Epicardial Action Potentials Research Articles

Class III antiarrhythmic effects of LY-190147 on defibrillation threshold.

Defibrillation strength shocks delivered within an action potential (AP) delay repolarization. Shock-induced AP duration extension (APDE) may prolong refractoriness and terminate or prevent reinitiation of reentry, favoring defibrillation. This study examined LY-190147 (LY) effects on defibrillation threshold (DFT) in 11 dogs. Ventricular effective refractory period (VERP) and epicardial monophasic AP duration at 75% repolarization (APD75) were recorded at 300-, 400-, 500-, and 600-ms pacing cycle length (CL). APDE was measured as the time to 50% repolarization after a DFT strength shock delivered at 50, 25, and 0 ms before or 25 ms after VERP during pacing at 300 ms CL in 4 of the dogs. We made all recordings before drug administration and after infusions of 0.03, 0.3, and 3.0 mg/kg LY, using 1.5-h dosing intervals. LY lowered DFT in a saturating dose-response manner whether expressed as shock peak voltage (V) or energy. LY decreased DFT-V from 357 +/- 77 V before drug to 331 +/- 60 V (-6 +/- 12%), 290 +/- 43 V (-17 +/- 13%, p < 0.001), and 312 +/- 45 V (-11 +/- 12%, p < 0.05) at 0.03, 0.3, and 3.0 mg/kg, respectively. Similarly, LY treatment decreased defibrillation energy requirements from 6.9 +/- 2.7 J before drug by 7 +/- 25%, 26 +/- 24%, and 12 +/- 25% at the same doses. At 300-600 ms CL, LY prolonged APD75 by an average of 10 +/- 8% at 0.03 mg/kg, 17 +/- 6% at 0.3 mg/kg, and 24 +/- 9% at 3 mg/kg. At these CL, LY prolonged VERP by an average of 4 +/- 6% at 0.03 mg/kg, 15 +/- 10% at 0.3 mg/kg, and 11 +/- 9% at 3 mg/kg. APDE was increased from 62 +/- 9 ms before to 68 +/- 14, 80 +/- 16 (p < 0.001) and 72 +/- 13 ms (p < 0.05) at 0.03, 0.3, and 3.0 mg/kg LY, respectively. Therefore, LY prolonged VERP and APDE and affected DFT in the same saturating dose-response manner. LY may facilitate defibrillation by increasing the duration of postshock refractoriness.

Thyroid status and diabetes modulate regional differences in potassium currents in rat ventricle.

1. The rate dependence and recovery kinetics of the Ca(2+)-independent transient (I(t)) and steady-state or 'pedestal' (Iss) outward potassium (K+) currents were studied in single myocytes isolated from epicardial and endocardial regions of rat left ventricles. The whole-cell, suction microelectrode method was used to measure baseline (fully reactivated) I(t), as well as its rate-dependent attenuation. Results from a group of control animals were compared with data from three other groups having an experimentally altered hormonal status. 2. I(t) was significantly smaller in endocardial cells than in epicardial cells, in part due to a very large difference in the recovery kinetics of this current in endocardial cells. This was reflected in a pronounced rate-dependent prolongation of endocardial action potentials. In contrast, the non-inactivating 'pedestal' current, Iss, was very similar in magnitude and showed comparable rate dependence in cells from both epicardium and endocardium. 3. Changing the thyroid status had selective, differential actions on the amplitude and rate dependence of It in epicardial and endocardial cells. Under hypothyroid conditions there was a more pronounced reduction of baseline I(t) in epicardial than in endocardial cells. Moreover, a slowing of the recovery kinetics in epicardial cells resulted in an enhanced attenuation of this current at high rates. Changing thyroid status had no effect on the magnitude or rate dependence of Iss in cells from either region of the left ventricle. 4. Following establishment of hyperthyroid conditions, there was no significant change in I(t) magnitude at baseline. However, when compared with control data, the recovery of I(t) was considerably faster in endocardial cells, and marginally faster in epicardial cells. 5. Streptozotocin-induced diabetic conditions resulted in a much greater attenuation of I(t) in epicardial cells than in endocardial cells. Epicardial action potentials in these conditions showed prominent rate-dependent prolongation. Iss was reduced to a similar extent in cells from these two regions. 6. Our findings demonstrate that altered hormonal status can selectively change the amplitude and kinetics of It in the epi- and endocardium of rat left ventricle. These changes can reduce the epicardial-endocardial gradients in the magnitude and recovery kinetics of It and hence diminish the intrinsic differences in both action potential duration and refractoriness.

