Activation of dopamine D2 receptor promotes pepsinogen secretion by suppressing somatostatin release from the mouse gastric mucosa

2022 ◽  
Author(s):  
Xiao-Yu Liu ◽  
Li-Fei Zheng ◽  
Yan-Yan Fan ◽  
Qian-Ying Shen ◽  
Yao Qi ◽  
...  
Keyword(s):  
Gastric Mucosa ◽  
Receptor Antagonist ◽  
Receptor Agonist ◽  
Dopamine D2 Receptor ◽  
Ex Vivo ◽  
Local Effect ◽  
Chief Cells ◽  
Pepsinogen Secretion ◽  
D Cells

In vivo administration dopamine (DA) receptor (DR)-related drugs modulates gastric pepsinogen secretion. However, DRs on gastric pepsinogen-secreting chief cells and DA D2 receptor (D2R) on somatostatin-secreting D cells were subsequently acquired. In this study, we aimed to further investigate the local effect of DA on gastric pepsinogen secretion through DRs expressed on chief cells or potential D2Rs expressed on D cells. To elucidate the modulation of DRs in gastric pepsinogen secretion, immunofluorescence staining, ex vivo incubation of gastric mucosa isolated from normal and D2R-/- mice were conducted, accompanied by measurements of pepsinogen or somatostatin levels using biochemical assays or enzyme-linked immunosorbent assays. D1R, D2R, and D5R-immunoreactivity (IR) were observed on chief cells in mouse gastric mucosa. D2R-IR was widely distributed on D cells from the corpus to the antrum. Ex vivo incubation results showed that DA and the D1-like receptor agonist SKF38393 increased pepsinogen secretion, which was blocked by the D1-like receptor antagonist SCH23390. However, D2-like receptor agonist quinpirole also significantly increased pepsinogen secretion, and D2-like receptor antagonist sulpiride blocked the promotion of DA. Besides, D2-like receptors exerted an inhibitory effect on somatostatin secretion, in contrast to their effect on pepsinogen secretion. Furthermore, D2R-/- mice showed much lower basal pepsinogen secretion but significantly increased somatostatin release and an increased number of D cells in gastric mucosa. Only SKF38393, not quinpirole, increased pepsinogen secretion in D2R-/- mice. DA promotes gastric pepsinogen secretion directly through D1-like receptors on chief cells and indirectly through D2R-mediated suppression of somatostatin release.

B1 and B2 bradykinin receptors on adventitial fibroblasts of cerebral arteries are coupled to recombinant eNOS

2000 ◽  
Vol 278 (2) ◽  
pp. H367-H372 ◽  
Author(s):  
Masato Tsutsui ◽  
Hisashi Onoue ◽  
Yasuhiko Iida ◽  
Leslie Smith ◽  
Timothy O'Brien ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Receptor Agonist ◽  
Vascular Tone ◽  
Ex Vivo ◽  
In Vivo Studies ◽  
Enos Gene ◽  
No Production ◽  
Bradykinin Receptors ◽  
Adventitial Fibroblasts ◽  
Basilar Arteries

Our previous ex vivo and in vivo studies reported that expression of the recombinant endothelial nitric oxide (NO) synthase (eNOS) gene in adventitial fibroblasts recovers NO production in arteries without endothelium in response to bradykinin. The present study was designed to characterize subtypes of bradykinin receptors on adventitial fibroblasts coupled to the activation of recombinant eNOS. Endothelium-denuded segments of canine basilar arteries were transduced with β-galactosidase (β-Gal) gene or eNOS gene ex vivo, using a replication-defective adenoviral vector (1010 plaque-forming units/ml) for 30 min at 37°C. Twenty-four hours later, isometric force recording or cGMP measurement was carried out. B1 bradykinin receptor agonist (des-Arg9-bradykinin, 10− 10-10− 8mol/l) did not significantly affect vascular tone in control or β-Gal gene-transduced canine basilar arteries without endothelium. In contrast, this agonist caused concentration-dependent relaxations in recombinant eNOS gene-transduced arteries without endothelium. Relaxations to B1 receptor agonist in the eNOS arteries were abolished by B1 receptor antagonist (des-Arg9-[Leu8]bradykinin, 6 × 10− 9 mol/l) but not by B2 receptor antagonist (Hoe-140, 5 × 10− 8 mol/l). Bradykinin did not significantly alter vascular tone in control or β-gal arteries without endothelium, whereas this peptide (10− 11-10− 8mol/l) induced concentration-dependent relaxations, as well as an increase in cGMP formation in endothelium-denuded eNOS-transduced arteries. Stimulatory effects of bradykinin were prevented in the presence of a B2 receptor antagonist but not in the presence of a B1 receptor antagonist. B1 and B2 receptor antagonists had no effect on relaxations to substance P, confirming the selectivity of the compounds. Our results suggest that B1 and B2 bradykinin receptors are coupled to activation of recombinant eNOS expressed in adventitial fibroblasts.

