PubMed Health⌕ Search

Biomedical subjects

J S Ingwall

Publications and source records attributed to J S Ingwall.

At least 91 records · Page 5Linked to original sources
PubMed1987

Tolerance to hypoxia of myocardium from adult and aged spontaneously hypertensive rats.

Myocardial mechanics and high-energy phosphate content [ATP and creatine phosphate (CrP)] of isolated left ventricular papillary muscle preparations from male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) were compared at 6 and 18 mo of age. In comparison with oxygenated (95% O2-5% CO2) glucose-supplied (5.5 mM) papillary muscles from hearts of WKY rats, papillary muscles from hypertrophied hearts of the 18-mo-old SHR exhibited a prolonged time to peak tension, electromechanical delay time, and an increase in resting tension measured at the apex of the length-tension curve. Adenine nucleotide (ATP and ADP) contents of oxygenated papillary muscles were not significantly different between SHR and WKY strains at 6 or 18 mo of age, but CrP content of hearts from adult WKY and SHR were higher than for aged WKY and SHR rats. For up to 30 min of hypoxia (95% N2-5% CO2), muscles from the 18-mo-old SHR and WKY rats demonstrated improved tolerance to hypoxia compared with muscles from younger animals. However, at 60 min of hypoxia the 18-mo-old SHR demonstrated lower active tension and adenylate energy charge [(1/2 ADP + ATP)/(ATP + ADP + AMP)]. At higher glucose concentrations (22 mM), both 18-mo-old WKY and SHR demonstrated improved tolerance to hypoxia; moreover, the differences between strains were no longer evident. Following reoxygenation with 5.5 mM glucose, contracture tension and CrP content recovered to near prehypoxic control levels, whereas developed tension and ATP content remained moderately depressed for all groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1987

Contractile failure and high-energy phosphate turnover during hypoxia: 31P-NMR surface coil studies in living rat.

Cardiac failure appears rapidly during severe hypoxia and precedes a substantial reduction in adenosine triphosphate content. Reduced adenosine triphosphate turnover, in the presence of nearly normal content, may be the metabolic basis for contractile failure during hypoxia. To measure both the myocardial content and the turnover rates of high-energy phosphate compounds during hypoxia, we performed 31P-nuclear magnetic resonance studies by placing a surface coil directly over the left ventricle in intubated rats that were instrumented for hemodynamic measurements and ventilated with either 21, 10, or 8% O2. Normoxia produced a hemodynamic and metabolic steady state for 4 hours and hypoxia for at least 60 minutes. Under normoxic ventilation (n = 10, mean +/- SD), the arterial PO2 was 96 +/- 14, pH 7.38 +/- 0.11, and systolic blood pressure 96 +/- 8 mm Hg; under hypoxic ventilation with 10% O2 (n = 5), the arterial PO2 was 57 +/- 10, pH 7.39 +/- 0.09, and systolic pressure 68 +/- 10; and under hypoxic ventilation with 8% O2 (n = 5), the PO2 was 52 +/- 7, pH 7.37 +/- 0.04, and systolic pressure 51 +/- 4. Hypoxic ventilation with 10 or 8% O2 decreased the creatine phosphate content from 51.4 +/- 5.4 mumol/g dry wt to 39.3 +/- 5.4 and 45.6 +/- 4.1 and depressed adenosine triphosphate slightly from 25.0 mumol/g dry wt to 21.8 +/- 2.1 and 21.9 +/- 1.0, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphatases↗
PubMed1987

Effects of norepinephrine infusion on myocardial high-energy phosphate content and turnover in the living rat.

