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M J Shattock

Publications and source records attributed to M J Shattock.

At least 37 records · Page 2Linked to original sources
PubMed1996

Electrophysiological characteristics of repetitive ischemic preconditioning in the pig heart.

S-T segment changes have been cited as evidence for preconditioning in the human heart during repeated angioplasty inflations. Opening of preformed collaterals, however, could explain these observations. We have measured the profile of S-T segment and monophasic action potential (MAP) changes in a species with low collateralization. Open-chested pigs were subjected to two cycles of 8-min LAD occlusion and 8-min reperfusion prior to 60-min ischemia and 2-h reperfusion. Two epicardial ECGs and MAP were continuously recorded from the ischemic zone and one ECG from the normal zone. Flow was measured using Xenon washout. Infarct (IS) and risk zone (RZ) sizes were assessed after reperfusion in a subset of six pigs and confirmed profound protection with preconditioning (IS/RZ = 14 +/- 9% v 42 +/- 3% in controls, P < 0.05). S-T segment elevation was smaller early in the 2nd or 3rd (0-3 min) ischemic cycles than in the 1st. In contrast, in the 1st ischemic cycle, MAP duration after 3 min was reduced to 90 +/- 2% control and this was further reduced in the 2nd and 3rd ischemic episodes to 74 +/- 4% and 77 +/- 3% respectively. Thus, preconditioning increased APD shortening while simultaneously decreasing S-T segment elevation during the early minutes of ischemia. It therefore seems unlikely that the ability of preconditioning to limit S-T segment changes is related to limitations in APD shortening. All electrophysiological differences were lost later during ischemia. Collateral flow during the three ischemic cycles was 4.8 +/- 3.7, 5.8 +/- 2.3 and 5.6 +/- 2.9% (n = 5/grp, ns) respectively. Thus, in the absence of a significant increase in collateral flow. S-T segment and MAP changes provide an index of preconditioning but only during the first few minutes of occlusion. S-T segment changes observed during PTCA may therefore reflect genuine preconditioning in man although the contribution of ischemia-induced increases in collateral flow cannot be ignored.

Action Potentials↗
PubMed1995

Modulation of cardiac Na(+)-K+ pump current: role of protein and nonprotein sulfhydryl redox status.

Oxidant stress alters protein structure and function, possibly through the modification of the redox status of regulatory protein sulfhydryl groups. We used the sulfhydryl-blocking reagent p-chloromercuriphenylsulfonic acid (pCMPSA), applied selectively and independently to either the intracellular or extracellular environment, to study the relationship between blocking protein sulfhydryl groups and Na(+)-K+ pump current (i.p.). In guinea pig ventricular myocytes voltage clamped at -30 mV, extracellular pCMPSA (50, 100, and 400 microM) caused a concentration-dependent reduction in holding current. The selective intracellular administration of pCMPSA (100 microM) induced a similar inhibition of i.p., albeit over a longer time course. The inhibition of ip resulting from either the intracellular or extracellular application of pCMPSA (100 microM) was reversed, in part, by the extracellular application of dithiothreitol (3 mM). An intracellular oxidant stress was also imposed by using diethyl maleate to deplete the intracellular nonprotein sulfhydryl content [represented by reduced glutathione (GSH)]. In myocytes isolated from diethyl maleate-treated guinea pigs *860 mg/kg i.p., 30 min before study), intracellular GSH was depleted by 93% and i.p. was depressed by 38% at all membrane potentials tested. We propose that Na(+)-K+ pump function may be related to protein and nonprotein sulfhydryl status. Protein sulfhydryl oxidation and glutathione depletion may account, in part, for a depression in Na(+)-K+ pump activity during reperfusion-induced oxidant stress.

4-Chloromercuribenzenesulfonate↗
PubMed1994

Sodium pump current measured in cardiac ventricular myocytes isolated from control and potassium depleted rabbits.