A novel oral dual amylin and calcitonin receptor agonist (KBP-042) exerts antiobesity and antidiabetic effects in rats

2014 ◽  
Vol 307 (1) ◽  
pp. E24-E33 ◽  
Author(s):  
Kim V. Andreassen ◽  
Michael Feigh ◽  
Sara T. Hjuler ◽  
Sofie Gydesen ◽  
Jan Erik Henriksen ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Receptor Agonist ◽  
Ex Vivo ◽  
Calcitonin Receptor ◽  
Insulin Tolerance ◽  
Receptor Pharmacology ◽  
Zdf Rats ◽  
Calcitonin Receptors

The present study investigated a novel oral dual amylin and calcitonin receptor agonist (DACRA), KBP-042, in head-to-head comparison with salmon calcitonin (sCT) with regard to in vitro receptor pharmacology, ex vivo pancreatic islet studies, and in vivo proof of concept studies in diet-induced obese (DIO) and Zucker diabetic fatty (ZDF) rats. In vitro, KBP-042 demonstrated superior binding affinity and activation of amylin and calcitonin receptors, and ex vivo, KBP-042 exerted inhibitory action on stimulated insulin and glucagon release from isolated islets. In vivo, KBP-042 induced a superior and pronounced reduction in food intake in conjunction with a sustained pair-fed corrected weight loss in DIO rats. Concomitantly, KBP-042 improved glucose homeostasis and reduced hyperinsulinemia and hyperleptinemia in conjunction with enhanced insulin sensitivity. In ZDF rats, KBP-042 induced a superior attenuation of diabetic hyperglycemia and alleviated impaired glucose and insulin tolerance. Concomitantly, KBP-042 preserved insulinotropic and induced glucagonostatic action, ultimately preserving pancreatic insulin and glucagon content. In conclusion, oral KBP-042 is a novel DACRA, which exerts antiobesity and antidiabetic efficacy by dual modulation of insulin sensitivity and directly decelerating stress on the pancreatic α- and β-cells. These results could provide the basis for oral KBP-042 as a novel therapeutic agent in type 2 diabetes.

D1 and D2 dopaminergic systems in the rat basolateral amygdala are involved in anxiogenic-like effects induced by histamine

2011 ◽  
Vol 26 (4) ◽  
pp. 564-574 ◽  
Author(s):  
Maryam Bananej ◽  
Ahmad Karimi-Sori ◽  
Mohammad Reza Zarrindast ◽  
Shamseddin Ahmadi
Keyword(s):  
Receptor Antagonist ◽  
Receptor Agonist ◽  
Basolateral Amygdala ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
Dopamine D1 Receptor ◽  
D1 Receptor ◽  
Dopamine D2 ◽  
D1 And D2 Receptors ◽  
Male Wistar Rats

Involvement of the dopamine receptors in the basolateral amygdala (BLA) in the effects of histamine on anxiety-like behaviors of the elevated plus maze in male Wistar rats was investigated. The results showed that bilateral intra-BLA injections of histamine (2.5, 5 and 7.5 µg/rat) induced an anxiogenic-like effect, revealed by decreases in percentage of open arm time (%OAT) and open arm entries (%OAE). Intra-BLA administration of dopamine D1 receptor agonist, SKF38393 (0.25 µg/rat), and dopamine D2 receptor agonist, quinpirole (0.03 and 0.05 µg/rat), decreased %OAT but not %OAE. Conversely, intra-BLA administration of dopamine D1 receptor antagonist, SCH23390 (0.5 and 1 µg/rat), and dopamine D2 receptor antagonist, sulpiride (0.3 and 0.5 µg/rat), increased %OAT and %OAE, suggesting an anxiolytic-like effect for both drugs. Interestingly, co-administration of a silent dose of SCH23390 or sulpiride prevented anxiogenic-like effects of SKF38393 and quinpirole, respectively. Conjoint administration of a sub-effective dose of SKF38393 (0.125 µg/rat) or quinpirole (0.01 µg/rat) along with lower doses of histamine (1 and 2.5 µg/rat) induced anxiolytic-like effects. On the other hand, intra-BLA pretreatment with a silent dose of SCH23390 (0.25 µg/rat) or sulpiride (0.1 µg/rat) prevented the anxiogenic-like effect of higher doses of histamine (5 and 7.5 µg/rat). No significant change was observed in total closed arm entries, as an index for motor activity of the animals. It can be concluded that the dopamine D1 and D2 receptors in the BLA may be involved in the anxiogenic-like effects induced by histamine.

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