Biomedical subjects

W E Cascio

Publications and source records attributed to W E Cascio.

At least 37 records · Page 2Linked to original sources

PubMed1998

A superfusion system to study border zones in confluent cultures of neonatal rat heart cells.

We present a new experimental method to study intracellular ion regulation in cultured cardiomyocytes at a border zone separating two different and distinct environments. Our system uses a dual-flow superfusion chamber to produce two different but adjacent environments over a monolayer of cardiomyocytes. Fluorescent microscopy of fluorescein showed that the transition between the two environments was nearly linear and was 220-320 micron wide depending on fluid viscosity and velocity. We superfused cultured monolayers on one side with a solution at pH 6.5 and on the other side with a solution at pH 7.4. We observed a sharply demarcated difference in intracellular pH (pHi) between the two halves of the cell monolayer as measured with the fluorescent pHi indicator carboxy-seminaphthorhodafluor-1. The demarcation of pHi corresponded well with the demarcation of the border measured with fluorescein. We conclude that our superfusion system will facilitate the study of intercellular communication and interactions across boundaries of cardiac tissue where different ionic or metabolic conditions are present, for example, between ischemic and nonischemic myocardium.

Animals↗

PubMed1998

pHi and pHo at different depths in perfused myocardium measured by confocal fluorescence microscopy.

Confocal microscopy and the H+-sensitive fluorophore carboxyseminaphthorhodafluor-1 (SNARF-1) were used to measure either intracellular pH (pHi) or extracellular pH (pHo) in isolated, arterially perfused rabbit papillary muscles. Single-excitation, dual-emission fluorescent images of the endocardial surface and underlying myocardium to a depth of 300 micron were simultaneously recorded from perfused cylindrical muscles suspended in a controlled atmosphere oriented oblique to the focal plane. Contraction was inhibited by the addition of butanedione monoxime. In separate muscles, pHo was measured during continuous perfusion of SNARF-1 free acid. pHi measurements were made after the muscle was loaded with SNARF-1/AM and the extracellular space was cleared of residual fluorophore. Initial experiments demonstrated the uniformity of ratiometric measurements as a function of pH, image depth, and fluorophore concentration, thereby establishing the potential feasibility of this method for quantitative intramural pH measurements. In subsequent experiments, the method was validated in isolated, arterially perfused rabbit papillary muscle during normal arterial perfusion and as pHi and pHo were altered by applying CO2 externally, exchanging HEPES and bicarbonate buffers, and changing pHi with NH4Cl washout. We conclude that in situ confocal fluorescent microscopy can measure pHi and pHo changes at the endocardial surface and deeper endocardial layers in arterially perfused ventricular myocardium. This method has the potential to study pHi regulation in perfused myocardium at boundaries where diffusion of gases, metabolites, and peptides are expected to modify processes that regulate pHi.

Acidosis↗

PubMed1998

Heart rate variability at rest and during mental stress in patients with coronary artery disease: differences in patients with high and low depression scores.

This study tested the hypothesis that coronary artery disease (CAD) patients with high depressed mood scores differ in sympatho-vagal balance during mental stress compared to patients with low depressed mood scores. Using electrocardiographic monitoring, heart variability data from spectral analysis and hemodynamic parameters were obtained prior to and during mental stress from 34 men and 7 women. A public speaking task was used as the mental stressor. Patients were grouped by a median split of their Minnesota Multiphasic Personality Inventory-Depression score. During mental stress, patients with higher depression scores had greater changes in peak heart rate (p < .05) and low frequency to high frequency power ratio (p < 0.05) than patients with lower scores suggesting a shift toward more sympathetic activity during mental stress. These findings may be related to the reported relation between depression and survival risk in patients with CAD.

Journal Article↗

PubMed1998

Multiple metabolic syndrome is associated with lower heart rate variability. The Atherosclerosis Risk in Communities Study.

