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1. Binding of MG-ADP to both heart and fast skeletal myosin was found with 3 methods to proceed in 2 steps. One mole of MG-ADP binds with high affinity (K approximately equal to 10(6) M-1) and subsequently a second with lower affinity (K approximately equal to 10(2)-10(4) M-1) per myosin. Only one mole of MG-ADP was found to bind with the high affinity to isolated myosin heads. This implies that binding of MG-ADP to intact myosin exhibits negative cooperativity. 2. When a nucleotide is bound, the 2 heads of a single myosin molecule adopt different conformations since on each head a different type of essential thiol group was found to be the most reactive towards N-ethylmaleimide. In the presence of MG-pyrophosphate a thiol-1 is the most reactive essential group in both heads. Therefore, the nucleoside moiety seems to be required for this latter type of head-head interaction.
Basic Res Cardiol
PMID:Evidence for head-head interactions in myosin from cardiac and skeletal muscles. 19 85

Physical quantities and equations are used to define the laws of natural and engineering sciences. Clarity has been brought in equal measure into the the theory of physical quantities and the SI-system of units due to the basic work of Wallot and that of national and international institutions. For practical use in this paper, the most important rules and definitions for the formulation of physical equations are treated in an elementary form and the ease of their use is demonstrated in the following examples: speed of a car, capacitance of a plate capacitor, thermal emission of the cathode of an x-ray tube, oxygen uptake in cardiology, mole concentration and mass concentration of a substance in a solution. In addition, some important quantities and units of cardiology were summarized in a table.
Clin Cardiol 1979 Aug
PMID:Notation of physical equations no longer a problem. 26 80

The maximum shortening velocity of the isolated, externally unloaded papillary muscle of cats, as can be obtained by quick-releases in the initial phase of isometric contractions, is clearly dependent on the Ca++-concentration of the bath solution as well as on the preload: In the range of 0.55 m-mole/1 to 4.4 m-mole/1 a doubling of the Ca++-concentration induces a mean increase of 23% in Vmax; in a range of muscle length assumed to be of physiological relevance, a rise in the extension of 10% of Lmax results in a mean augmentation of 20% in Vmax. In order to reveal possible differences in the effect of calcium and various degrees of filament overlap, firstly, isometric mechanograms were measured under low Ca++-concentration at the muscle length of Lmax. By correspondingly lowering the muscle extension under increased Ca++-concentration the reproduction of almost the entire rising phase of these isometric mechanograms was obtained. Both these experimental conditions result in congruent force-velocity relations and consequently in identical values for Vmax. It must therefore be concluded that there exists an inner relationship between the initial time-course of the isometric force and the force-velocity relations measured during this period. The interpretation of this fact involves weighing the hypothesis of an inner frictional force dependent on velocity against that of a maximum shortening velocity dependent on the number of activated cross-bridges. The resultant consequences for the estimation of the contractile qualities of the myocardium are discussed.
Basic Res Cardiol
PMID:The effect of preload and Ca++-ions on the time-course of the isometric force and on the force-velocity relation: is Vmax dependent on the number of activated cross-bridges? 87 Dec 97

To assess the metabolic effects of myocardial substrate alteration in patients with coronary artery disease, glucose-insulin-potassium solution was administered intravenously for 30 minutes to 14 men with stable angiographically documented coronary artery disease. The glucose-insulin-potassium solution (300 g of glucose, 50 units of regular insulin and 80 mEq of potassium chloride per liter of water) was infused at a constant rate in each patient, but individual infusion rates ranged from 0.013 to 0.032 ml/kg per min (4 to 10 mg glucose/kg per min) in the 14 patients. Simultaneous arterial and coronary sinus samples were obtained at 15 minute intervals during a stable 30 minute control period and again at 15 minute intervals during the infusion; samples were assayed for glucose, lactate, free fatty acid and oxygen content. In all 14 patients, during the glucose-insulin-potassium infusion, arterial glucose and lactate increased and arterial free fatty acid levels fell; the magnitude of the changes in arterial lactate and free fatty acids was related to the rate of infusion. Arterial-coronary sinus differences (A-Cs) for glucose, lactate and free fatty acid levels correlated with the arterial concentrations of these substrates (r = 0.66, 0.87 and 0.79, respectively). Regression analyses demonstrated myocardial thresholds for the uptake of these substrates as follows: glucose 79 mg/100 ml; lactate 300 mu mole/liter; and free fatty acids 100 to 200 mu Eq/liter. Finally and most importantly, the reduction in A-Cs oxygen values after glucose-insulin-potassium infusion correlated with the reduction in A-Cs free fatty acid levels (r = 0.64, P less than 0.0001). This observation suggests that, in patients with coronary artery disease, glucose-insulin-potassium infusion may significantly diminish myocardial oxygen requirements by reduction of myocardial free fatty acid utilization and simultaneous enhancement of myocardial carbohydrate utilization. Myocardial substrate availability may be an important determinant of myocardial oxygen demand in patients with coronary artery disease. Infusion of glucose-insulin-potassium solution has the potential to alter myocardial substrate availability, thus improving the balance between myocardial oxygen demand and supply.
Am J Cardiol 1975 Dec
PMID:Effects of glucose-insulin-potassium on myocardial substrate availability and utilization in stable coronary artery disease. Studies on myocardial carbohydrate, lipid and oxygen arterial-coronary sinus differences in patients with coronary artery disease. 119 50