Simulation of ECG from two pairs of action potentials

A simple model for simulation of ECG is presented with the purpose to mimic some common ECG configurations and to generate a hypothesis regarding their electrophysiological background. Action potentials (AP) were simulated on a personal computer from ion currents as described previously (Wohlfart & Arlock, 1993). The difference between two APs of a pair was used to create an electrogram (EG). The subendocardial AP of the pair was triggered by means of a simulated current injection and the subepicardial Ap was triggered from the first AP due to electric coupling within the pair. The subendocardial APs were of longer duration than the epicardial AP because of differences in background currents. A second pair of APs representing another ventricular site was simulated in an analogous way and this pair was activated somewhat later in time. ECG was calculated as the difference between the two EGs. Right-bundle branch block could be imitated by reducing the coupling between the APs representing the right ventricle. Left-bundle branch block was generated in an analogous way. ECG in acute myocardial infarction was created after making one of the epicardial APs ischaemic in appearance (reduced amplitude, short duration). Status-post infarction ECG (Q-wave and negative T) was produced by reducing the influence from the EG of the infarcted area. Negative T and increased R-wave as in hypertrophy could also be reproduced. Down sloping ST-segment and negative T as in subendocardial ischaemia was also possible to imitate. The simulations showed that biphasic T-waves or T and U-waves follows when the two EGs are separated properly in time.

Quinacainol, a new antiarrhythmic with Class I antiarrhythmic actions in the rat

The antiarrhythmic and electrophysiological actions of quinacainol, a new Class I antiarrhythmic, were assessed in rats. Electrophysiological actions of quinacainol were assessed in vivo in terms of drug-induced changes in ECG, responses to left ventricular electrical stimulation, and changes in epicardial intracellular potentials to precisely characterize the electrophysiological effects of this putative subclass Ic antiarrhythmic compound. Antiarrhythmic actions were assessed in conscious rats subjected to occlusion of the LAD coronary artery. Antiarrhythmic actions occurred with 2.0 and 4.0 mg/kg, whereas 8.0 mg/kg was pro-arrhythmic. At doses of 0.5 mg/kg and above quinacainol increased threshold currents and for ventricular fibrillation. Doses of 2.0 mg/kg and above increased ventricular refractoriness. From 1.0 to 8.0 mg/kg quinacainol reduced dV/dt max of phase 0 of epicardial action potentials but only 8.0 mg/kg increased action potential duration. The Q-T interval was also increased with the highest dose. Quinacainol dose-relatedly increased P-R interval whereas QRS did not change. Thus the Class I electrophysiological properties of quinacainol over the dose range tested did not fit accurately into a single subclass of the various subclasses of Class I. However, the Class Ic actions seen with 2.0 and 4.0 mg/kg were associated with antiarrhythmic actions.

Differences in the effect of metabolic inhibition on action potentials and calcium currents in endocardial and epicardial cells.

Ischemia-induced electrophysiological changes are more prominent in epicardial cells than in endocardial cells. Epicardial action potentials shorten more than endocardial action potentials during ischemia. Since the L-type Ca2+ current plays an important role in the maintenance of action potential duration, we hypothesized that the Ca2+ current is affected more in epicardial cells than in endocardial cells during ischemia. To test this hypothesis, we examined the effect of metabolic inhibition, a major component of ischemia, on action potentials and the Ca2+ current in single cells isolated from the endocardial and epicardial layers of the feline left ventricle. The membrane voltage and current were measured by using the whole-cell mode of the patch-clamp technique. During control periods, action potentials recorded from epicardial myocytes had lower amplitude, a prominent notch between phases 1 and 2, and shorter action potential duration compared with those recorded from endocardial myocytes. However, the amplitude and current-voltage relation of the Ca2+ current were similar in endocardial and epicardial cells at test potentials of -30 to 60 mV elicited from a holding potential of -40 mV. The time course of inactivation of the Ca2+ current also was identical in the two cell types. After 15 minutes of superfusion with glucose-free Tyrode's solution containing 1 mM CN-, action potential duration was reduced by 13 +/- 7% in endocardial cells and by 80 +/- 9% in epicardial cells (p less than 0.01). The peak Ca2+ current was reduced by 21 +/- 9% in endocardial cells and by 37 +/- 6% in epicardial cells (p less than 0.01). We conclude that enhanced depression of the Ca2+ current may account in part for the greater action potential shortening in epicardial cells during ischemia and metabolic inhibition.

