Adiponectin Receptor Agonist, AdipoRon, Causes Vasorelaxation Predominantly Via a Direct Smooth Muscle Action

2016 ◽  
Vol 23 (3) ◽  
pp. 207-220 ◽  
Author(s):  
Kwangseok Hong ◽  
Sewon Lee ◽  
Rong Li ◽  
Yan Yang ◽  
Miles A. Tanner ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Receptor Agonist ◽  
Adiponectin Receptor ◽  
Muscle Action

Abstract 246: Adiporon, an Adiponectin Receptor Agonist, Inhibits P70s6kinase Signaling in Vascular Smooth Muscle Cells: Implications Toward Suppression of Injury-induced Neointima Formation in Mice

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Arwa Fairaq ◽  
Lakshman Segar
Keyword(s):  
Insulin Resistance ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Small Molecule ◽  
Femoral Artery ◽  
Receptor Agonist ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Adiponectin Receptor ◽  
Neointima Formation

Background: Hypoadiponectinemia is closely correlated with insulin resistance and coronary artery disease. The use of exogenous adiponectin as a rational therapy to reduce cardiovascular disease risk has been hampered in a clinical setting due to its large molecular size and short plasma half-life. Recent studies demonstrate that Adiporon, a small molecule adiponectin receptor agonist, improves insulin resistance and glycemic control in type 2 diabetic mice. The present study is aimed at examining the likely regulatory effects of Adiporon on vascular smooth muscle cell (VSMC) phenotype. Methods: Using human aortic VSMCs, we examined the effects of AdipoRon (5 to 100 μM) on platelet-derived growth factor (PDGF, 30 ng/ml)-induced proliferative signaling events. In addition, we examined the effects of orally-administered AdipoRon (50 mg/kg/d) on injury-induced neointima formation in CJ57BL6 mice. Morphometric analysis of injured femoral artery was performed using H&E and EVG-stained sections. Results: Exposure of VSMCs to AdipoRon resulted in a significant decrease in PDGF-induced proliferation by ~63.8% and cyclin D1 expression by ~92.5% (n = 3). In addition, AdipoRon treatment led to significant diminutions in PDGF-induced phosphorylation of Akt, p70S6K, and its downstream targets that include 4E-BP1 and ribosomal protein S6, as revealed by immunoblot analysis (n = 3). Importantly, Adiporon administration (50mg/kg/d, PO) for three weeks led to a significant attenuation of neointima formation by ~63.7% in the injured femoral artery (n = 5-8). Conclusion: The present findings suggest that Adiporon (a small molecule adiponectin receptor agonist) may inhibit neointima formation after arterial injury by targeting p70S6K signaling in VSMCs. Future studies should investigate the likely vasoprotective effects of Adiporon in the mouse models of obesity and atherosclerosis.

NUMERICAL SIMULATION OF THE ROLE OF CO-TRANSMISSION BY ACETYLCHOLINE AND SEROTONIN ON MOTILITY OF THE GUT

2006 ◽  
Vol 06 (04) ◽  
pp. 399-428
Author(s):  
R. MIFTAHOF
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Transit Time ◽  
Receptor Agonist ◽  
Muscle Cells ◽  
Receptor Antagonists ◽  
One Dimensional ◽  
Circular Smooth Muscle ◽  
Spatio Temporal ◽  
Stimulation Of

