AbstractBackgroundThromboxane A2 (TXA2) participates in many pathophysiological processes of coronary artery disease. However, its mechanism of TXA2‐induced contraction in the coronary artery remains to be clarified. A multi myograph system was used to measure the isometric tension of the mouse coronary arteries and identify the effect and pathway of TXA2 analogues U46619. Confocal laser scanning microscopy was used to measure the intracellular calcium concentration ([Ca2+]i) in mouse coronary artery smooth muscle cells. Results from the experiment had shown that contraction in coronary artery was generated by U46619 in a concentration‐dependent manner, which was completely abolished by a specific TXA2 receptor blocker, GR32191. PI‐PLC inhibitors U73122 and D609 and Rho‐Kinase inhibitor Y‐27632 can block the U46619 elicited coronary artery contraction in a dose‐dependent manner. Then, the vasoconstriction response to U46619 was obviously inhibited by two pan‐PKC inhibitors chelerythrine or Gӧ6983, and a selective PKCδ inhibitor rottlerin, but was not blocked by a selective PKCζ inhibitor PKC‐PS or a selective PKCβ inhibitor hispidin. Meanwhile, the PKC activator PDBu‐induced vasoconstriction was significantly inhibited by 1 μmol/L nifedipine, then mostly inhibited by 100 μmol/L 2‐APB and 10 μmol/L Y27632. We further found that the response to U46619 was inhibited, respectively, by three calcium channel blockers nifedipine, SKF96356 or 2‐APB in a concentration‐dependent manner. Although Store‐operated Ca2+ (SOC) channels generated the increase of [Ca2+]i in mouse coronary artery smooth muscle cells, SOC channels did not contribute to the vasoconstriction in mouse coronary arteries. Caffeine‐induced sarcoplasmic reticulum (SR) Ca2+ release could obviously induce coronal vasoconstriction. In addition, NPPB, a cell membrane Ca2+ activated C1− channel blocker, could obviously inhibit the U46619‐induced vasoconstriction. The U46619‐induced mouse coronary artery contraction was involved in the increase in [Ca2+]i mediated by Cav1.2, TRPC channels and SR release through the activation of G‐protein‐coupled TP receptors and the kinases signalling pathway in TP downstream proteins, while SOC channels did not participate in the vasoconstriction.

01 Jul 2019·Clinical and Experimental Pharmacology and PhysiologyQ4 · MEDICINE

Mechanisms of U46619‐induced contraction in mouse intrarenal artery

Q4 · MEDICINE

Article

Author: Kuang, Su‐Juan ; Li, Xin ; Yan, Hong ; Yang, Hui ; Kwok, Yat Sze (Shelia) ; Mai, Li‐Ping ; Liu, Lin ; Wong, Gordon ; Rao, Fang ; Lin, Qiu‐Xiong ; Zhang, Qian‐Huan ; Deng, Chun‐Yu ; Zhang, Meng‐Zhen ; Yang, Min

