Absence of mitochondrial activation during levosimendan inotropic action in perfused paced guinea pig hearts as demonstrated by modular control analysis

Levosimendan is a calcium sensitizer developed for the treatment of heart failure. It increases contractile force by enhancing the sensitivity of myofilaments to calcium. Besides this sensitizing effect, the drug has also been reported to show some inhibitory action on phosphodiesterase 3 (PDE3). The inotropic effects of levosimendan have been studied on guinea pig paced perfused hearts by using modular control analysis (MoCA) (Diolez P, Deschodt-Arsac V, Raffard G, Simon C, Santos PD, Thiaudiere E, Arsac L, Franconi JM. Am J Physiol Regul Integr Comp Physiol 293: R13–R19, 2007.), an integrative approach of heart energetics using noninvasive 31P NMR. The aim was to evaluate quantitatively the respective effects of this drug on energy supply and demand modules. Under our experimental conditions, 0.7 μM levosimendan induced a 45% increase in paced heart output associated with a 7% decrease in phosphocreatine and a negligible increase in oxygen consumption. Because MoCA allows in situ study of the internal regulations in intact beating heart energetics, it was applied to describe quantitatively by which routes levosimendan exerts its inotropic action. MoCA demonstrated the absence of any significant effect of the drug on the supply module, which is responsible for the lower increase in oxygen consumption, compared with epinephrine, which increases the ratio between myocardial oxygen consumption and cardiac contraction. This result evidences that, under our conditions, a possible effect of levosimendan on PDE3 activity and/or intracellular calcium remains very low on mitochondrial activity and insignificant on integrated cardiac energetics. Thus, levosimendan inotropic effect on guinea pig heart depends almost entirely on the calcium-sensitizing properties leading to myofilament activation and the concomitant activation of energy supply by the decrease in PCr, therefore improving energetic efficiency of contraction.

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Influence of energy supply and calcium on the low sodium induced changes in the transmembrane potential and contraction of guinea pig papillary muscle

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y70-042 ◽

1970 ◽

Vol 48 (4) ◽

pp. 241-253 ◽

Cited By ~ 5

Author(s):

K. Prasad

Keyword(s):

Guinea Pig ◽

Action Potential ◽

Papillary Muscle ◽

Energy Supply ◽

Cardiac Contraction ◽

Force Of Contraction ◽

Inotropic Effects ◽

Low Sodium ◽

Small Change ◽

Induced Changes

The effects of changes in extracellular concentrations (25, 50, 100, 140 mM) of NaCl on the simultaneously recorded action potential (AP) and contraction of guinea pig papillary muscle in the presence of various concentrations of glucose (0, 5, 20, 30, 50 mM) and CaCl2 (0, 0.5, 1.0, 2.5 mM) were investigated. Low sodium (25 mM) produced a marked shortening of the action potential duration (APD) associated with a marked increase in the force of contraction but a small change in AP amplitude. A direct relation between extracellular NaCl and cardiac contraction was observed. There was no relation between AP amplitude and cardiac contraction. Low sodium induced shortening of the APD was greater in the absence of glucose than in its presence while the increase in the force contraction induced by low Na was markedly reduced in the absence of glucose. Low sodium was practically ineffective in restoring the contraction of papillary muscle in the absence of CaCl2. A calcium concentration dependent increase in the force of contraction was associated with a corresponding shortening of the APD in low sodium. Anoxia markedly reduced the positive inotropic effects of low sodium and enhanced the low sodium induced shortening of the APD in the papillary muscle. Glucose produced a marked lengthening of the APD which was shortened during anoxia but it was effective only slightly in lengthening the APD shortened by low sodium. The effects of ouabain in the muscles in the presence of low sodium were reduced. It is suggested that the changes in the APD accompanied by changes in the contraction in the guinea pig papillary muscle might be associated with NaCl-induced changes in the membrane ATPase. The low sodium induced increase in the force of contraction seems to be dependent upon both calcium and energy supply.

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Cardiac performance as a function of intracellular oxygen tension in buffer-perfused hearts

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2001.281.6.h2463 ◽

2001 ◽

Vol 281 (6) ◽

pp. H2463-H2472 ◽

Cited By ~ 39

Author(s):

Kenneth A. Schenkman

Keyword(s):

Oxygen Consumption ◽

Guinea Pig ◽

Oxygen Tension ◽

Myocardial Oxygen Consumption ◽

Arterial Oxygen Tension ◽

Left Ventricular ◽

Cardiac Contraction ◽

Arterial Oxygen ◽

Adenosine Release ◽

Lactate Release

Critical intracellular myocardial oxygen tension was determined by optical spectroscopic measurement of myoglobin oxygen saturation in crystalloid-perfused guinea pig hearts. Accurate end-point determinations of the maximally oxygenated and deoxygenated myoglobin were made. Hearts were subjected to a steady decrease in perfusate oxygen tension while left ventricular developed pressure, maximal left ventricular dP/d t, myocardial oxygen consumption, lactate release, and adenosine release were measured as indices of myocardial function. Intracellular myoglobin was found to be only 72% saturated under baseline conditions with an arterial oxygen tension of >600 mmHg at 37°C. Baseline intracellular oxygen tension was 6.3 mmHg. Myocardial oxygen consumption was decreased by 10% when the oxygen tension fell to 5.7 mmHg, and cardiac contraction decreased 10% when oxygen tension was 4.1 mmHg. Adenosine release and, finally, lactate release began to increase at sequentially lower oxygen tensions. The present results indicate that the buffer-perfused guinea pig heart at 37°C has an intracellular oxygen tension just above the threshold for impaired function.

