Inhibition of Inositol(1,4,5)Trisphosphate Generation by Endothelin-1 During Postischemic Reperfusion

Woodcock, Elizabeth A.; Reyes, Nancy; Jacobsen, Alexander; Du, Xiao‐Jun

doi:10.1161/01.cir.99.6.823

Cited by 20 publications

(13 citation statements)

References 30 publications

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“…ET may as a potent vasoconstrictor elicit arrhythmias secondary to coronary vasoconstriction (35, 565, 566), although observations that ET-induced ventricular arrhythmias may precede overt evidence of myocardial ischemia have led to suggestions that it could also have a direct arrhythmogenic effect (35,565). On the other hand, reperfusion of ischemic rat hearts in the presence of ET-1 did not cause the expected reperfusion-induced increase in inositol 1,4,5-trisphosphate (IP 3 ); given the proarrhythmogenic potential of IP 3 , ET-1-induced inhibition of IP 3 generation during myocardial reperfusion would represent a novel antiarrhythmic mechanism (242,627). Accordingly, given the many contradictory reports on the arrhythmogenic properties of ET-1, which may vary depending on pathophysiological concomitant events, anti-ET-1 therapy should be established with caution.…”

Section: Cardiac Endothelium and Rhythmicity Of The Heartmentioning

confidence: 99%

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Cardiac Endothelial-Myocardial Signaling: Its Role in Cardiac Growth, Contractile Performance, and Rhythmicity

Brutsaert

2003

Physiological Reviews

613

544

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Experimental work during the past 15 years has demonstrated that endothelial cells in the heart play an obligatory role in regulating and maintaining cardiac function, in particular, at the endocardium and in the myocardial capillaries where endothelial cells directly interact with adjacent cardiomyocytes. The emerging field of targeted gene manipulation has led to the contention that cardiac endothelial-cardiomyocytal interaction is a prerequisite for normal cardiac development and growth. Some of the molecular mechanisms and cellular signals governing this interaction, such as neuregulin, vascular endothelial growth factor, and angiopoietin, continue to maintain phenotype and survival of cardiomyocytes in the adult heart. Cardiac endothelial cells, like vascular endothelial cells, also express and release a variety of auto- and paracrine agents, such as nitric oxide, endothelin, prostaglandin I2, and angiotensin II, which directly influence cardiac metabolism, growth, contractile performance, and rhythmicity of the adult heart. The synthesis, secretion, and, most importantly, the activities of these endothelium-derived substances in the heart are closely linked, interrelated, and interactive. It may therefore be simplistic to try and define their properties independently from one another. Moreover, in relation specifically to the endocardial endothelium, an active transendothelial physicochemical gradient for various ions, or blood-heart barrier, has been demonstrated. Linkage of this blood-heart barrier to the various other endothelium-mediated signaling pathways or to the putative vascular endothelium-derived hyperpolarizing factors remains to be determined. At the early stages of cardiac failure, all major cardiovascular risk factors may cause cardiac endothelial activation as an adaptive response often followed by cardiac endothelial dysfunction. Because of the interdependency of all endothelial signaling pathways, activation or disturbance of any will necessarily affect the others leading to a disturbance of their normal balance, leading to further progression of cardiac failure.

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Section: Cardiac Endothelium and Rhythmicity Of The Heartmentioning

confidence: 99%

“…In addition, potential antiarrhythmic properties of ET are discussed above (see sect. III) (244,426,627).…”

Section: F Role Of Etmentioning

confidence: 99%

Cardiac Endothelial-Myocardial Signaling: Its Role in Cardiac Growth, Contractile Performance, and Rhythmicity

Brutsaert

2003

Physiological Reviews

613

544

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“…In fact, there is a relationship between an increase in IP 3 in ventricular cells and the incidence of arrhythmias 41 and IP 3 inhibition and antiarrhythmic effect in reperfused myocardium. 42 The role of Purkinje cells in initiating these IP 3 -dependent arrhythmias was not stated. In this study, by isolating and studying spontaneous Ca 2+ release events in Purkinje cells that are the substrate for the arrhythmias in this canine model, we have shown that an agent effective in blocking IP 3 receptors also is effective in reducing spontaneous Ca 2+ release events.…”

