including secondhand smoke (SHS), has significant detrimental vascular effects, but its effects on myogenic tone of small resistance arteries and the underlying mechanisms are understudied. Although it is apparent that SHS contributes to endothelial dysfunction, much less is known about how this toxicant alters arterial myocyte contraction, leading to alterations in myogenic tone. The study's goal is to determine the effects of SHS on mesenteric arterial myocyte contractility and excitability. C57BL/6J male mice were randomly assigned to either filtered air (FA) or SHS (6 hours/day, 5 days/week) exposed groups for a 4, 8, or 12-weeks period. Third and fourth-order mesenteric arteries and arterial myocytes were acutely isolated and evaluated with pressure myography and patch clamp electrophysiology, respectively. Myogenic tone was found to be elevated in mesenteric arteries from mice exposed to SHS for 12 weeks but not for 4 or 8 weeks. These results were correlated with an increase in L-type Ca2+ channel activity in mesenteric arterial myocytes after 12 weeks of SHS exposure. Moreover, 12 weeks SHS exposed arterial myocytes have reduced total potassium channel current density, which correlates with a depolarized membrane potential (Vm). These results suggest that SHS exposure induces alterations in key ionic conductances that modulate arterial myocyte contractility and myogenic tone. Thus, chronic exposure to an environmentally relevant concentration of SHS impairs mesenteric arterial myocyte electrophysiology and myogenic tone, which may contribute to increased blood pressure and risks of developing vascular complications due to passive exposure to cigarette smoke.

Effects of Volatile Anesthetics on Acetylcholine-induced Relaxation in the Rabbit Mesenteric Resistance Artery 

1995 ◽  
Vol 82 (1) ◽  
pp. 188-204 ◽  
Author(s):  
Takashi Akata ◽  
Mikio Nakashima ◽  
Kenji Kodama ◽  
Walter A. Boyle ◽  
Shosuke Takahashi
Keyword(s):  
Endothelial Function ◽  
Sodium Nitroprusside ◽  
Volatile Anesthetic ◽  
Volatile Anesthetics ◽  
Mesenteric Arteries ◽  
K Channel ◽  
Resistance Arteries ◽  
Anesthetic Action ◽  
Endothelium Dependent Relaxation