SummaryThromboxane A2 (TXA2) has been implicated in the pathogenesis of vascular complications, but the underlying mechanism remains unclear. The contraction of renal arterial rings in mice was measured by a Multi Myograph System. The intracellular calcium concentration ([Ca2+]i) in vascular smooth muscle cells (VSMCs) was obtained by using a fluo‐4/AM dye and a confocal laser scanning microscopy. The results show that the U46619‐induced vasoconstriction of renal artery was completely blocked by a TXA2 receptor antagonist GR32191, significantly inhibited by a selective phospholipase C (PI‐PLC) inhibitor U73122 at 10 μmol/L and partially inhibited by a Phosphatidylcholine ‐ specific phospholipase C (PC‐PLC) inhibitor D609 at 50 μmol/L. Moreover, the U46619‐induced vasoconstriction was inhibited by a general protein kinase C (PKC) inhibitor chelerythrine at 10 μmol/L, and a selective PKCδ inhibitor rottlerin at 10 μmol/L. In addition, the PKC‐induced vasoconstriction was partially inhibited by a Rho‐kinase inhibitor Y‐27632 at 10 μmol/L and was further completely inhibited together with a putative IP3 receptor antagonist and store‐operated Ca2+ (SOC) entry inhibitor 2‐APB at 100 μmol/L. On the other hand, U46619‐induced vasoconstriction was partially inhibited by L‐type calcium channel (Cav1.2) inhibitor nifedipine at 1 μmol/L and 2‐APB at 50 and 100 μmol/L. Last, U46619‐induced vasoconstriction was partially inhibited by a cell membrane Ca2+ activated C1− channel blocker 5‐Nitro‐2‐(3‐phenylpropylamino) benzoic acid (NPPB) at 50 and 100 μmol/L. Our results suggest that the U46619‐induced contraction of mouse intrarenal arteries is mediated by Cav1.2 and SOC channel, through the activation of thromboxane‐prostanoid receptors and its downstream signaling pathway.

01 Nov 2017·The Journal of PhysiologyQ2 · MEDICINE

Sex differences in the role of phospholipase A₂‐dependent arachidonic acid pathway in the perivascular adipose tissue function in pigs

Q2 · MEDICINE

Article

Author: Roberts, Richard E. ; Ahmad, Abdulla A. ; Randall, Michael D.

Key points

The fat surrounding blood vessels (perivascular adipose tissue or PVAT) releases vasoactive compounds that regulate vascular smooth muscle tone.

There are sex differences in the regulation of vascular tone, but, to date, no study has investigated whether there are sex differences in the regulation of blood vessel tone by PVAT.

This study has identified that the cyclooxygenase products thromboxane and PGF2α are released from coronary artery PVAT from pigs.

Thromboxane appears to mediate the PVAT‐induced contraction in arteries from females, whereas PGF2α appears to mediate the contraction in arteries from males.

These sex differences in the role of these prostanoids in the PVAT‐induced contraction can be explained by a greater release of thromboxane from PVAT from female animals and greater sensitivity to PGF2α in the porcine coronary artery from males.

AbstractPrevious studies have demonstrated that perivascular adipose tissue (PVAT) causes vasoconstriction. In this present study, we determined the role of cyclooxygenase‐derived prostanoids in this contractile response and determined whether there were any sex differences in the regulation of vascular tone by PVAT. Contractions in isolated segments of coronary arteries were determined using isolated tissue baths and isometric tension recording. Segments were initially cleaned of PVAT, which was then re‐added to the tissue bath and changes in tone measured over 1 h. Levels of PGF2α and thromboxane B2 (TXB2) were quantified by ELISA, and PGF2α (FP) and thromboxane A2 (TP) receptor expression determined by Western blotting. In arteries from both male and female pigs, re‐addition of PVAT caused a contraction, which was partially inhibited by the cyclooxygenase inhibitors indomethacin and flurbiprofen. The FP receptor antagonist AL8810 attenuated the PVAT‐induced contraction in arteries from males, whereas the TP receptor antagonist GR32191B inhibited the PVAT‐induced contraction in arteries from females. Although there was no difference in PGF2α levels in PVAT between females and males, PGF2α produced a larger contraction in arteries from males, correlating with a higher FP receptor expression. In contrast, release of TXB2 from PVAT from females was greater than from males, but there was no difference in the contraction by the TXA2 agonist U46619, or TP receptor expression in arteries from different sexes. These findings demonstrate clear sex differences in PVAT function in which PGF2α and TXA2 antagonists can inhibit the PVAT‐induced vasoconstriction in male and female PCAs, respectively.

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Phase 3	GB	GSK Plc	-
Coronary Restenosis	Phase 3	JP	GSK Plc	-
Myocardial Ischemia	Phase 3	GB	GSK Plc	-
Venous Thrombosis	Phase 3	JP	GSK Plc	-

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