Biomedical subjects

J R Neely

Publications and source records attributed to J R Neely.

At least 37 records · Page 2Linked to original sources

PubMed1987

Coenzyme A degradation in the heart: effects of diabetes and insulin.

Coenzyme A (CoA) degradation was studied in isolated working hearts from acutely diabetic rats (48 h). Hearts from diabetic rats had elevated levels of total CoA (752 +/- 15 nmol/g dry) compared to control (537 +/- 14 nmol/g dry). When hearts from diabetic animals were perfused for 5 mins with perfusate containing pyruvate, (5 mM) and glucose (11 mM) CoA levels remained unchanged. Addition of palmitate, (1.2 mM) and glucose (11 mM) to the perfusate, however, resulted in a rapid drop in CoA levels to 672 +/- 19 nmol/g dry. Palmitate had no effect on CoA levels in control hearts which did not have elevated levels of CoA. Addition of insulin to the buffer containing glucose and palmitate prevented the decrease in CoA levels in diabetic hearts. The level of long chain acyl CoA in diabetic hearts perfused with pyruvate was 105 +/- 11 nmol/g dry, and did not change when insulin was present in the perfusate. In the presence of palmitate, levels of long chain acyl CoA increased from 76 +/- 16 to 149 +/- 13 nmol/g dry, and, in this case, addition of insulin caused a further increase to 192 +/- 18 nmol/g dry. Thus, the lower rate of CoA degradation in the presence of insulin was associated with a rise in long chain acyl CoA levels. In a separate series of experiments, CoA levels were increased in control hearts in vitro (from 537 +/- 14 to 842 +/- 19 nmol/g dry). Subsequent perfusion of these hearts that contained elevated CoA with palmitate also resulted in a rapid drop of CoA to 655 +/- 17 nmol/g dry.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Stimulation of myocardial coenzyme A degradation by fatty acids.

Coenzyme A (CoA) levels were increased in isolated hearts from 537 +/- 14 to 818 +/- 44 nmol/g dry wt by perfusion for 45 min under conditions known to stimulate CoA synthesis (5). Subsequently, perfusion of these hearts with buffer containing glucose (11 mM) and pyruvate (5 mM) for 3 min had no effect on CoA levels (789 +/- 42 nmol/g dry wt). However, perfusion with a buffer containing glucose (11 mM) and palmitate (1.2 mM) decreased CoA levels to 683 +/- 34 nmol/g dry wt within 3 min. This decrease in CoA appeared to occur in the cytosolic compartment with no change in mitochondrial CoA content and was associated with a rise in tissue content of long-chain acyl-CoA. An increased incorporation of fatty acids into triglycerides was associated with the rise in total acyl-CoA suggesting that long-chain acyl-CoA levels were elevated in the cytosolic compartment. Perfusion conditions which maximally increased acyl-CoA levels also maximally stimulated CoA degradation. These observations suggest that the cytosolic degradation of CoA is related to high levels of long-chain acyl-CoA in this compartment. Use of these perfusion conditions in future studies should help define the pathway of CoA degradation and determine the mechanisms which control cellular levels of CoA.

Animals↗

PubMed1986

Limitation of myocardial infarct size by metabolic interventions that reduce accumulation of fatty acid metabolites in ischemic myocardium.

The effects on myocardial damage of metabolic interventions by nicotinic acid, oxfenicine, or a combination of the two were assessed in open-chest dogs exposed to coronary artery occlusion for 6 hours. The accumulation of metabolites of free fatty acids (FFAs) was studied in tissue samples of the left ventricle taken 60 minutes after coronary occlusion in separate animals. The percentage of the hypoperfused zone that evolved to infarction was 96 +/- 3% (mean +/- SEM) in control dogs, 74 +/- 4% in dogs treated with nicotinic acid (p less than 0.05 vs control dogs), 72 +/- 2% in dogs treated with oxfenicine (p less than 0.05 vs control dogs), and 54 +/- 5% in dogs with combined nicotinic acid and oxfenicine (p less than 0.05 vs control dogs, p less than 0.05 vs nicotinic acid and oxfenicine). Arterial FFA concentration was markedly reduced in dogs treated with nicotinic acid and those treated with combination nicotinic acid and oxfenicine. The accumulation of long-chain acyl carnitine was substantially reduced in the ischemic myocardium after nicotinic acid, oxfenicine, and a combination of the two, whereas the lowering of long-chain acyl CoA was less pronounced. Thus, nicotinic acid and oxfenicine, which depress myocardial FFA metabolism by different mechanisms, both reduce myocardial infarct size and their effects are additive.

