Myocytes Isolated from Rejecting Transplanted Rat Hearts Exhibit a Nitric Oxide-mediated Reduction in the Calcium Current

Ziolo, Mark T.; Harshbarger, C H; Roycroft, Karen E.; Smith, Jacquelyn M.; Romano, Fred D.; Sondgeroth, Korie; Wahler, Gordon M.

doi:10.1006/jmcc.2001.1420

Cited by 27 publications

(24 citation statements)

References 30 publications

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“…We have previously shown that aminoguanidine is a specific inhibitor of iNOS in cardiac myo- cytes. 10,22 Thus, decreasing RyR activity may be a key mechanism in NO-induced reduction of ␤-adrenergic responsiveness.…”

Section: No ␤-Adrenergic Stimulation and Ca 2؉ Sparksmentioning

confidence: 99%

Expression of Inducible Nitric Oxide Synthase Depresses β-Adrenergic–Stimulated Calcium Release From the Sarcoplasmic Reticulum in Intact Ventricular Myocytes

2001

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Background-␤-Adrenergic hyporesponsiveness in many cardiomyopathies is linked to expression of inducible nitric oxide synthase (iNOS) and increased production of NO. The purpose of this study was to examine whether iNOS expression alters the function of the sarcoplasmic reticulum (SR) Ca 2ϩ release channel (ryanodine receptor, RyR) during ␤-adrenergic stimulation. Methods and Results-Expression of iNOS was induced by lipopolysaccharide (LPS) injection (10 mg/kg) 6 hours before rat myocyte isolation. Confocal microscopy (fluo-3) was used to measure Ca 2ϩ spark frequency (CaSpF, reflecting resting RyR openings) and Ca 2ϩ transients. CaSpF was greatly increased by the adenylate cyclase activator forskolin (100 nmol/L) in normal myocytes (iNOS not expressed), but this effect was suppressed (by 77%) in LPS myocytes (iNOS expressed). When NO production by iNOS was inhibited by aminoguanidine (1 mmol/L), there was a further increase in the forskolin-induced CaSpF in LPS myocytes (to levels similar to the forskolin-stimulated CaSpF in normal myocytes). This effect was also seen in myocytes isolated from a failing human heart. There was no effect of aminoguanidine on forskolin-stimulated CaSpF in normal myocytes. ODQ (10 mol/L), an inhibitor of NO stimulation of guanylate cyclase, did not restore the forskolin-induced rise in CaSpF in LPS myocytes. Aminoguanidine also increased twitch Ca 2ϩ transient amplitude in LPS myocytes after forskolin application (independent of changes in SR Ca 2ϩ load). Conclusions-iNOS/NO depresses ␤-adrenergic-stimulated RyR function through a cGMP-independent pathway (eg, NO-and/or peroxynitrite-dependent redox modification). This mechanism limits ␤-adrenergic responsiveness and may be an important signaling pathway in cardiomyopathies, including human heart failure.

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Section: No ␤-Adrenergic Stimulation and Ca 2؉ Sparksmentioning

confidence: 99%

Expression of Inducible Nitric Oxide Synthase Depresses β-Adrenergic–Stimulated Calcium Release From the Sarcoplasmic Reticulum in Intact Ventricular Myocytes

2001

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“…In the case of the mouse cardiac myocytes, the investigators found no difference in calcium current between cardiac myocytes isolated from isografts and allografts. However, β-adrenergic challenging of cardiac myocytes revealed impaired contractile activity in myocytes from rat allografts [110] but again not in mouse allografts [111]. The differences in the findings are unknown but may simply represent species differences or differential level of rejection in each species.…”

Section: Inos and Contractile Dysfunction In Allograft-derived Cardiamentioning

confidence: 89%

“…First, the addition of L-arginine to bathing media decreased myocyte shortening in cells derived from both rat and mouse cardiac allografts but not did not decrease myocyte shortening in cells derived from isografts [108,111]. Second, the addition of the iNOS inhibitor, aminoguanidine, reversed the impaired contractile shortening and the decreased calcium current in rat cardiac allograft myocytes [109,111]. Collectively, despite the acknowledged caveats of use of aminoguanidine, these studies appear to show that in early rejection the contractile abnormalities due to NO derived from iNOS are still reversible.…”

Section: Inos and Contractile Dysfunction In Allograft-derived Cardiamentioning

confidence: 97%

The complex role of iNOS in acutely rejecting cardiac transplants

Pieper

Roza

2008

Free Radical Biology and Medicine

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This review summarizes the evidence for a detrimental role of nitric oxide (NO) derived from inducible NO synthase (iNOS) and/or reactive nitrogen species such as peroxynitrite in acutelyrejecting cardiac transplants. In chronic cardiac transplant rejection, iNOS may have an opposing beneficial component. The purpose of this review is primarily to address issues related to acute rejection which is a recognized risk factor for chronic rejection. The evidence for a detrimental role is based upon strategies involving non-selective NOS inhibitors, NO neutralizers, selective iNOS inhibitors and iNOS gene deletion in rodent models of cardiac rejection. The review is discussed in the context of the impact on various components including graft survival, histological rejection and cardiac function which may contribute in toto to the process of graft rejection. Possible limitations of each strategy are discussed in order to understand better the variance in published findings including issues related to the potential importance of cell localization of iNOS expression. Finally, the concept of a dual role of NO and its down-stream product, peroxynitrite, in rejection vs. immune regulation is discussed.

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“…6,7 NOS1 (nNOS) and NOS3 (eNOS) are constitutively expressed and produce low amounts of NO (regulated by [Ca 2ϩ -calmodulin] i levels). NOS2 (iNOS) is expressed during inflammatory responses (eg, cytokines, sepsis, heart failure) and continuously produces large amounts of NO (compared with NOS1 and NOS3), 7 independent of Ca 2ϩ . NO can increase or decrease contractility.…”

Section: Nitric Oxide and Cardiac Functionmentioning

confidence: 99%

“…Since NOS2 is not localized (cytosolic) and produces large amounts of NO, NOS2 signaling is probably less "compartmentalized" and can affect various EC coupling related proteins/processes (eg, I Ca , RyRs, and energetics). 7,15,16 These effects can contribute to cardiac dysfunction in various diseases where myocyte NOS2 is expressed (eg, rejection of transplanted hearts). 17 NOS3 seems to depress contractility.…”

Section: Nitric Oxide and Cardiac Functionmentioning

confidence: 99%