Using 31P-nuclear magnetic resonance, we studied the relationship between myocardial high-energy phosphate content and flux values for the creatine kinase reaction in the living rat under inotropic states achieved during norepinephrine infusion and halothane anesthesia. Under 2% halothane anesthesia (n = 4), 1% halothane anesthesia (n = 5) and norepinephrine infusion (n = 4), rats developed rate-pressure products of 19.5 +/- 1.6, 32.0 +/- 3.5, and 48.5 +/- 2.0 X 1,000 mmHg/min, respectively. Adenosine triphosphate content was not affected by inotropic state, ranging from 24.3 +/- 1.1 to 25.6 +/- 1.1 mumol/g dry weight, but creatine phosphate content varied inversely and reversibly with cardiac performance from 45.6 +/- 6.0 under 2% halothane to 26.0 +/- 6.5 mumol/g dry weight during norepinephrine infusion. The flux values for the creatine kinase reaction were 15.4 +/- 4.6, 20.5 +/- 2.0, and 30.1 +/- 7.9 mumol/g dry weight per s under 2% halothane, 1% halothane, and 1% halothane with norepinephrine, respectively. These results suggest that the turnover of myocardial high-energy phosphate compounds, not their tissue contents, matches cardiac performance during inotropic stimulation.

Adenosine Triphosphate↗
PubMed1987

Intracellular high-energy phosphate transfer in normal and hypertrophied myocardium.

The understanding of the physiologic role of the creatine kinase reaction has evolved in parallel with investigative technology. Since the creatine kinase reaction replenishes hydrolyzed ATP so rapidly, early studies detected only creatine phosphate hydrolysis during muscular contraction. Direct observation of ATP hydrolysis required creatine kinase inhibition and suggested that creatine phosphate provided an energy reserve. Elegant studies with isolated heart mitochondria provided evidence that the creatine kinase reaction regulates the rate of oxidative phosphorylation. The 31P nuclear magnetic resonance technique of magnetization transfer permitted the direct investigation of the creatine kinase reaction in intact organs and confirmed the classic observation that chemical flux through the creatine kinase reaction is coupled to mitochondrial energy production. Hearts from 18-month-old spontaneously hypertensive rats have as much as a 50% decrease in mitochondrial creatine kinase activity. Preliminary magnetization transfer studies in such a heart show a depressed relation between creatine kinase flux and cardiac performance. The results suggest that creatine kinase flux, as measured by magnetization transfer, is determined in part by creatine kinase isozyme composition and that these biochemical changes are associated with long-standing cardiac hypertrophy.

Animals↗
PubMed1986

Stabilization of a derangement in adenosine triphosphate metabolism during sustained, partial ischemia in the dog heart.

Severe myocardial ischemia in dogs (perfusion 10% of normal) caused progressive deterioration in adenosine triphosphate (ATP) metabolism. Between 1/2 hour and 5 hours, myocardial ATP content fell from 55 to 6% of normal, and the sum of adenine nucleotides fell from 66 to 14% of normal. Moderate ischemia (perfusion 20 to 70%) also disturbed ATP metabolism, but to a lesser degree. Moreover, there was no significant change in the concentration of any ATP metabolite between 1/2 hour and 5 hours of moderate ischemia. ATP content was 66 and 52% of normal, and adenine nucleotide content was 73 and 59% of normal at 1/2 hour and 5 hours, respectively. Trivial ischemia (perfusion 80% or greater) barely perturbed ATP metabolism at either 1/2 hour or 5 hours. Thus, in contrast to severe or trivial ischemia, prolonged moderate ischemia produced a derangement in ATP metabolism that persisted and was relatively stable for 5 hours.

Adenosine Triphosphate↗
PubMed1986

The energetics of myocardial stretch. Creatine kinase flux and oxygen consumption in the noncontracting rat heart.

