Phospholipase C and Src Modulate Angiotensin II-Induced Cyclic AMP Production in Preglomerular Microvascular Smooth-Muscle Cells From Spontaneously Hypertensive Rats

Jackson, Edwin K.; Gillespie, Delbert G.; Jackson, T. L.

doi:10.1097/fjc.0b013e31802ee3d5

Cited by 5 publications

(4 citation statements)

References 35 publications

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“…We selected isoproterenol as the stimulus because this drug is a β‐adrenoceptor agonist and β‐adrenoceptors are positively coupled to adenylyl cyclase. Moreover, in previous studies, we observed that isoproterenol robustly increased cAMP levels in PGVSMC 24,25 . In the present study, isoproterenol caused a large increase in extracellular levels of cAMP and this increase was strongly suppressed, indeed nearly totally inhibited, by MRP4 siRNA.…”

Section: Discussionsupporting

confidence: 76%

Multidrug resistance protein 4 mediates cAMP efflux from rat preglomerular vascular smooth muscle cells

Cheng

Ren²,

Jackson

2010

Clin Exp Pharma Physio

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SUMMARY1. Our previous studies show that stimulation of adenylyl cyclase in preglomerular vascular smooth muscle cells (PGVSMCs) increases extracellular 3',5'-cAMP; however, the mechanism by which PGVSMCs transport intracellular 3',5'-cAMP into the extracellular milieu is unknown. 2.We hypothesize that multidrug resistance protein 4 (MRP4) is the primary transporter mediating efflux of intracellular 3',5'-cAMP from PGVSMCs.3. Both RT-PCR and real-time PCR detected MRP4 mRNA in PGVSMCs in culture. Moreover, Western blotting using an antibody specific for MRP4 gave rise to a 150 kDa signal consistent with the presence of MRP4 protein in PGVSMCs. 4.Specifically-designed siRNA reduced MRP4 mRNA expression by 71% (p=0.0075) and MRP4 protein by 80% (p=0.0004). 5.Isoproterenol (1 μmol/L) increased intracellular 3',5'-cAMP, which resulted in efflux of 3',5'-cAMP into the medium. siRNA knockdown of MRP4 significantly reduced basal extracellular 3',5'-cAMP and nearly abolished isoproterenol-induced increases in extracellular 3',5'-cAMP (p=0.0143, interaction between isoproterenol and MRP4 siRNA in 2-factor analysis of variance). In isoproterenol-treated cells, MRP4 siRNA decreased the ratio of extracellular 3',5'-cAMP to intracellular 3',5'-cAMP by 72% (p=0.0019). 6.We conclude that MRP4 is the dominant 3',5'-cAMP transporter in PGVSMCs.

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Section: Discussionsupporting

confidence: 76%

Multidrug resistance protein 4 mediates cAMP efflux from rat preglomerular vascular smooth muscle cells

Cheng

Ren²,

Jackson

2010

Clin Exp Pharma Physio

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“…Activation of phospholipase C is a key link in numerous metabotropic receptors, including the receptors stimulated in the present study. Inhibition of the function of phospholipase C leads to a reduction in calcium ion concentration in the cytoplasm of cells activated by stimulation of α1-adrenergic receptors (23,24), endothelin type A (25) and angiotensin II receptor type-1 (26).…”

Section: Discussionmentioning

confidence: 99%

Effect of 2,4,6-trimethyl-N-[3-(trifluoromethyl)phenyl]benzene-sulfonamide on calcium influx in three contraction models

et al. 2015

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2,4,6-Trimethyl--[3-(trifluoromethyl)phenyl]benzenesulfonamide (m-3M3FBS) activates phospholipase C and stimulates apoptosis; however, in smooth muscle cells it may increase the perfusion pressure. The main aim of the present study was to evaluate the physiological effect of direct stimulation of phospholipase C on vascular smooth muscle reactivity using three contraction models. Experiments were performed on the isolated and perfused tail artery of Wistar rats. The contraction force in the present model was measured by an increased level of perfusion pressure with a constant flow. Concentration-response curves (CRCs) obtained for phenylephrine, arg-vasopressin, mastoparan-7 and Bay K8644 presented a sigmoidal association. In comparison to the control curves, CRCs in the presence of m-3M3FBS were significantly shifted to the left except for Bay K8644. Analyses of calcium influx suggest that in the presence of m-3M3FBS the calcium influx from intra- and extracellular calcium stores was significantly higher. The results of the present experiments suggest that m-3M3FBS significantly increases the reactivity of vascular smooth muscle stimulated with metabotropic receptors or G-protein by an increase in calcium influx from intra- and extracellular calcium stores. The current knowledge regarding the apoptotic pathway shows the significance of calcium ions involved in this process, thus, m-3M3FBS may induce apoptosis by an increase of cytoplasmic calcium concentration; however, simultaneously, the use of this mechanism in therapy must be preceded by a molecular modification that eliminates a possible vasoconstriction effect.