OBJECTIVE: The aim was to investigate cardiac muscle sodium pump function following chronic potassium depletion in rabbits. METHODS: Sodium pump current was measured using the whole cell voltage clamp technique in ventricular myocytes from control rabbits or rabbits with chronic dietary potassium depletion, under conditions designed to minimise all other electrogenic channels, pumps, and exchangers. The effects of changes in external [K+] and intracellular [Na+] were investigated. Experiments were performed on ventricular myocytes enzymatically isolated from adult rabbits, average weight 2.5 kg, which were fed either a control (n = 6), or a potassium deficient diet (n = 8) for 25 d. RESULTS: Potassium depletion significantly increased the sodium pump current density recorded with 10 mM extracellular [K+] and 50 mM [Na+] in the pipette (conditions which activate an estimated 98% of the maximally available pump current), from 1.53(SEM 0.05) pA.pF-1 (control, n = 4) to 1.740(0.06) pA.pF-1 (potassium depleted, n = 4; p < 0.05). The relationship between sodium pump current and extracellular [K+] (30 mM [Na+] in pipette) showed a significant leftward shift in myocytes from potassium depleted animals, such that the Km was reduced from 1.270(0.10) (control, n = 4) to 0.72(0.11) mM (potassium depleted, n = 4; p < 0.05). The effect of varying pipette [Na+] on sodium pump current was examined in cells superfused with 5 mM [K+]. The Km was again reduced from 19.44 mM (control) to 16.91 mM (potassium depleted). The Hill coefficients for activation of the pump by potassium and sodium were essentially unchanged, as was the shape of the current-voltage relationship. CONCLUSIONS: These results suggest that chronic potassium depletion results in an adaptation of the cardiac sodium pump such that pump activity can be maintained, or even enhanced, despite a fall in plasma [K+]. This adaptation is achieved by both alterations in ionic sensitivity to potassium and sodium, and an increase in maximum activity. The latter may reflect an increase in sodium pump site density. These changes are likely to account for the preservation of intracellular [K+] in cardiac muscle during chronic potassium deficiency.

Animals↗
PubMed1993

Preconditioning and reperfusion arrhythmias in the isolated rat heart: true protection or temporal shift in vulnerability?

OBJECTIVE: The relationship between arrhythmia severity during reperfusion and the duration of preceding ischaemia is bell shaped. Although ischaemic preconditioning can protect against reperfusion induced arrhythmias it is not clear if this is achieved by a true reduction in arrhythmia severity or by a temporal shift in the bell shaped relationship occurring as a consequence of increased ischaemic tolerance. METHODS: Isolated rat hearts (n = 12 per group) were Langendorff-perfused with whole blood from a support rat. Regional ischaemia and reperfusion were induced using a ligature around the left main coronary artery. Cardiac rhythm was recorded continuously. RESULTS: Repeated cycles of preconditioning (5 min ischaemia and 5 min reperfusion) led to a progressive reduction in the incidence of reperfusion induced ventricular fibrillation following 10 minutes of ischaemia (92%, 66%, 42%, and 8% following 0, 1, 2, and 3 cycles respectively). Three cycles of preconditioning reduced the incidence of reperfusion induced ventricular fibrillation after each of 10 (83% to 17%; p < 0.05), 15 (92% to 42%; p < 0.05), 20 (67% to 25%), 30 (33% to 0%), and 40 (25% to 0%) minutes of ischaemia. Preconditioning also led to a reduced incidence of reperfusion induced ventricular tachycardia following 10 minutes of ischaemia (100% to 42%; p < 0.05). There was no evidence of a temporal shift in the bell shaped relationships: peak incidences of reperfusion induced ventricular fibrillation and ventricular tachycardia each occurred after 15 minutes of ischaemia in both control and preconditioned groups. CONCLUSIONS: In isolated blood perfused rat hearts serial preconditioning cycles provide cumulative protection against reperfusion induced ventricular arrhythmias. This protection occurs over a wide range of ischaemic durations without altering the temporal relationship between the duration of ischaemia and arrhythmia severity. This may indicate that antiarrhythmic protection is not a consequence of anti-ischaemic mechanisms.

Animals↗
PubMed1993

Measurement of Na(+)-K+ pump current in isolated rabbit ventricular myocytes using the whole-cell voltage-clamp technique. Inhibition of the pump by oxidant stress.