Section: Implications Of Findingsmentioning

confidence: 99%

2APB- and JTV519(K201)-sensitive micro Ca2+ waves in arrhythmogenic Purkinje cells that survive in infarcted canine heart

Boyden

Dun²,

Barbhaiya³

et al. 2004

Heart Rhythm

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Objectives/Background-Studies from several laboratories have implicated intracellular Ca 2+ dynamics in the modulation of electrical activity. We have reported that abnormal Ca 2+ wave activity is the underlying cause of afterdepolarization-induced electrical activity in subendocardial Purkinje cells that survive in the 48-hour infarcted canine heart. These cells form the focus of arrhythmias at this time postcoronary artery occlusion.Methods-We studied the effects of agonists and antagonists on the abnormal Ca 2+ release activity of Purkinje cell aggregates dispersed from the subendocardium 48 hours postcoronary artery occlusion (IZPCs). Studies were completed using epifluorescent microscopy of Fluo-3 loaded Purkinje cells.Results-Similar to our previous report, highly frequent traveling micro Ca 2+ transients(μCaiTs) and cell-wide Ca 2+ waves were seen in IZPCs in the absence of any drug. Isoproterenol (ISO) increased μCaiTs and cell-wide Ca 2+ waves in Purkinje cells dispersed from the normal heart (NZPCs). In IZPCs, ISO increased cell-wide wave frequency but had no effect on the already highly frequent micro Ca 2+ wave transient activity, suggesting that ISO lowers the threshold of cell-wide generators responding to micro Ca 2+ transients. Drugs that block inward sodium or calcium currents (verapamil, tetrodotoxin) had no effect on Ca 2+ activity in Purkinje cells. Antagonists of intracellular Ca 2+ release channels [ryanodine, JTV519(K201)] greatly suppressed spontaneous Ca 2+ release events in IZPCs. 2APB, an agent that blocks IP 3 receptors, greatly reduced the frequency of Ca 2+ events in IZPCs.Conclusions-In arrhythmogenic Purkinje cells that survive in the infarcted heart, agents that block or inhibit intracellular Ca 2+ release channel activity reduced Ca 2+ waves and could be antiarrhythmic.

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“…Intracellular application of Ins(1,4,5)P 3 causes action potential prolongation and degeneration (9) including activation of proarrhythmic sodium-calcium exchange (10). Furthermore, arrhythmias occurring during ischemia and reperfusion correlate with cardiac Ins(1,4,5)P 3 content (11)(12)(13)(14)(15)(16)(17). In the face of evidence for a pathological role of Ins(1,4,5)P 3 in the myocardium (reviewed in Ref.…”

mentioning

confidence: 99%

“…Suppression of Ins(1,4,5)P 3 generation under physiological conditions in NCM, as previously suggested for adult rat heart (29), lends support to the view that increases in Ins(1,4,5)P 3 are deleterious to the heart (18). Direct intracellular application of Ins(1,4,5)P 3 causes action potential degeneration (9, 10) and Ins(1,4,5)P 3 generation has been shown to be related to the initiation of arrhythmias under ischemia and reperfusion conditions (11)(12)(13)(14)(15)(16)(17). It is therefore possible that the abbreviated InsP pathway present in cardiac myocytes protects the heart from Ins(1,4,5)P 3 generation and consequent arrhythmias, presumably arising from enhanced Ca 2ϩ release from the cardiac sarcoplasmic reticulum.…”

mentioning

confidence: 99%

Ca2+-activated but Not G Protein-mediated Inositol Phosphate Responses in Rat Neonatal Cardiomyocytes Involve Inositol 1,4,5-Trisphosphate Generation

