Metabolic changes during ischaemia and their role in contractile failure in isolated ferret hearts.

Elliott, A.; Smith, Godfrey L.; Eisner, David; Allen, David G.

doi:10.1113/jphysiol.1992.sp019274

Cited by 87 publications

(60 citation statements)

References 49 publications

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“…The reduction in contractile performance during ischemia has been previously suggested to be due to metabolic changes associated with the loss of creatine phosphate, increased intracellular acidosis, and the accumulation of inorganic phosphate and lactate. [25][26][27][28] During reoxygenation after the 15-minute period of hypoxia, the contractile performance of electrically stimulated rat papillary muscle was markedly depressed by 40% for up to 60 minutes, consistent with the findings of previous studies with ischemia/reperfusion 1,2 and hypoxia/reoxygenation. 3 Since L-NA, SOD, and uric acid markedly suppressed the observed depression of contractile function during posthypoxic reoxygenation, NO-derived endogenous ONOO Ϫ formation is mainly responsible for the suppression of force generation during reoxygenation.…”

Section: Discussionsupporting

confidence: 89%

Inhibition of Rat Cardiac Muscle Contraction and Mitochondrial Respiration by Endogenous Peroxynitrite Formation During Posthypoxic Reoxygenation

Xie

Kaminski

Wolin

1998

Circulation Research

105

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Abstract-This study was designed to investigate the potential role of endogenous peroxynitrite (ONOO Ϫ ) formation in the inhibition of cardiac muscle contractility and mitochondrial respiration during posthypoxic reoxygenation. Isometric contraction of isolated rat left ventricular posterior papillary muscle was virtually eliminated at the end of an exposure to 15 minutes of hypoxia and remained 40Ϯ5% depressed an hour after the reintroduction of O 2 . O 2 uptake by rat left ventricular cardiac muscle, measured by a Clark-type O 2 electrode, was also inhibited by 24Ϯ2% at 10 minutes after reoxygenation. The inhibition of contractility and respiration during posthypoxic reoxygenation was markedly attenuated by the NO synthase inhibitor nitro-L-arginine, exogenous superoxide dismutase, and the ONOO Ϫ scavenger urate but not by the hydroxyl radical scavenger mannitol. Generation of ONOO Ϫ with the NO donor S-nitroso-Nacetylpenicillamine (SNAP) plus the superoxide-releasing agent pyrogallol caused an irreversible inhibition of cardiac contractile and respiratory function. Unlike ONOO Ϫ , exogenous (SNAP) and endogenous (bradykinin) sources of NO inhibited contractility in a reversible manner. Under conditions of comparable amounts of respiratory inhibition in unstimulated incubated muscle, the NO-dependent agents and the mitochondrial antagonist NaCN produced a smaller degree of suppression of contractility compared with ONOO Ϫ and posthypoxic reoxygenation. These results are consistent with a contributing role for endogenous ONOO Ϫ formation in the inhibition of cardiac muscle contractility and mitochondrial respiration during posthypoxic reoxygenation. (Circ Res. 1998;82:891-897.)

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Section: Discussionsupporting

confidence: 89%

Inhibition of Rat Cardiac Muscle Contraction and Mitochondrial Respiration by Endogenous Peroxynitrite Formation During Posthypoxic Reoxygenation

Xie

Kaminski

Wolin

1998

Circulation Research

105

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“…Increase in impulse frequency rate from 1 to 3 Hz causes a decrease in pH i by ∼0.3 units in isolated sheep Purkinje fibers (37). pH i decreases more dramatically during global ischemia in a perfused rat heart model (38) when pH i drops to ∼6.2, which accounts for much of the observed failure of contraction (36). A pH i decrease from 7.2 to 6.8 in cells expressing Cx45 would reduce g j more than twofold.…”

Section: Discussionmentioning

confidence: 99%

“…This pH-dependent modulation of GJ channels may be critical under severe pathological conditions, because the uncoupling effect of low pH i may reduce propagation of metabolic stress from damaged cells to healthy neighbors (34,35) or prevent rescue of stressed cells by healthier neighbors, as discussed later. Brief periods of global ischemia can produce fast intracellular acidosis of ∼0.4 pH units in isolated ferret hearts (36). Increase in impulse frequency rate from 1 to 3 Hz causes a decrease in pH i by ∼0.3 units in isolated sheep Purkinje fibers (37).…”