Free radical-induced oxidant stress has been implicated in ischemia and reperfusion-induced injury in the heart. A number of studies have reported that oxidant stress reduces the activity of isolated Na+,K(+)-ATPase enzyme. We have studied the effects of oxidant stress on the Na(+)-K+ pump current recorded in isolated rabbit ventricular myocytes using the whole-cell voltage-clamp technique. Singlet oxygen and superoxide were generated by the photoactivation of rose bengal (50 nM). The compositions of Tyrode's and pipette solutions were designed to block channel currents and electrogenic Na(+)-Ca2+ exchange. Cells were dialyzed with a pipette solution containing 30 mM sodium via wide-tipped (1-2-M omega) electrodes, and outward Na(+)-K+ pump current was recorded during a voltage-ramp protocol. The validity of using such a ramp protocol was confirmed by comparison with steady-state Na(+)-K+ pump current measurements made at the end of 200-msec square-clamp steps. Active currents were abolished by potassium-free Tyrode's solution or ouabain (100 microM), and Na(+)-K+ pump current was defined as the Ko-sensitive fraction of recorded currents. The activation of Na(+)-K+ pump current by intracellular sodium and extracellular potassium revealed a concentration of potassium necessary for half-maximal activation of 18.7 mM for Nai and 1.88 mM for Ko. Oxidant stress inhibited Na(+)-K+ pump current at all voltages, such that after a 10-minute exposure to photoactivated rose bengal, Na(+)-K+ pump current measured at 0 mV was reduced by approximately 50%. The voltage dependence of Na(+)-K+ pump current was, however, not profoundly affected by oxidant stress. Passive membrane currents recorded in the absence of all major electrogenic ion channels, exchangers, or pumps were unaffected by oxidant stress. This observation suggests that, over the time course during which Na(+)-K+ pump inhibition and calcium overload occur, oxidant stress does not cause nonspecific membrane damage and changes in the passive resistance of the lipid bilayer. The inhibition of Na(+)-K+ pump activity by oxidant stress may contribute to ischemia/reperfusion injury and reperfusion-induced cellular calcium overload.

Animals↗
PubMed1992

Effects of potassium channel modulation during global ischaemia in isolated rat heart with and without cardioplegia.

OBJECTIVE: The opening of potassium (K+) channels during regional ischaemia may, by inducing rapid contractile arrest, be an intrinsic energy sparing mechanism. Thus K+ channel openers (for example, lemakalim) exert significant anti-ischaemic effects, whereas glibenclamide exacerbates ischaemic contracture and limits postischaemic functional recovery. The aim of the study was to investigate the ability of these compounds to influence ischaemic injury when used either alone or in combination with rapid arrest induced by a high K+ cardioplegic solution. METHODS: Contractile function of isolated Langendorff perfused rat hearts was assessed using an intraventricular balloon. Hearts were subjected to normothermic global ischaemia (20 min) or cardioplegic arrest (35 min) with and without glibenclamide or lemakalim. Lemakalim (10 mumol.litre-1) or glibenclamide (10 mumol.litre-1) was given, in the presence or absence of cardioplegia, for 2 min immediately prior to the onset of ischaemia. The rate of ischaemia induced contractile failure, the severity of ischaemic contracture, and the degree of postischaemic functional recovery were all measured. RESULTS: In the absence of cardioplegia, the time to contractile arrest in control hearts was 133 (SEM 4) s. This was increased by glibenclamide, to 145(6) s, and decreased by lemakalim, to 112(6) s. The time to onset of ischaemic contracture [8(1) min] was accelerated by glibenclamide [4(1) min] and delayed by lemakalim [14(1) min]. Lemakalim significantly improved the recovery of left ventricular developed pressure from 49(7)% in control hearts to 65(3)%, and left ventricular end diastolic pressure from 41(3) to 21(4) mm Hg. Hearts pretreated with glibenclamide showed similar recoveries to control hearts. During reperfusion, lemakalim exerted a transient vasodilator effect whereas glibenclamide caused a transient vasoconstriction. When either glibenclamide or lemakalim was added to a high K+ cardioplegic solution and hearts rendered ischaemic for 35 min, the ability of both compounds to influence ischaemic contracture and postischaemic functional recovery was lost. In additional studies the effect of lemakalim on the relative times to ischaemia induced mechanical failure and electrical arrest was assessed. In control hearts the time to contractile failure was 128(5) s and the time to electrical arrest was 241(30) s, while in the lemakalim treated hearts the values were 103(2) s and 509(161) s, respectively. In the lemakalim group all the hearts showed sustained ventricular arrhythmias; in the control group there were no arrhythmias. CONCLUSIONS: Lemakalim can exert a significant anti-ischaemic effect when given alone. This effect is lost when it is used in combination with high K+ cardioplegia. The anti-ischaemic properties of lemakalim may thus be limited to its ability to accelerate contractile arrest.

