Biomedical subjects
Publications and source records attributed to T R Snow.
Even with heroic procedures, it is not yet possible to prevent cell death during a myocardial infarction; however, preconditioning has revealed an endogenous process capable of providing significant protection to the heart from such a fatal result. Mechanisms by which preconditioning operates have not yet been unraveled but its resolution has clear clinical significance.
The effects of triiodothyronine (T3) on the force frequency responses of isometrically contracting rabbit papillary muscles were studied in the presence of d-glucose, pyruvate or butyrate. The stimulation frequency was varied from 0.1 to 0.5 Hz, and the maximum developed tension and its maximum (Tmx) and minimum (Tmn) time derivative were measured. T3 concentrations ranged from 0.1 to 4.0 ng/ml. The addition of T3 resulted in a substrate-dependent increase in twitch tension; with the largest increases being: d-glucose 118 +/- 7%, pyruvate 143 +/- 6%, butyrate 123 +/- 11%; Tmx:d-glucose 121 +/- 8%, pyruvate 157 +/- 5%, butyrate 138 +/- 12%, and Tmn:d-glucose 150 +/- 10%, pyruvate 159 +/- 6%, butyrate 163 +/- 14%. All three measures of contractility showed a dose-dependent increase reaching a maximum value at a T3 concentration between 1 and 2 ng/ml. These data show that T3 induces an inotropic response in rabbit papillary muscles which is manifested within, approximately 30 min, and that the greatest increase is seen in Tmn.
Reperfusion following a transient ischemic insult has been shown to result in a delayed recovery of myocardial function. A reduction in plasma triiodothyronine (T3) has been reported in these acute cardiovascular challenges. To test whether the replacement of T3 can facilitate the recovery of myocardial function following a transient regional ischemia, we investigated cardiac performance for 3 h after a 15-min, left anterior descending coronary artery occlusion in a canine model. Three groups of dogs were studied: I--control (n = 10); II--receiving T3 (0.25 micrograms/kg i.v. and 0.25 micrograms/kg/h for 3 h, n = 9), and III--receiving T3 (0.25 micrograms/kg i.v. and 0.5 micrograms/kg/h for 3 h, n = 9). Three hours following reperfusion, the T3 level in blood was significantly decreased in group I. Concomitantly, local segmental shortening was reduced from preocclusion control levels in group I (15.2 to 5.1%, p < 0.05), but recovered in both treated groups. The endsystolic elastance (Ees) and the external work (EW) efficiency (EW/PVA) in group I were depressed from preocclusion control (Ees = 95.5 +/- 0.8%; EW/PVA = 90.2 +/- 1.8%, both p < 0.05), the effective arterial elastance (Ea) and ventriculoarterial coupling (Ea/Ees) in group I were still elevated from preocclusion control (Ea = 122.5 +/- 5.1%; Ea/Ees = 128.3 +/- 5.3%, both p < 0.05). But these measures of global cardiac performance in the treated groups recovered following reperfusion, and the extent of recovery was dose dependent. These data suggest that T3 facilitates recovery of the stunned myocardium by improvement in local and global contractile function, in ventriculoarterial coupling, and in the energy efficiency.
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BACKGROUND: Activated protein C, the body's natural anticoagulant, may play a role in protecting the heart during and following an occlusion of the left anterior descending coronary artery (LAD) in the porcine heart. METHODS AND RESULTS: Infusion of 1 unit thrombin over 30 seconds into the LAD of juvenile pigs produced a prolongation of the Xa clotting time (153 +/- 14%) in blood drawn from the anterior interventricular vein (AIV). The action of the anticoagulant was blocked by a polyclonal immunoglobulin G antibody directed against porcine activated protein C. A brief (30 seconds) occlusion of the LAD induced a similar prolongation of the Xa clotting time (138 +/- 11%), which was also blocked by the polyclonal antibody. To determine whether activated protein C helps sustain the heart during and following a 2-minute occlusion, three groups of pigs were studied: 11 controls, six receiving activated porcine protein C, and nine receiving a monoclonal antibody (HPC4) that blocks protein C activation. Relative to the controls, HPC4-treated animals recovered function, as measured by the maximum time derivative of left ventricular pressure and segmental shortening, more slowly and were not able to sustain this recovery. Animals receiving activated protein C recovered more quickly and sustained this recovery. CONCLUSIONS: These data indicate that an ischemic insult induces rapid activation of protein C in the coronary microcirulation and that blocking this activation impairs recovery.