Acetylcarnitine↗

PubMed1986

Fatty acid metabolism in hearts containing elevated levels of CoA.

Palmitate metabolism was determined in isolated perfused hearts containing elevated levels of coenzyme A (CoA). CoA levels were elevated by perfusing hearts with Krebs-Henseleit buffer containing 0.1 mM cysteine, 0.2 mM dithiothreitol, 15 microM pantothenic acid, and no energy substrate. After 45 min, CoA levels had increased from 537 +/- 14 to 818 +/- 44 nmol/g dry wt. When these hearts containing high CoA were subsequently perfused as working hearts with buffer containing 11 mM glucose and 1.2 mM palmitate, long chain acyl CoA levels increased (94 +/- 5-305 +/- 6 nmol/g dry wt). Oxidation of exogenous palmitate (as measured by 14CO2 production from [U-14C]palmitate) was significantly depressed in hearts containing elevated CoA levels. This apparent reduction in fatty acid oxidation was not due to increased glucose or glycogen utilization. When the concentration of palmitate was decreased to 0.4 mM, acyl CoA levels increased much less, and the apparent rate of [14C]palmitate oxidation was unaffected by elevated CoA. Hearts containing high CoA also incorporated [14C]palmitate into triacylglycerols to a greater extent than did control hearts. To determine whether the apparent decrease in exogenous palmitate oxidation resulted from an increased utilization of unlabeled endogenous triacylglycerol fatty acid, [14C]palmitate specific activity was measured in myocardial acylcarnitine. The specific activity of this pool of fatty acid was similar in both control hearts and hearts containing elevated CoA. Thus dilution of the total cellular [14C]acyl carnitine by triacylglycerol hydrolysis was not sufficient to account for the decrease in [U-14C]palmitate oxidation. The possibility that a small pool of rapidly turning over acyl carnitine becomes dilated is discussed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Metabolic rates in normal and infarcted myocardium.

The effects of myocardial infarction in rat hearts on the utilization of fatty acids and glucose by the surviving, non-infarcted tissue were studied. Hearts were removed from the animals one-week post-infarcted and perfused in the isolated working heart preparation. Oxygen consumption and oxidation of palmitate and glucose were determined at two levels of cardiac work. Rates of substrate oxidation were estimated by 14CO2 production from [14C]-labeled substrates. This approach to measuring metabolic rates may seriously under-estimate the true oxidative rate particularly when measuring oxidation of long-chain fatty acids. Because of the large endogenous stores of fatty acids in tissue lipids, the [14C]-specific activity of the intracellular metabolites involved in the free fatty acids oxidation pathway do not equilibrate with the specific activity of the perfusate fatty acids oxidation pathway do not equilibrate with the specific activity of the perfusate fatty acid even when 14CO2 production has reached an apparent steady state. When comparing an experimental condition to the normal heart, a lower rate of 14CO2 production may not necessarily indicate a lower rate of oxidation of free fatty acids, but a difference in the rate of turnover of endogenous sources of unlabeled fatty acid such that the specific activity of intracellular metabolites equilibrate with extracellular labeled substrate to a lesser extent than in the normal heart. At physiological concentrations of fatty acids, a shift from fatty acid to carbohydrate oxidation occurred in the hypertrophied, surviving tissue following myocardial infarction in the rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

The properties and regulation of pantothenate kinase from rat heart.

Pantothenate kinase (ATP:D-pantothenate 4'-phosphotransferase, EC 2.7.1.33), the first enzyme in the pathway of CoA synthesis, was partially purified from rat heart. A study of the properties of the kinase showed that it possesses a broad pH optimum between 6 and 9, is activated or inhibited nonspecifically by various anions, and has MgATP as the nucleotide substrate. The Km for MgATP is 0.6 mM and that for pantothenate is 18 microM. CoA and acyl esters of CoA are inhibitors of the kinase with the inhibition by acetyl-CoA being only slightly greater than that by free CoA. The inhibition by free CoA is uncompetitive with respect to pantothenate concentration, with a Ki for inhibition of 0.2 microM. L-Carnitine was found to be a nonessential activator of the kinase. This compound had no effect by itself but specifically reversed the inhibition of the kinase by CoA. The Ka for deinhibition by L-carnitine is 0.27 mM. Free carnitine content was measured in perfused hearts and is found to vary in correlation with perfusion conditions that are known to alter rates of intracellular phosphorylation of pantothenate. These properties of pantothenate kinase provide a potential mechanism for the control of CoA synthesis. The enzyme is regulated by feedback inhibition by CoA and its acyl esters and this inhibition is modified by changes in the concentration of free carnitine.

