Formyl peptide receptor induces vascular unresponsiveness to noradrenaline via disruption of actin polymerization
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Vascular hyporeactivity to adrenergic stimulation is a significant independent prognostic factor of mortality in sepsis. Loss of vascular tone occurs through complex, multifactorial mechanisms that have not been fully elucidated. Formyl peptide receptor (FPR) is an innate immune system receptor that is activated by bacterial and mitochondrial fragments called N‐formyl peptides. Previously, we have observed that FPR stimulation with both mitochondrial and bacterial N‐formyl peptides leads to reduced noradrenaline‐induced contraction in resistance arteries and hypotension. Therefore, we first hypothesized that the absence of FPR would increase vascular noradrenaline contraction. To test this hypothesis we used male, 8–10 week old wild‐type (WT; C57BL/6) or FPR‐1 knockout (KO) mice to measure vascular function in mesenteric resistance arteries (MRA, diameter ~180 μm) and aorta. Surprisingly our hypothesis was refuted, since the absence of global FPR induced similar hyporesponsiveness to noradrenaline‐induced contraction (10 −10 –10 −4 M) in all arterial beds (E max : MRA: WT: 10.6 ± 0.4 vs. FPR‐1 KO: 8.3 ± 0.5 mN, p<0.05; Aorta: WT: 5.4 ± 1.2 vs. FPR‐1 KO: 0.6 ± 0.2 mN, p<0.05). This result suggested that the absence of FPR mimics its desensitization which leads to vascular unresponsiveness to noradrenaline. Loss of vascular tone and desensitization to adrenergic agents could be a result of cytoskeleton disruption. In fact, it is known that FPR activation by N‐formyl peptides leads to changes in cytoskeleton‐regulating proteins in leukocytes. Consequently, we hypothesized that the mechanistic pathway that leads to vascular unresponsiveness following FPR desensitization and/or absence is due to a disruption in actin polymerization. To assess if FPR‐1 interferes with actin polymerization, some arteries from WT or FPR‐KO mice were incubated with cytochalasin B (CYTO B, 10 −6 M) (inhibits both the rate of actin polymerization and the interaction of actin filaments in solution) or jasplakinolide (JASP, 10 −7 M) (promotes actin‐stabilizing and polymerization). JASP increased noradrenaline‐induced contraction only in arteries from FPR‐1 KO. On the other hand, CYTO abolished noradrenaline‐induced‐contraction in arteries from both strains of mice, suggesting that actin polymerization is crucial for noradrenaline‐induced contraction. Overall, these data suggest that FPR hyperstimulation, which leads to desensitization, and absence induces vascular unresponsiveness in conductance and resistance arteries via disruption of actin polymerization. Given that patients with sepsis have high levels of N‐formyl peptides (bacterial and mitochondrial), FPR desensitization can occur in these patients due to its hyperstimulation. Since noradrenaline administration is known to be ineffective at reversing vascular collapse and hypotension in septic patients, perhaps reconstituting FPR sensitization and/or actin polymerization could be putative treatment targets. Support or Funding Information Research Support: National Institutes of Health (NIH: 1K99GM118885‐01)Keywords:
Mesenteric arteries
ABSTRACT The characteristics of the contraction of vascular smooth muscle were examined in thoracic aorta and ischiadic artery of chickens aged 3, 6, 10 and 18 weeks. High K + solution induced a sustained contraction in smooth muscle preparations of aorta and ischiadic artery in vitro . The contraction of the ischiadic artery became greater with age, whereas the contraction of the aortic preparation did not. In the ischiadic artery, the magnitude of the contraction divided by the weight of the muscle preparation was constant at all ages studied. However, those in the aortic preparation decreased with age. These results suggest that the changes in the contractile responses of vascular smooth muscle owing to the age of chickens vary widely according to the preparations of blood vessels, and that the functional smooth muscle cells in the thoracic aorta of chicken do not increase with age.