Myocardial ischemia is associated with profound electrophysiologic derangements which occur within minutes and are rapidly reversible with reperfusion, suggesting that subtle and reversible biochemical alterations within or near the sarcolemma contribute. Our efforts have concentrated on two structurally similar amphipathic metabolites, long-chain acylcarnitine and lysophosphatidylcholine. Studies performed in vitro in isolated tissue indicate that incorporation of either metabolite into the sarcolemma at concentrations of 1-2 mole %, as verified using electron microscopic (EM) autoradiography, elicits profound electrophysiologic derangements analogous to those seen in the ischemic heart in vivo. In isolated myocytes in vitro, the electrophysiologic derangements elicited by hypoxia are associated with a marked 70-fold increase in the endogenous sarcolemmal accumulation of long-chain acylcarnitine. Inhibition of carnitine acyltransferase I (CAT-I) not only prevents the accumulation of long-chain acylcarnitine in isolated myocytes exposed to severe hypoxia, but also markedly attenuates the electrophysiologic alterations. Several lines of experimental evidence, including measurements in venous effluents as well as cardiac lymph, indicate that lysophosphatidylcholine (LPC) accumulates to a large extent in the extracellular space during ischemia. This extracellular accumulation may be secondary to release from vascular endothelium, smooth muscle or blood cell elements. In crude homogenates of myocardial tissue, the total enzymic activity for catabolism of LPC far exceeds the total activity for synthesis of LPC mediated by phospholipase A2 (PLA2) catalyzed hydrolysis of phosphatidylcholine (PC). Therefore, inhibition of catabolism would be required for net accumulation of LPC to occur. Three enzymes responsible for the catabolism of LPC are inhibited by either long-chain acylcarnitine or acidic pH. Thus, accumulation of long-chain acylcarnitine and acidosis contribute to the increase in LPC observed in ischemic tissue. In this report, we provide evidence that accumulation of long-chain acylcarnitine occurs very rapidly in ischemic myocardium in vivo, coincident with the development of electrophysiologic alterations leading to malignant arrhythmias as verified using 3-dimensional cardiac mapping procedures. Following a brief, 2-min period of ischemia, long-chain acylcarnitine content increased four-fold in the ischemic region, concomitant with the development of electrophysiologic abnormalities observed during this period. Additionally, we demonstrate that modification of intracellular lipolysis by beta-adrenergic receptor stimulation or blockade does not influence long-chain acylcarnitine accumulation following this 2-min interval of ischemia. These results suggest that production of long-chain acylcarnitine is not limited by the intracellular free fatty acid concentration early in ischemia.(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Cell Cardiol 1991 Feb
PMID:Amphipathic lipid metabolites and their relation to arrhythmogenesis in the ischemic heart. 203 71