Acetyl Coenzyme A↗

PubMed1985

Regulation of pantothenate kinase from various tissues of the rat.

The relative tissue activities of pantothenate kinase range from 1 to 5 nmol . min-1 . g-1 wet wt for heart, brain, kidney, and liver. The enzyme partially purified from each tissue is inhibited by CoA, but there is a 10-fold greater potency of inhibition of the heart enzyme compared to those from the other tissues. With the heart and liver enzyme, this difference in potency of CoA inhibition may be a reflection of the differing cytosolic CoA concentrations in these tissues. L-Carnitine specifically reversed the inhibition of each enzyme by CoA. It is concluded that L-carnitine may be a regulator of CoA synthesis in each tissue.

Animals↗

PubMed1985

Inhibition of carnitine palmitoyl-CoA transferase activity and fatty acid oxidation by lactate and oxfenicine in cardiac muscle.

High concentrations of lactate and oxfenicine inhibit fatty acid oxidation in cardiac muscle. The site of this inhibition was investigated in isolated perfused rat hearts. In hearts perfused with glucose (11 mM) and [U-14 C]palmitate (1.0 mM), addition of 5 mM lactate caused a 38% reduction in 14CO2 production. Tissue levels of long-chain acyl carnitine decreased suggesting that inhibition occurred at either fatty acyl CoA synthetase or carnitine-acyl CoA transferase. Cytosolic levels of acyl-CoA are low compared with mitochondrial levels and changes in acyl-CoA within the cytosolic compartment cannot be estimated directly. Consequently, the rate of conversion of 14C-palmitate to neutral lipids was used as an indicator of cytosolic acyl CoA levels. Lactate caused a 100% increase in 14C-fatty acid conversion to triglycerides suggesting that cytosolic levels of acyl-CoA increased in association with decreased acyl-carnitine. This indicates that lactate inhibited FFA oxidation at the level of carnitine-acyl CoA transferase. Oxfenicine (2 mM) reduced fatty acid oxidation by 45%, decreased acyl-carnitine levels by 80%, and increased conversion of 14C-palmitate to neutral lipids by 44%, suggesting that oxfenicine also inhibits fatty acid oxidation at the level of carnitine-acyl CoA transferase. These data further indicate that carnitine-acyl CoA transferase is an important site of control in the pathway of fatty acid oxidation.

Acyl Coenzyme A↗

PubMed1985

Coenzyme A metabolism.

The metabolism of coenzyme A and control of its synthesis are reviewed. Pantothenate kinase is an important rate-controlling enzyme in the synthetic pathway of all tissues studied and appears to catalyze the flux-generating reaction of the pathway in cardiac muscle. This enzyme is strongly inhibited by coenzyme A and all of its acyl esters. The cytosolic concentrations of coenzyme A and acetyl coenzyme A in both liver and heart are high enough to totally inhibit pantothenate kinase under all conditions. Free carnitine, but not acetyl carnitine, deinhibits the coenzyme A-inhibited enzyme. Carnitine alone does not increase enzyme activity. Thus changes in the acetyl carnitine-to-carnitine ratio that occur with nutritional states provides a mechanism for regulation of coenzyme A synthetic rates. Changes in the rate of coenzyme A synthesis in liver and heart occurs with fasting, refeeding, and diabetes and in heart muscle with hypertrophy. The pathway and regulation of coenzyme A degradation are not understood.

Acetyl Coenzyme A↗

PubMed1985

Chronic infarction decreases maximum cardiac work and sensitivity of heart to extracellular calcium.

