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J S Ingwall

Publications and source records attributed to J S Ingwall.

At least 109 records · Page 6Linked to original sources
PubMed1983

Developmental regulation of mRNA in mouse heart.

The myocardium contains abundant translatable mRNAs that change during development. Maximal cell-free synthesis of [3H]leucine-, [35S]methionine-, and [35S]cysteine-labeled translation products directed by poly(A)-containing mRNAs from 12-, 14-, and 17-day fetal; 5-day-old neonatal; and 30-day-old adult mouse heart was determined by using one- and two-dimensional polyacrylamide gels. Three general developmental patterns of heart-specific mRNA translation products were observed: two translatable mRNAs were most abundant in 12-day fetal heart; five mRNAs were most abundant in 14- and 17-day fetal heart and occurred only at low concentrations in 12-day fetal and adult heart; four mRNAs, including mRNAs coding for actin, tropomyosin, and myosin light chains 1 and 2, were most abundant in the adult heart. Thus, differentiating cardiac muscle is characterized by a complex pattern of mRNA regulation.

Animals↗
PubMed1983

A flow- and time-dependent index of ischemic injury after experimental coronary occlusion and reperfusion.

The purpose of the present study was to determine whether an ischemic index--expressed as the product of flow deprivation (FD) and the duration of occlusion (T), FD X T--correlated with biochemical and early morphologic alterations of the subendocardial myocardium and could predict ultimate development of irreversible injury after coronary reperfusion. Myocardial biopsy specimens for measurement of ATP and other purines and for ultrastructure studies were obtained in vivo during coronary occlusion in a canine model and were considered relative to development of necrosis after coronary reperfusion. FD X T correlated negatively with ATP content [ATP, nmol/mg of cardiac protein = 23.6 - 0.24(FD X T) + 0.0007(FD X T)2; r = -0.81] and with a semiquantitative early histologic index of damage (r = 0.70). Values of (FD X T) less than 18 were associated with reversible injury--i.e., complete salvage after coronary reperfusion. (FD X T) greater than 18 was associated with varying degrees of necrosis; necrosis was severe (78 +/- 12% of subendocardial biopsy specimens) when ATP less than 10 nmol/mg of protein and total purine pool was decreased by 50%. FD X T correlated with the eventual percentage of subendocardial necrosis (r = 0.85). Accordingly, as an index of ischemic injury, FD X T may be useful in assessing whether ischemic myocardial tissue will benefit from early restoration of blood flow to the ischemic area.

Animals↗
PubMed1983

Effects of ischemic-like insult on myocardial thallium-201 accumulation.

Despite extensive clinical use of thallium-201 (201TI) for myocardial imaging, the effect of ischemia on myocardial accumulation and release of 201TI independent of flow has not been fully defined. Therefore, myocardial accumulation of 201TI in response to ischemic-like myocardial injury was assessed in vitro using the cultured fetal mouse heart preparation. Cultured fetal mouse hearts (n = 311) were subjected to injury simulating ischemia by deprivation of oxygen and oxidizable substrates for periods ranging from 15 minutes to 10 hours. The extent of irreversible injury was determined by the percentage of lactic dehydrogenase (LDH) lost from the hearts to the culture medium during recovery from injury. Injury was essentially reversible at 1 hour of insult. The fraction of 201TI content in injured compared with control hearts was not significantly lower after 1 hour of insult. By 3 hours of insult, irreversible injury as assessed by loss of LDH was detectable and the extent of injury increased progressively through 10 hours. During the 3-10-hour period of irreversible injury, 201TI accumulation within injured hearts compared with controls was related in a monotonically decreasing fashion to the loss of LDH as described by a mathematical kinetic model that fit the observations closely (R2 greater than 0.99). These results indicate that in this organ culture preparation, in which there is effectively an unlimited reservoir of 201TI and no confounding effects of perfusion, the time-dependent 201TI accumulation is determined by the extent of irreversible injury.

Animals↗
PubMed1983

Evaluation of high-energy phosphate metabolism during cardioplegic arrest and reperfusion: a phosphorus-31 nuclear magnetic resonance study.

