Inhibition of Thromboxane A2-Induced Arrhythmias and Intracellular Calcium Changes in Cardiac Myocytes by Blockade of the Inositol Trisphosphate Pathway

• DOI: 10.1124/jpet.109.157677
• Publication Date: 2009-09-10T01:46:59Z
• Authors: M.J. Wacker; L.M. Kosloski; W.J.R. Gilbert; C.D. Touchberry; D.S. Moore; J.K. Kelly; M. Brotto; J.A. Orr
• Keywords: Calcium in biology

We have recently reported that left atrial injections of the thromboxane A₂ (TXA₂) mimetic, (5<i>Z</i>)-7-[(1<i>R</i>,4<i>S</i>,5<i>S</i>,6<i>R</i>)-6-[(1<i>E</i>,3<i>S</i>)-3-hydroxy-1-octenyl]-2 -oxabicyclo[2.2.1]hept-5-yl]-5-heptenoic acid (U46619), induced ventricular arrhythmias in anesthetized rabbit. Data from this study led us to hypothesize TXA₂ may be inducing direct actions on myocardium induce these arrhythmias. The aim was further elucidate mechanism responsible for report TXA₂R is expressed at both gene and protein levels samples adult rabbits. In addition, mRNA identified single, isolated cardiac myocytes. Furthermore, treatment myocytes with U46619 increased intracellular calcium a dose-dependent manner increases were blocked by specific antagonist, 7-(3-((2-((phenylamino)carbonyl)hydrazino)methyl)-7-oxabicyclo(2.2.1)hept-2-yl)-5-heptenoic (SQ29548). Pretreatment an inhibitor inositol trisphosphate (IP₃) formation, gentamicin, or IP₃ receptors, 2-aminoethoxydiphenylborate (2-APB), increase calcium. vivo pretreatment rabbits either gentamicin 2-APB subsequently inhibited formation elicited U46619. These data support hypothesis can via action arrhythmogenic inhibitors pathway. summary, provides novel evidence TXA₂-induced rationale as potential target TXA₂-mediated