Disparate effects of three types of extracellular acidosis on left ventricular function

Berger, David S.; Fellner, Susan K.; Robinson, Kimberly A.; Vlasica, Katherine; Godoy, Iván; Shroff, Sanjeev G.

doi:10.1152/ajpheart.1999.276.2.h582

Cited by 21 publications

(19 citation statements)

References 35 publications

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“…Brooks [ 17 ] has also made the case that lactate itself may be an important signaling molecule for tissues under stress via changes in redox state. Acidosis and catecholamines help to limit the potential negative electrophysiological effects of hyperkalemia on the heart [ 106 ], and as a form of acidosis, lactic acidosis is much less inhibitory of myocardial contractility than equivalent hypercapnic or mineral acidoses [ 10 ]. Because the reduction of pyruvate to lactate by lactate dehydrogenase is proton consuming [ 123 ] it has been suggested in fact that the acidosis of exercise might be worse without lactate formation [ 71 ].…”

Section: Acidosis and Hypoxia With Exercisementioning

confidence: 99%

Hypoxia and Its Acid–Base Consequences: From Mountains to Malignancy

Swenson

2016

Advances in Experimental Medicine and Biology

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Hypoxia, depending upon its magnitude and circumstances, evokes a spectrum of mild to severe acid-base changes ranging from alkalosis to acidosis, which can alter many responses to hypoxia at both non-genomic and genomic levels, in part via altered hypoxia-inducible factor (HIF) metabolism. Healthy people at high altitude and persons hyperventilating to non-hypoxic stimuli can become alkalotic and alkalemic with arterial pH acutely rising as high as 7.7. Hypoxia-mediated respiratory alkalosis reduces sympathetic tone, blunts hypoxic pulmonary vasoconstriction and hypoxic cerebral vasodilation, and increases hemoglobin oxygen affinity. These effects and others can be salutary or counterproductive to tissue oxygen delivery and utilization, based upon magnitude of each effect and summation. With severe hypoxia either in the setting of profound arterial hemoglobin desaturation and reduced O2 content or poor perfusion (ischemia) at the global or local level, metabolic and hypercapnic acidosis develop along with considerable lactate formation and pH falling to below 6.8. Although conventionally considered to be injurious and deleterious to cell function and survival, both acidoses may be cytoprotective by various anti-inflammatory, antioxidant, and anti-apoptotic mechanisms which limit total hypoxic or ischemic-reperfusion injury. Attempts to correct acidosis by giving bicarbonate or other alkaline agents under these circumstances ahead of or concurrent with reoxygenation efforts may be ill advised. Better understanding of this so-called "pH paradox" or permissive acidosis may offer therapeutic possibilities. Rapidly growing cancers often outstrip their vascular supply compromising both oxygen and nutrient delivery and metabolic waste disposal, thus limiting their growth and metastatic potential. However, their excessive glycolysis and lactate formation may not necessarily represent oxygen insufficiency, but rather the Warburg effect-an attempt to provide a large amount of small carbon intermediates to supply the many synthetic pathways of proliferative cell growth. In either case, there is expression and upregulation of many genes involved in acid-base homeostasis, in part by HIF-1 signaling. These include a unique isoform of carbonic anhydrase (CA-IX) and numerous membrane acid-base transporters engaged to maintain an optimal intracellular and extracellular pH for maximal growth. Inhibition of these proteins or gene suppression may have important therapeutic application in cancer chemotherapy.

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Section: Acidosis and Hypoxia With Exercisementioning

confidence: 99%

Hypoxia and Its Acid–Base Consequences: From Mountains to Malignancy

Swenson

2016

Advances in Experimental Medicine and Biology

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“…Brenner has described the turnover kinetics model [3] which includes two states of cross-bridge attachment; strongly attached force producing cross-bridges, and weakly bound cross-bridges (non-force producing). Campbell [7] and Shroff et al [1] have extended Brenner's two state model to a three state model with a third cross-bridge cycling step of calcium bound to troponin C, though non force producing (X co ), as depicted in this figure. The kinetic processes in this model of myofilament interaction are: (1) Calcium cycling and troponin C calcium binding kinetics; (2) Regulatory unit kinetics of the thin filament with rate constants for 'on' and 'off' states reflecting tropomyosin (as bar along thin filament) moving upwards or downwards relative to actin.…”

Section: The Myofilament Force-calcium Relationshipmentioning

confidence: 99%

The Myofilament Force-Calcium Relationship as a Target for Positive Inotropic Therapy in Congestive Heart Failure

MacGowan

2005

Cardiovasc Drugs Ther

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To-date positive inotropic therapy in the treatment of congestive heart failure has resulted in adverse effects on long term survival. These agents increase calcium cycling through beta-adrenergic stimulation or phosphodiesterase inhibition. An alternative method of producing positive inotropy is to increase the myofilament sensitivity to calcium. This can occur at several levels within the myofilament, and has potential benefits with respect to avoiding increased calcium cycling and producing a more favourable energy efficient positive inotropy. A potential adverse effect of increasing calcium sensitivity is slowed relaxation and diastolic dysfunction. We have learnt a considerable amount about the function of specific sites within the myofilament by the use of genetically engineered mouse models, which have shown diverse effects of various myofilament sites on global left ventricular function. Levosimendan is a novel inotropic agent that has several mechanisms of action including calcium sensitization, and is undergoing clinical trials at present. This review article will provide a comprehensive molecular, biophysical and physiological insight into the concepts underlying the myofilament force-calcium relationship and its potential as a target for positive inotropic therapy in heart failure.

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“…and myocardium (Orchard and Kentish, 1990) and can also increase passive tension (Berger et al, 1999;Miyake et al, 2003). In principle, active contraction may be enhanced by sHSP protective effects on actin, troponin, or myosin.…”

Section: Discussionmentioning

confidence: 99%

“…Contractility of myocytes is strongly affected by intracellular acidosis (Orchard and Kentish, 1990). Studies also suggested that acidosis increases the passive stiffness of the heart (Berger et al, 1999) and of skeletal muscles (Miyake et al, 2003). Intracellular acidosis induced by ischemic stress caused severe diastolic dysfunction in a double-knockout mouse model deficient for B-crystallin and HSPB2 (Golenhofen et al, 2006;Pinz et al, 2008).…”

Section: Titin Spring Elements Act As Monomers In Vitromentioning

confidence: 99%