Hypothermic potassium cardioplegia is now commonly used to protect the myocardium during surgically induced ischemia. Because the potassium-related membrane depolarization has been shown to increase calcium influx, we undertook this study to define the effects of varying the calcium content in hyperkalemic perfusates and the effects of using magnesium instead of or in addition to potassium as the arresting agent on the ability of hearts to recover normal function after ischemic arrest. We subjected isolated perfused working rat hearts to 60 minutes of cardioplegic arrest followed by 30 minutes of reperfusion, and measured high-energy phosphate levels every 2 1/2 minutes by phosphorus-31 nuclear magnetic resonance spectroscopy. These data were correlated with postischemic recovery of function. Our results show that potassium cardioplegia may be harmful when the calcium concentration is greater than 1 mM. The kalemic injury is significantly reduced when the calcium content is lowered to 0.25 mM and the greatest extent of preservation is provided by a calcium-poor perfusate (0.25 mM) containing 13 mM magnesium. The beneficial effects of magnesium are not enhanced by subsequent addition of potassium. Close correlations were found between all observed metabolic changes during arrest and the degree of recovery of contractile performance after reperfusion. We conclude that the ability of the myocardium to maintain or resynthesize high-energy phosphate after cardioplegic arrest may be an important determinant of postischemic mechanical performance. These results show that phosphorus-31 nuclear magnetic resonance spectroscopy is a valuable method for evaluating interventions to reduce the severity of ischemic damage.

Adenosine Triphosphate↗
PubMed1982

Phosphorus nuclear magnetic resonance spectroscopy of cardiac and skeletal muscles.

Phosphorus nuclear magnetic resonance spectroscopy (P-31 NMR) has been used to assess dynamic aspects of the metabolism of phosphorus-containing compounds in intact cells, organs, and animals. This review describes the NMR experiment and the kinds of information the P-31 NMR spectrum provides for intact, functioning cardiac and skeletal muscles. The P-31 NMR spectrum not only identifies which phosphorus-containing compounds are present in high concentration, namely adenosine 5'-triphosphate (ATP) and creatine phosphate, but also provides information about their chemical environment (including pH) and intracellular distribution. The method is quantitative and nondestructive and permits repetitive measurements in an intact functioning organ. For the perfused heart, it is possible to manipulate the chemical and gaseous composition of the perfusate and to define the effects of, for example, ischemia and reperfusion on the metabolism of ATP and creatine phosphate in the same sample. Using saturation-transfer NMR techniques, it is also possible to measure rates of certain reactions, including creatine kinase and adenylate kinase, in the intact cell. NMR can also be used as an imaging modality.

Adenosine Triphosphate↗
PubMed1982

Inosine: a protective agent in an organ culture model of myocardial ischemia.

Fetal mouse hearts in organ culture provide a model of ischemic-like injury in which the myocardial protective effect of pharmacological agents can be studied independent of blood flow. To investigate the potential protective effect of a diffusable purine under ischemic-like conditions, we used 4 mM inosine in fetal mouse heart organ cultures deprived of oxygen and oxidizable substrates for 1-10 hours. We studied hearts (n = 258) immediately after simulated ischemia (early) and after a 20-hour recovery period (late), by utilizing three indices of myocardial viability. Thallium-201 accumulation is an early marker of myocardial viability during injury, whereas the percentage of lactic dehydrogenase release from hearts to culture medium and the percentage of irreversibly injured myocytes assessed by planimetry of midventricular histological sections are late markers, used after recovery from injury. At 10 hours of injury, thallium-201 accumulation was 38% greater in inosine-supplied hearts, 3.50 +/- 0.16 vs. 2.54 +/- 0.08 (counts/min per mg wet weight)/(counts/min per microliter medium) (mean +/- SEM) (P less than 0.001). After recovery from 10 hours of injury, lactic dehydrogenase release was 29% less in inosine-supplied hearts, 35 +/- 3% vs. 49 +/- 3% (P less than 0.001). After recovery from 8 hours of injury, the percentage of histologically irreversibly injured tissue was 23% less in inosine-supplied hearts, 60 +/- 7% vs. 78 +/- 3% (P less than 0.05). These data indicate that inosine has a protective effect on fetal mouse myocardium during simulated ischemia and suggest that inosine deserves further evaluation.

Animals↗
PubMed1981

[A new method to evaluate myocardial preservation techniques (author's transl)].

Nuclear magnetic resonance (NMR) is a non-invasive technique which, when using 31Phosphorus (as is usually the case), provides sequential determinations of the concentrations of high energy phosphate compounds and of intracellular pH in tissues subjected to electro-magnetic pulses. NMR can now be applied to the whole heart and makes it possible to record simultaneously biochemical and haemodynamic data. Referring to personal cases, the authors emphasize the value of NMR as a new device for evaluating myocardial preservation techniques during both ischaemia and reperfusion.