Rat hearts were infarcted in vivo by ligation of the left ventricular coronary artery to cause an initial 40% loss of viable tissue by weight. Due to compensatory hypertrophy of the surviving myocardium and progression of the infarct to scar tissue, the infarct represented approximately 25% by weight of the whole heart after 1 wk. After 1 or 3 wk, these infarcted hearts were removed and perfused in vitro by the working hearts technique. Ventricular pressure development and positive dP/dt were lower in infarcted hearts compared with sham-operated ones. O2 consumption and glucose utilization by viable tissue per unit pressure development was the same in normal and infarcted hearts. Levels of creatine phosphate and free creatine were decreased, but ATP and total adenine nucleotides were well maintained. The inotropic response to decreases in extracellular [Ca2+] was much greater in infarcted hearts than in sham controls. Prenalterol increased ventricular function proportionally more in infarcted than in the sham-operated hearts, suggesting that down regulation of beta receptors was not a problem. The infarcted hearts were much more sensitive to verapamil than control hearts. It is concluded that the depressed function of the noninfarcted tissue of chronically infarcted hearts is due in part to loss of functioning tissue mass and in part to decreased sensitivity to extracellular Ca2+.

Adenosine Triphosphate↗

PubMed1985

Recovery of ventricular function in reperfused ischemic rat hearts exposed to fatty acids.

The relationship between tissue levels of fatty acid metabolites in ischemic and reperfused hearts and recovery of mechanical function of these hearts on reperfusion was studied. Isolated rat hearts were exposed to global ischemia for periods up to 60 min under various conditions of coronary flow, O2 supply, and fatty acid concentrations and were then reperfused for either 15 or 30 min under aerobic conditions both with and without fatty acids present. Tissue levels of ATP, creatine phosphate, long-chain acyl CoA, and long-chain acyl carnitine were determined at the end of the ischemic and reperfusion periods. In some experiments K+ arrest during ischemia was used to prevent adenine nucleotide depletion both in the absence and presence of high fatty acids. Although the ability of these hearts to recover their preischemic mechanical function varied from 8 to 90% and tissue levels of acyl CoA and acyl carnitine during ischemia varied from 3- to 10-fold depending on the condition, no correlation was found between the recovery of function during reperfusion and either the presence of fatty acid or high levels of tissue long-chain acyl CoA and carnitine esters during ischemia.

Acyl Coenzyme A↗

PubMed1984

Pantothenate kinase and control of CoA synthesis in heart.

Control of coenzyme A (CoA) synthesis was studied in isolated perfused rat hearts. The data obtained support the hypothesis that phosphorylation of pantothenic acid by pantothenate kinase is the flux-generating reaction in the pathway of CoA synthesis. This reaction operated in the cell far removed from its thermodynamic equilibrium; it was saturated with substrates under all conditions studied; and the concentration of substrate changed in the opposite direction to flux when flux was altered. The reaction was subject to control by external factors associated with oxidation of glucose, pyruvate, or palmitate. CoA synthesis from 4'-phosphopantothenic acid was not inhibited by glucose and pyruvate, suggesting that pantothenate kinase is the only reaction in the pathway that is controlled in isolated hearts. Maximum rates of CoA synthesis in perfused hearts with pantothenate kinase stimulation were dependent on a supply of exogenous cysteine. Perfusate [14C]cysteine was incorporated into intermediates of this pathway and CoA. When protected from oxidation to cystine by low concentrations of dithiothreitol, 0.1 mM cysteine in the perfusate resulted in maximum rates of CoA synthesis. Evidence was obtained that indicates that addition of cysteine relieves a substrate limitation at the 4'-phosphopantothenyl cysteine synthase reaction.

Animals↗

PubMed1984

Role of glycolytic products in damage to ischemic myocardium. Dissociation of adenosine triphosphate levels and recovery of function of reperfused ischemic hearts.

The mechanism of irreversible damage to ischemic myocardium was investigated in the perfused rat heart. The time of transition from reversible to irreversible damage to contractile function was accelerated by accumulation of glycolytic products and increases in extracellular calcium. Both of these effects were largely independent of adenine nucleotide levels in the tissue. With zero coronary flow and 1.25 mM calcium the decrease in ability of the heart to recover ventricular function with reperfusion after 30 minutes of ischemia was directly correlated with accumulation of glycolytic products (as estimated by tissue lactate) during ischemia. The extent of lactate accumulation during ischemia was varied by preperfusing the hearts for 0, 10, or 15 minutes under anoxic, high coronary flow conditions to deplete tissue glycogen prior to ischemia, and by adding lactate back to the perfusate of these hearts during the ischemic period. Recovery of ventricular function was inversely related to tissue lactate during ischemia and varied from 28 to 92%, even though there was little or no change in tissue levels of residual adenosine triphosphate. Increasing extracellular calcium accelerated the time of onset of irreversible damage with little or no change in residual adenosine triphosphate levels. At any given calcium concentration, the time-dependent declines in the ability of the heart to recover ventricular function was also largely independent of adenosine triphosphate levels. These studies suggest a major role of anaerobic glycolytic products (lactate, hydrogen ion, or NADH) in ischemic damage to the heart that is unrelated to loss of tissue adenine nucleotides. With zero or low flow ischemia, this effect may result in irreversible damage to the myocardium before adenine nucleotides are reduced to critically low levels.