Purified porcine atrial muscarinic acetylcholine receptors were reconstituted into lipid vesicles with three different G proteins (Gi, Go and Gn)1 purified from porcine cerebrum. All the G proteins interacted with the receptor as evidenced by GTP-sensitive high affinity binding with acetylcholine, and stimulation by acetylcholine of GTP gamma S binding and GTPase activities. The curves of displacement by acetylcholine of [3H]QNB binding were explained by assuming two sites with the same affinity for [3H]QNB but different affinities for acetylcholine. The proportion of the high affinity site increased from 3 to 7% up to 82 to 83% of total binding sites with increasing G protein concentration, and essentially the same results were obtained with the three G proteins. The GTPase activities of Gi, Go and Gn in the reconstituted vesicles were 2.7-, 1.7- and 1.6-times higher, respectively, in the presence of 1 mM acetylcholine than those in the presence of 10 microM atropine. An obvious enhancement by acetylcholine of the GTP gamma S binding was observed in the presence of 10 to 100 microM GDP, while the enhancement was minimal, if at all, in the absence of GDP. When the molar ratios of reconstituted Gi, Go and Gn to muscarinic receptors were 54, 84 and 107, respectively, the acetylcholine-induced increase in the [35S]GTP gamma S binding was as much as 12, 35 and 27 mol with Gi, Go and Gn, respectively, per mole of the receptor molecule, indicating that the muscarinic receptors interact with G proteins catalytically.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Cell Cardiol 1990 Mar
PMID:Interaction of atrial muscarinic receptors with three kinds of GTP-binding proteins. 211 1

We studied the interaction of amiodarone hydrochloride (Cordarone) and its major metabolite desethylamiodarone with the muscarinic receptor in purified canine cardiac sarcolemmal vesicles by measuring equilibrium binding of the muscarinic antagonist [3H]quinuclidinyl benzilate (QNB) and carbachol displacement of [3H]-QNB. At a [3H]-QNB concentration of 0.02 nM, equilibrium binding was inhibited by amiodarone and desethylamiodarone with an IC50 of 6.86 x 10(-6) M and 2.25 x 10(-6) M, respectively. The presence of increasing concentrations of [3H]-QNB in the incubation medium was able to reverse the inhibition seen with 1 x 10(-6) M amiodarone. Scatchard analysis of [3H]-QNB saturation isotherms (37 degrees C, pH 7.4) in the presence of 1 x 10(-6) M amiodarone showed an apparent increase in equilibrium dissociation constant (Kd) over control from 0.045 +/- 0.002 nM to 0.084 +/- 0.001 nM while maximal binding capacity (Bmax) was unaffected: 10.8 +/- 1.14 and 10.5 +/- 1.48 pmol/mg (means +/- S.E.M., n = 3), respectively. The inhibitory effect of amiodarone on equilibrium binding was highly dependent on the drug:membrane phospholipid mole ratio with effects beginning at a ratio of less than 0.1:1. Hill plot analysis was consistent with the interaction of [3H]-QNB at a single site in the presence or absence of amiodarone. Amiodarone (3 x 10(-6) M) decreased the pseudo-first order forward rate constant of [3H]-QNB (0.02 nM) with the muscarinic receptor (kobs = 4.05 +/- 0.61 x 10(-4)/s under control conditions and 2.36 +/- 0.15 x 10(-4)/s in the presence of amiodarone).(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Cell Cardiol 1989 May
PMID:Interaction of amiodarone and desethylamiodarone with the cardiac muscarinic receptor in vitro. 277 4

Phospholipase A2 (PLA2) inhibits ligand binding to sarcolemmal muscarinic receptors in heart. To determine whether this effect of PLA2 is mediated by membrane accumulation of non-esterified fatty acids (FFA), the effect of selected fatty acids on the binding of 3H-quinuclidinyl benzylate (3H-QNB) to purified canine sarcolemmal membranes before and after PLA2 treatment was examined. Equilibrium 3H-QNB binding was inhibited by 5 min exposure of membrane vesicles to oleic, linoleic or arachidonic acid (IC50 = 6.3 +/- 0.9, 9.9 +/- 1.1, and 6.8 +/- 0.4 microM, respectively); the saturated fatty acids, stearic and palmitic acid (10 microM) had no effect. Scatchard analysis of equilibrium binding isotherms showed that the effect of the unsaturated fatty acids to inhibit 3H-QNB binding reflected a decrease of Bmax and a reduction of the affinity of the remaining receptors. The effect of unsaturated fatty acids was dependent on the mole ratio of fatty acid to membrane phospholipid present (FFA/PL ratio). Washing of fatty acid-treated membranes with bovine serum albumin (BSA) resulted in partial recovery of both maximal binding (Bmax) and affinity. The fatty acid-induced reduction of Bmax was also attenuated if binding was started by simultaneous addition of 3H-QNB and FFA. Similarity of the FFA induced effects on 3H-QNB binding to sarcolemmal muscarinic receptors to those induced by PLA2 suggest that membrane accumulation of unsaturated fatty acids underlies in part the effect of PLA2. Furthermore, modification of the receptor-ligand interaction by changes in the membrane lipid composition may be prevented by ligand occupation of the receptor.
J Mol Cell Cardiol 1989 May
PMID:Inhibition of 3H-quinuclidinyl benzylate binding to cardiac muscarinic receptor by long chain fatty acids can be attenuated by ligand occupation of the receptor. 277 5