Thoracic aorta
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To elucidate the mechanism of contraction of the smooth muscle of the rat's aorta, its response to norepinephrine (NE), 5-hydroxytrypatamine (5-HT) and potassium chloride (KCI) was determined before and after pretreatment with reserpine and beta-diethylamionethyl 2-2-diphenylpropyl acetate (SKF 525-A). Unlike the rabbit's aorta, contraction of the rat's aorta induced by NE was inhibited by SKF 525-A. After the induction of maximal contraction, SKF 525-A induced a graded rapid relaxation after KCl, less so after 5-HT, and least after NE. Pretreatment with reserpine failed to induce supersensitivity to NE. After incubation in a Ca++-free or Na+ and Ca++-free Krebs solution, the rat's aorta failed to contract even on the addition of Ca++ or NE.
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AIM: To investigate the actions of lipopolysaccharid (LPS) on the contractility of vascular smooth muscle cells (VSMCs) caused by KCl and to analyse the possible action of NO through observing the effects of nitric oxide synthase inhibitor N W Nitric L Arginine (L NNA) and NO precursor L arginine. METHODS: VSMCs of SD rat aorta were cultured in vitro and microweb measurement method was used to examine the contractility of VSMCs. INOS expression was observed using immunohistochemistry method. RESULTS:5×10 -1 ～1 g/L LPS markedly inhibited the contraction of VSMCs induced by KCL. 5×10 -4 mol/L L NNA and 5×10 -3 mol/L L arginine, when added alone, had no effect on the contraction of VSMCs. 5×10 -4 mol/L L NNA could block the inhibitory effect of LPS on VSMC contraction. The effect of L NNA could be antagonized by L arginine (5×10 -3 mol/L) and positive staining of iNOS appeared in LPS group in immunohistochemistry experiment. CONCLUSION: LPS inhibits the contraction of VSMCs, which may be the result of increased NO production by VSMCs.
Contractility
Nitroarginine
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Objective To explore the relaxation effect of angiotensin1-7(Ang1-7)or acetylcholine(Ach)on rats aorta contraction,which were induced by angiotensin Ⅱor phenyladrenalin.Methods Aorta of rats were placed in constant temperature[(37±0.5) ℃]filling device,and the relaxation reaction induced by Ang1-7 or Ach was recorded by physiological recorder.Results The inhibition effect of Ach on the aorta contaction induced by phenyladrenalin was stronger than Ang1-7(P0.05),their half concentrations of inhibition(IC50)were[(175±36)×10-9] mol·L-1 and[(227±14)×10-9] mol·L-1.The inhibition effect of Ang1-7 on the aorta contraction induced by anyiotensin Ⅱ was stronger than Ach(P0.05),and their IC50 were[(157±8)×10-9] mol·L-1and [(273±12)×10-9] mol·L-1 respectively.Conclusion The relaxation effect of Ang1-7 on rats aorta contraction induced by angiotensin Ⅱ was stronger,but weaker when the contraction was induced by phenyladrenalin,than acetylcholine.
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Mesenteric arteries
Stroke
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Group psychotherapy
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Background: This study was performed to examine the protective effects of iganidipine, a new water-soluble calcium antagonist, on the morphological and functional changes of arteries in Dahl salt-sensitive (Dahl-S) rats. Methods and Results: Vehicle and iganidipine were administered orally to Dahl-S rats fed a high-salt diet (HSD) for 8 weeks. Aorta, superior mesenteric arteries (SMA), and peri pheral mesenteric arteries (PMA) were examined light-microscopically or electron- microscopically. Relaxant responses of isolated aorta and SMA were recorded isometrically. In rats fed HSD, blood pressure was markedly increased. Light microscopy showed intimal and medial hypertrophy, periarteritis, and narrowed arterial lumen in the PMA. Transmis sion and scanning electron microscopy or light microscopy showed medical thickness in the aorta and SMA and hypertrophy of endothelial cells and dilatation of the subendothelial space only in the aorta. In the SMA, both endothelium-dependent relaxation (EDR) and endothelium-independent relaxations (EIR) were reduced to a similar extent. In the aorta, the EDR was more markedly attenuated than the EIR. Iganidipine at 3 mg/kg/day showed a 24-h sustained hypotensive effect and completely prevented the morphological and func tional changes in both arteries. Iganidipine at 1 mg/kg/day, which lowered blood pressure only for several hours, decreased the injuries in PMA and aortic endothelium and moder ately restored the EDR in the aorta. Iganidipine at 0.3 mg/kg/day had no effects. Conclusions: In Dahl-S rats fed an HSD, iganidipine completely prevented all the changes at a sustained-hypotensive dose and prevented the injuries of PMA and aortic endothelium and the reduction of EDR in the aorta at a nonsustained hypotensive dose. Nonhemody namic effects of iganidipine may be partly involved in its protective effects against arterial injuries.
