Prevention of transcoronary macromolecular leakage after ischemia-reperfusion by the calcium entry blocker nisoldipine. Direct observations in isolated rat hearts.

McDonagh, Paul F.; Roberts, D J

doi:10.1161/01.res.58.1.127

Cited by 46 publications

(6 citation statements)

References 38 publications

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“…47 It seems to be associated with endothelial Ca 2+ overload and is prevented by calcium entry blockade. 47 The present results suggest that at least part of the leaks that become manifest on resumption of coronary flow are formed during perfusional arrest.…”

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confidence: 99%

Effect of oxygen withdrawal on active and passive electrical properties of arterially perfused rabbit ventricular muscle.

Riegger

Alperovich

Kléber

1989

Circulation Research

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Oxygen withdrawal from myocardial cells leads to changes of the transmembrane action potential (mainly action potential shortening), to cellular uncoupling, and to changes of vascular permeability. This study was aimed at the simultaneous measurement of electrical activity and passive electrical properties (extracellular and intracellular longitudinal resistance) in arterially perfused rabbit papillary muscles under different conditions of changed oxygen supply. These included 1) complete anoxia (erythrocyte-free perfusate), 2) hypoxia (Po 2 between 23-28 mm Hg, erythrocytes present) in the presence and absence of glucose, and 3) normoxia with erythrocyte-free perfusate. Similarly to myocardial ischemia, rapid cellular uncoupling occurred only after an initial stable period of approximately 17 minutes, and it required complete anoxia. The marked shortening of the action potential developed before cellular uncoupling. In six out of eight experiments, the fibers were inexcitable when uncoupling started. In severe hypoxia, no significant change of internal longitudinal resistance was observed over 35-40 minutes. The time course of the extracellular longitudinal resistance was different from the change in intracellular resistance: A marked decrease occurred almost immediately after the onset of oxygen withdrawal. This decrease was followed by a small increase in conduction velocity, which was most likely due to a change in the interstitial compartment (edema). It was observed during anoxic as well as during hypoxic perfusion. We conclude that 1) cellular uncoupling in arterially perfused tissue requires almost complete oxygen lack and occurs with a delay of more than 10 minutes, 2) marked action potential shortening precedes uncoupling, and therefore can not simply be attributed to an increase in free, intracellular calcium, and 3) vascular endothelial function is more sensitive to oxygen withdrawal than the myocyte. (Circulation Research 1989;64:532-541) R emoval of the oxygen supply from ventricular myocardium leads to rapid changes of electrical activity 1 and to the early development of malignant ventricular arrhythmias.2 Two experimental models are widely used for investigation of metabolic and electrical changes associated with inadequate myocardial oxygen supply. These include the production of 1) myocardial anoxia or hypoxia by decreasing the oxygen content of the coronary perfusate, or 2) myocardial ischemia by the arrest of coronary flow. The essential difference between these two conditions is the complete absence of extracellular washout in the case of myocardial ischemia. This causes products of ischFrom the Department of Physiology, University of Berne, Beme, Switzerland.Supported by the Swiss National Science Foundation (Grant 3.903.0-85 to A.G.K.) and the Swiss Foundation of Cardiology.Address for correspondence: Andrt G. Kteber, MD, Department of Physiology, University of Beme, Bflhlplatz 5, CH-3012, Berne, Switzerland.Received March 31, 1988; accepted August 18, 1988. emic metabolism (e.g., lact...

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confidence: 99%

Effect of oxygen withdrawal on active and passive electrical properties of arterially perfused rabbit ventricular muscle.

Riegger

Alperovich

Kléber

1989

Circulation Research

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“…Calcium entry blockade also has been shown to ameliorate vascular leakage in the isolated, perfused arrested heart model. 30 Interestingly, in the latter study, the perfusate was free of leukocytes and platelets, suggesting that the cause of the increased microvascular leakage permeability after ischemia-reperfusion may be by direct alteration of the endothelium. These observations support our hypothesis that the prevention of loss of endothelial permselectivity to macromolecules after ischemia-reperfusion is related to the ability of verapamil to block calcium entry to both microvascular and blood-formed elements.…”

Section: Release Of Eicosanoidsmentioning

confidence: 70%

Calcium entry blockade prevents leakage of macromolecules induced by ischemia-reperfusion in skeletal muscle.