Adenosine Diphosphate↗

PubMed1983

Effects of increased cardiac work on pyruvate dehydrogenase activity in hearts from diabetic animals.

The effects of increased cardiac work and availability of pyruvate on the activation of pyruvate dehydrogenase (PDH) was studied in hearts isolated from diabetic rats. Diabetes resulted in complete inactivation of myocardial PDH. At low levels of cardiac work, PDH in hearts perfused with glucose or glucose plus insulin as substrate remained in the inactive form even after 25 min of in vitro perfusion indicating that the factors causing inactivation in the diabetic animal were not easily reversed in vitro. Raising the level of ventricular pressure development from 60 to 180 mmHg caused only a small increase in the percent of active PDH (from 0.3 to 16%). Comparable values in control hearts were 61 and 96% active PDH. Addition of high levels of perfusate pyruvate along with glucose increased the percent active PDH from 0.3 to 45 at 60 mmHg ventricular pressure. Although pyruvate increased active PDH the effect was much less than in normal hearts (85% active under comparable conditions). Increased ventricular pressure development (180 mmHg) in diabetic hearts receiving pyruvate caused a further activation of PDH to 66% but again this effect was much less than occurred in normal hearts (96% active). Inactivation of PDH in hearts from diabetic animals could not be accounted for by high mitochondrial levels of known effectors such as NADH/NAD, acetyl CoA/CoA and ATP/ADP. Increasing cardiac work resulted in decreased mitochondrial levels of NADH, acetyl CoA and ATP, but these changes had little effect on PDH activity. The date indicate that PDH in hearts of diabetic animals is resistant to activation by increased cardiac work and high tissue levels of pyruvate.

Adenine Nucleotides↗

PubMed1983

Effects of ischemia and reperfusion on pyruvate dehydrogenase activity in isolated rat hearts.

The effects of myocardial ischemia and reperfusion on pyruvate dehydrogenase (PDH) activity were studied in isolated rat hearts. PDH remained largely (80%) in the active form during 10 min of whole heart ischemia in hearts receiving 11 mM glucose as substrate. With reperfusion, PDH was converted to the inactive form (45% by 2 min) and then returned slowly to control levels. Addition of pyruvate (10 mM) to the glucose containing perfusate during reperfusion prevent the reperfusion inactivation of PDH (96% active). The maintenance of a high percent of PDH in the active form during ischemia occurred in spite of high mitochondrial ratios of NADH/NAD and acetyl CoA/CoA and was related to a very low mitochondrial ATP/ADP ratio. The low ATP and high ADP would restrict PDH kinase phosphorylation and inactivation of PDH during ischemia. Reperfusion resulted in a rapid increase in mitochondrial ATP/ADP ratio and the increased availability of ATP as substrate for the kinase coupled with continued high levels of NADH and acetyl CoA which stimulate kinase activity may have accounted for the early inactivation of PDH with reperfusion. Addition of pyruvate to the perfusate probably inhibited the PDH kinase and prevent the reperfusion inactivation of PDH.

Acyl Coenzyme A↗

PubMed1983

Mechanism of pyruvate dehydrogenase activation by increased cardiac work.