Electrophysiological mechanisms of co-transmission by serotonin (5-HT) and acetylcholine (ACh), co-expression of their receptor types, i.e., 5-HT type 3 and 4, nicotinic cholinerginc (nACh) and muscarinic cholinergic (μACh), and effects of selective and non-selective 5-HT3 and 5-HT4 receptor agonists/antagonists, on electromechanical activity of the gut were studied numerically. Two series of numerical experiments were performed. First, the dynamics of the generation and propagation of electrical signals interconnected with the primary sensory (AH) neurons, motor (S) neurons and smooth muscle cells were studied in a one-dimensional model. Simulations showed that stimulation of the 5-HT3 receptors reduced the threshold of activation of the mechanoreceptors by 17.6%. Conjoint excitation of the 5-HT3 and 5-HT4 receptors by endogenous serotonin converted the regular firing pattern of electrical discharges of the AH and S neurons to a beating mode. Activation confined to 5-HT3 receptors, located on the somas of the adjacent AH and S type neurons, could not sustain normal signal transduction between them. It required ACh as a co-transmitter and co-activation of the nACh receptors. Application of selective 5-HT3 receptor antagonists inhibited dose-dependently the production of action potentials at the level of mechanoreceptors and the soma of the primary sensory neuron and increased the threshold activation of the mechanoreceptors. Normal mechanical contractile activity depended on co-stimulation of the 5-HT4 and μACh receptors on the membrane of smooth muscle cells. In the second series of simulations, which involved a spatio-temporal model of the functional unit, effects of co-transmission by ACh and 5-HT on the electromechanical response in a segment of the gut were analyzed. Results indicated that propagation of the wave of excitation between the AH and S neurons within the myenteric nervous plexus in the presence of 5-HT3 receptor antagonists was supported by co-release of ACh. Co-stimulation of 5-HT3, nACh and μACh receptors impaired propulsive activity of the gut. The bolus showed uncoordinated movements. In an ACh-free environment Lotronex (GlaxoSmithKline), a 5-HT3 receptor antagonist, significantly increased the transit time of the pellet along the gut. In the presence of ACh, Lotronex produced intensive tonic-type contractions in the longitudinal and circular smooth muscle layers and eliminated propulsive activity. The 5HT4 receptor agonist, Zelnorm (Novartis), preserved the reciprocal electromechanical relationships between the longitudinal and circular smooth muscle layers. The drug changed the normal propulsive pattern of activity to an expulsive (non-mixing) type. Treatment of the gut with selective 5HT4 receptor antagonists increased the transit time by disrupting the migrating myoelectrical complex. Cisapride (Janssen), a mixed 5HT3 and 5HT4 receptor agonist, increased excitability of the AH and S neurons and the frequency of slow waves. Longitudinal and circular smooth muscle syncytia responded with the generation of long-lasting tonic contractions, resulting in a "squeezing" type of pellet movement. Comparison of the theoretical results obtained on one-dimensional and spatio-temporal models to in vivo and in vitro experimental data indicated satisfactory qualitative, and where available, quantitative agreement.

Adiponectin receptor agonist AdipoRon attenuates calcification of osteoarthritis chondrocytes by promoting autophagy

2020 ◽  
Vol 121 (5-6) ◽  
pp. 3333-3344 ◽  
Author(s):  
Zhi‐xi Duan ◽  
Chao Tu ◽  
Qing Liu ◽  
Shuang‐qing Li ◽  
Yi‐han Li ◽  
...  
Keyword(s):  
Receptor Agonist ◽  
Adiponectin Receptor ◽  
Osteoarthritis Chondrocytes

Receptor mechanisms of serotonin-induced prenodal lymphatic constriction in the canine forelimb

1998 ◽  
Vol 274 (2) ◽  
pp. H650-H654 ◽  
Author(s):  
David E. Dobbins
Keyword(s):  
Smooth Muscle ◽  
Muscle Contraction ◽  
Muscle Activity ◽  
Receptor Agonist ◽  
Perfusion Pressure ◽  
Smooth Muscle Contraction ◽  
Constant Flow ◽  
Vasoactive Agents ◽  
Arterial Infusion

Numerous endogenous vasoactive agents have been shown to cause lymphatic smooth muscle contraction. In this study, we assessed the ability of serotonin (5-HT) to alter lymphatic smooth muscle activity and elucidated the receptor mechanisms of 5-HT’s actions. Both intralymphatic and intra-arterial administration of 5-HT significantly increased lymphatic smooth muscle activity in lymphatics perfused at constant flow, as indicated by an increase in lymphatic perfusion pressure. The 5-HT-induced increase in lymphatic perfusion pressure is attenuated but not blocked by the intra-arterial infusion of phentolamine, suggesting the involvement of α-adrenoreceptors and 5-HT receptors. Intralymphatic infusion of the 5-HT2-receptor-agonist α-methylserotonin significantly increased lymphatic perfusion pressure, either alone or when administered into an α-receptor blocked preparation, whereas the 5-HT1-receptor-agonist carboxyamidotryptamine maleate did not effect the prenodal lymphatics. These data indicate that the lymphatic smooth muscle contraction produced by 5-HT is mediated both by lymphatic α-adrenoreceptors and 5-HT2 receptors.

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