Thromboxane A2 receptor mediation of calcium and calcium transients in rat cardiomyocytes

Dogan, Selami; Turnbaugh, Donald; Zhang, Min; Cofie, Daniel Q.; Fugate, Robert D.; Kem, David C.

doi:10.1016/s0024-3205(97)00024-6

Cited by 9 publications

(12 citation statements)

References 16 publications

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“…Next, we wanted to determine whether direct application of U46619 to isolated, adult rabbit cardiac myocytes induces changes in intracellular calcium. This is in agreement with other studies that have also found that TXA 2 mimetics can induce increases in intracellular calcium in neonatal rat cardiac myocytes (Hoffmann et al, 1993;Dogan et al, 1997). We found that the U46619-induced increases in cytosolic calcium were inhibited by the specific TXA 2 R antagonist SQ29548, which supports our previous work (Wacker et al, 2006), demonstrating that SQ29548 also inhibited the U46619-induced arrhythmias.…”

Section: Discussionsupporting

confidence: 93%

“…Previous studies have shown that there are binding sites for TXA 2 Rs in the heart of various species (Lasserre et al, 1992;Bowling et al, 1994) and that TXA 2 can induce changes in intracellular calcium in neonatal rat cardiac myocytes (Hoffmann et al, 1993;Dogan et al, 1997). Therefore, the purpose of this study was to determine the mechanism by which activation of TXA 2 Rs could induce changes in intracellular calcium in vitro and arrhythmias in vivo.…”

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confidence: 93%

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

Wacker

Kosloski²,

Gilbert³

et al. 2009

J Pharmacol Exp Ther

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

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Section: Discussionsupporting

confidence: 93%

mentioning

confidence: 93%

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

Wacker

Kosloski²,

Gilbert³

et al. 2009

J Pharmacol Exp Ther

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“…7. As mentioned previously TXA 2 has also been shown to increase intracellular Ca 2+ in cardiac myocytes (Dogan et al 1997). Given that Ca 2+ overload is prominently involved in the development of necrotic/apoptotic cell death during early reperfusion (Halestrap 2009; Murphy and Steenbergen 2008) it seems likely that TXA 2 could have simultaneously contributed to both the exacerbated infarct size as well as the coronary responses in the 100 μg MWCNT group.…”

Section: Discussionsupporting

confidence: 54%

“…Interestingly, hearts isolated from rats instilled with the highest concentration (100 μg) of MWCNTs did not demonstrate the same magnitude of LVDP reduction by the end of reperfusion that was seen with lower MWCNT doses. TXA 2 is linked to cardiac I/R and increased arrhythmias (Coker et al 1981), and TXA 2 has been shown to elevate intracellular Ca 2+ in cardiac myocytes (Dogan et al 1997). Given that our study shows MWCNT instillation promoted increased ET-1 release from isolated hearts during early reperfusion, and our vascular data that suggests coronary tone is enhanced through TXA 2 release in response to ET-1, perhaps MWCNT activation of the ET-1/TXA 2 axis enhances contractility of cardiac myocytes, preserving some ventricular function in the face of expanding injury.…”

Section: Discussionmentioning

confidence: 99%

Pulmonary instillation of multi-walled carbon nanotubes promotes coronary vasoconstriction and exacerbates injury in isolated hearts

et al. 2012

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The growing use of multi-walled carbon nanotubes (MWCNTs) across industry has increased human exposures. We tested the hypothesis that pulmonary instillation of MWCNT would exacerbate cardiac ischemia/reperfusion (I/R) injury. One day following intratracheal instillation of 1, 10, or 100 μg MWCNT in Sprague-Dawley rats, we used a Langendorff isolated heart model to examine cardiac I/R injury. In the 100 μg MWCNT group we report increased premature ventricular contractions at baseline and increased myocardial infarction. This was associated with increased endothelin-1 (ET-1) release and depression of coronary flow during early reperfusion. We also tested if isolated coronary vascular responses were affected by MWCNT instillation and found trends for enhanced coronary tone, which were dependent on ET-1, cyclooxygenase, thromboxane, and Rho-kinase. We conclude that instillation of MWCNT promoted cardiac injury by depressing coronary flow, invoking vasoconstrictive mechanisms involving ET-1, cyclooxygenase, thromboxane, and Rho-kinase.

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“…In studies with isolated cardiomyocytes, U-46619 has been shown to induce changes in calcium dynamics (11,19) and elicit phosphoinositide turnover and activation of the phospholipase C and IP 3 pathway (31). Therefore, it is possible that TxA 2 receptors are expressed in cardiac myocytes (23).…”

Section: Discussionmentioning

confidence: 99%

Thromboxane A₂-induced arrhythmias in the anesthetized rabbit

Wacker

Best

Kosloski

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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Experiments were conducted in the anesthetized rabbit to investigate mechanisms for arrhythmias that occur after left atrial injection of the thromboxane A(2) (TxA(2)) mimetic U-46619. Arrhythmias were primarily of ventricular origin, dose dependent in frequency, and TxA(2) receptor mediated. The response was receptor specific since arrhythmias were absent after pretreatment with a specific TxA(2) receptor antagonist (SQ-29548) and did not occur in response to another prostaglandin, PGF(2alpha). Alterations in coronary blood flow were unlikely the cause of these arrhythmias because coronary blood flow (as measured with fluorescent microspheres) was unchanged after U-46619, and there were no observable changes in the ECG-ST segment. In addition, arrhythmias did not occur after administration of another vasoconstrictor (phenylephrine). The potential involvement of autonomic cardiac efferent nerves in these arrhythmias was also investigated because TxA(2) has been shown to stimulate peripheral nerves. Pretreatment of animals with the beta-adrenergic receptor antagonist propranolol did not reduce the frequency of these arrhythmias. Pretreatment with atropine or bilateral vagotomy resulted in an increased frequency of arrhythmias, suggesting that parasympathetic nerves may actually inhibit the arrhythmogenic activity of TxA(2). These experiments demonstrate that left atrial injection of U-46619 elicits arrhythmias via a mechanism independent of a significant reduction in coronary blood flow or activation of the autonomic nervous system. It is possible that TxA(2) may have a direct effect on the electrical activity of the heart in vivo, which provides significant implications for cardiac events where TxA(2) is increased, e.g., after myocardial ischemia or administration of cyclooxygenase-2 inhibitors.

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Thromboxane A2 receptor mediation of calcium and calcium transients in rat cardiomyocytes

Cited by 9 publications

References 16 publications

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

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

Pulmonary instillation of multi-walled carbon nanotubes promotes coronary vasoconstriction and exacerbates injury in isolated hearts

Thromboxane A₂-induced arrhythmias in the anesthetized rabbit

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Thromboxane A2 receptor mediation of calcium and calcium transients in rat cardiomyocytes

Cited by 9 publications

References 16 publications

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

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

Pulmonary instillation of multi-walled carbon nanotubes promotes coronary vasoconstriction and exacerbates injury in isolated hearts

Thromboxane A2-induced arrhythmias in the anesthetized rabbit

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

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

Thromboxane A₂-induced arrhythmias in the anesthetized rabbit