OBJECTIVE: To test at the population level whether people with multiple metabolic syndrome (MMS) disorders have reduced cardiac autonomic activity (CAA). RESEARCH DESIGN AND METHODS: We examined the association between the level of CAA and MMS disorders, at the degree of clustering and the segregate combination levels, using a random sample of 2,359 men and women aged 45-64 years from the biracial, population-based Atherosclerosis Risk in Communities (ARIC) Study. Supine resting 2-min beat-to-beat heart rate data were collected. High-frequency (HF) (0.15-0.35 Hz) and low-frequency (LF) (0.025-0.15 Hz) spectral powers, the ratio of LF to HF, and the SD of all normal R-R intervals (SDNN) were used as the conventional indices of heart rate variability (HRV) to measure CAA. The MMS disorders included hypertension, type 2 diabetes, and dyslipidemia. RESULTS: HRV indices were significantly lower in individuals with MMS disorders. The multivariable adjusted mean HF was 0.85 (beat/min)2 in subjects with all three MMS disorders, in contrast to 1.31 (beat/min)2 in subjects without any MMS disorder. At the segregated combination level, the multivariable adjusted means +/- SEM of HF were 1.34 +/- 0.05, 1.16 +/- 0.05, 1.01 +/- 0.17, and 1.34 +/- 0.05 (beat/min)2, respectively, for subjects without any MMS disorder, with hypertension only, with diabetes only, and with dyslipidemia only, and the means +/- SEM of HF were 0.93 +/- 0.04, 0.70 +/- 0.15, and 1.20 +/- 0.05 (beat/min)2, respectively, for subjects with diabetes and hypertension, diabetes and dyslipidemia, and hypertension and dyslipidemia. An increase in fasting insulin of 1 SD was associated with 88% higher odds of having a lower HF. The pattern of associations was similar for LF and SDNN. CONCLUSIONS: These findings suggest that MMS disorders adversely affect cardiac autonomic control and a reduced cardiac autonomic control may contribute to the increased risk of subsequent cardiovascular events in individuals who exhibit MMS disorders.

Arteriosclerosis↗

PubMed1997

Selective loading of Rhod 2 into mitochondria shows mitochondrial Ca2+ transients during the contractile cycle in adult rabbit cardiac myocytes.

A strategy of cold loading of the Ca2+-indicating fluorophore Rhod 2-AM followed by warm incubation was developed to selectively label mitochondria of adult rabbit cardiac myocytes. After electrical stimulation, mitochondrial Rhod 2 fluorescence observed by confocal microscopy increased and then rapidly decayed to baseline. In regions between mitochondria, the fluorescent transients were small or absent. Subsequent addition of calcium ionophore increased mitochondrial but not cytosolic fluorescence, confirming the mitochondrial localization of Rhod 2. These experiments directly demonstrate rapid mitochondrial free Ca2+ transients during the contractile cycle in rabbit cardiac myocytes.

Adenosine Triphosphate↗

PubMed1997

A conducting salt-based amperometric biosensor for measurement of extracellular lactate accumulation in ischemic myocardium.

In this paper, fabrication, characterization, and physiological application of a miniaturized amperometric lactate biosensor are described. The sensor is based on cross-linked lactate oxidase and tetrathiafulvalene-tetracyano-quinodimethane (TTF-TCNQ) charge transfer complex. The sensor was developed for continuous quantitative measurement of the lactate accumulation in ischemic myocardium under severe depletion of oxygen. The sensor was evaluated in vitro at an applied potential of 0.15 V vs Ag/AgCl; it proved to combine all the performance characteristics desired for the present application, such as proper response in absence of oxygen, good operational stability, good accuracy and precision (103.5 +/- 1.2%), adequate response time (t95% = 80 s), and wide linear dynamic range up to 27 mM (r = 0.9998) in N2-saturated solutions and at 37 degrees C. The prepared sensors (n = 12) showed sensitivity of 380 +/- 90 nA/mM, and a background current of 240 +/- 50 nA. The lower limit of detection is 0.4 +/- 0.15 mM with a S/N ratio equal to 3. Results obtained for direct lactate monitoring in ischemic rabbit papillary muscle under no-flow conditions and PO2 < 6 mm Hg are presented.