Animals↗
PubMed1992

Action potential duration and endocardial modulation of myocardial contraction in the ferret.

OBJECTIVE: Endocardial endothelium releases substances which modulate myocardial contraction. Selective endocardial removal abbreviates contraction by removing a contraction prolonging substance "endocardin". The aim of the study was to investigate whether changes in action potential duration underlie these contractile effects. METHODS: The contractile effects of shortening the action potential were first characterised, using a potassium channel "opener" cromakalim (3 microM). Transmembrane action potentials were then recorded in isolated ferret papillary muscles before and after endocardial removal. RESULTS: Cromakalim-induced action potential abbreviation reduced contractile twitch duration. Endocardial removal itself however did not alter action potential duration. CONCLUSIONS: Endocardial modulation of cardiac contraction does not involve changes in action potential duration.

Action Potentials↗
PubMed1992

Role of Na-activated K channel, Na-K-Cl cotransport, and Na-K pump in [K]e changes during ischemia in rat heart.

The contribution of Na-activated K channel, the furosemide-sensitive (Na-K-Cl) cotransport, and Na-K pump to extracellular potassium accumulation during global ischemia was investigated using pharmacological blockade of these pathways. R 56865 (a blocker of the Na-activated K channel), furosemide, or ouabain was included in the perfusate before ischemia in the isolated rat heart preparation, and the extracellular K concentration ([K]e) was monitored during 30 min of global ischemia. In control hearts, [K]e showed an early rise (up to 9.0 +/- 0.2 mM from the baseline of 5.9 mM), a fall (to a minimum of 6.7 +/- 0.2 mM), and a late rise (to 14.1 +/- 0.4 mM by the end of ischemia). R 56865 (0.1 and 1 microM) suppressed the early [K]e rise to 50% of the control level. The late rise in [K]e was also significantly suppressed by the higher dose of R 56865. Furosemide (0.1 and 1 mM) reduced the early K accumulation by 35% but did not affect the rise of [K]e during the late ischemic phase. Blockade of Na-K pump by 10 microM ouabain did not increase [K]e during any phase of ischemia and, in fact, 100 microM ouabain profoundly suppressed the early rise in [K]e. We therefore suggest that the Na-activated K channel, the furosemide-sensitive cotransport, and changes in the activity of the Na-K pump may all contribute to extracellular K accumulation during ischemia. However, in addition to these pathways, it seems likely that other pathways for transsarcolemmal K efflux contribute to cellular K loss during ischemia in the isolated rat heart.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Functional and electrophysiological effects of oxidant stress on isolated ventricular muscle: a role for oscillatory calcium release from sarcoplasmic reticulum in arrhythmogenesis?