The effects of endotoxemia on basic cardiovascular function were examined in the in situ hearts of five anesthetized rhesus monkeys. Cardiovascular function was assessed by each heart's ability to maintain sufficient oxygen delivery, as measured by the reduction-oxidation state of cytochrome aa3 during periods of increased work and decreased oxygen availability. In addition, the effects of endotoxemia on the baroreflex loop were tested by infusion of the alpha-agonist phenylephrine (5 micrograms/kg). Finally, the oxidative capacity of heart mitochondria, isolated 4 h after the infusion of endotoxin, was determined. Immediately following the 30 min intravenous infusion of endotoxin (10 mg/kg), there was a reduction of cytochrome aa3 evident in the paced heart (200 beats/min) exposed to a brief hypoxic episode. This reduction indicates a loss of the ability of the heart to adjust oxygen delivery to the metabolic needs of the subepicardium. The pressor response to phenylephrine was also affected immediately following infusion, decreasing to 14.5 +/- 9.2% of control at 4 h. The chronotropic response to phenylephrine, mediated by the baroreceptor reflex, was reduced at t = 30 mins and was essentially abolished 3 h after infusion. There was no diminution of the oxidative capacity of the isolated mitochondria. These data indicate that endotoxemia has early depressive effects on the cardiovascular system in nonhuman primates.
The apparent membrane fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene has been reported to be lower in intact erythrocytes than in isolated erythrocyte membranes. Although this difference was once suggested to be caused by the fluidizing effect associated with the loss of erythrocyte proteins during membrane isolation, it is currently thought to be an artifact resulting from intense light scattering properties of intact erythrocytes which overwhelm extrapolation methods of correcting for light scattering. This study confirmed that, at erythrocyte concentrations greater than 10(7) cells/ml, this difference was caused by intense light scattering; however, at erythrocyte concentrations less than 4.0 X 10(6) cells/ml, the anisotropy values for erythrocytes and isolated membranes are identical, demonstrating that intense light scattering can be overcome with dilute suspensions of cells.
The effects of moderate levels of carbon monoxide (CO) on the oxidation-reduction state of cytochrome a,a3 (cyt a,a3) were examined in the hearts of twelve dogs with a prior myocardial infarction. Exposure to ten minutes CO produced a carboxyhemoglobin (CO-Hb) level of 9.4%, a level experienced by heavy smokers. Accompanying the exposure to CO, cyt a,a3 became more reduced; 17.4% +/- 4.7%. Exposure to CO was accompanied by an increase of 33% +/- 4% in the rate of cyt a,a3 reduction following occlusion of the left circumflex coronary artery and a decrease of 24% +/- 8% in the rate of cyt a,a3 oxidation with release. There was also a decrease in the magnitude of cyt a,a3 reduction from 86% +/- 9% to 70% +/- 11%. These results indicate that moderate levels of CO trap cyt a,a3 in the reduced state which impairs the ability of the heart to recover from transient ischemic episodes.
This study was conducted to resolve the conflicting reports regarding the ability of inositol 1,4,5-trisphosphate (IP3) to elicit the release of Ca2+ from isolated sarcoplasmic reticulum derived from skeletal muscle. Three different conditions were employed, one of which has been reported to produce an IP3 induced release of Ca2+. Sarcoplasmic reticulum vesicles with and without intact feet structures failed to respond to added IP3. In addition, IP3 had no effect on the Ca2+-induced release of Ca2+. These results suggest that, unlike other tissue, IP3 does not mobilize the release of Ca2+ from skeletal muscle sarcoplasmic reticulum. IP3 is therefore unlikely to be the physiological signal linking transverse-tubule depolarization with Ca2+ release from the sarcoplasmic reticulum.
