| Autor: |
Drimousis, Stelina, Markus, Irit, Murphy, Tim V., Perera, D. Shevy, Phan-Thien, Kim-Chi, Zhang, Li, Liu, Lu |
| Zdroj: |
The Journal of Pharmacology and Experimental Therapeutics; October 2020, Vol. 375 Issue: 1 p28-39, 12p |
| Abstrakt: |
The tachykinin NK2receptor plays a key role in gastrointestinal motor function. Enteric neurons release neurokinin A (NKA), which activates NK2receptors on gastrointestinal smooth muscle, leading to contraction and increased motility. In patients with diarrhea-predominant irritable bowel syndrome, the NK2receptor antagonist ibodutant had a greater therapeutic effect in females than males. The present study aimed to determine whether gender influences the expression and activity of NK2receptors in human colonic smooth muscle. In vitro functional studies were performed to examine the contractile responses of colonic muscle strips to NKA and the selective NK2receptor agonist [Lys5,MeLeu9,Nle10]NKA(4-10). Contractions were also measured in the presence of ibodutant to determine its antagonistic potency. The signal transduction pathways coupled to NK2receptor activation were investigated using second messenger inhibitors. Western blot and fluorescent immunohistochemistry were conducted to determine the protein expression and localization of NK2receptors. NK2receptor–mediated contractility was greater in females compared with males. When against NKA, ibodutant was more potent in females. NK2receptor expression increased with age in females, but not in males. Phospholipase C–mediated signaling was less prominent in females compared with males, whereas Ca2+sensitization via Rho kinase and protein kinase C appeared to be the dominant pathway in both genders. The distribution of NK2receptors in the human colon did not differ between the genders. Overall, gender differences exist in the expression and activity of NK2receptors in colonic smooth muscle. These gender distinctions should be considered in the therapeutic development of NK2receptor agents. |
| Databáze: |
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