STUDY OBJECTIVE: The aim was to investigate the cellular basis of oxidant stress induced arrhythmias by studying the influence of oxidant stress on the contractile and electrophysiological function of isolated cardiac muscle. DESIGN: Oxidant stress was induced by the photoactivation of rose bengal added to the solution superfusing isolated ventricular muscles from a number of species. Measurements of contractile and electrophysiological function were made under control conditions, during exposure to oxidant stress, and under a number of experimental conditions. EXPERIMENTAL MATERIAL: Isolated superfused papillary muscles or trabeculae from rat, rabbit, or frog hearts were used in all studies. MEASUREMENTS AND MAIN RESULTS: The contractile response to oxidant stress was assessed by measuring isometric developed tension and resting tension throughout the experiment, and the electrophysiological response was assessed by recording action potentials using conventional 3 M KCl filled intracellular electrodes. Oxidant stress induced a transient positive inotropy, after-contractions, and eventually contracture. Associated with these contractile changes were prolongation of the action potential, early afterdepolarisations, oscillations in resting membrane potential, and automaticity. These effects were concentration and species dependent and the oscillations in both tension and membrane potential were abolished by inhibition of calcium release from the sarcoplasmic reticulum with caffeine. CONCLUSIONS: The contractile and electrophysiological effects of rose bengal induced oxidant stress are consistent with a cellular calcium overload. The observation that the oscillations in tension and membrane potential were abolished by caffeine and that these effects were species dependent (rat greater than rabbit greater than frog) suggests a role for oscillatory sarcoplasmic reticulum calcium release in these effects. The oscillations in membrane potential and the automaticity induced by rose bengal are likely to underlie the arrhythmias observed in isolated hearts exposed to oxidant stress that have previously been described.

Animals↗
PubMed1991

Effects of oxidant stress on steady-state background currents in isolated ventricular myocytes.

Free radicals and oxidant stress have previously been shown to induce depolarization, transient action potential prolongation, and automaticity. We have investigated the ionic basis of these electrophysiological changes in isolated rabbit ventricular cells. Oxidant stress was generated by the photoactivation of rose bengal, and, in current-clamp experiments, the effects of oxidant stress on the action potential were confirmed. In voltage-clamp studies, oxidant stress decreased both inward and outward current through the inward-rectifier potassium channel, and the slope conductance (measured at the voltage-axis intercept near the resting membrane potential) was decreased from 40 +/- 8 to 25 +/- 6 nS (n = 6). Transient inward currents were induced on repolarization after a depolarizing clamp step, suggesting that the cells were calcium overloaded. In addition, oxidant stress activated a steady-state membrane conductance that showed a slight outward-going rectification and a reversal potential of approximately 0 mV. Evidence is presented to indicate that this reflects an increase in the conductance of the calcium-activated nonselective cation channel. The slope conductance of this calcium-activated channel (measured at the voltage-axis intercept) increased with prolonged exposure to oxidant stress (from 0.5 to 12 nS after 7 min), indicating that the intracellular free calcium increased gradually during the maintained application of rose bengal. These results suggest that oxidant stress depolarizes the cell membrane by reducing the inward-rectifier potassium current and by activating a calcium-activated membrane conductance. Both factors may contribute to the oxidant stress-induced changes in action potential duration and automaticity.

Action Potentials↗
PubMed1991

Membrane potential fluctuations and transient inward currents induced by reactive oxygen intermediates in isolated rabbit ventricular cells.

The cellular basis of reactive oxygen intermediate-induced arrhythmias was investigated in isolated rabbit ventricular cells using the whole-cell voltage- and current-clamp techniques. Singlet oxygen and superoxide were generated by the photoactivation of rose bengal. Single ventricular cells exposed to rose bengal (10-100 nM) exhibited spontaneous membrane potential fluctuations at plateau potentials and at the level of the resting membrane potential. The voltage fluctuations induced in the resting potential occasionally triggered repetitive action potential discharges. At the resting membrane potential, the magnitude and dominant frequency of the voltage fluctuations were 1-3 mV and 1.5 Hz, respectively. At plateau potentials, the amplitude of the voltage fluctuations was about 2-5 mV, and the dominant oscillatory frequency was 2.6 Hz. In voltage-clamp experiments, transient inward currents were induced on repolarization after a depolarizing clamp step. Oscillatory currents also occurred occasionally during clamp steps to positive potentials. The peak frequencies of transient inward currents recorded at -20 and -70 mV were approximately 3.7 and 2.3 Hz, respectively, indicating that these currents may underlie the arrhythmogenic membrane potential fluctuations observed in current-clamp experiments. The rose bengal-induced transient inward currents were shown to be dependent on the magnitude and duration of the preceding voltage step. Studies of the voltage dependence of transient inward currents showed that these currents remained inward even at positive potentials (+30 mV), and replacement of extracellular sodium with lithium decreased transient inward current to approximately 10% of its initial value. Thus, the major component of oxidant stress-induced inward current appears to be electrogenic Na-Ca exchange. This oscillatory transient inward current may be responsible for the arrhythmias induced in isolated hearts exposed to reactive oxygen intermediates, and since oxidant stress has been implicated in reperfusion injury, it is possible that similar oscillatory currents may underlie reperfusion-induced arrhythmias.