Background Vascular endothelium plays an important role in the regulation of vascular tone. Volatile anesthetics have been shown to attenuate endothelium-mediated relaxation in conductance arteries, such as aorta. However, significant differences in volatile anesthetic pharmacology between these large vessels and the small vessels that regulate systemic vascular resistance and blood flow have been documented, yet little is known about volatile anesthetic action on endothelial function in resistance arteries. Furthermore, endothelium-dependent relaxation mediated by factors other than endothelium-derived relaxing factor (EDRF) has recently been recognized, and there is no information available regarding volatile anesthetic action on non-EDRF-mediated endothelium-dependent relaxation. Methods Employing isometric tension recording and microelectrode methods, the authors first characterized the endothelium-dependent relaxing and hyperpolarizing actions of acetylcholine (ACh) in rabbit small mesenteric arteries, and tested the sensitivities of these actions to EDRF pathway inhibitors and K+ channel blockers. They then examined the effects of the volatile anesthetics isoflurane, enflurane, and sevoflurane on ACh-induced endothelium-dependent relaxation that was sensitive to EDRF inhibitors and that which was resistant to the EDRF inhibitors but sensitive to blockers of ACh-induced hyperpolarization. The effects of the volatile anesthetics on endothelium-independent sodium nitroprusside (SNP)-induced relaxation were also studied. Results Acetylcholine concentration-dependently caused both endothelium-dependent relaxation and hyperpolarization of vascular smooth muscle. The relaxation elicited by low concentrations of ACh (&lt; or = 0.1 microM) was almost completely abolished by the EDRF inhibitors NG-nitro-L-arginine (LNNA), oxyhemoglobin (HbO2), and methylene blue (MB). The relaxation elicited by higher concentrations of ACh (&gt; or = 0.3 microM) was only attenuated by the EDRF inhibitors. The remaining relaxation, as well as the ACh-induced hyperpolarization that was also resistant to EDRF inhibitors, were both specifically blocked by tetraethylammonium (TEA &gt; or = 10 mM). Sodium nitroprusside, a NO donor, produced dose-dependent relaxation, but not hyperpolarization, in the endothelium-denuded (E[-]) strips, and the relaxation was inhibited by MB and HbO2, but not TEA (&gt; or = 10 mM). One MAC isoflurane, enflurane, and sevoflurane inhibited both ACh relaxation that was sensitive to the EDRF inhibitors and the ACh relaxation resistant to the EDRF inhibitors and sensitive to TEA, but not SNP relaxation (in the E[-] strips). An additional finding was that the anesthetics all significantly inhibited norepinephrine (NE) contractions in the presence and absence of the endothelium or after exposure to the EDRF inhibitors. Conclusions The results confirm that ACh has a hyperpolarizing action in rabbit small mesenteric resistance arteries that is independent of EDRF inhibitors but blocked by the K+ channel blocker TEA. The ACh relaxation in these resistance arteries thus appears to consist of distinct EDRF-mediated and hyperpolarization-mediated components. Isoflurane, enflurane, and sevoflurane inhibited both components of the ACh-induced relaxation in these small arteries, indicating a more global depression of endothelial function or ACh signaling in endothelial cells, rather than a specific effect on the EDRF pathway. All these anesthetics exerted vasodilating action in the presence of NE, the primary neurotransmitter of the sympathetic nervous system, which plays a major role in maintaining vasomotor tone in vivo. This strongly indicates that the vasodilating action of these anesthetics probably dominates over their inhibitory action on the EDRF pathway and, presumably, contributes to their known hypotensive effects in vivo. Finally, the vasodilating action of these anesthetics is, at least in part, independent from endothelium.

scholarly journals The direct renin inhibitor aliskiren improves vascular remodelling in transgenic rats harbouring human renin and angiotensinogen genes

2013 ◽  
Vol 125 (4) ◽  
pp. 183-189 ◽  
Author(s):  
Carmine Savoia ◽  
Emanuele Arrabito ◽  
Rosa Parente ◽  
Lidia Sada ◽  
Luca Madaro ◽  
...  
Keyword(s):  
Body Mass ◽  
Fold Increase ◽  
Mesenteric Arteries ◽  
Angiotensin Converting Enzyme Inhibition ◽  
No Production ◽  
Vascular Remodelling ◽  
Resistance Arteries ◽  
Transgenic Rats ◽  
Direct Renin Inhibitor ◽  
Plasma Nitrite

In the present study, we tested the hypothesis that chronic treatment with the direct rennin inhibitor aliskiren improves the remodelling of resistance arteries in dTGR (double-transgenic rats). dTGR (5 weeks) were treated with aliskiren (3 mg/kg of body mass per day) or ramipril (1 mg/kg of body mass per day) for 14 days and compared with age-matched vehicle-treated dTGR. BP (blood pressure) was similarly reduced in both aliskiren-treated and ramipril-treated rats compared with control dTGR (167±1 and 169±2 mmHg compared with 197±4 mmHg respectively; P<0.05). The M/L (media-to-lumen) ratio assessed on pressurized preparations was equally reduced in aliskiren-treated and ramipril-treated rats compared with controls (6.3±0.5 and 6.4±0.2% compared with 9.8±0.4% respectively; P<0.05). Endothelium-dependent and -independent relaxations were similar among the groups. L-NAME (NG-nitro-L-arginine methyl ester) significantly reduced acetylcholine-induced dilation in drug-treated dTGR. This effect was significantly more prominent in aliskiren-treated rats. eNOS (endothelial NO synthase) expression showed a 2-fold increase only in aliskiren-treated dTGR as compared with controls (P<0.01) and ramipril-treated dTGR (P<0.05). Plasma nitrite, as an index of NO production, was significantly increased in dTGR treated with either aliskiren or ramipril compared with controls. Only aliskiren induced a 2-fold increase in plasma nitrite, which was significantly greater than that induced by ramipril (P<0.05). gp91phox expression and ROS (reactive oxygen species) production in aorta were significantly and similarly reduced by both drugs. In conclusion, equieffective hypotensive doses of aliskiren or ramipril reduced the M/L ratio of mesenteric arteries and improved oxidative stress in dTGR. However, only aliskiren increased further NO production in the vasculature. Hence, in dTGR, direct renin inhibition induces favourable effects similar to that induced by ACE (angiotensin-converting enzyme) inhibition in improving vascular remodelling through different mechanisms.