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Development of an automated closed-loop β-blocker delivery system to stably reduce myocardial oxygen consumption without inducing circulatory collapse in a canine heart failure model: a proof of concept study

Journal of Clinical Monitoring and Computing ◽

10.1007/s10877-021-00717-w ◽

2021 ◽

Author(s):

Takuya Nishikawa ◽

Kazunori Uemura ◽

Yohsuke Hayama ◽

Toru Kawada ◽

Keita Saku ◽

...

Keyword(s):

Heart Failure ◽

Oxygen Consumption ◽

Myocardial Oxygen Consumption ◽

Atrial Pressure ◽

Right Atrial ◽

Canine Heart ◽

Circulatory Collapse ◽

Inotropic Effects ◽

Administration System ◽

Β Blocker

AbstractBeta-blockers are well known to reduce myocardial oxygen consumption (MVO2) and improve the prognosis of heart failure (HF) patients. However, its negative chronotropic and inotropic effects limit their use in the acute phase of HF due to the risk of circulatory collapse. In this study, as a first step for a safe β-blocker administration strategy, we aimed to develop and evaluate the feasibility of an automated β-blocker administration system. We developed a system to monitor arterial pressure (AP), left atrial pressure (PLA), right atrial pressure, and cardiac output. Using negative feedback of hemodynamics, the system controls AP and PLA by administering landiolol (an ultra-short-acting β-blocker), dextran, and furosemide. We applied the system for 60 min to 6 mongrel dogs with rapid pacing-induced HF. In all dogs, the system automatically adjusted the doses of the drugs. Mean AP and mean PLA were controlled within the acceptable ranges (AP within 5 mmHg below target; PLA within 2 mmHg above target) more than 95% of the time. Median absolute performance error was small for AP [median (interquartile range), 3.1% (2.2–3.8)] and PLA [3.6% (2.2–5.7)]. The system decreased MVO2 and PLA significantly. We demonstrated the feasibility of an automated β-blocker administration system in a canine model of acute HF. The system controlled AP and PLA to avoid circulatory collapse, and reduced MVO2 significantly. As the system can help the management of patients with HF, further validations in larger samples and development for clinical applications are warranted.

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Respiratory Metabolism During Pregnancy in the Guinea Pig

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1957.190.3.425 ◽

1957 ◽

Vol 190 (3) ◽

pp. 425-428 ◽

Cited By ~ 2

Author(s):

Richard M. Hoar ◽

William C. Young

Keyword(s):

Heart Rate ◽

Oxygen Consumption ◽

Guinea Pig ◽

Metabolic Rate ◽

Adrenal Cortex ◽

Guinea Pigs ◽

Sharp Decrease ◽

Zona Fasciculata ◽

Respiratory Metabolism ◽

Morphological Differences

Oxygen consumption and heart rate during pregnancy were measured in untreated, thyroxin-injected and thyroidectomized guinea pigs given I131. From impregnation until parturition, oxygen consumption increased 7.9% in untreated females. The increase continued until 5 days postpartum when a sharp decrease occurred. The increase is not accounted for by growth of the fetal mass. Comparable increases occurred in thyroxin-injected (16.2%) and thyroidectomized (11.9%) females, although the levels throughout were higher and lower, respectively, than in intact females. Heart rate did not increase. On the contrary, statistically significant decreases occurred in the untreated and thyroxin-injected females. Although the mechanism associated with the increased metabolic rate is not known, the possibility of thyroid participation would seem to be excluded. Involvement of the adrenal cortex is suggested by morphological differences in the cells of the zona fasciculata in pregnant and nonpregnant females and by evidence cited from other studies.

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Contractile effects of cardiac neuropeptides in isolated canine atrial and ventricular muscles

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1989.257.4.h1082 ◽

1989 ◽

Vol 257 (4) ◽

pp. H1082-H1087 ◽

Cited By ~ 1

Author(s):

D. F. Rigel ◽

I. L. Grupp ◽

A. Balasubramaniam ◽

G. Grupp

Keyword(s):

Isometric Force ◽

Contractile Force ◽

Adrenergic Blockade ◽

Canine Heart ◽

Inotropic Action ◽

Inotropic Effects ◽

Calcitonin Gene ◽

Positive Inotropic Effects ◽

The Right ◽

Ventricular Trabeculae

Contractile effects of the cardiac neuropeptides vasoactive intestinal polypeptide (VIP), peptide histidine isoleucine (PHI), neuropeptide Y (NPY), calcitonin gene-related peptide (CGRP), and neurotensin (NT) were compared with those of l-isoproterenol (ISO) in isolated canine atrial and ventricular trabeculae muscles stimulated to contract at 1 Hz. In ventricular muscles, ISO, VIP, and PHI augmented developed isometric force by approximately 100%. VIP and PHI were three times and 1/10, respectively, as potent as ISO. VIP also exhibited positive inotropic effects in atrial trabeculae. The contractile responses to VIP were unchanged after beta-adrenergic blockade with nadolol at a concentration (10 microM) that shifted the ISO dose-response curve two to three orders of magnitude to the right. In atrial and ventricular trabeculae, NPY (1 microM) attenuated contractile force by 36 +/- 8 and 30 +/- 4%, respectively. Each peptide also caused comparable increases or decreases in the rate of development of force and the rate of relaxation. CGRP and NT caused no significant changes in developed force in either atrial or ventricular muscles in concentrations up to 1 microM. Our results indicate a potential positive inotropic action of endogenous VIP and PHI and a cardiodepressant effect of endogenous NPY in the canine heart.

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