Repolarization differences between guinea pig atrial endocardium and epicardium: evidence for a role of Ito

It has long been known that ventricular epicardial action potential duration (APD) is shorter than endocardial, and recent evidence suggests that a larger transient outward current (Ito) in epicardium is responsible for the difference. To evaluate possible corresponding regional variations in atrial tissue, we studied guinea pig atrial epicardial and endocardial action potentials using standard microelectrode techniques. Epicardial APD was consistently shorter than endocardial, but the difference was greatly diminished by rapid pacing or early premature activation, situations in which Ito availability should be limited. 4-Aminopyridine (4-AP), at concentrations (0.5 mM) producing specific Ito blockade, increased APD significantly in atrial epicardium without affecting endocardium. The effect of 4-AP on APD was most marked at slow rates, at which Ito would be greatest, and was negligible at rapid rates or during premature activation, during which Ito would be largely inactivated. At larger concentrations (5 mM) 4-AP caused an equalization of epicardial and endocardial APD. The equimolar substitution of strontium for calcium did not affect APD at slow rates and increased APD (particularly in endocardium) at rapid rates, suggesting that the Ito underlying endocardial-epicardial differences was unlikely to be calcium dependent. We conclude that epicardial-endocardial differences in APD, well documented in ventricular tissue, can also occur in atrial tissue and that the underlying ionic mechanisms appear to be similar.

Antiarrhythmic properties of tedisamil (KC8857), a putative transient outward K+ current blocker

1. Rats were used to evaluate the antiarrhythmic properties of tedisamil, a novel agent with the electrophysiological properties of a Class III antiarrhythmic drug. Tedisamil was tested against coronary artery occlusion-induced arrhythmias in conscious animals. 2. The actions of tedisamil on the ECG, as well as responses to electrical stimulation, were compared with those on the configuration of epicardial intracellular action potentials recorded in vivo. 3. Tedisamil (1-4 mg kg-1, i.v.) caused bradycardia, elevated blood pressure and dose-dependently reduced ventricular fibrillation (VF) induced by occlusion of the left anterior descending coronary artery. Other ischaemia-associated arrhythmias were not so well suppressed. Antiarrhythmic activity was greatest when the tedisamil-induced bradycardia was prevented by electrically-pacing the left ventricle. 4. Tedisamil dose-dependently lengthened the effective refractory period and prevented electrically-induced VF. In vivo, tedisamil (0.5-4 mg kg-1, i.v.) prolonged the duration of epicardial intracellular action potentials by up to 400%. 5. Results showed that tedisamil possessed antifibrillatory actions in rats that were related to Class III electrophysiological actions as revealed by electrical stimulation and electrophysiological analyses.

Differences in the electrophysiological response of canine ventricular subendocardium and subepicardium to acetylcholine and isoproterenol. A direct effect of acetylcholine in ventricular myocardium.