Previous studies have suggested that flux through the creatine kinase reaction is coupled to cardiac performance and to the rate of adenosine triphosphate synthesis in the intact, beating heart. To define the effect of passive myocardial stretch on creatine kinase kinetics, we measured the rate constants and chemical fluxes for both directions of the creatine kinase reaction with the 31P-nuclear magnetic resonance technique of magnetization transfer in isolated, arrested rat hearts at four levels of left ventricular pressure and volume. Adenosine triphosphate synthesis was estimated from oxygen consumption measurements. As left ventricular pressure rose from 0 to 24 mm Hg and oxygen consumption increased by 20%, we observed a twofold increase in the rate constants and fluxes (mean +/- SD, n = 4-7) for the creatine kinase reaction. The forward rate constant increased from 0.33 +/- 0.03 to 0.80 +/- 0.08, and the reverse rate increased from 0.34 +/- 0.11 to 0.74 +/- 0.32/sec. The forward and reverse fluxes for the creatine kinase reaction increased from 12.0 +/- 3.4 to 26.5 +/- 5.8 and from 9.1 +/- 3.4 to 19.1 +/- 3.4 mumol/g dry weight per sec, respectively. At each level of left ventricular pressure, the forward and reverse rate constants were the same. However, as left ventricular pressure increased, the ratio of the forward to the apparent reverse fluxes for the creatine kinase reaction increased. The relationships between the rate constant or flux through the creatine kinase reaction vs. left ventricular pressure were linear. In addition to providing further support for the coupling between creatine kinase and mitochondrial adenosine triphosphate synthesis, these results suggest that flux through the creatine kinase reaction and adenosine triphosphate synthesis increases with myocardial stretch in the intact, noncontracting heart.

Adenosine Triphosphate↗
PubMed1986

Acute alterations in diastolic left ventricular chamber distensibility: mechanistic differences between hypoxemia and ischemia in isolated perfused rabbit and rat hearts.

Changes in diastolic chamber distensibility (DCD) during hypoxemia and ischemia were studied in isolated-buffer-perfused rabbit hearts. Two minutes of hypoxemia (low PO2 coronary flow) resulted in a shift of the diastolic pressure-volume curve to the left, i.e., distensibility was decreased (hypoxemic contracture). In contrast, 2 minutes of ischemia (zero coronary flow) resulted in an initial shift of the diastolic pressure-volume curve to the right indicating increased distensibility, which was followed by a later (30 minutes) shift to the left (ischemic contracture). Two minutes of ischemia superimposed on hypoxemia caused complete reversal of contracture. A quick stretch and release applied to the myocardium reversed late ischemic contracture but did not effect early hypoxemic contracture. The role of intracellular pH in modulating changes in DCD during hypoxia and ischemia was studied using phosphorus-31 nuclear magnetic resonance spectroscopy of isolated-buffer-perfused rat hearts that demonstrated changes in DCD similar to rabbit hearts during hypoxemia and ischemia. Intracellular pH decreased from 7.03 +/- 0.02 to 6.87 +/- 0.03 (p less than .01) during 2 minutes of ischemia but did not change significantly during 4 minutes of hypoxemia. When 2 minutes of ischemia were superimposed on hypoxemia, pH decreased from 6.99 +/- 0.01 during hypoxemia to 6.88 +/- 0.02 after 2 minutes of ischemia (p less than .01), concomitant with the complete reversal of hypoxemic contracture. These results suggest different mechanisms for late ischemic and early hypoxemic contracture and also suggest an explanation for the opposite initial changes in DCD seen after brief periods of ischemia and hypoxemia. The early development of contracture during hypoxemia and rapid redevelopment of diastolic tension after quick stretching are consistent with the hypothesis that hypoxemic contracture results from persistent Ca++-activated diastolic tension secondary to impaired calcium resequestration by the sarcoplasmic reticulum. In contrast, the late development of contracture during global ischemia and reversal by quick stretching is compatible with rigor bond formation. The initial increase in distensibility during early ischemia and the reversal of hypoxemic contracture by a brief period of superimposed ischemia probably is the result of two factors present during ischemia but not during hypoxemia: the collapse of the coronary vasculature and loss of the "erectile" effect and, the rapid development of intracellular acidosis, which has been shown to affect myofibrillar calcium sensitivity, and this may lead to a decrease in Ca++ activated diastolic tension.

Acidosis↗
PubMed1985

The creatine kinase system in normal and diseased human myocardium.

