Greater glycogen utilization during β1- than β2-adrenergic receptor stimulation in the isolated perfused rat heart

2007 ◽  
Vol 293 (6) ◽  
pp. E1828-E1835 ◽  
Author(s):  
Patrick McConville ◽  
Edward G. Lakatta ◽  
Richard G. Spencer
Keyword(s):  
Rat Heart ◽  
Adrenergic Receptor ◽  
Left Ventricular ◽  
Rate Pressure Product ◽  
Lv Function ◽  
Adrenergic Stimulation ◽  
Functional Responses ◽  
Perfused Rat Heart ◽  
Phosphorylation Potential ◽  
Isolated Perfused Rat Heart

Differences in energy metabolism during β1- and β2-adrenergic receptor (AR) stimulation have been shown to translate to differences in the elicited functional responses. It has been suggested that differential access to glycogen during β1- compared with β2-AR stimulation may influence the peak functional response and modulation of the response during sustained adrenergic stimulation. Interleaved 13C- and 31P-NMR spectroscopy was used during β1- and β2-AR stimulation at matched peak workload (2.5 times baseline) in the isolated perfused rat heart to monitor glycogen levels, phosphorylation potential, and intracellular pH. Simultaneous measurements of left ventricular (LV) function [LV developed pressure (LVDP)], heart rate (HR), and rate-pressure product (RPP = LVDP × HR) were also performed. The heart was perfused under both substrate-free (SF) conditions and with exogenous glucose (G). The greater glycogenolysis was observed during β1- than β2-AR stimulation with G (54% vs. 38% reduction, P = 0.006) and SF (92% vs. 79% reduction, P = 0.04) perfusions. The greater β1-AR-mediated glycogenolysis was correlated with greater ability to sustain the initial contractile response. However, with SF perfusion, the duration of this ability was limited: excessive early glycogen depletion caused an earlier decline in LVDP and phosphorylation potential during β1- than β2-AR stimulation. Therefore, endogenous glycogen stores are depleted earlier and to a greater extent, despite a slightly weaker overall inotropic response, during β1- than β2-AR stimulation. These findings are consistent with β1-AR-specific PKA-dependent glycogen phosphorylase kinase signaling.

Temporal dynamics of inotropic, chronotropic, and metabolic responses during β1- and β2-AR stimulation in the isolated, perfused rat heart

2005 ◽  
Vol 289 (3) ◽  
pp. E412-E418 ◽  
Author(s):  
P. McConville ◽  
R. G. Spencer ◽  
E. G. Lakatta
Keyword(s):  
Rat Heart ◽  
Temporal Dynamics ◽  
High Energy ◽  
Left Ventricular ◽  
Metabolic Responses ◽  
Inotropic Response ◽  
Functional Responses ◽  
Perfused Rat Heart ◽  
Chronotropic Response ◽  
Isolated Perfused Rat Heart

During the β-adrenergic receptor (β-AR)-mediated stress response in the heart, the relations between functional responses and metabolism are ill defined, with the distinction between β1- and β2-AR subtypes creating further complexity. Specific outstanding questions include the temporal relation between inotropic and chronotropic responses and their metabolic correlates. We sought to elucidate the relative magnitudes and temporal dynamics of the response to β1- and β2-AR stimulation and the energy expenditure and bioenergetic state related to these responses in the isolated perfused rat heart. Inotropic [left ventricular developed pressure (LVDP) and dP/d t], chronotropic [heart rate (HR)], and metabolic responses were measured during β1- ( n = 9; agonist: norepinephrine) and β2- ( n = 9; agonist: zinterol) AR stimulation. Myocardial oxygen consumption (MV̇o2) was measured using fiber-optic oximetry, and high-energy phosphate levels and intracellular pH were measured using 31P NMR spectroscopy. A multiple-dose protocol was used, with near-maximal β-AR stimulation at the highest doses. In both β1 and β2 groups, there were dose-dependent increases in LVDP, dP/d t, HR, and MV̇o2. The inotropic response showed more rapid onset, washout, and variation during dose than did the chronotropic response and was closely correlated with MV̇o2. This suggests that the myocardial bioenergetic state is more closely related to the inotropic response than to the chronotropic response. In addition, β1-AR stimulation resulted in a greater magnitude and rate of onset of inotropic and MV̇o2 responses than did β2-AR stimulation during maximal stimulation. However, a similar decrease in intracellular energy charge was seen in the two groups, consistent with a greater rate of oxidative phosphorylation during β1- than during β2-AR stimulation.

scholarly journals Use of the Isolated Perfused Heart for Evaluation of Cardiac Toxicity

1990 ◽  
Vol 18 (4a) ◽  
pp. 497-510 ◽  
Author(s):  
Peter G. Anderson ◽  
Stanley B. Digerness ◽  
Jerald L. Sklar ◽  
Paul J. Boor
Keyword(s):  
Rat Heart ◽  
Coronary Flow ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Heart Weight ◽  
Isolated Perfused Heart ◽  
Heart Model ◽  
Perfused Heart ◽  
Perfused Rat Heart ◽  
Isolated Perfused Rat Heart