Animals↗
PubMed1991

Reactive oxygen species modify the structure and function of the cardiac sarcoplasmic reticulum calcium-release channel.

Restoration of blood flow to the ischemic myocardium prevents continuing cell necrosis, but reperfusion may cause irreversible damage to potentially salvable tissue, possibly through the generation of toxic reactive oxygen species. Intracellular calcium overload, secondary to membrane lipid peroxidation, has been proposed as a general pathogenic mechanism. However, using the photosensitisation of rose bengal to generate singlet oxygen and superoxide radicals, we demonstrate a direct effect of reactive oxygen species on the cardiac sarcoplasmic reticulum calcium-release channel. Exposure of heavy sarcoplasmic reticulum vesicles to reactive oxygen species in vitro resulted in the progressive loss of specific [3H]ryanodine binding and the degradation of high molecular weight proteins identified by polyacrylamide gel electrophoresis. The gating of single channels incorporated into artificial planar phospholipid bilayers was modified during the exposure to reactive oxygen species: an initial increase in open probability being followed by irreversible loss of channel function. Degradation by reactive oxygen species of specific proteins, such as the calcium-release channel, may contribute to in vivo reperfusion injury.

Animals↗
PubMed1989

Rat vs. rabbit ventricle: Ca flux and intracellular Na assessed by ion-selective microelectrodes.

Trans sarcolemmal Ca movements in rabbit and rat ventricular muscle were compared using extracellular double-barreled Ca-selective microelectrodes. In rabbit ventricle, steady-state twitches were associated with transient extracellular Ca (Cao) depletions, indicative of Ca uptake during the twitch. In contrast, steady-state twitches in rat ventricle were associated with net cellular Ca extrusion. Rest periods in rabbit ventricle lead to a net loss of cell Ca and resumption of stimulation induces a net uptake of Ca by the cells. Conversely, in rat ventricle rest periods lead to cellular Ca gain and resumption of stimulation induces a net Ca loss from the cells. Thus stimulation is associated with net Ca gain in rabbit ventricle and net Ca loss in rat ventricle. These observations provide an explanation for some of the functional differences between rat and rabbit ventricle (e.g., negative force-frequency staircase and rest potentiation in rat vs. positive staircase and rest decay in rabbit). Resting intracellular Na activity (alpha iNa) was 12.7 +/- 0.6 mM in rat and 7.2 +/- 0.5 mM in rabbit ventricle. This alpha iNa in rat ventricle is sufficiently high that Ca entry via Na-Ca exchange is thermodynamically favored at the resting membrane potential. This may explain why rest potentiation is observed in rat ventricle. In contrast, the lower alpha iNa in rabbit ventricle would favor Ca extrusion via Na-Ca exchange at rest (and consequent rest decay). In rat ventricle, the increase of intracellular [Ca] ([Ca]i) associated with contraction, coupled with the short action potential duration, strongly favor Ca extrusion via Na-Ca exchange and explain the observed Cao accumulation observed during twitches in rat. The high plateau of the rabbit ventricular action potential tends to prevent Ca extrusion via Na-Ca exchange during the contraction and explains the Cao depletions observed in rabbit. It is concluded that the higher alpha iNa and shorter action potential duration in rat vs. rabbit ventricle can explain many of the functional differences observed in these tissues.

Animals↗
PubMed1988

Differences in action potential configuration in ventricular trabeculae correlate with differences in density of transverse tubule-sarcoplasmic reticulum couplings.