Mesenteric arteries
Thoracic aorta
Lumen (anatomy)
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This study was designed to investigate the effects of angiotensinⅡ on non-anoxia and anoxia SHR aorta and guinea pig aorta. We found that AngⅡ3￣300 nmol·L-1 significantly increased the contraction of guinea pig aorta in dose-dependent manner. Aorta contraction in guinea pig was more sensitive to AngⅡthan in non-anoxia SHR. After anoxia, the aorta contraction induced by AngⅡ was markedly increased in guinea pig but not in aorta of SHR. In addition, anoxia significant dicreased the content of AngⅡ of SHR aorta. However, there was no difference between non-anoxia and anoxia aorta of guinea pig in the concentration of AngⅡ.The results suggested that contraction responses of aorta to AngⅡ may be different between SHR and the guinea pig.
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Valeriana Officinalis Var.Latifolia Miq Regulates Vascular Smooth Muscle Cell Contraction and Growth
Objective To investigate the effects of valeriana officinalis var .Latifolia miq (VOL) on the contraction and growth of cultuted rat vascular smooth muscle cell(VSMC). Method Aortic medial smooth muscle cells of wistar rat were cultured and passaged. The VSMCs were stimulated to contract by angiotentin Ⅱ(Ang Ⅱ 10 -3 mmol/L), and the contraction were measured. 3H-TdR and 3H-Leucine incorporation of VSMCs were performed at different time points after the addition of drugs. Results VOL could significantly inhibit the Ang Ⅱ-stimulated contraction of VSMCs, L-NAMEcould not affect VOL's ability to inhibit contraction. VOLcould significantly inhibit the incorporation of 3H-TdR and 3H-Leucine into VSMCs in does-dependent manner. Conclusion VOL could significantly suppress the Ang Ⅱ-stimulated contraction and growth of cultured rat VSMCs.
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The relationship between the accumulation of NKY-722 and its vasoinhibitory effect on KCl-induced contraction was examined in canine mesenteric arteries. NKY-722 showed a high level of accumulation in canine mesenteric arteries and reached near maximal levels at 60 min. The tissue/medium ratio measured at 60 min was independent of the bath concentration of NKY-722 (10(-9), 10(-8) and 10(-7) M). NKY-722 (10(-9) and 10(-7) M) attenuated the KCl (30 mM)-induced contraction of canine mesenteric arteries, and this effect was dependent on the pretreatment time (5-60 min). The vasoinhibitory effect of NKY-722 (during incubation) on KCl-induced contraction correlated with its accumulation in the vascular preparations. Preparations were incubated with NKY-722 (5 x 10(-9) M) for 60 min and repetitively washed out, showing that the accumulation of NKY-722 decreased slowly over 300 min. When the preparations were incubated with NKY-722 (5 x 10(-9) M) for 60 min, the vasoinhibitory effect on KCl-induced contraction remained for over 300 min after repetitive washouts. The vasoinhibitory effect of NKY-722 (during washout) on KCl-induced contraction also correlated with its accumulation in the vascular preparations. The present experiments indicate that NKY-722 accumulates in canine mesenteric arteries at high levels and should be washed out slowly, and suggest that NKY-722 accumulation in vessel walls may contribute to the long duration of its antihypertensive effect.
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