The isolated perfused rat heart model can be used to evaluate cardiotoxicity, and is especially useful in distinguishing direct vs indirect cardiac injury. Various perfusion systems can be used to characterize the pathophysiologic as well as morphologic changes induced by drugs or chemicals of interest. The isolated perfused heart was used in the studies described herein to characterize the mechanism of allylamine cardiotoxicity. Rat hearts were perfused with Krebs-Henseleit buffer containing 10 mm allylamine and a latex balloon was inserted into the left ventricle to monitor pressure. Coronary flow in hearts perfused with 10 mm allylamine was similar to control hearts at 5, 10, and 30 min, but was reduced by 1 hr (11.5 ± 0.6 ml/min/g wet heart weight vs 16.0 ± 0.7, p < 0.01). Peak left ventricular systolic pressure increased in hearts perfused with allylamine for 5 min (156 ± 8 mm Hg vs 103 ± 9, p < 0.01), but by 2 hr was decreased compared to controls (89 ± 6 vs 105 ± 5, p < 0.05). End diastolic pressure was markedly increased at 2 hr (58 ± 3 vs 4 ± 0.8, p < 0.01). Morphologically, allylamine perfused hearts exhibited significant contraction band changes as well as numerous cells with marked swelling of the sarcoplasmic reticulum. The findings in this study suggest that allylamine produces direct myocardial damage that appears to be independent of coronary flow. These studies demonstrate that the isolated perfused rat heart model can be used to evaluate mechanisms of acute cardiotoxicity.

scholarly journals Differences in the Bioenergetic Response of the Isolated Perfused Rat Heart to Selective β 1 - and β 2 -Adrenergic Receptor Stimulation

Circulation ◽  
2003 ◽  
Vol 107 (16) ◽  
pp. 2146-2152 ◽  
Author(s):  
Patrick McConville ◽  
Kenneth W. Fishbein ◽  
Edward G. Lakatta ◽  
Richard G.S. Spencer
Keyword(s):  
Rat Heart ◽  
Adrenergic Receptor ◽  
Receptor Stimulation ◽  
Perfused Rat Heart ◽  
Isolated Perfused Rat Heart

Effect of extracellular pH on function and metabolism of isolated perfused rat heart

1965 ◽  
Vol 209 (6) ◽  
pp. 1075-1080 ◽  
Author(s):  
Lionel H. Opie
Keyword(s):  
Glucose Uptake ◽  
Flow Rate ◽  
Rat Heart ◽  
Left Ventricular ◽  
Extracellular Ph ◽  
Mechanical Activity ◽  
Perfused Rat Heart ◽  
Isolated Perfused Rat Heart ◽  
Oxidation Rates ◽  
Lactate And Pyruvate

The extracellular pH of the isolated perfused rat heart was varied from 6.9 to 8.0 usually by altering the bicarbonate content of the buffer. Isovolumic left ventricular contractility was measured by an intraventricular balloon. The peak systolic pressure was dependent on the coronary flow rate. At a constant flow rate the peak pressure and cardiac rate were unchanged at 7.4–8.0 but declined at about pH 7.1. The uptake and fate of pyruvate-1-C14 (6 mm) and palmitate-1-C14 (0.7 mm) were similar at pH 7.1–8.0. Compared with pH 7.4, oxidation rates of glucose-U-C14 (5 mm) and acetate-2-C14 (5 mm) were unchanged at pH 7.1, but were greater at pH 8.0. Other increases at pH 8.0 (glucose 5 mm) were in glucose uptake, lactate and pyruvate formation, and the percentage of the glucose uptake accounted for by the sum of C14O2, lactate, and pyruvate formed. It is concluded that in spite of decreased mechanical activity at pH 7.1, Krebs cycle activity is unaltered by pH changes from 7.1 to 8.0, whereas glycolysis and acetate oxidation increase above pH 7.4.

scholarly journals Anthrax edema toxin has cAMP-mediated stimulatory effects and high-dose lethal toxin has depressant effects in an isolated perfused rat heart model

2011 ◽  
Vol 300 (3) ◽  
pp. H1108-H1118 ◽  
Author(s):  
Caitlin W. Hicks ◽  
Yan Li ◽  
Shu Okugawa ◽  
Steven B. Solomon ◽  
Mahtab Moayeri ◽  
...  
Keyword(s):  
Rat Heart ◽  
Left Ventricular ◽  
Lethal Toxin ◽  
Heart Model ◽  
In Vivo Models ◽  
Inotropic Effects ◽  
Perfused Rat Heart ◽  
Isolated Perfused Rat Heart ◽  
Edema Toxin

While anthrax edema toxin produces pronounced tachycardia and lethal toxin depresses left ventricular (LV) ejection fraction in in vivo models, whether these changes reflect direct cardiac effects as opposed to indirect ones related to preload or afterload alterations is unclear. In the present study, the effects of edema toxin and lethal toxin were investigated in a constant pressure isolated perfused rat heart model. Compared with control hearts, edema toxin at doses comparable to or less than a dose that produced an 80% lethality rate (LD80) in vivo in rats (200, 100, and 50 ng/ml) produced rapid increases in heart rate (HR), coronary flow (CF), LV developed pressure (LVDP), dP/d tmax, and rate-pressure product (RPP) that were most pronounced and persisted with the lowest dose ( P ≤ 0.003). Edema toxin (50 ng/ml) increased effluent and myocardial cAMP levels ( P ≤ 0.002). Compared with dobutamine, edema toxin produced similar myocardial changes, but these occurred more slowly and persisted longer. Increases in HR, CF, and cAMP with edema toxin were inhibited by a monoclonal antibody blocking toxin uptake and by adefovir, which inhibits the toxin's intracellular adenyl cyclase activity ( P ≤ 0.05). Lethal toxin at an LD80 dose (50 ng/ml) had no significant effect on heart function but a much higher dose (500 ng/ml) reduced all parameters ( P ≤ 0.05). In conclusion, edema toxin produced cAMP-mediated myocardial chronotropic, inotropic, and vasodilatory effects. Vasodilation systemically with edema toxin could contribute to shock during anthrax while masking potential inotropic effects. Although lethal toxin produced myocardial depression, this only occurred at high doses, and its relevance to in vivo findings is unclear.

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