Animals↗

PubMed1996

Correlation of ischemia-induced extracellular and intracellular ion changes to cell-to-cell electrical uncoupling in isolated blood-perfused rabbit hearts. Experimental Working Group.

BACKGROUND: The relationships between the metabolic, ionic, and electrical changes of acute ischemia have not been determined precisely because they have been studied under different experimental conditions. We used ion-selective electrodes, nuclear magnetic resonance spectroscopy, and the four-electrode method to perform four series of experiments in the isolated blood-perfused rabbit heart loaded with 5F-BAPTA during 30 to 35 minutes of no-flow ischemia. We sought to determine the relationship between changes in phosphocreatine (PCr), adenosine triphosphate (ATP), intracellular calcium ([CA2+]i), intracellular pH (pHi) extracellular potassium ([K+]e), extracellular pH (pHe), and whole-tissue resistance (rt). METHODS AND RESULTS: In the first 8 minutes of ischemia, [K+]e rose from 4.9 to 10.8 mmol/L, PCr fell by 90%, ATP decreased by 25%, and pHi and pHe decreased by 0.5 U, while [Ca2+]i and rt changed only slightly. Between 8 and 23 minutes, [K+]e changed only slightly; pHi, pHe, and ATP continued to fall, and [Ca2+]i rose. rt did not increase until >20 minutes of ischemia, when pHi was <6.0 and [Ca2+]i had increased more than three-fold. The increase in rt, indicating electrical uncoupling, coincided with the third phase of the [K+]e change. CONCLUSIONS: Our study suggests that cellular uncoupling occurs only after a significant rise in [Ca2+]i and fall in pHi and that these ionic and electrical changes can be identified by the change in [K+]e. Our study underscores the importance of using a common model while attempting to formulate an integrated picture of the ionic, metabolic, and electrical events that occur during acute ischemia.

Adenosine Triphosphate↗

PubMed1996

The pH paradox in ischemia-reperfusion injury to cardiac myocytes.

During myocardial ischemia, a large reduction of tissue pH develops, and tissue pH returns to normal after reperfusion. In recent studies, we evaluated the role of pH in ischemia/reperfusion injury to cultured cardiac myocytes and perfused papillary muscles. Acidosis (pH < or = 7.0) protected profoundly against cell death during ischemia. However, the return from acidotic to normal pH after reperfusion caused myocytes to lose viability. This worsening of injury is a 'pH paradox' and was mediated by changes of intracellular pH (pH(i)), since manipulations that caused pH(i), to increase more rapidly after reperfusion accelerated cell killing, whereas manipulations that delayed the increase of pH(i) prevented loss of myocyte viability. Specifically, inhibition of the Na+/H+ exchanger with dimethylamiloride or HOE694 delayed the return of physiologic pH(i) after reperfusion and prevented reperfusion-induced cell killing to both cultured myocytes and perfused papillary muscle. Dimethylamiloride and HOE694 did not reduce intracellular free Ca2+ during reperfusion. By contrast, reperfusion with dichlorobenzamil, an inhibitor of Na+/Ca2+ exchange, decreased free Ca2+ but did not reduce cell killing. Thus, the pH paradox is not Ca(2+)-dependent. Our working hypothesis is that ischemia activates hydrolytic enzymes, such as phospholipases and proteases, whose activity is inhibited at acidotic pH. Upon reperfusion, the return to normal pH releases this inhibition and hydrolytic injury ensues. Increasing pH(i) may also induce a pH-dependent mitochondrial permeability transition and activate the myofibrillar ATPase, effects that increase ATP demand and compromise ATP supply. In conclusion, acidotic pH is generally protective in ischemia, whereas a return to physiologic pH precipitates lethal reperfusion injury to myocytes.

Animals↗

PubMed1996

Ventricular fibrillation induction using nonsynchronized low energy external shock during rapid ventricular pacing: method of induction when fibrillation mode of ICD fails.