We measured creatine kinase activity, isozyme composition, and total creatine content in biopsy samples of left ventricular myocardium from 34 adults in four groups: subjects with normal left ventricles, patients with left ventricular hypertrophy due to aortic stenosis, patients with coronary artery disease without left ventricular hypertrophy, and patients with coronary artery disease and left ventricular hypertrophy due to aortic stenosis. As compared with specimens of normal left ventricles, those from all patients with left ventricular hypertrophy had lower creatine kinase activity, higher MB creatine kinase isozyme content and activity, and lower creatine content. Specimens from the patients without left ventricular hypertrophy had normal creatine kinase activity, increased MB creatine kinase isozyme content and activity, and decreased total creatine content. The normal ventricles showed almost no MB isozyme content or activity. These data suggest that changes in the creatine kinase system occur in both pressure-overload hypertrophy and coronary artery disease. Patients with myocardial infarction who have mild or no preexisting fixed coronary artery disease or pressure-overload hypertrophy would not be expected to have elevation of serum MB creatine kinase.

Adult↗
PubMed1985

Reaction rates of creatine kinase and ATP synthesis in the isolated rat heart. A 31P NMR magnetization transfer study.

The NMR technique of magnetization transfer can be used to define intracellular reaction kinetics. In order to determine the relationship between ATP synthesis and flux through the creatine kinase reaction in the intact heart, we used this technique to measure flux through the creatine kinase reaction in the isolated, isovolumic rat heart at five levels of cardiac performance and oxygen consumption. The unidirectional reaction rate constants (s-1) calculated from a two-site exchange model for both the forward and reverse creatine kinase reactions increased with cardiac performance and oxygen consumption. As the rate-pressure product varied from 0 to 44.7 X 10(3) mm Hg/min and oxygen consumption rose from 5.9 to 45.8 mumol of O2/g dry weight/min, kforward increased from 0.27 to 1.30 and kreverse increased from 0.31 to 1.14. The relationship between creatine kinase flux and oxygen consumption, and thus ATP synthesis, took the form of the Michaelis-Menten equation. Rates of ATP synthesis estimated from magnetization transfer were similar to values calculated from oxygen consumption. The longitudinal relaxation time of creatine phosphate (2.06 s), the gamma-phosphorus atom of ATP (0.75 s), and inorganic phosphate (0.81 s) did not change with cardiac performance. These results show that myocardial energy transfer via the creatine kinase reaction is closely coupled to energy production.

Adenosine Triphosphate↗
PubMed1985

Alterations in the distribution of high-energy phosphates during ischemia in a canine model of reperfusion-induced ventricular fibrillation.

High-energy phosphate metabolites of the canine heart were analyzed before coronary artery occlusion and after 15 minutes of ischemia, and the results were then correlated with the occurrence of ventricular fibrillation upon reperfusion (RVF). Animals which developed VF upon reperfusion after 15 minutes of ischemia had lower levels of creatine phosphate and endocardial adenosine triphosphate (ATP), and increased accumulation of the catabolites of ATP metabolism, inosine and hypoxanthine. Animals which developed RVF also had lower levels of regional myocardial blood flow in the center of the ischemic zone during the period of coronary occlusion. Occluded bed size was the same in dogs which did and did not develop RVF. These data suggest that VF upon reflow is associated with more severe ischemia and an increase in high-energy phosphate catabolism during the period of ischemia.

Adenine Nucleotides↗
PubMed1985

23Na and 39K nuclear magnetic resonance studies of perfused rat hearts. Discrimination of intra- and extracellular ions using a shift reagent.

High-resolution 23Na and 39K nuclear magnetic resonance (NMR) spectra of perfused, beating rat hearts have been obtained in the absence and presence of the downfield shift reagent Dy(TTHA)3- in the perfusing medium. Evidence indicates that Dy(TTHA)3- enters essentially all extracellular spaces but does not enter intracellular spaces. It can thus be used to discriminate the resonances of the ions in these spaces. Experiments supporting this conclusion include interventions that inhibit the Na+/K+ pump such as the inclusion of ouabain in and the exclusion of K+ from the perfusing medium. In each of these experiments, a peak corresponding to intracellular sodium increased in intensity. In the latter experiment, the increase was reversed when the concentration of K+ in the perfusing medium was returned to normal. When the concentration of Ca2+ in the perfusing medium was also returned to normal, the previously quiescent heart resumed beating. In the beating heart where the Na+/K+ pump was not inhibited, the intensity of the intracellular Na+ resonance was less than 20% of that expected. Although the data are more sparse, the NMR visibility of the intracellular K+ signal appears to be no more than 20%.