Adenosine Triphosphate↗
PubMed1981

Limitations of potassium cardioplegia during cardiac ischemic arrest: a phosphorus 31 nuclear magnetic resonance study.

Cold K+ cardioplegia is commonly used to preserve the myocardium during surgical ischemia. Since the K+-induced membrane depolarization could cause a Ca2+-mediated breakdown of adenosine triphosphate, this study compared the influence of different electrolytes on high-energy phosphate metabolism during cardioplegic arrest phosphate metabolism during cardioplegic arrest and subsequent recovery of mechanical function. An isolated working heart was subjected to hypothermic ischemia for one hour. Metabolic studies were assessed on phosphorus 31 nuclear magnetic resonance (NMR). Results show that (1) K+ cardioplegia is harmful when the Ca2+ content is equal to 2 mEq/I; (2) deleterious effects of K+ are markedly reduced by lowering the Ca2+ content; (3) the most adequate preservation is provided by a Mg2+-rich-Ca2+-poor perfusate; (4) this protection is not enhanced by addition of K+. Finally, 31P NMR appears particularly appropriate for evaluating myocardial protection techniques since it allows noninvasive serial monitoring of high-energy phosphate content and subsequent correlation with functional recovery after ischemia.

Adenosine Triphosphate↗
PubMed1981

Recovery from prolonged abnormalities of canine myocardium salvaged from ischemic necrosis by coronary reperfusion.

The purpose of this study was to determine whether or not the biochemical, functional, and ultrastructural abnormalities produced by brief temporary coronary occlusions (unassociated with necrosis) ever resolve and, if so, when they do. Anesthetized open-chest dogs were subjected to 15 min of coronary artery occlusion followed by 72 hr, 7 days, or 14 days of reperfusion. Serial in vivo myocardial biopsies were performed for measurement of ATP and for ultrastructural analysis. Regional function was evaluated by sonomicrometry. Mean (+/- SEM) myocardial ATP concentration was 36.6 +/- 1.2 nmol/mg of cardiac protein in nonischemic subendocardium and 18.9 +/- 1.5 in ischemic subendocardium after 15 min of ischemia. ATP remainede performed for measurement of ATP and for ultrastructural analysis. Regional function was evaluated by sonomicrometry. Mean (+/- SEM) myocardial ATP concentration was 36.6 +/- 1.2 nmol/mg of cardiac protein in nonischemic subendocardium and 18.9 +/- 1.5 in ischemic subendocardium after 15 min of ischemia. ATP remainede performed for measurement of ATP and for ultrastructural analysis. Regional function was evaluated by sonomicrometry. Mean (+/- SEM) myocardial ATP concentration was 36.6 +/- 1.2 nmol/mg of cardiac protein in nonischemic subendocardium and 18.9 +/- 1.5 in ischemic subendocardium after 15 min of ischemia. ATP remained depressed in the reperfused previously ischemic subendocardium at both 90 min (68% of nonischemic value) and 72 hr (78% of nonischemic value) but returned to normal at 7 days. Regional systolic function and cardiac ultrastructural abnormalities required 7 days for full recovery. Histologic and histochemical analysis did not reveal necrosis at any time. Therefore, biochemical, functional, and ultrastructural abnormalities induced by brief periods of transient coronary occlusion not associated with necrosis do resolve completely but the recovery period is prolonged.

Adenosine Triphosphate↗
PubMed1981

Prolonged abnormalities of myocardium salvaged by reperfusion.