The enzyme, myosin light chain kinase, has been purified to homogeneity from bovine aortic vascular smooth muscle. Approximately 10 mg of enzyme could be obtained from 1 kg of fresh aortas with an overall yield of 26% of the original activity. The vascular myosin light chain kinase has a molecular weight of 160 000 by sodium dodecyl sulfate polyacrylamide gel electrophoresis. Antiserum raised to the aortic myosin light chain kinase in rabbits strongly inhibited phosphotransferase activity. In addition, the antiserum was used to identify myosin kinase in a crude homogenate of vascular smooth muscle by radioimmunoblotting. A single species of the enzyme (Mr = 160 000) was identified. The bovine aortic myosin kinase could be phosphorylated by both cyclic AMP- and GMP-dependent protein kinases. Approximately 2 mols PO4/mole of enzyme could be incorporated by the cyclic AMP-dependent protein kinase in the absence of calmodulin. If Ca2+ and calmodulin were included in the reaction mixture, phosphate incorporation by the cyclic AMP-dependent protein kinase was reduced to 1 mol and phosphorylation by cyclic GMP-dependent protein kinase was completely inhibited. These results were confirmed by tryptic peptide mapping. Two distinct phosphopeptides were identified: site-1 and site-2. Both could be phosphorylated by the cyclic AMP-dependent protein kinase but only site-1 was phosphorylated by the cyclic GMP-dependent enzyme. In the presence of Ca2+ and calmodulin, phosphorylation by cAMP-dependent protein kinase was restricted to site-1. The effect of phosphorylation on myosin light chain kinase activity was determined. Only phosphorylation by cyclic AMP-dependent protein kinase was found to alter the requirement of myosin kinase for calmodulin. The K0.5 (i.e. the concentration of calmodulin required for half-maximal enzyme activation) for calmodulin was 5 nM for the unphosphorylated myosin kinase. With 2 mol PO4/mol myosin kinase incorporated, the K0.5 for calmodulin was increased to 82 nM. When only 1 mol PO4/mol myosin kinase was incorporated, no effect on calmodulin requirement was observed. Moreover, single site phosphorylation had no effect on other activity parameters, including Km for ATP and for light chains. Our studies suggest that cyclic AMP-dependent protein kinase may play an important role in the regulation of vascular myosin kinase activity. Moreover, our results indicate that cyclic GMP-dependent protein kinase does not affect calmodulin-activation of myosin kinase or several other activity parameters.
J Mol Cell Cardiol 1985 Sep
PMID:Phosphorylation of myosin light chain kinase from vascular smooth muscle by cAMP- and cGMP-dependent protein kinases. 299 88

The concentration-dependent effects of ouabain on the contractility of postnatally developing rat heart ventricles were studied. Ouabain caused a positive inotropic effect in right ventricular strips of neonatal rats up to the age of about 30 days but a negative inotropic effect in the adult cardiac tissue. When extracellular Ca concentration was lowered from 2.5 to 1.0 mmol/l and the rate of stimulation was simultaneously elevated from 0.2 to 1.0 Hz a clear positive inotropic effect was also generated in the adult rat heart. The positive inotropic effect of ouabain showed a biphasic developmental pattern: the contractile force first grew from birth to about 15 days of age but steeply declined near to the adult level during the 3rd postnatal week. The force response to ouabain occurred within two distinct dose-ranges. In the newborn only the high-dose (above 3 X 10(-6) mol/l) effect was seen but in rats older than 5 days a mixed low-dose (below 3 X 10(-6) mole/l)/high-dose effect was apparent. In both ranges the positive inotropic effect of ouabain seemed to be dependent on caffeine sensitive Ca store, perhaps the sarcoplasmic reticulum. It is suggested that during the 3rd postnatal week a transition from extracellular to intracellular Ca stores occurs in the rat heart, which is reflected as a changing inotropic effect of ouabain on the developing cardiac tissue.
Basic Res Cardiol
PMID:Postnatal changes in the inotropic effect of ouabain on the rat heart ventricle. 359 85


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