The ability of different substrates to affect myocardial function is well established but the mechanism for this effect has yet to be determined. To explore this area further, the studies described below were designed to determine the effect of different metabolic substrates, glucose or pyruvate, on myocardial response to hypercapnia. To assess this response, both the mechanical performance and the intracellular pH (pHi) were continuously measured. Intracellular pH was measured using the changes in absorbance of the vital staining dye, neutral red (NR). Although the presence of either substrate did not affect the response to hypercapnia, the addition of pyruvate was accompanied by a significant change in pHi. Specifically, there was a monotonic decrease in pHi comparable to that observed when PCO2 is increased from 5% to 10% (delta OD = -0.018 +/- 0.002 CO2; delta OD = -0.020 +/- 0.002 PYR, respectively). The mechanical response was similar for both; developed tension (tau) decreased initially (97 +/- 6% v. 93 +/- 8%) and then recovered (115 +/- 4% v. 101% +/- 5%). However, the changes in the maximum rate of relaxation, i.e. minimum time derivative: (tau mn) were dependent on the cause of the decrease in pHi. With hypercapnia, tau mn initially decreased and this was followed by a recovery phase which was 147 +/- 8% of the initial value. With pyruvate, tau mn decreased to 81 +/- 5% of control and was followed by no recovery. Because of the difference in the changes in tau mn, the effects of theophylline [3, 5] on these responses were determined. There was no effect on the response to an increase in PCO2. However, with theophylline present, the addition of pyruvate was accompanied by an increase in pHi (delta OD = + 0.005 +/- 0.001). The mechanical response was consistent with this increase and was similar to that seen when PCO2 is decreased from 10% to 5%. Specifically, there was an increase in tau (122 +/- 7%) followed by a small decrease (113 +/- 4%). Tissue assays for lactate showed a significant increase with the introduction of pyruvate. However, this increase was not affected by the presence of theophylline despite the opposite response of pHi. The data suggest that pyruvate affects myocardial function by altering pHi, and this effect is not due to an increase in lactate. In addition, the data are consistent with the model that the heart is capable of accommodating changes in pHi with only transient effects on contractile function.
Based on the hypothesis that Ca2+ plays an important role in coordinating the rates of substrate catabolism with those of mechanical power utilization, experiments were designed to answer two questions. First, to what extent do the separate Ca2+ pools (e.g., Na+-Ca2+ exchange, sarcoplasmic reticulum (SR] contribute to this messenger Ca2+ pool; and second, are the three catabolic pathways (glycolysis, beta-oxidation, and tricarboxylic acid (TCA] equally sensitive to regulation by Ca2+. To answer these questions, an assessment of the dynamic relation between metabolism and mechanical performance in rabbit papillary muscle was employed which used the slope (coupling coefficient: Mc) of the linear relation between the maximum oxidation of NADH accompanying an increase in contractile activity and the product of the peak isometric tension times the stimulation rate. Except for ketones, changes in superfusate [Ca2+] significantly decreased the coupling coefficient, suggesting a greater sensitivity of metabolism to mechanical requirement. Studies using ouabain indicated that this response was not attributable to Na+-Ca2+ exchange. Experiments with theophylline yielded two important results. First, the redox response of the respiratory chain can be significantly influenced by the available substrate. Second, the glycogenoltic complex associated with the SR may play an important role in ensuring adequate supplies of reducing equivalents and therefore may be a prime site for coordinating metabolism with mechanical performance. The data also suggest that glycolysis and beta-oxidation are more sensitive to regulation by messenger Ca2+ than the TCA cycle.
The experiments reported here were designed to determine whether stimulating glycogenolysis with theophylline affects the ability of isolated rabbit papillary muscles to sustain and recover from a transient hypoxic episode (15 min). Different substrates [glucose (Glc), pyruvate (Pyr), and butyrate (BA)] were used to either support the glycogen levels or permit their depletion. To evaluate the metabolic consequences, the dynamic relation (coupling coefficient) between the oxidation-reduction level of the intramitochondrial pyridine nucleotide NADH and the mechanical power was determined using a microfluorometer. In the absence of theophylline, the presence of Glc was associated with a smaller decrease in developed tension (tau) during the hypoxic period (Glc 53 +/- 5%) when compared with the nonglycolytic substrates (Pyr 33 +/- 5% or BA 31 +/- 6%). The extent of the recovery was not dependent on the available substrate. The addition of theophylline was accompanied by a substrate-dependent increase in tau: Glc 153 +/- 9%, Pyr 134 +/- 9%, and BA 116 +/- 7%. Theophylline increased the impact of the hypoxic episode on mechanical performance: Glc 17 +/- 4%, Pyr 4 +/- 4%, and BA 6 +/- 5%. With Glc, recovery was comparable to control. For the nonglycolytic substrates, recovery of mechanical function was depressed (Pyr 69 +/- 7%, BA 71 +/- 6%), and there was a significant loss of metabolic sensitivity. These data show that the inotropic response to theophylline is in part determined by the available substrate; theophylline exacerbates the impact of a hypoxic episode, and this effect may be due to the metabolic consequences of its presence.