Endothelial dysfunction and arterial pressure regulation during early diabetes in mice: roles for nitric oxide and endothelium-derived hyperpolarizing factor

2007 ◽  
Vol 293 (2) ◽  
pp. R707-R713 ◽  
Author(s):  
Sharyn M. Fitzgerald ◽  
Barbara K. Kemp-Harper ◽  
Helena C. Parkington ◽  
Geoffrey A. Head ◽  
Roger G. Evans
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Arterial Pressure ◽  
Early Stage ◽  
Mesenteric Arteries ◽  
No Production ◽  
Wild Type ◽  
Early Diabetes ◽  
Diabetes In Mice ◽  
Vehicle Treatment

We determined whether nitric oxide (NO) counters the development of hypertension at the onset of diabetes in mice, whether this is dependent on endothelial NO synthase (eNOS), and whether non-NO endothelium-dependent vasodilator mechanisms are altered in diabetes in mice. Male mice were instrumented for chronic measurement of mean arterial pressure (MAP). In wild-type mice, MAP was greater after 5 wk of Nω-nitro-l-arginine methyl ester (l-NAME; 100 mg·kg−1·day−1 in drinking water; 97 ± 3 mmHg) than after vehicle treatment (88 ± 3 mmHg). MAP was also elevated in eNOS null mice (113 ± 4 mmHg). Seven days after streptozotocin treatment (200 mg/kg iv) MAP was further increased in l-NAME-treated mice (108 ± 5 mmHg) but not in vehicle-treated mice (88 ± 3 mmHg) nor eNOS null mice (104 ± 3 mmHg). In wild-type mice, maximal vasorelaxation of mesenteric arteries to acetylcholine was not altered by chronic l-NAME or induction of diabetes but was reduced by 42 ± 6% in l-NAME-treated diabetic mice. Furthermore, the relative roles of NO and endothelium-derived hyperpolarizing factor (EDHF) in acetylcholine-induced vasorelaxation were altered; the EDHF component was enhanced by l-NAME and blunted by diabetes. These data suggest that NO protects against the development of hypertension during early-stage diabetes in mice, even in the absence of eNOS. Furthermore, in mesenteric arteries, diabetes is associated with reduced EDHF function, with an apparent compensatory increase in NO function. Thus, prior inhibition of NOS results in endothelial dysfunction in early diabetes, since the diabetes-induced reduction in EDHF function cannot be compensated by increases in NO production.

scholarly journals Pregnancy Enhances the Angiotensin (Ang)-(1–7) Vasodilator Response in Mesenteric Arteries and Increases the Renal Concentration and Urinary Excretion of Ang-(1–7)

Endocrinology ◽  
2003 ◽  
Vol 144 (8) ◽  
pp. 3338-3343 ◽  
Author(s):  
Liomar A. A. Neves ◽  
Aleck F. Williams ◽  
David B. Averill ◽  
Carlos M. Ferrario ◽  
Michael P. Walkup ◽  
...  
Keyword(s):  
Urinary Excretion ◽  
Excretion Rate ◽  
Virgin Female ◽  
Cardiovascular Regulation ◽  
Mesenteric Arteries ◽  
Female Rats ◽  
Resistance Arteries ◽  
Urinary Excretion Rate ◽  
Response Curves ◽  
Mesenteric Vessels