Third-generation implantable cardioverter defibrillators (ICD) are frequently implanted with nonthoracotomy systems and provide noninvasive methods for electrical stimulation and ventricular fibrillation induction. These modalities facilitate postoperative testing of the ICD. Rapid right ventricular burst pacing via the defibrillator is commonly used for initiation of ventricular tachyarrhythmias. However, with the available third-generation devices, ventricular fibrillation (VF) induction may be impossible in up to 19% of the patients. In these cases, transvenous placement of a right ventricular catheter has been required to generate VF and appropriately evaluate the device. We report a new technique of noninvasive induction of VF using a low energy external nonsynchronized shock delivered during ICD fibrillation induction pacing. In three patients, after all efforts to induce VF by the Ventritex Cadence V-100 had failed, a 20 J nonsynchronized shock was delivered during rapid RV pacing. This resulted in VF on the first attempt in all patients. This noninvasive technique of VF initiation may provide a useful clinical approach to ICD testing that eliminates the costs and risks of an invasive procedure.

Adult↗

PubMed1995

The Ib phase of ventricular arrhythmias in ischemic in situ porcine heart is related to changes in cell-to-cell electrical coupling. Experimental Cardiology Group, University of North Carolina.

BACKGROUND: This study was designed to test the hypothesis that the loss of cell-to-cell electrical interaction during ischemia modulates the amplitude of ischemia-induced TQ-segment depression (ie, the injury potential) and the occurrence of ventricular fibrillation (VF) during the so-called Ib phase of ventricular arrhythmias. METHODS AND RESULTS: Regional ischemia was induced by 60 minutes of mid-left anterior descending coronary artery ligation in open-chest swine (n = 10). Cell-to-cell electrical uncoupling was defined as the onset of the terminal rise in whole-tissue resistivity (Rt). Local activation times and TQ-segment changes (injury potential) were determined from unipolar electrograms. Extracellular K+ ([K+]e) and pH (pHe) were measured with plunge-wire ion-selective electrodes. VF occurred in 6 of 10 pigs during regional no-flow ischemia between 19 and 30 minutes after the arrest of perfusion. The occurrence of VF was positively correlated to the onset of cell-to-cell electrical uncoupling (R2 = .885). Cell-to-cell electrical uncoupling superimposed on changes of [K+]e and pHe contributed to the failure of impulse propagation between 19 and 30 minutes after the arrest of perfusion. During ischemia, maximum TQ-segment depression was -10 mV at 19 minutes, after which TQ-segment depression slowly recovered. The onset of the TQ-segment recovery was correlated to the second rise in Rt (R2 = .886). CONCLUSIONS: In the regionally ischemic in situ porcine heart, loss of cell-to-cell electrical interaction is related to the occurrence of VF and changes in the amplitude of the injury current. Cellular electrical uncoupling contributes to failure of impulse propagation in the setting of altered tissue excitability as a result of elevated [K+]e and low pHe. These data indicate that Ib arrhythmias and ECG changes during ischemia are influenced by the loss of cell-to-cell electrical interaction.

Animals↗

PubMed1995

Electrophysiologic changes in ischemic ventricular myocardium: I. Influence of ionic, metabolic, and energetic changes.

Myocardial ischemia leads to significant changes in the intracellular and extracellular ionic milieu, high-energy phosphate compounds, and accumulation of metabolic by-products. Changes are measured in extracellular pH and K+, and intracellular pH, Ca2+, Na+, Mg2+, ATP, ADP, and inorganic phosphate. Alterations of membrane currents occur as a consequence of these ionic changes, adrenergic receptor stimulation, and accumulation of lactate, amphipathic compounds, and adenosine. Changes in the volume of the extracellular and intracellular spaces contribute further to the ultimate perturbations of active and passive membrane properties that underlie alterations in excitability, abnormal automaticity, refractoriness, and conduction. These characteristic changes of electrophysiologic properties culminate in loss of excitability and failure of impulse propagation and form the substrate for ventricular arrhythmias mediated through abnormal impulse formation and reentry. The ability to detail the changes in ions, metabolites, and high-energy phosphate compounds in both the extracellular and intracellular spaces and to correlate them directly with the simultaneously occurring electrophysiologic changes have greatly enhanced our understanding of the electrical events that characterize the ischemic process and hold promise for permitting studies aimed at developing interventions that may lessen the lethal consequences of ischemia.