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Using standard microelectrode techniques, we evaluated effects of diminished oxygen tension on the magnitude and time course of frequency dependent changes in maximum diastolic transmembrane potential (MDP) and on alteration of action potential duration (APD) in feline Purkinje fibers. MDP was recorded continuously during a control period (cycle length (CL) = 1000 ms), during a 5-min period of rapid drive (CL = 400 ms) and following return to pacing CL = 1000 ms. Rapid drive resulted in hyperpolarization of MDP from control value; and after return to pacing CL = 1000 ms. MDP gradually depolarized, eventually attaining a steady state value within +/- 0.5 mV of the control value. The difference between hyperpolarized MDP value and final steady-state value was designated VH, and the decline of MDP towards steady-state value approximated an exponential function (time constant = tau VH). Exposure to reduced PO2 (75 +/- 2.1 mmHg vs. control 473 +/- 39.1 mmHg) (1 mmHg = 133.322 Pa) resulted in reduction in the magnitude of VH (6.2 +/- 3.43 mV vs. 7.8 +/- 2.73 mV, mean +/- SD, p less than 0.005) and shortening of APD within 0-24 min, while measurable prolongation of tau VH (75 +/- 18.5 vs. 54 +/- 9.0 s, p less than 0.005) began at 25-49 min following onset of reduced PO2. These observations suggest that rate-related changes of MDP in cardiac tissues are oxygen dependent, and they support previously reported analagous observations in nerve which suggested that frequency dependent potential changes may in part reflect alterations of electrogenic Na-K pump activity.
This study examines the effect of different substrates on mechanical performance of excised papillary muscles from rhesus monkeys which had been divided into a control group and an experimental group fed a high fat diet for 5 months prior to sacrifice. The results show that performance is affected by availabel substrate for both groups. The performance of the experimental group was depressed relative to control with the short chain fatty acid, butyrate (C4), producing a monotonically decreasing force-frequency response. Relative to the other mammals, isolated rhesus papillary muscles exhibited a protracted treppe which was sensitive to beta-adrenergic blockade with propranolol.
Langendorf perfused rat hearts (n = 25) were used to study the effects of changes in perfusate Ca2+ concentration ([Ca2+p]) on the relation between metabolism and mechanical performance with either glucose or pyruvate as the exogenous substrate. Increased [Ca2+p] (from 1.3 to 3.9 mM) produced an increase (243 +/- 38%) in left ventricular developed pressure regardless of the substrate. With glucose as the substrate, the NADH fluorescence intensity increased by 11.8 +/- 1.2% (n = 17) relative to control indicating a more reduced state of the respiratory chain. Increasing [Ca2+p] in the pyruvate perfused heart produced the expected NADH oxidation (-6.2 +/- 1.1%; n = 8). Hence the change in NADH fluorescence associated with increased [Ca2+p] is substrate dependent. The data show that, with glucose as the substrate but not with pyruvate, increases in [Ca2+p] increase the availability of reducing equivalents to the respiratory chain above the level necessary to compensate for the increased demand resulting from the greater contractile performance.
Changes in the intracellular H+ ion concentration (pHi) and in the oxidation-reduction state of the respiratory chain were measured spectrophotometrically in the isolated ventricle strip from the toad (Bufo marinus). The relative time course of the delta pHi as indicated by changes in light absorption of the pH dye neutral red, cytochrome c, and peak isometric twitch tension were compared during transient hypoxic episodes. The first detectable change in pH occurred 4.5 minutes after the peak twitch tension began to decrease with the onset of hypoxia. The initial decrease in tension and reduction of cytochrome c occurred at a similar time prior to the change in pHi. On reoxygenation, cytochrome c rapidly became oxidized, and the pHi and tension recovered more slowly. During acidification by increasing superfusate PCO2, pHi and tension decreased together, and cytochrome c did not change significantly. Thus, although changes in pHi do affect mechanical performance, these results show that mechanical dysfunction pursuant to hypoxia is not directly attributable to intracellular acidification.
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