A prolongation of the ventricular effective refractory period in response to cholinergic agonists or vagal stimulation has been demonstrated in a number of in vivo animal models. However, exposure of isolated myocardial tissues obtained from these hearts to as much as 10(-4) M acetylcholine has been shown to produce essentially no change in action potential duration or effective refractory period. The discrepancy between the in vivo and in vitro findings generally has been explained on the basis of accentuated antagonism, whereby parasympathetic agonists exert their influence through antagonism of the effects of beta-adrenergic tone in vivo. The fact that acetylcholine exerts little if any direct effect on the electrical activity of ventricular myocardium, although well accepted, is based exclusively on studies performed using endocardial preparations. Our recent demonstration of major electrophysiological differences between canine ventricular endocardium and epicardium prompted us to examine the effects of acetylcholine and the role of accentuated antagonism in these two tissue types. Using standard microelectrode techniques, we show that acetylcholine (10(-7)-10(-5) M) has little if any effect in canine ventricular endocardium but a pronounced effect to either prolong or markedly abbreviate action potential duration and effective refractory period in epicardium. These effects of acetylcholine on epicardium are attended by an accentuation of the spike and dome morphology of the action potential, are readily reversed with atropine, fail to appear when epicardium is pretreated with the transient outward current blocker 4-aminopyridine, are accentuated in the presence of isoproterenol (10(-7) to 5 x 10(-6) M), and persist in the presence of propranolol. Isoproterenol-induced abbreviation of action potential duration and effective refractory period is also shown to be more pronounced in epicardium than in endocardium; equimolar concentrations of acetylcholine completely antagonize the effects of isoproterenol in endocardium and epicardium. We conclude that acetylcholine exerts important direct effects on the electrical response of canine ventricular myocardium, which are accentuated in the presence of beta-adrenergic agonists. Our findings suggest the differential response of epicardium and endocardium to acetylcholine is due to the presence of a transient outward current-mediated spike and dome morphology in the epicardial action potential. Finally, the data suggest that acetylcholine may exert antiarrhythmic as well as arrhythmogenic effects through its actions to alter conduction and refractoriness.

The antiarrhythmic efficacy of intravenous anipamil against occlusion and reperfusion arrhythmias

1. Anipamil, a long acting analogue of verapamil, was tested for its actions against arrhythmias induced by ischaemia and reperfusion in conscious and anaesthetized rats, as well as for effects on epicardial intracellular action potentials. 2. When given 15 min or 4 h before coronary occlusion, 1 and 5 mg kg-1 anipamil reduced ischaemia-induced arrhythmias in conscious rats. The same doses also reduced arrhythmias when given 15 min before occlusion in acutely-prepared anaesthetized rats. ED50 values were between 1 and 5 mg kg-1. 3. The incidence of reperfusion arrhythmias depended upon the period of regional ischaemia prior to reperfusion such that the peak incidence occurred after 5-7 min of ischaemia. Anipamil (2.5 mg kg-1, i.v.) selectively abolished the reperfusion arrhythmias induced by short periods of ischaemia, although some antiarrhythmic effects were seen for all periods of ischaemia. 4. Anipamil slowed the rate of development of R-wave increases and S-T segment elevations induced by ischaemia, but did not reduce the maximum values they attained. 5. Anipamil (2.5 mg kg-1 i.v.) lacked Class I or III electrophysiological actions on intracellular action potentials recorded in vivo from the epicardium of rat hearts. 6. In conclusion, the antiarrhythmic actions of anipamil appeared to depend upon calcium antagonism which may have reduced arrhythmias by a combination of anti-ischaemic and direct anti-arrhythmic actions. Presumed anti-ischaemic actions changed the relationship between the duration of preceding ischaemia and resulting reperfusion arrhythmias.

Transient outward current prominent in canine ventricular epicardium but not endocardium.

Previous studies have denied the presence of a transient outward current (Ito) in ventricular myocardium of dog, sheep, and calf. Using conventional microelectrode techniques, we provide evidence for a significant contribution of Ito to epicardial, but not endocardial, activity of canine ventricular myocardium. The epicardial action potential when compared with that of endocardium shows a smaller phase 0 amplitude, a much more prominent phase 1, and a phase 2 amplitude that is greater than that of phase 0. Epicardial action potentials, unlike those of endocardium, display a "spike and dome" morphology that becomes progressively more accentuated at slower stimulation rates. Using the restitution of phase 1 amplitude as a marker for the process responsible for the spike and dome phenomenon, we were able to delineate two exponential components: 1) a slow component that recovers with a time constant of 350-570 msec and 2) a fast component with a time constant of 41-85 msec. The slow component was largely abolished by 1-5 mM 4-aminopyridine, an Ito blocker. The fast component was diminished by 4-aminopyridine, but it was also inhibited by ryanodine and by Sr2+ replacement of Ca2+, which are interventions known to inhibit the Ca2+-activated component of Ito. Following 4-aminopyridine and Sr2+ or ryanodine treatment, the epicardial responses more closely resembled those of endocardium. In summary, the data demonstrate a marked heterogeneity of active membrane properties in canine ventricular muscle. These observations may aid in understanding the basis for rate-dependent changes in the T wave of the ECG, supernormal conduction in ventricular muscle, the greater sensitivity of epicardium to ischemia, and the rate dependence of some cardiac arrhythmias.