Animals↗
PubMed1985

The relationships of high energy phosphates, tissue pH, and regional blood flow to diastolic distensibility in the ischemic dog myocardium.

Myocardial ischemia due to increased oxygen demand (pacing tachycardia plus critical coronary stenoses) alters diastolic distensibility and relaxation more than ischemia of comparable duration due to coronary occlusion. To investigate the relationship between myocardial diastolic function and metabolism, we compared myocardial high energy phosphate content, tissue pH, and regional blood flow for these two types of ischemia in anesthetized open-chest dogs. Myocardial biopsies were done with a high-speed air-turbine biopsy drill, permitting rapid (less than 1-second) freezing of tissue samples from both nonischemic and ischemic areas, while myocardial pH was measured with a hydrogen ion-selective polymer membrane implanted in the subendocardium. After 3 minutes of pacing tachycardia in dogs with critical coronary stenoses (demand-type ischemia, n = 14), regional systolic function (% segment shortening by ultrasonic crystals) was mildly depressed (from 19 +/- 2% control to 13 +/- 2% post-pacing, P less than 0.01), while left ventricular diastolic pressure-segment length relations shifted upward, indicating decreased distensibility of the ischemic myocardial segment. Associated with these changes in function, subendocardial adenosine triphosphate decreased (from 31.3 +/- 1.5 to 27.9 +/- 1.0 nmol/mg protein, P less than 0.01), as did creatine phosphate (53.8 +/- 2.1 to 39.6 +/- 2.5 nmol/mg protein, P less than 0.01), while myocardial pH declined slightly (delta pH = -0.14 +/- 0.02, P less than 0.01). In contrast, at 3 minutes of coronary artery occlusion (primary ischemia, n = 14), regional segment shortening was replaced by systolic bulging (% shortening decreased from 17 +/- 2% to -2 +/- 1% during occlusion, P less than 0.01), while left ventricular pressure-segment length relations were not shifted upward, and there was no decrease in diastolic distensibility of the ischemic segment. With coronary artery occlusion, subendocardial adenosine triphosphate declined slightly (33.2 +/- 0.5 to 29.2 +/- 2.0 nmol/mg, P less than 0.05), while creatine phosphate decreased substantially (51.1 +/- 2.3 to 7.8 +/- 1.4 nmol/mg protein, P less than 0.01). Myocardial pH fell strikingly (delta pH = -0.33 +/- 0.03, P less than 0.01), and the decline was 236% of that seen with demand-type ischemia. Regional myocardial blood flow (microsphere technique) showed a decreased endocardial:epicardial (endo:epi) ratio (1.04 +/- 0.04 control vs. 0.40 +/- 0.05 during pacing, P less than 0.01) and absolute subendocardial flow (1.02 +/- 0.47 to 0.47 +/- 0.05 ml/min per g, P less than 0.01) with demand-type ischemia.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1984

Inhibition of hypoxic myocardial contracture by Cobalt in the rat.

We studied the relationship between the slow inward current, tissue ATP content, and the development of hypoxic myocardial contracture in the rat. Resting tension and active isometric tension were measured using isolated left ventricular papillary muscle preparations. Action potentials and membrane currents were studied using a single sucrose gap voltage clamp technique. The slow inward current (isi) was partially inhibited by verapamil and completely inhibited by cobalt but was not reduced by ryanodine. Active tension was reduced by all three drugs. Non-stimulation, verapamil, and ryanodine did not prevent contracture development with hypoxia, but contracture was markedly reduced by pre-treatment with cobalt. Despite contrasting effects on contracture, both non-stimulation and cobalt partially prevented ATP depletion with hypoxia, suggesting that contracture is not directly related to total muscle ATP content. Cobalt appears to block hypoxic contracture via a mechanism other than simple blockade of isi, inhibition of contraction, or preservation of tissue ATP content.