Matkovich

Woodcock

2000

Journal of Biological Chemistry

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Generation of inositol 1,4,5-trisphosphate (Ins(1,4,5)P 3 ), 1 a Ca 2ϩ -mobilizing second messenger, is critical in mediating responses to hormone stimulation in a wide variety of cell types (1). Activation of phospholipase C (PLC) generates both Ins(1,4,5)P 3 and sn-1,2-diacylglycerol from the precursor phospholipid PtdIns(4,5)P 2 . However, all known PLC isozymes have the capacity to hydrolyze PtdIns and PtdIns(4)P as well as PtdIns(4,5)P 2 , although with lower potency (2, 3). While there is some difference in substrate selectivity between the three PLC classes (␤, ␥, and ␦), activity toward PtdIns(4,5)P 2 is somewhat higher than toward PtdIns(4)P when measurements are made using PLCs reconstituted in lipid vesicles (2, 3). Nonetheless, this suggests the possibility that cleavage of PtdIns(4)P in addition to PtdIns(4,5)P 2 could be a substantial contributor to the overall InsP response. Early studies of InsP responses led to the suggestion that generation of Ins(1,4,5)P 3 takes place during the initial stage of agonist stimulation, while the sustained InsP response depends on cleavage of PtdIns to Ins(1)P (4 -6). However, the lack of potent, readily available inhibitors of Ins(1,4,5)P 3 metabolism has meant that such ideas have never been substantiated, and Ins(1,4,5)P 3 has generally been assumed to be the primary source of all InsPs that accumulate in response to receptor stimulation, including InsPs generated in the myocardium.Beat-to-beat regulation of cardiac muscle Ca 2ϩ is primarily controlled by ryanodine receptors on the sarcoplasmic reticulum. Ins(1,4,5)P 3 -mediated Ca 2ϩ responses in cardiac myocytes are relatively slow and weak and have been characterized as Ca 2ϩ oscillations (7, 8) which have potential proarrhythmic activity. Intracellular application of Ins(1,4,5)P 3 causes action potential prolongation and degeneration (9) including activation of proarrhythmic sodium-calcium exchange (10). Furthermore, arrhythmias occurring during ischemia and reperfusion correlate with cardiac Ins(1,4,5)P 3 content (11)(12)(13)(14)(15)(16)(17). In the face of evidence for a pathological role of Ins(1,4,5)P 3 in the myocardium (reviewed in Ref. 18), it is important to better understand the mechanisms responsible for its generation in cardiac myocytes and also the mechanisms suppressing its generation under physiological circumstances.Rat neonatal cardiomyocytes (NCM) represent a convenient system for the modelling of myocardial signaling. InsP responses to norepinephrine (NE) in myocytes are mediated via ␣ 1 -adrenergic receptors, coupling via G q to PLC-␤ isoforms (19,20) of which PLC-␤1 and PLC-␤3 are expressed in heart (21-23). Our initial studies indicated that NE stimulation in NCM was largely insensitive to the PtdIns(4,5)P 2 -binding agent neomycin (24), unlike findings in other cell types, implying that responses are largely independent of Ins(1,4,5)P 3 . This prompted us to examine the source of InsPs in NCM generated in response to ␣ 1 -adrenergic activation. In this study, we present the first dire...

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Inhibition of Inositol(1,4,5)Trisphosphate Generation by Endothelin-1 During Postischemic Reperfusion

Abstract: Inhibition of Ins 1,4,5P3 generation during myocardial reperfusion by endothelin-1 represents a novel antiarrhythmic mechanism.

Cited by 20 publications

References 30 publications

Cardiac Endothelial-Myocardial Signaling: Its Role in Cardiac Growth, Contractile Performance, and Rhythmicity

Cardiac Endothelial-Myocardial Signaling: Its Role in Cardiac Growth, Contractile Performance, and Rhythmicity

2APB- and JTV519(K201)-sensitive micro Ca2+ waves in arrhythmogenic Purkinje cells that survive in infarcted canine heart

Ca2+-activated but Not G Protein-mediated Inositol Phosphate Responses in Rat Neonatal Cardiomyocytes Involve Inositol 1,4,5-Trisphosphate Generation

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