A simple model for demonstration of STT-changes in ECG.

This study is based on the idea that the STT part of the electrocardiogram in a small segment of the heart wall can be accurately constructed by calculating the difference between one subendocardial and one epicardial action potential. The following simulations were performed on computer and graphically presented. Endocardial ischaemia producing depression of the ST segment, downward sloping of the ST segment and negative T waves. Epicardial injury causing either a real or a pseudo ST elevation. Abnormal conduction between endocardium and epicardium (Increased delay between endocardial and epicardial excitation or reversed excitation path) producing discordant R and T waves. Analysis of STT changes are discussed on the background of these simulations. The proposed model for a segmental ECG was extrapolated to the whole heart by considering the contribution from each of 8 segments to a resultant heart vector.

On the possibility of directly relating the pattern of ventricular surface activation to the pattern of body surface potential distribution.

A system of three 320-element spheres was employed to represent the endocardial and epicardial surfaces of the left ventricle and the body surface. The two inner (heart) spheres were considered electrogenic, and each active subunit was given an onset time and a monophasic action potential; these subunits were treated as source dipoles for successive instants in time. The potential distribution at any instant resulting on the outer (torso) surface was calculated from adding together the corresponding proportionate effects of all active subunits, each treated as dipolar sources. This result was compared to multipolar reduction of simultaneous endocardial and epicardial action potential patterns which, when combined, gave a net multipolar generator content enabling outer pattern approximation. The identity between the patterns of torso surface potential, systematically calculated from multiple dipoles, and those produced from the multipolar reduction provided three insights: 1) the whole surface treatment of the multipolar method is faster, 2) both show an offset term related to the monophasic nature of the sources and similar to that found in live data, and 3) such a model may provide a vehicle for experimentally testing the contribution of intramural sources to body surface potential maps.

Transmembrane action potentials and the electrocardiogram in rats with renal hypertension

The results of previous studies of the relation between the surface electrocardiogram and cellular transmembrane potentials have suggested that the T wave configuration of the ECG is the result of a difference in the duration of endocardial and epicardial action potentials. Ventricular hypertrophy induced by renal hypertension in rats is associated with lengthening of action potential duration and a reproducible decrease in T wave magnitude. Therefore, this model was used to study the relation between the surface T wave configuration and regional differences in action potential duration. ECGs were recorded from hypertensive (HBP) and sham-operated (SHAM) rats. The hearts from these animals were removed and transmembrane action potentials were recorded by standard microelectrode techniques from endocardial and epicardial preparations. We found that the normally peaked T waves seen in the ECG of SHAM rats was reduced by 35% in the ECG of HBP rats. This reduction of T wave magnitude was associated with similar duration of epicardial and endocardial action potentials in HBP rats. However, peaked T wave in SHAM ECG was not accompanied by a significant disparity in the duration of the epicardial and endocardial action potentials. Thus, there is no simple, consistent correlation between surface T wave configuration and regional differences in intracellular action potential duration in rats.

Role of adrenocortical hormones on the ontogenesis of ventricular action potential of rat myocardium

The ontogenesis of the rat epiventricular action potential was studied using hearts isolated from fetuses aged 13.5 to 21.5 days and from newly born animals. The resting membrane potential (RP), the overshoot (OS) and the maximal rate of depolarization of the action potential ( V ̇ max ) were slightly but significantly increased during the studied period of gestation through to the second day following birth. From the 16th day of gestation, the duration of action potential (APD) began to decrease gradually to attain a characteristic triangular shape at birth. Under these in vitro conditions the intrinsic cardiac frequency did not vary during the period investigated. The duration of the cardiac action potential recorded at the end of the gestation was greater for fetuses which had been deprived of hypophyseal hormonal influence by decapitation on day 15.5 or 16.5 than for control fetuses of the same litter. Maternal adrenalectomy performed on day 13.5 of gestation did not affect cardiac electrogenesis in normal fetuses but led to the absence of the normal shortening of the action potential in decapitated fetuses. This effect was prevented by cortisol as well as d-aldosterone administered to the fetus on day 19.5 of gestation. In conclusion, corticoids of fetal and/or maternal origin appear to play an important role in the modifications of the repolarization phase of the epicardial action potential during the final days of gestation.