The effects of increased cardiac work, pyruvate and insulin on the state of pyruvate dehydrogenase (PDH) activation and rate of pyruvate decarboxylation was studied in the isolated perfused rat heart. At low levels of cardiac work, 61% of PDH was present in the active form when glucose was the only substrate provided. The actual rate of pyruvate decarboxylation was only 5% of the available capacity calculated from the percent of active PDH. Under this condition, the rate of pyruvate decarboxylation was restricted by the slow rate of pyruvate production from glycolysis. Increasing cardiac work accelerated glycolysis, but production of pyruvate remained rate limiting for pyruvate oxidation and only 40% of the maximal active PDH capacity was used. Addition of insulin along with glucose reduced the percent of active PDH to 16% of the total at low cardiac work. This effect of insulin was associated with increased mitochondria NADH/NAD and acetyl CoA/CoA ratios. With both glucose and insulin the calculated maximum capacity of active PDH was about the same as measured rates of pyruvate oxidation indicating that pyruvate oxidation was limited by the activation state of PDH. In this case, raising the level of cardiac work increased the active PDH to 85% and although pyruvate oxidation was accelerated, measured flux through PDH was only 73% of the maximal activity of active PDH. With pyruvate as added exogenous substrate, PDH was 82% of active at low cardiac work probably due to pyruvate inhibition of PDH kinase. In this case, the measured rate of pyruvate oxidation was 64% of the capacity of active PDH. However, increased cardiac work still caused further activation of PDH to 96% active. Thus, actual rates of pyruvate oxidation in the intact tissue were determined by (1) the supply of pyruvate in hearts receiving glucose alone, (2) by the percent of active PDH in hearts receiving both glucose and insulin at low work and (3) by end-product inhibition in hearts receiving glucose and insulin at high work or at all levels of work with pyruvate as substrate. The increase in active PDH with higher levels of cardia work was associated most closely with reduced mitochondrial NADH/NAD ratios and with decreased acetyl CoA/CoA ratios when insulin or pyruvate were present.

Adenine Nucleotides↗

PubMed1983

Sodium dependence of carnitine transport in isolated perfused adult rat hearts.

In heart muscle, the intracellular carnitine concentration is approximately 40 times higher than the plasma carnitine concentration, suggesting the existence of an active transport process. At physiological serum carnitine concentrations (44 microM), 80% of total myocardial carnitine uptake occurs via a carrier-mediated transport system. The mechanism of this carrier-mediated transport was studied in isolated perfused rat hearts. Carnitine transport showed an absolute dependence on the extracellular sodium concentration. The rate of carnitine transport was linearly related to the perfusate sodium concentration at every perfusate carnitine concentration examined (15-100 microM). Total removal of extracellular sodium completely abolished the carrier-mediated transport. Decreasing the perfusate potassium concentration from a control of 5.9 to 0.6 mM stimulated transport by 35%, whereas increasing the extracellular potassium concentration from 5.9 to 25 mM reduced transport by 60%. The carrier-mediated transport was inversely proportional to the extracellular potassium concentration. Acetylcholine (10(-3) M), isoproterenol (10(-7) M), or ouabain (10(-3) did not alter the rate of carnitine transport. Addition of tetrodotoxin (10(-5) stimulated carnitine transport by about 40%, while gramicidin S (5 X 10(-6) M) decreased uptake by about 18% relative to control. The data provide evidence that carnitine transport by cardiac cells occurs by a Na+-dependent cotransport mechanism that is dependent on the Na+ electrochemical gradient.

Acetylcholine↗

PubMed1983

Decreased myocardial function and myosin ATPase in hearts from diabetic rats.

The effect of diabetes on cardiac function was determined in isolated rat hearts. Diabetes was induced by injection of alloxan (doses ranged from 37.5 to 60 mg/kg body wt), and the heart were removed and perfused in the working heart preparation. Doses of alloxan ranging from 37.5 to 42 mg/kg did not consistently alter cardiac function even though serum glucose was elevated and serum thyroid hormones were reduced. Injection of 45 mg/kg of alloxan caused a large increase in serum glucose and a larger decrease in thyroid hormones. In this case, ventricular function was more consistently depressed after 1-2 wk. Function was not altered 48 h after injection of 60 mg kg of alloxan. However, when animals were given 60 mg/kg of alloxan and then maintained on insulin for 7 days, depressed cardiac function developed within 4 days after the insulin treatment was stopped. The decline in function involved a decrease in heart rate peak systolic pressure, and left ventricular +dP/dt. It was associated with greatly reduced serum thyroid hormones (both T3 and T4) and lower ventricular Ca2+-activated myosin ATPase activity. Fasting of rats for 4 days also resulted in decreased serum T3 and T4, depressed cardiac function (although heart rate was unchanged), and lower Ca2+-activated myosin ATPase activity.

Adenosine Triphosphatases↗