Animals↗

PubMed1995

Failure of impulse propagation in a mathematically simulated ischemic border zone: influence of direction of propagation and cell-to-cell electrical coupling.

INTRODUCTION: It is suggested that heterogeneous extracellular potassium concentration, cell-to-cell coupling, and geometric nonuniformities of the ischemic border zone contribute to the incidence of unidirectional block and subsequent development of lethal ventricular arrhythmias. METHOD AND RESULTS: A discrete electrical network was used to model a single cardiac fiber with a [K+]e gradient characteristic of an ischemic border zone. Directional differences in propagation were evaluated by creating discrete regions with increased gap junctional resistance within the [K+]e gradient. Furthermore, the effect of homogeneity/heterogeneity of call length on impulse propagation through the [K+]e gradient in the presence of increased gap junctional resistance was evaluated. The results indicate that failure of impulse propagation occurs at the junction between partially uncoupled and normally coupled cells. Furthermore, propagation failure was more likely to occur as the impulse propagated from a region of high [K+]e to low [K+]e. Heterogeneity in cell length contributes to the variability in the occurrence of unidirectional and bidirectional block. CONCLUSIONS: The onset of cellular uncoupling in an ischemic border zone may interact with the inherent [K+]e gradient leading to unidirectional conduction block. This mechanism may be important for the generation of reentrant arrhythmias at the ischemic border zone.

Action Potentials↗

PubMed1995

Hypercapnic acidosis and dimethyl amiloride reduce reperfusion induced cell death in ischaemic ventricular myocardium.

OBJECTIVE: The aim was to investigate the effects of slowing the recovery of ischaemia induced intracellular acidosis with hypercapnic acidosis or dimethyl amiloride (DMA) on the extent of reperfusion induced cell death. METHODS: Isolated arterially perfused rabbit papillary muscles and septa were suspended in a controlled atmosphere and perfused with a modified Tyrode solution containing erythrocytes and trypan blue (500 microM). Ischaemia was produced by arrest of perfusion and withdrawal of atmospheric O2. Extracellular pH of the muscle during reperfusion was controlled by adjusting the pH of the perfusate (pH 6.6 or pH 7.6 with and without DMA 20 microM) and changing the PCO2 of the chamber atmosphere. After 30 min of reperfusion following 30 min (group A) or 60 min (group B) of ischaemia, papillary muscles were fixed with paraformaldehyde. Cell death was assessed by trypan blue staining of nuclei in histological sections of the papillary muscles. RESULTS: The magnitude of cell death was greatest after reperfusion with pH 7.6 as measured by the percentage of nuclei staining with trypan blue (15.1% in group A; 41.8% in group B). By contrast, reperfusion at pH 6.6 reduced cell killing (group A, 3.6%; group B, 7.2%). Reperfusion at pH 7.6 with DMA (20 microM) also reduced trypan blue uptake (group A, 2.8%; group B, 3.8%). Despite the attenuation of cell death afforded by acidosis or Na+/H+ exchange inhibition, significant swelling of the extracellular space and microvascular injury was noted. CONCLUSIONS: Hypercapnic acidosis and Na+/H+ exchange inhibition during reperfusion attenuate lethal reperfusion injury to ventricular myocardium and extend to the intact myocardium the concept of the "pH paradox" in which recovery of intracellular pH after reperfusion is a precipitating factor in lethal cell injury.

Acidosis↗

PubMed1994

Marked activation delay caused by ischemia initiated after regional K+ elevation in in situ pig hearts.

