Bradykinin improves postischaemic recovery in the rat heart: role of high energy phosphates, nitric oxide, and prostacyclin

The decrease in myocardial contractility during ischemia, hypoxia, and extracellular acidosis has been attributed to intracellular acidosis. Previous studies of the relationship between pH and contractile state have utilized respiratory or metabolic acidosis to alter intracellular pH. We developed a model in the working perfused rat heart to study the effects of intracellular acidosis with normal external pH and optimal O2 delivery. Intracellular pH and high-energy phosphates were monitored by 31P nuclear magnetic resonance spectroscopy. Hearts were perfused to a steady state with a medium containing 10 mM NH4Cl (extracellular pH, 7.4). The subsequent washout of NH3 from the cytosol generated a slight acidosis (from intracellular pH 7.0 to 6.8) which was associated with little change in the determinants of O2 consumption (rate-pressure product) and O2 delivery (coronary flow). Acidosis induced a substantial decrease in aortic flow and stroke volume which was associated with little change in peak systolic pressure. Results were qualitatively similar at different external [Ca2+] (1.75, 2.5, 3.15 mM) and preload (12 or 21 cmH2O) but were most prominent at the lowest external [Ca2+] and left atrial pressure. In contrast to this model of isolated intracellular acidosis, hearts subject to a respiratory (extracellular plus intracellular) acidosis showed a marked reduction in pressure development. It was concluded that 1) for the same intracellular acidosis the influence on tension development was more pronounced with a combined extra- and intracellular acidosis than with an isolated intracellular acidosis, and 2) stroke volume at constant preload was impaired by intracellular acidosis even though changes in developed pressure were minimal. These observations suggest that isolated intracellular acidosis has adverse effects on diastolic compliance and/or relaxation.

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Cardioprotective Effects of Propofol and Sevoflurane in Ischemic and Reperfused Rat Hearts

Anesthesiology ◽

10.1097/00000542-199911000-00027 ◽

1999 ◽

Vol 91 (5) ◽

pp. 1349-1349 ◽

Cited By ~ 55

Author(s):

Sanjiv Mathur ◽

Parviz Farhangkhgoee ◽

Morris Karmazyn

Keyword(s):

High Energy ◽

Left Ventricular ◽

High Energy Phosphates ◽

Constant Flow Rate ◽

Rat Hearts ◽

Reperfusion Period ◽

Coronary Syndromes ◽

Cardioprotective Effects ◽

Developed Pressure

Background Sodium ion-hydrogen ion (Na(+)-H(+)) exchange inhibitors are effective cardioprotective agents. The N(+)-H(+) exchange inhibitor HOE 642 (cariporide) has undergone clinical trials in acute coronary syndromes, including bypass surgery. Propofol and sevoflurane are also cardioprotective via unknown mechanisms. The authors investigated the interaction between propofol and HOE 642 in the ischemic reperfused rat heart and studied the role of adenosine triphosphate-sensitive potassium (K(ATP)) channels in the myocardial protection associated with propofol and sevoflurane. Methods Isolated rat hearts were perfused by the Langendorff method at a constant flow rate, and left ventricular function and coronary pressures were assessed using standard methods. Energy metabolites were also determined. To assess the role of K(ATP) channels, hearts were pretreated with the K(ATP) blocker glyburide (10 microM). Hearts were then exposed to either control buffer or buffer containing HOE 642 (5 microM), propofol (35 microM), sevoflurane (2.15 vol%), the K(ATP) opener pinacidil (1 microM), or the combination of propofol and HOE 642. Each heart was then subjected to 1 h of global ischemia followed by 1 h of reperfusion. Results Hearts treated with propofol, sevoflurane, pinacidil, or HOE 642 showed significantly higher recovery of left ventricular developed pressure and reduced end-diastolic pressures compared with controls. The combination of propofol and HOE 642 provided superior protection toward the end of the reperfusion period. Propofol, sevoflurane, and HOE 642 also attenuated the onset and magnitude of ischemic contracture and preserved high-energy phosphates (HEPs) compared with controls. Glyburide attenuated the cardioprotective effects of sevoflurane and abolished the protection observed with pinacidil. In contrast, glyburide had no effect on the cardioprotection associated with propofol treatment. Conclusion HOE 642, propofol, and sevoflurane provide cardioprotection via different mechanisms. These distinct mechanisms may allow for the additive and superior protection observed with the combination of these anesthetics and HOE 642.

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Nitric oxide synthase inhibition reduces O2cost of force development and spares high-energy phosphates following contractions in pump-perfused rat hindlimb muscles

Experimental Physiology ◽

10.1113/expphysiol.2005.032698 ◽

2006 ◽

Vol 91 (3) ◽

pp. 581-589 ◽

Cited By ~ 8

Author(s):

David J. Baker ◽

Daniel J. Krause ◽

Richard A. Howlett ◽

Russell T. Hepple

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

High Energy ◽

High Energy Phosphates ◽

Force Development ◽

Hindlimb Muscles ◽

Oxide Synthase

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Role of cation gradients in hypercontracture of myocytes during simulated ischemia and reperfusion

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1993.264.6.h1896 ◽

1993 ◽

Vol 264 (6) ◽

pp. H1896-H1906 ◽

Cited By ~ 9

Author(s):

M. Nishida ◽

S. Borzak ◽

B. Kraemer ◽

J. P. Navas ◽

R. A. Kelly ◽

...

Keyword(s):

Ventricular Myocytes ◽

Extracellular Fluid ◽

High Energy ◽

Ischemia And Reperfusion ◽

High Energy Phosphates ◽

Twitch Contraction ◽

Adult Rat ◽

Simulated Ischemia ◽

The Relationship

We examined the relationship between transsarcolemmal cation gradients and hypercontracture of cardiac myocytes in ischemia and reperfusion using adult rat ventricular myocytes superfused with buffer mimicking normal or ischemic extracellular fluid. Contractile performance of electrically stimulated cells was recorded by an optical video system simultaneously with measurements of intracellular Ca2+ concentration ([Ca2+]i) using fura-2 or intracellular pH (pHi) using 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein. While cells were exposed to simulated ischemia buffer, the transsarcolemmal H+ gradient was abolished, [Ca2+]i transient stopped, and twitch contraction of myocytes ceased. Upon reperfusion with normal buffer, H+ gradient was quickly restored, Ca2+ transients restarted with transient increase in systolic Ca2+, and twitch contraction restarted with development of hypercontracture, which continued after [Ca2+]i returned to preischemic level even in the presence of near-normal concentrations of high-energy phosphates. When the transsarcolemmal proton, Na+, and Ca2+ gradients were altered so that Na+ entry via Na(+)-H+ exchange and Ca2+ entry via Ca(2+)-Na+ exchange were made less favorable, the transient systolic overshoot of Ca2+ at reperfusion and development of hypercontracture was largely avoided. These results suggest that Na+ and then Ca2+ entry via the Na(+)-H+ and Na(+)-Ca2+ exchangers, respectively, probably contribute to the increase in [Ca2+]i and hypercontracture of myocytes at time of reperfusion in this model.

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