The purpose of this study was to determine if biochemical, functional, and ultrastructural abnormalities persist in nonnecrotic postischemic myocardium salvaged by coronary reperfusion. Anesthetized dogs were subjected to 15 min of occlusion of the left anterior descending (LAD) coronary artery followed by 3 days of reperfusion. Biopsies were obtained for measurement of adenosine 5'-triphosphate (ATP) and creatine phosphate (CP) nmol/mg protein), and regional function was evaluated using sonomicrometry. Myocardial ATP concentration after 15 min of occlusion was 37 +/- 1 nmol/mg cardiac protein in nonischemic subendocardium and 19 +/- 2 nmol/mg in ischemic subendocardium. After the hearts underwent 90 min and 72 h of reperfusion, ATP remained significantly depressed in reperfused subendocardium with values of 25 +/- 5 and 29 +/- 2 nmol/mg, respectively (P less than 0.05 and P less than 0.01 compared with the nonischemic zone in which ATP remained normal). CP levels fell during ischemia but returned to normal by 90 min of reperfusion. Percent systolic shortening of myocardial segments fell from +18 +/- 1% (active shortening) to -13 +/- 2% (passive lengthening) during ischemia and was still significantly depressed at +11 +/- 1% (P less than 0.05 vs. preocclusion) at 72 h of reperfusion. Histological examination showed no necrosis, but ultrastructural abnormalities were present. Therefore brief periods of myocardial ischemia are not associated with necrosis but result in functional, biochemical, and ultrastructural abnormalities, which are present for at lest 3 days after coronary reperfusion.

Adenosine Triphosphate↗
PubMed1981

Maturation of energy metabolism in the lamb: changes in myosin ATPase and creatine kinase activities.

Studies have been carried out to assess maturation of myofibrillar and mitochondrial proteins in fetal (113 to 140 days gestation), neonatal (30 min to 21 days postpartum), and adult sheep hearts. Ca++-activated myosin ATPase activity was approximately 20% lower in fetal than in adult left ventricular myocardium (1.13 +/- 0.06, n = 12, versus 1.36 +/- 0.07, n = 9, mumoles P1 per g protein per sec; P less than 0.025). In fetal and neonatal hearts (but not in adult hearts), myosin ATPase activity was slightly higher (approximately 14%; P less than 0.001) in right ventricular tissue than in left ventricular tissue. In contrast to these small changes in myosin ATPase activity, large changes indicative of maturation of energy metabolism occurred in the creatine kinase system: between 115 days gestation and 21 days postpartum, total creatine kinase activity increased nearly 8-fold (0.2 to 1.6 IU/mg cardiac mass), the MM-creatine kinase isozyme increased 7-fold (0.2 to 1.5 IU/mg wet weight), and mitochondrial creatine kinase increased more than 25-fold (less than 0.01 to 0.27 IU/mg wet weight). The total creatine pool, but not the ATP pool, increased (from approximately 6 to approximately 15 nmoles/g tissue). Neither the concentration nor isozyme distribution of lactate dehydrogenase, a glycolytic enzyme, changed during this 7-wk period of development.

Adenosine Triphosphatases↗
PubMed1980

Nuclear magnetic resonance imaging: potential cardiac applications.

During the past several years, the production of high resolution images of organs in intact animals and human beings using nuclear magnetic resonance (nmr) has generated much interest and raised the possibility that the technique could be usefully applied to clinical problems. Because the images are derived from biochemical as well as structural information, valuable data relating to the metabolic status of the tissues and organs may be obtained. Furthermore, nuclear magnetic resonance imaging involves no potentially hazardous ionizing radiation. The technology of the technique is complex and much work remains to be done defining the biochemical and physiologic basis of such images, but the potential rewards of defining the metabolic state of organs such as heart and brain in the intact animal and human justify continued research.

Animals↗
PubMed1980

The cell substratum modulates skeletal muscle differentiation.

During chick embryogenesis, massive alterations occur in the migrating cell's substratum, or extracellular matrix. The possibility that some of the components of this milieu play a regulatory role in cell differentiation was explored in a cell-culture system derived from embryonic chick skeletal muscle tissue. In particular, the effects of collagen and the glycosaminoglycans were studied. Collagen is required for muscle cell attachment and spreading onto plastic and glass tissue-culture dishes. A major constituent of the early embryonic extracellular space, hyaluronate (HA), while having no significant effect on collagen-stimulated cell attachment and spreading, was found to inhibit myogenesis. The muscle-specific M subunit of creatine kinase was preferentially inhibited. Control experiments indicated that the inhibition was specifically caused by HA and not by other glycosaminoglycans. A general metabolic inhibition of the cultures was not observed. Muscle cells could bind to HA-coated beads at all stages of differentiation but were inhibited only when HA was added within the first 24 h of culture. Endogenous GAG in the culture is normally degraded during the first 24 h after plating as well; this may parallel the massive degradation of HA that occurs in the early embryo in vivo. These findings suggest a regulatory role for HA in modulating skeletal muscle differentiation, with degradation of an inhibitory component of the cell substratum a requirement for myogenesis.

Animals↗