BACKGROUND: Conduction mediated by the slow inward (Ca2+) current occurs in vitro under specific experimental conditions but has not been documented in ventricular muscle in vivo during regional myocardial ischemia, perhaps because certain constituents of ischemia (including hypoxia and acidosis) may inhibit the Ca2+ current in this setting. We hypothesized that slow conduction mediated by the Ca2+ current could occur during acute ischemia in situations in which the extracellular K+ rise was more marked relative to the degree of acidosis, as may occur at ischemic boundaries. METHODS AND RESULTS: In open-chest, anesthetized swine, an arterial shunt from the carotid artery to the mid-left anterior descending coronary artery was created through which a solution of KCl was infused to raise extracellular K+ ([K+]e) to approximately 9.4 mmol/L before the initiation of ischemia, which we termed "K(+)-modified ischemia." Ischemia initiated at a normal [K+]e ("unmodified ischemia") resulted in a mean activation delay in the center of the ischemic zone of 55 +/- 26 milliseconds after 5 minutes of ischemia and a decrease in epicardial longitudinal conduction velocity from 53 to 21 cm/s before the onset of conduction block. K(+)-modified ischemia resulted in a mean activation delay in the center of the ischemic zone of 181 +/- 8 milliseconds and a decrease in epicardial longitudinal conduction to less than 10 cm/s. K(+)-modified ischemia was associated with ventricular fibrillation in 85% of episodes compared with 28% of episodes of unmodified ischemia (P < .01). Verapamil prevented the occurrence of marked activation delay during K(+)-modified ischemia, producing local activation block following a maximum activation delay of 74 +/- 25 milliseconds. In two experiments, responses mediated by the slow inward current were produced by regional K+ elevation to 15 to 16 mmol/L, followed by concomitant regional administration of epinephrine (10(-7) mol/L). Regional [K+]e elevation alone to this level resulted in local activation block following a maximum activity delay of 70 to 80 milliseconds, whereas administration of epinephrine in combination with high [K+]e resulted in return of local activation with an activation delay of 160 to 180 milliseconds (ie, similar to that during K(+)-modified ischemia). CONCLUSIONS: Compared with unmodified ischemia, K(+)-modified ischemia resulted in marked activation delay and a high incidence of ventricular fibrillation. Based on measurements of longitudinal conduction velocity, the inhibitory effect of verapamil, and the results of experiments with high [K+]e plus epinephrine, we conclude that the marked activation delay during K(+)-modified ischemia represents conduction mediated by the slow inward current. Because the conditions produced by K(+)-modified ischemia (high [K+]e with minimal acidosis) are similar to conditions in and near ischemic border regions, we hypothesize that responses mediated by the slow inward current may occur in such regions during unmodified ischemia and may participate in the development of reentrant arrhythmias.

Animals↗

PubMed1992

Implications of inferior ST-segment elevation accompanying anterior wall acute myocardial infarction for the angiographic morphology of the left anterior descending coronary artery morphology and site of occlusion.

Inferior ST-segment elevation during anterior wall acute myocardial infarction (AMI) due to left anterior descending (LAD) coronary artery occlusion is unusual and was not previously investigated. This study tested the hypothesis that inferior ST-segment elevation during anterior AMI predicts a specific angiographic morphology that satisfies 2 necessary conditions: (1) mass of ischemic anterior wall myocardium is relatively small, resulting in a weaker anterior injury current and less reciprocal inferior ST-segment depression; and (2) there is concomitant inferior wall transmural ischemia that further shifts the inferior ST segments upward. The study group consisted of 42 consecutive patients with anterior AMI undergoing angiography at 4.1 days (range 0 to 14). Coronary angiograms were examined for 3 features: (1) site of LAD artery occlusion (a distal obstruction implying a smaller mass of ischemic anterior wall myocardium), (2) LAD artery extension onto inferior wall of left ventricle (termed a "wrap around" vessel), and (3) collateral flow from LAD artery to inferior wall. The latter 2 features would be expected to contribute to inferior wall transmural ischemia. Acute inferior ST-segment elevation (sum of ST-segment deviation in leads II, III and aVF greater than or equal to 3.0 mm) was seen in 7 patients (16%). A greater number of LAD artery branches proximal to the site of occlusion was significantly correlated with less inferior ST-segment depression (r = 0.59, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1992

Early changes in extracellular potassium in ischemic rabbit myocardium. The role of extracellular carbon dioxide accumulation and diffusion.

