Pharmacological study on the enhancing effects of U46619 on guinea pig urinary bladder smooth muscle contraction induced by acetylcholine and α,β-methylene ATP and the possible involvement of protein kinase C

Article

Author: Komura, Akane ; Xu, Keyue ; Ikeda, Masahiro ; Hojo, Misaki ; Obara, Keisuke ; Ou, Guanghan ; Tanaka, Yoshio ; Kato, Rina ; Yoshioka, Kento ; Fujisawa, Miki

We examined whether U46619 (a prostanoid TP receptor agonist) could enhance the contractions of guinea pig urinary bladder smooth muscle (UBSM) in response to acetylcholine (ACh) and an ATP analog (α,β-methylene ATP (αβ-MeATP)) through stimulation of the UBSM TP receptor and whether protein kinase C (PKC) is involved. U46619 (10^-7 M) markedly enhanced UBSM contractions induced by electrical field stimulation and ACh/αβ-MeATP (3 × 10^-6 M each), the potentiation of which was completely suppressed by SQ 29,548 (a TP receptor antagonist, 6 × 10^-7 M). PKC inhibitors did not attenuate the ACh-induced contractions enhanced by U46619 although they partly suppressed the U46619-enhanced, αβ-MeATP-induced contractions. While phorbol 12-myristate 13-acetate (PMA, a PKC activator, 10^-6 M) did not enhance ACh-induced contractions, it enhanced αβ-MeATP-induced contractions, an effect that was completely suppressed by PKC inhibitors. αβ-MeATP-induced contractions, both with and without U46619 enhancement, were strongly inhibited by diltiazem. U46619/PMA enhanced 50 mM KCl-induced contractions, the potentiation of which was partly/completely attenuated by PKC inhibitors. These findings suggest that U46619 potentiates parasympathetic nerve-associated UBSM contractions by stimulating UBSM TP receptors. PKC-increased Ca²⁺ influx through voltage-dependent Ca²⁺ channels may partially play a role in purinergic receptor-mediated UBSM contractions enhanced by TP receptor stimulation.

01 Aug 2023·Prostaglandins & Other Lipid Mediators

TXA2 mediates LPA1-stimulated uterine contraction in late pregnant mouse

Article

Author: Singh, Thakur Uttam ; Kumar, Dinesh ; Parida, Subhashree ; Kishor Kumar, Dg ; Pavithra, S. ; Panigrahi, Manjit ; Prakash, E.

Lysophosphatidic acid (LPA) is known to increase uterine contraction in the estrus cycle and early pregnancy, however, the effect of LPA in late pregnant uterus and its mechanisms are not clear. In the present study, we show the LPA receptor subtypes expressed and the mechanism of LPA-induced contractions in late pregnant mouse uterus. We determined the relative mRNA expression of LPA receptor genes by quantitative PCR and elicited log concentration-response curves to oleoyl-L-α-LPA by performing tension experiments in the presence and absence of nonselective and selective receptor antagonists and inhibitors of the TXA2 pathway. LPA1 was the most highly expressed receptor subtype in the late pregnant mouse uterus and LPA1/2/3 agonist (Oleoyl-L-α LPA) elicited increased contractions in this tissue that had lesser efficacy compared to oxytocin. LPA1/3 antagonist, Ki-16425, and a potent LPA1 antagonist (AM-095) significantly inhibited the LPA-induced contractions. Further, the nonselective COX inhibitor, indomethacin, and potent thromboxane A2 synthase inhibitor, furegrelate significantly impaired LPA-induced contractions. Moreover, selective thromboxane receptor (TP) antagonist, SQ-29548, and Rho kinase inhibitor, Y-27632 almost eliminated LPA-induced uterine contractions. LPA1 stimulation elicits contractions in the late pregnant mouse uterus using the contractile prostanoid, TXA2 and may be targeted to induce labor in uterine dysfunctions/ dystocia.

01 Jun 2023·European Journal of Pharmacology

Mineralocorticoid receptors contribute to ethanol-induced vascular hypercontractility through reactive oxygen species generation and up-regulation of cyclooxygenase 2

Article

Author: Castro, Michele M. ; Carnio, Evelin C. ; Awata, Wanessa M. C. ; Assis, Victor O. ; Tirapelli, Carlos R. ; de Mello, Marcela M. B. ; Dourado, Thales M. H.

The effects on blood pressure produced byethanol consumption include both vasoconstriction and activation of the renin-angiotensin-aldosterone system (RAAS), although the detailed relationship between these processes is yet to be accomplished. Here, we sought to investigate the contribution of mineralocorticoid receptors (MR) to ethanol-induced hypertension and vascular hypercontractility. We analyzed blood pressure and vascular function of male Wistar Hannover rats treated with ethanol for five weeks. The contribution of the MR pathway to the cardiovascular effects of ethanol was evaluated with potassium canrenoate, a MR antagonist (MRA). Blockade of MR prevented ethanol-induced hypertension and hypercontractility of endothelium-intact and -denuded aortic rings. Ethanol up-regulated cyclooxygenase (COX)2 and augmented vascular levels of both reactive oxygen species (ROS) and thromboxane (TX)B₂, a stable metabolite of TXA₂. These responses were abrogated by MR blockade. Hyperreactivity to phenylephrine induced by ethanol consumption was reversed by tiron [a scavenger of superoxide (O₂∙^-)], SC236 (a selective COX2 inhibitor) or SQ29548 (an antagonist of TP receptors). Treatment with the antioxidant apocynin prevented the vascular hypercontractility, as well as the increases in COX2 expression and TXA₂ production induced by ethanol consumption. Our study has identified novel mechanisms through which ethanol consumption promotes its deleterious effects in the cardiovascular system. We provided evidence for a role of MR in the vascular hypercontractility and hypertension associated with ethanol consumption. The MR pathway triggers vascular hypercontractility through ROS generation, up-regulation of COX2 and overproduction of TXA₂, which will ultimately induce vascular contraction.

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