Abstract The vasoactive effect of angiotensin (Ang)-(1–7) in mesenteric resistance arteries together with its plasma and kidney concentration and urinary excretion was assessed in pregnant and virgin rats. Mesenteric arteries (230–290 μm) were mounted in a pressurized myograph system and Ang-(1–7) concentration-dependent response curves (10−10–10−5m) were determined in arteries preconstricted with endothelin-1 (10−7m). The Ang-(1–7) response was investigated in vessels with and without pretreatment with the Ang-(1–7) antagonist [d-[Ala7]-Ang-(1–7)] (10−7m). Ang-(1–7) caused a significantly enhanced, concentration-dependent dilation of mesenteric vessels (EC50 = 2.7 nm) from pregnant compared with virgin female rats. d-[Ala7]-Ang-(1–7) eliminated the vasodilator effect of Ang-(1–7). There was no significant change in plasma concentration of Ang-(1–7) in pregnant animals. On the other hand, 24 h urinary excretion and kidney concentration of Ang-(1–7) were significantly higher in pregnant animals. The increased mesenteric dilation to Ang-(1–7) with enhanced kidney concentration and 24 h urinary excretion rate of Ang-(1–7) suggests an important role for this peptide in cardiovascular regulation during pregnancy.

scholarly journals Computational design and experimental characterization of a novel β-common receptor inhibitory peptide

Peptides ◽  
2018 ◽  
Vol 104 ◽  
pp. 1-6 ◽  
Author(s):  
Cody R. Kilar ◽  
Sivakumar Sekharan ◽  
Larysa Sautina ◽  
YanPeng Diao ◽  
Shahar Keinan ◽  
...  
Keyword(s):  
Computational Design ◽  
Experimental Characterization ◽  
Inhibitory Peptide ◽  
Common Receptor

Simulated microgravity alters rat mesenteric artery vasoconstrictor dynamics through an intracellular Ca2+ release mechanism

2008 ◽  
Vol 294 (5) ◽  
pp. R1577-R1585 ◽  
Author(s):  
Patrick N. Colleran ◽  
Bradley J. Behnke ◽  
M. Keith Wilkerson ◽  
Anthony J. Donato ◽  
Michael D. Delp
Keyword(s):  
Temporal Dynamics ◽  
Orthostatic Intolerance ◽  
Mesenteric Arteries ◽  
Release Mechanism ◽  
Resistance Arteries ◽  
Receptor Mrna ◽  
Cardiovascular Deconditioning ◽  
Rat Mesenteric Artery ◽  
Mrna And Protein Expression

Previous work has shown that orthostatic hypotension associated with cardiovascular deconditioning results from inadequate peripheral vasoconstriction. We used the hindlimb-unloaded (HU) rat in this study as a model to induce cardiovascular deconditioning. The purpose of this study was to test the hypothesis that 14 days of HU diminishes vasoconstrictor responsiveness of mesenteric resistance arteries. Mesenteric resistance arteries from control ( n = 43) and HU ( n = 44) rats were isolated, cannulated, and pressurized to 108 cm H2O for in vitro experimentation. Myogenic (intralumenal pressure ranging from 30 to 180 cm H2O), KCl (2–100 mM), norepinephrine (NE, 10−9–10−4 M) and caffeine (1–20 mM) induced vasoconstriction, as well as the temporal dynamics of vasoconstriction to NE, were determined. The active myogenic and passive pressure responses were unaltered by HU when pressures remained within physiological range. However, vasoconstrictor responses to KCl, NE, and caffeine were diminished by HU, as well as the rate of constriction to NE (C, 14.8 ± 3.6 μm/s vs. HU 7.6 ± 1.8 μm/s). Expression of sarcoplasmic reticulum Ca2+ATPase 2 and ryanodine 3 receptor mRNA was unaffected by HU, while ryanodine 2 receptor mRNA and protein expression were diminished in mesenteric arteries from HU rats. These data suggest that HU-induced and microgravity-associated orthostatic intolerance may be due, in part, to an attenuated vasoconstrictor responsiveness of mesenteric resistance arteries resulting from a diminished ryanodine 2 receptor Ca2+ release mechanism.

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