The role of local accumulation and diffusion of CO2 to modify cellular loss and extracellular accumulation of K+ during the initial, reversible phase of myocardial ischemia was investigated in isolated, cylindrical papillary muscles of the rabbit. The muscles were blood-perfused through their vascular tree and placed in a (permanently flowing) humidified gas mixture with predetermined partial pressures of N2, O2, and CO2. Ischemia was produced by total arrest of perfusion and O2 withdrawal from the gas mixture. With surface PCO2 kept constant during ischemia, [K+]o varied markedly with muscle geometry. After 10 minutes of ischemia, K+ accumulation was approximately 2.5 mM in muscles with a radius of 0.35 mm and approximately 14 mM in muscles with a radius of 0.9 mm, indicating that a large fraction of K+ accumulation was dependent on diffusion of a volatile metabolite. Computer simulation of CO2 accumulation and diffusion within a tissue cylinder suggested a close phenomenological relation between PCO2 and [K+]o in ischemia. This was confirmed by the finding that an increase of tissue PCO2 in small cylinders before or during ischemia by externally applied CO2 produced an increase in K+ accumulation. The importance of CO2 diffusion for local inhomogeneities in K+ within the same preparation was demonstrated by showing [K+]o gradients with simultaneous or consecutive measurements between the papillary muscle cylinders and the adjacent septum and within 300 microns from the surface of the papillary muscle cylinders. These gradients predict an inhomogeneity of impulse conduction that might contribute to the genesis of ventricular arrhythmias. Besides the demonstration that accumulation and diffusion introduce inhomogeneities of [K+]o in ischemia, our results suggest that a significant component of cellular ischemic K+ loss is associated with production and extrusion of metabolic acid. On the basis of previous measurements of pHo and pHi in identical conditions, possible mechanisms of ischemic cellular K+ loss are discussed.

Animals↗

PubMed1991

Effects of ryanodine and BAY K 8644 on membrane properties and conduction during simulated ischemia.

We studied the effect of 1.0 microM ryanodine and 0.1 microM BAY K 8644 (putative modulators of intracellular calcium) on the changes in action potential characteristics, cellular coupling, and longitudinal conduction induced by simulated ischemia (9.0 mM K, 6.5 pH, 0 glucose, 20 mmHg PO2) in superfused guinea pig papillary muscles. Simulated ischemia (SI) depolarized the resting membrane by 5 mV and caused a 28% decrease in action potential upstroke (Vmax), a 65% decrease in action potential duration at 90% (APD90), a 40% increase in internal longitudinal resistance (ri), and a 17% decrease in conduction velocity as compared with the 9-K Tyrode control solution. These changes were reversible and reproducible. The decrease in Vmax induced by SI was greater than that associated with a K(+)-induced change in resting membrane potential (RMP). Ryanodine lessened the SI-induced APD90 shortening by 26%, the decrease in Vmax by 42%, the increase in ri by 33%, and the decrease in conduction velocity by 21%. BAY K 8644 did not alter SI-induced APD90 shortening but augmented the decrease in Vmax by 23%, the increase in ri by 67%, and the decrease in conduction velocity by 59%. Neither ryanodine nor BAY K 8644 altered the SI-induced changes in RMP. Our results suggest that changes in intracellular calcium during SI not only influence cellular coupling but also contribute to the apparent non-RMP-dependent component of the change in Vmax and to the change in APD90 induced by SI.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1991

Local myocardial biochemical and ionic alterations during myocardial ischaemia and reperfusion.

Acute myocardial ischaemia and reperfusion result in a series of inhomogeneous metabolic, ionic and neurohumoral events that explain the associated mechanical and electrical events, including cardiac death. The time course of the hydrolysis of high energy phosphates, the rise in extracellular potassium and the fall in intracellular and extracellular pH induced by acute no-flow ischaemia have been well characterised. However, the time course of the changes in intracellular sodium, calcium and magnesium levels is less clear. It appears that the changes in intracellular calcium may be pivotal to many of the biochemical and electrophysiological changes produced by the abrupt cessation of coronary arterial inflow and the associated interruption of venous washout. Consequently, agents that modify the handling of calcium by the sarcolemma and the sarcoplasmic reticulum have a significant impact on many of the metabolic, ionic and electrical abnormalities characterising acute ischaemia and reperfusion.

Coronary Disease↗