Sharma 2017 MiPschool Obergurgl

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Vipin Sharma
Role of ATP-sensitive potassium (KATP) and maxi potassium (BKCa) channels in beta3-adrenoceptors mediated tocolytic effect and involvement of associated mitochondrial calcium dynamics pathways in buffaloes (Bubalus bubalis).

Link: MitoEAGLE

Sharma V, Choudhury S, Nair SV, Jaitley P, Nakade UP, Sharma A, Yadav RK, Garg SK (2017)

Event: MiPschool Obergurgl 2017

COST Action MitoEAGLE

Considerable progress in understanding the relationship between Ca2+ signalling cascades and mitochondrial physiology has been accumulated over the last few years due to the development of more advanced optical techniques and electrophysiological approaches. In summary, although major advances in understanding the molecular physiology of myometrium have been achieved, there is a pressing need to understand human uterine contractile activity and the role of other channels and receptors such as chloride, sodium, ryanodine and the role of nucleotides such as adenosine, adenosine diphosphate (ADP), and ATP in human myometrium. The role of CICR is still unclear in myometrium and needs further elucidation. There is also a need to fully understand the role of mitochondria in calcium homeostasis. These investigations and the development with the action of agonists and antagonists on uterine smooth muscle will add more to our understanding of uterine physiology and lead to more successful approaches in diagnosing and managing the reproductive disorders such as preterm labor, dysmenorrhea, prolonged labor, and weak uterine contractions (dystocia). It is apparent that understanding the normal physiology of uterine contractions and relaxation at the molecular and cellular level would help clinicians and healthcare providers to modulate unnecessary uterine activity if problems arise throughout Calcium Signaling pregnancy and to plan a suitable therapeutic target according to each problem.

This study was undertaken to elucidate the cellular coupling mechanism of beta3-adrenergic receptors with potassium channels in myometrium of non-pregnant buffaloes. In materials and methods the uteri of diestrous stage buffaloes were collected from local abattoir and myometrial strips were prepared from the mid-cornual region of uterus for measurement of isometric tension.

Result shows that Both BRL-37344 and SAR150640, two specific agonists of β3-adrenoceptors, produced dose-dependent inhibitory effect on myometrial spontaneity and this effect was blocked by SR 59230A, a selective β3 specific adrenoceptorantagonist. BRL-37344 was found to be more potent than SAR 150640 as the respective pD2 values were found to be 7.22 ± 0.09 (n = 7) and 3.27 ± 2.67 (n = 6). Further, potassium channel blockers, namely-glybenclamide (10 μM), tetraethyl ammonium (1 mM) and iberiotoxin (100 nM) significantly shifted the dose response curve of BRL-37344 towards right with reduction in efficacy (Rmax). However, 4-aminopyridine (1 mM) failed to alter the tocolytic effect of BRL-37344.

Our conclusion shows that results suggest by beta3-adrenergic receptors mediate an additional mechanism of myometrial relaxation in buffaloes and, besides direct involvement of β3-adrenoceptor, their tocolytic effect is also mediated through KATP and BKCa channels in buffalo myometrium. Therefore, beta3-adrenergic receptors seem to be a potential alternative target for management of pre-term labour; however, similar studies are warranted on uterus of pregnant animals.


Bioblast editor: Kandolf G


Labels:


Organism: Bovines  Tissue;cell: Genital 




Event: B2, Poster 


Affiliations

Dept Pharmacol & Toxicol College Veterinary Science Animal Husbandry U.P. Pandit Deen Dayal Upadhyaya pashu Chikitsa Vigyan Vishwavidyalaya Evam Go-Anusandhan Sansthan, Mathura, India.- asvipinsharma10@gmail.com


Figures

Sharma Figure1 MiPschool Obergurgl 2017.jpg

Figure 1. (a) Representative physiograph recordings showing the effect of BRL 37344, a β3-agonist, in the absence and presence of SR59230A, a specific β3-antagonist, on isolated myometrial strips of non-pregnant buffaloes. Comparative line diagrams showing the mean concentration response curves of BRL 37344 (b) or SAR 150640 (c) in the absence and presence of SR59230 A.Vertical bars represent SEM. *P <0.05 in comparison to BRL 37344 alone.











Sharma Figure2 MiPschool Obergurgl 2017.jpg

Figure 2. Regulation of UCP1 abundance and activity in brown adipose tissue Noradrenergic stimulation of β3-adrenergic receptors triggers cAMP-responsive pathways that act in two ways: 1) enhancing transcription of Ucp1 and 2) initiating PKA-dependent lipolysis to release fatty acids that acutely activate UCP1.


References

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  2. Bardou M, Dousset B, Deneux-Tharaux C, Smadja C, Naline E, Chaput JC, Naveau S, Manara L, Croci T, Advenier C (2007) Is the beta3-adrenoceptor (ADRB3) a potential target for uterorelaxant drugs? BMC Pregnancy Childbirth. 7:S14.
  3. Hakak Y, Shrestha D, Goege MC, Behan DP, Chalmers DT (2003) Global analysis of G-protein-coupled receptor signaling in human tissues. FEBS Lett 550:11-17.
  4. Lirussi F, O’Brien M, Wendremaire M, Goirand F, Sagot P, Dumas M, Morrison JJ, Bardou M (2010) SAR150640, a selective b3-adrenoceptor agonist, prevents human myometrial remodelling and activation of matrix metalloproteinase in an in vitro model of chorioamnionitis. Br J Pharmacol 159:1354–66.