Action Potentials↗
PubMed1984

The hypertrophied myocardium accumulates the MB-creatine kinase isozyme.

Myocardial hypertrophy was produced in the dog by volume overload, secondary to hypertension, and pressure overload to left or right ventricles and in the rat by pressure overload to the left or right ventricles, by elevating thyroxine-levels and secondary to spontaneous hypertension in order to test whether there are changes in the creatine kinase system in hypertrophied heart. Although there was little or no change in total creatine kinase activity, there were changes in the distribution of the creatine kinase isozymes. In the dog, a 4-10-fold increase in the tissue content of MB-creatine kinase was observed for heart chambers with a 40-90% increase in the ratio of ventricular weight to body weight. In the rat, MB-creatine kinase also accumulated in hypertrophied ventricles. For the spontaneously hypertensive rat, the correlation between increased fetal creatine kinase isozymes and increased ratio of ventricular weight to body weight was excellent (r approximately 0.92). During the transition from compensated hypertrophy to failure in the spontaneously hypertensive rat, there is a 50% decrease in mitochondrial creatine kinase activity. P-31 NMR magnetization transfer experiments suggest that flux through the creatine kinase reaction is 3-fold lower than normal in these failing hearts. These results show that there are changes in the distribution of the creatine kinase isozymes in hypertrophied heart and suggest that one of these changes characterizes compensated hypertrophy (increased fetal-type creatine kinase isozymes) while another characterizes the transition to failure (decreased mitochondrial creatine kinase).

Animals↗
PubMed1984

Effects of moderate pressure overload cardiac hypertrophy on the distribution of creatine kinase isozymes.

Myocardial activities and isozyme distributions of creatine kinase (CK) and lactate dehydrogenase (LDH) were measured in rats with moderate pressure overload hypertrophy. Three weeks after aortic banding, the ratio of left ventricular (LV) weight to body weight increased by 30%. Values for enzyme activity in the hypertrophied LV were compared to values for control rats as well as to the contralateral relatively unaffected right ventricle (RV). In rats with moderate LV hypertrophy, total CK activity was unchanged. The percent MB-CK increased significantly (p less than 0.01) only in the hypertrophied LV, from 13 +/- 1% to 19 +/- 1% of total CK, while the sum of MM and mitochondrial-CK decreased from 86 +/- 3 to 80 +/- 3% (p less than 0.01). LDH activity increased (p less than 0.05) only in the hypertrophied ventricle from a control of 2.90 +/- 0.13 to 3.21 +/- 0.13 IU/mg protein, while the ratio of LDH activity at high to low substrate increased from 0.12 +/- 0.02 to 0.14 +/- 0.02 (p less than 0.05). Thus, the development of moderate pressure overload hypertrophy in the LV is associated with normal levels of total CK, but the percentage of MB-CK increases selectively in the primarily affected ventricle. Also, total LDH and LDH activity at high to low substrate concentration increases significantly in LV hypertrophy.

Animals↗
PubMed1983

Effects of reduced coronary flow on thallium-201 accumulation and release in an in vitro rat heart preparation.

To study the relation between myocardial thallium-201 (TI-201) uptake, TI-201 release, and reduced coronary flow, isolated Langendorff rat hearts (n = 8) were perfused for 3 hours at constant flows ranging from physiologic (12 ml/min) to severely ischemic (1.5 ml/min); thallium activity was monitored with a scintillation probe. Each heart was perfused for 1 hour with thallium buffer, followed by 2 hours with thallium-free buffer at the same flow rate. Accumulation curves for all 4 flows were monoexponential. However, release curves during the 2 hours of washout with thallium-free buffer demonstrated a biexponential configuration. The early fast release component decreased with reductions in coronary flow, and the later slow release component did not vary significantly with flow. These data show that thallium clearance has at least 2 components: a rapid (possibly extracellular) component related to coronary flow and a slow (possibly intracellular) component independent of coronary flow. These findings should be useful in providing a better understanding of thallium redistribution observed clinically.

Animals↗