Paul¹,

Bekker²,

Durán³

1990

Circulation Research

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Calcium kinetics and its intracellular mobilization are important in all biological processes. We used verapamil to examine the effect of calcium entry blockade on microvascular transport of macromolecules in ischemia-reperfusion injury. The rat cremaster muscle was splayed, placed in a Lucite intravital chamber, and suffused with bicarbonate buffer. The clearance of fluorescein isothiocyanate-conjugated dextran (FITC-dextran 150) was measured as an index of microvascular transport. After determination of baseline data (clearance of FITC-dextran 150, 3.0±0.5 ,1/5 min/g), the muscle was made ischemic for 2 hours by clamping its vascular pedicle and subsequently was reperfused for 2 hours. Ischemia-reperfusion produced a marked increase in FITC-dextran clearance. After a peak of 12±2-fold increase observed in the first 15 minutes into reperfusion, FITC-dextran 150 clearance decreased in magnitude and stabilized at about sixfold above baseline. Verapamil did not change the baseline clearance values. Importantly, verapamil inhibited the ischemia-induced increase in clearance and maintained the values at or near the baseline levels. We simultaneously determined the rate of release of 6-ketoprostaglandin F1, (6-keto-PGFIa) and thromboxane B2 (TXB2) into the suffusate. Verapamil decreased the baseline values of 6-keto-PGF1. and increased those of TXB2.Verapamil inhibited the ischemia-reperfusion-induced increase in 6-keto-PGFia but did not alter the effect of ischemia-reperfusion on TXB2. Our main results demonstrate the effectiveness of verapamil in preventing microvascular alterations leading to increased leakage of macromolecules. (Circulation Research 1990;66:1636-1642 C alcium entry blockade contributes to preserving myocardial function after ischemiareperfusion damage. Its mechanisms of protection include vasodilation, enhancement of collateral flow, and reduction of oxygen demand by stabilizing mitochondrial activity.1 Skeletal muscle, which has a metabolic rate lower than heart, can tolerate circulatory interruption for up to 6 hours without irreversible damage to the myocytes.2 However, microcirculatory derangements such as increased leakage of macromolecules and no reflow

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“…After MI, the ischemic tissue undergoes severe changes in cellular and extracellular matrix composition leading to an increase in the extracellular volume [ 56 , 57 ]. Acute myocardial injury, defined by cardiomyocyte death and endothelial damage, leads to increased leakage of plasma macromolecules [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

MRI with gadofosveset: A potential marker for permeability in myocardial infarction

Lavin¹,

Protti²,

Lorrio

et al. 2018

Atherosclerosis

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Background and aimsAcute ischemia is associated with myocardial endothelial damage and microvessel formation, resulting in leakage of plasma albumin into the myocardial extravascular space. In this study, we tested whether an albumin-binding intravascular contrast agent (gadofosveset) allows for improved quantification of myocardial permeability compared to the conventional extracellular contrast agent Gd-DTPA using late gadolinium enhancement (LGE) and T1 mapping in vivo.MethodsMI was induced in C57BL/6 mice (n = 6) and cardiac magnetic resonance imaging (CMR) was performed at 3, 10 and 21 days post-MI using Gd-DTPA and 24 h later using gadofosveset. Functional, LGE and T1 mapping protocols were performed 45 min post-injection of the contrast agent.ResultsLGE images showed that both contrast agents provided similar measurements of infarct area at all time points following MI. Importantly, the myocardial R1 measurements after administration of gadofosveset were higher in the acute phase-day 3 (R1 [s−1] = 6.29 ± 0.29) compared to the maturation phase-days 10 and 21 (R1 [s−1] = 4.76 ± 0.30 and 4.48 ± 0.14), suggesting that the uptake of this agent could be used to stage myocardial remodeling. No differences in myocardial R1 were observed after administration of Gd-DTPA at different time points post-MI (R1 [s−1] = 3d: 3.77 ± 0.37; 10d: 2.74 ± 0.06; 21d: 3.35 ± 0.26). The MRI results were validated by ex vivo histology that showed albumin leakage in the myocardium in the acute phase and microvessel formation at later stages.ConclusionsWe demonstrate the merits of an albumin-binding contrast agent for monitoring changes in myocardial permeability between acute ischemia and chronic post-MI myocardial remodeling.

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Prevention of transcoronary macromolecular leakage after ischemia-reperfusion by the calcium entry blocker nisoldipine. Direct observations in isolated rat hearts.

Cited by 46 publications

References 38 publications

Effect of oxygen withdrawal on active and passive electrical properties of arterially perfused rabbit ventricular muscle.

Effect of oxygen withdrawal on active and passive electrical properties of arterially perfused rabbit ventricular muscle.

Calcium entry blockade prevents leakage of macromolecules induced by ischemia-reperfusion in skeletal muscle.

MRI with gadofosveset: A potential marker for permeability in myocardial infarction

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