Section: Discussionmentioning

confidence: 99%

pH-dependent modulation of voltage gating in connexin45 homotypic and connexin45/connexin43 heterotypic gap junctions

Palacios-Prado

Briggs

Skeberdis

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Intracellular pH (pH i ) can change during physiological and pathological conditions causing significant changes of electrical and metabolic cell-cell communication through gap junction (GJ) channels. In HeLa cells expressing wild-type connexin45 (Cx45) as well as Cx45 and Cx43 tagged with EGFP, we examined how pH i affects junctional conductance (g j ) and g j dependence on transjunctional voltage (V j ). To characterize V j gating, we fit the g j -V j relation using a stochastic four-state model containing one V j -sensitive gate in each apposed hemichannel (aHC); aHC open probability was a Boltzmann function of the fraction of V j across it. Using the model, we estimated gating parameters characterizing sensitivity to V j and number of functional channels. In homotypic Cx45 and heterotypic Cx45/Cx43-EGFP GJs, pH i changes from 7.2 to ∼8.0 shifted g j -V j dependence of Cx45 aHCs along the V j axis resulting in increased probability of GJ channels being in the fully open state without change in the slope of g j dependence on V j . In contrast, acidification shifted g j -V j dependence in the opposite direction, reducing open probability; acidification also reduced the number of functional channels. Correlation between the number of channels in Cx45-EGFP GJs and maximal g j achieved under alkaline conditions showed that only ∼4% of channels were functional. The acid dissociation constant (pK a ) of g j -pH i dependence of Cx45/Cx45 GJs was ∼7. The pK a of heterotypic Cx45/Cx43-EGFP GJs was lower, ∼6.7, between the pK a s of Cx45 and Cx43-EGFP (∼6.5) homotypic GJs. In summary, pH i significantly modulates junctional conductance of Cx45 by affecting both V j gating and number of functional channels.cell-cell coupling | pH-dependent gating | EGFP | hemichannel | connexon C hanges in intracellular pH (pH i ) take place under different physiological and pathological conditions, and H + ions have a broad effect on cell function including cell-cell electrical and metabolic communication mediated by gap junctions (GJs) and paracrine signaling through nonjunctional/unapposed hemichannels (1-4). Modest pH i changes have been observed under normal physiological conditions [e.g., changes of neuronal activity or the resting potential (5, 6)], and greater changes occur under pathological conditions such as hypoxia, ischemia, or epilepsy (4,7,8).During the last decade, significant progress has been made toward understanding the molecular mechanisms of pH-dependent modulation of GJs and hemichannels (2, 9-12). Several domains in the cytoplasmic loop and C terminus of connexin43 (Cx43) appear to be involved in pH-dependent gating (2, 9, 11, 12). Furthermore, pH-dependent interaction of connexins with other cytoplasmic proteins may be important in the remodeling of connexins and in protection from lesion spread after local ischemic injury (13,14).GJs provide channels with an inner diameter of ∼1.4 nm between the interiors of the coupled cells. This link allows the spread of electrical potential and small metabolites. Each GJ cha...

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“…Changes of cardiac pH i will occur during whole body acid-base disturbances (25) and during changes in the metabolic workload placed on the heart (2,8). A large drop in pH i also occurs during myocardial ischemia, where it accounts for much of the observed inotropic decline (1,9).…”

mentioning

confidence: 99%

Novel method for measuring junctional proton permeation in isolated ventricular myocyte cell pairs

Swietach

Vaughan‐Jones

2004

American Journal of Physiology-Heart and Circulatory Physiology

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Metabolic changes during ischaemia and their role in contractile failure in isolated ferret hearts.

Cited by 87 publications

References 49 publications

Inhibition of Rat Cardiac Muscle Contraction and Mitochondrial Respiration by Endogenous Peroxynitrite Formation During Posthypoxic Reoxygenation

Inhibition of Rat Cardiac Muscle Contraction and Mitochondrial Respiration by Endogenous Peroxynitrite Formation During Posthypoxic Reoxygenation

pH-dependent modulation of voltage gating in connexin45 homotypic and connexin45/connexin43 heterotypic gap junctions

Novel method for measuring junctional proton permeation in isolated ventricular myocyte cell pairs

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