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“…Activation of PLC is a key event in numerous metabotropic receptors, the physiological response of which was assessed in the present study. Inhibition of PLC function leads to a reduction in the calcium ion concentration in the cytoplasm of cells activated by the stimulation of α1-adrenergic receptors (13,18,19), endothelin receptor type A (20) and angiotensin II receptor type-1 (21). Furthermore, it has been demonstrated that the increase in cytoplasmic calcium concentration induced by PLC is significant at the molecular level and able to induce a significant physiological reponse (14).…”

Section: Discussionmentioning

confidence: 99%

2,4,6-Trimethyl-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide increases calcium influx in lipopolisaccharide-pre-treated arteries

Grześk

Szadujkis-Szadurska

Bloch-Bogusławska

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. It has been demonstrated that 2,4,6-trimethyl-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide (m-3M3FBS) activates phospholipase C (PLC) and stimulates apoptosis in smooth muscle cells, which may increase vascular reactivity. The primary aim of the present study was to evaluate the physiological effects of the direct stimulation of PLC by m-3M3FBS on vascular smooth muscle reactivity in arteries pre-treated with lipopolysaccharides (LPS) as a model of septic shock. Experiments were performed on isolated and perfused tail arteries of Wistar rats. The contraction force in the model was measured by assessing increases in perfusion pressure at a constant flow. Parameters describing the concentration-response curves (CRCs) obtained for phenylephrine and arginine-vasopressin in the presence of LPS confirmed a decrease in vessels reactivity. In comparison with the controls, m-3M3FBS treatment caused a significant increase in LPS-untreated as well as pre-treated arteries. Furthermore, in the presence of m-3M3FBS, calcium influx from intra-as well as extracellular calcium stores was significantly higher for LPS-untreated and pre-treated arteries. The results of the present study suggested that m-3M3FBS significantly increased the reactivity of vascular smooth muscle cells pre-treated with LPS by increasing the calcium influx from intra-and extracellular calcium stores. Further studies investigating this mechanism are required to evaluate whether this pathway may be a potential therapeutic strategy to treat sepsis. IntroductionNitric oxide synthase (NOS) is an enzyme that catalyzes a reaction which generates nitric oxide in two different stages. The first stage is the oxidation of L-arginine to N-omega-hydroxy-L-arginine, which is degraded to L-citrulline in the second stage by NOS and oxygen, and accompanied by the release of nitric oxide from endothelial cells. There are three main types of nitric oxide synthase: NOS-1, -2 and -3. NOS-2 is localized mainly in macrophages, striated heart muscle, liver, vascular smooth muscle or vascular endothelium, and is activated as a response to infection, inflammation or sepsis following the release of pro-inflammatory cytokines, including interleukin (IL)-1, interferon (IFN)-γ or tumor necrosis factor (TNF)-α. The activated enzyme is active for a few h and synthesizes large quantities of nitric oxide (1). Nitric oxide produced by NOS-3 acts predominantly as a regulator of muscle tension in the local regulation of vascular tone. It is also a factor inhibiting the adhesion and aggregation of platelets, as well as angiogenesis. The role of NOS-3 as part of the initiation of NOS-2 activation in the presence of lipopolysaccharides (LPS) has been investigated over the past decade. The first study suggesting that NOS-3 has a role in the generation of NO-associated hyporeactivity during early sepsis was published in 2001 (2,3). A study on isolated animal tissue treated with short acting LPS (~5 h) showed a statistically significant inhibition of NOS-2 expression following blockad...

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Phospholipase C and Src Modulate Angiotensin II-Induced Cyclic AMP Production in Preglomerular Microvascular Smooth-Muscle Cells From Spontaneously Hypertensive Rats

Cited by 5 publications

References 35 publications

Multidrug resistance protein 4 mediates cAMP efflux from rat preglomerular vascular smooth muscle cells

Multidrug resistance protein 4 mediates cAMP efflux from rat preglomerular vascular smooth muscle cells

Effect of 2,4,6-trimethyl-N-[3-(trifluoromethyl)phenyl]benzene-sulfonamide on calcium influx in three contraction models

2,4,6-Trimethyl-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide increases calcium influx in lipopolisaccharide-pre-treated arteries

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