The goal of the present study was to identify structural correlates to an observed variability in the response of ventricular muscle action potential configuration to ryanodine. In a previous study, rabbit ventricular trabeculae were shown to display either a shortened action potential (Group I) or lengthened action potential (Group II) in response to the negative inotropic drug ryanodine. The configuration of control action potentials were also different in these two groups. Action potentials in Group I trabeculae exhibited a prominent early repolarization and low plateau, while those in Group II exhibited a small early repolarization and high plateau. Electron microscope morphometric data showed that there is a significant, positive linear correlation between the number of transverse tubules displaying internal couplings with sarcoplasmic reticulum and the change in action potential duration in the presence of ryanodine. No other differences in internal coupling structure were observed. Although variability in the prominence of M-lines was also apparent between myocytes in both Group I and Group II, there is no correlation between the M-line prominence and ryanodine-induced change in electrophysiological behavior. No other structural variability was noted between Group I and Group II trabeculae. It is suggested that the difference in electrophysiological characteristics in the two groups might be due to a difference in T-tubular density. This hypothesis seems most plausible if there is a differential distribution of ion channels between the surface membrane and T-tubular membrane.

Action Potentials↗
PubMed1987

Two different electrophysiological responses to ryanodine: evidence for two populations of muscles isolated from the rabbit right ventricle.

We have observed that small trabeculae isolated from the rabbit right ventricle can be grouped into two populations on the basis of action potential configuration and electrophysiological response to ryanodine. These two populations have been designated Groups I and II. Action potentials in Group I muscles were characterized by a long action potential, a fast early phase of repolarization and shortened when exposed to 0.1 microM ryanodine (from 210 +/- 22 (6) ms (Mean +/- S.E.M. (n)) to 176 +/- 20 (6). Group II muscles showed a shorter action potential with a higher plateau phase and was prolonged by 0.1 microM ryanodine (from 175 +/- 7 (9) ms to 236 +/- 18 (9) ms). No significant difference in the mechanical response to ryanodine was observed between the two groups. Two populations of muscles, isolated from the rabbit right ventricle, have been previously described and distinguished on the basis of the presence or absence of transverse (T) tubules. We have attempted to correlate the electrophysiological observations with the presence or absence of (T) tubules. Electron microscopic examination, however, revealed that T-tubules were clearly present in both groups of trabeculae and therefore the two populations cannot be distinguished simply on the basis of the presence or absence of T-tubules. It was considered possible that the difference in the two populations may be related to the existence, and/or predominance, of two transient outward currents (one activated by SR Calcium release and the other that is 4-aminopyridine (4-AP) sensitive). The relative importance of these two currents to repolarization may be different in the two groups. This was investigated by adding ryanodine in the presence of 4-AP. The differential response to ryanodine seen in the two groups was, however, still observed in the presence of 4-AP. In these experiments, three out of seven muscles showed a decrease in action potential duration and four out of seven showed an increase. Other possible explanations for the differences in the two groups of muscles, and their response to ryanodine, are discussed.

Action Potentials↗
PubMed1987

The ionic basis of the anti-ischemic and anti-arrhythmic properties of magnesium in the heart.

The role of magnesium (Mg) in the prevention of ischemia-induced injury during cardioplegic arrest and in the treatment of cardiac arrhythmias has been considered. Although Mg possesses negative inotropic properties, potassium (K) is more effective than Mg in inducing cardiac arrest. The rationale for the inclusion of Mg in cardioplegic solutions therefore lies not in its cardioplegic properties, but in its ability to influence other cellular events such as the loss of Mg and K and perhaps to counter the detrimental effects of ischemia by antagonizing calcium (Ca) overload. Most of the Mg in the cardiac cell is complexed with high energy phosphate compounds and the loss of Mg during ischemia may restrict the repletion of ATP upon reperfusion and so impair the return of normal contractile function. The ability of Mg to limit K efflux from the cell is of importance not only in the prevention of ischemia-induced K loss but also in the treatment of digitalis-induced arrhythmias. Elevation of extracellular Mg has been shown to reduce the intracellular sodium ion activity ([Na]i) and this decline in [Na]i can be related to the negative inotropic properties of Mg. Mg may therefore exert some of its antiarrhythmic and antiischemic effects by limiting [Na]i-stimulated Ca influx (or facilitating Ca efflux) and hence preventing cellular Ca overload.

Animals↗