The effects of palmitate on intracellular potentials recorded from langendorff-perfused guinea-pig hearts in normoxia and hypoxia, and during perfusion at reduced rate of flow

Epicardial ventricular action potentials were recorded from guinea-pig hearts perfused by the Langendorff method. In the presence of glucose (11 m m ), palmitate (0.6 m m ) complexed to albumin (1%) was found to have no effect on the action potential in normoxia, or in severe hypoxia (3% O 2 ), but exacerbated the shortening of action potential duration occurring in moderate hypoxia (25% O 2 ), or during successive periods of reduced flow perfusion. Palmitate delayed and decreased the fall of action potential duration occurring in the absence of glucose, but was unable to prevent it completely.

Serum lipid pattern in ischemic heart disease--study on fatty acid composition and pre-beta-lipoprotein

With respect to the mechanism of formation of ST-T wave in the electrocardiogram, various hypotheses have been proposed by many investigators. However, it cannot be said that any of these has been entirely accepted. The author assumed that the formation of ST-T wave would be attributable to temporal and spacial difference in the electrical current occur-red in various parts of the ventricle. Such a differ-ence may be observed between the epicardial and endocardial sites. From this point of view, the following investigations on the repolarization phase of transmembrane action potentials of the endocardial and epicardial sites were performed. Method Ventricular muscle of the rabbit was subjected to the experiment. The preparation was perfused constantly flowing with oxygenated Tyrode solution at a constant temperature (37°C). The transmembrane action potential (AP) is recorded through a microelectrode of Ling-Gerad type filled with 3M KCl (resistance 20-30 MΩ). The driving stimuli were delivered through a monopolar silver wire electrode attached to the ven-tricular surface. In some experiments, two microelectrodes were concurrently inserted into the epicardium and endocardium. Monopolar surface electrogram was also simultaneously recorded. Results 1. Comparison of action potential configurations between the endocardial and epicardial sites As indicated in Fig. 1 and Table I, no significant difference was recognized in action potential amplitude as well as resting potential between the epicardial and endocardial sites, while significant difference was observed in duration of AP between the epicardial and endocardial sites (Table II). The mean value of the maximum rate of rise recorded from the epicardial and endocardial sites were 217.6 ± 60.4 volt/sec and 508.5 ± 86.1 volt/sec, respectively, the latter being significantly greater than the former (Fig. 2. Table III). 2. Effects of stimulus frequency on the epicardial and endocardial APs Effect of change in frequency of electrical stimulation on the AP of the endocardial and epicardial sites was observed (Fig. 3). At a higher rate of stimulation, the duration of the AP was markedly reduced and the amplitude of resting and action potentials slightly decreased. At a lower rate, the duration was prolonged while the amplitude of resting and action potentials was slightly decreased. A linear relationship was observed between the duration of the AP and stimulus frequency, the frequency ranging from 0.2 cps to 6 cps. The patterns of change in the AP by frequency change were virtually identical between the endocardial and epicardial sites.

A.D.C. magnet power supply for 125 V, 500 A with controlled silicon rectifiers

Dispersion of action potential repolarization is known to be an important arrhythmogenic factor in cardiopathies such as Brugada syndrome. In this work, we analyze the effect of a variation in sodium current (INa) inactivation and a heterogeneous rise of transient outward current (Ito) in the probability of reentry in epicardial tissue. We use the Luo–Rudy model of epicardial ventricular action potential to study wave propagation in a one-dimensional fiber. Spatial dispersion in repolarization is introduced by splitting the fiber into zones with different strength of Ito. We then analyze the pro-arrhythmic effect of a variation in the relaxation time and steady-state of the sodium channel fast inactivating gate h. We quantify the probability of reentry measuring the percentage of reexcitations that occurs in 200 beats. We find that, for high stimulation rates, this percentage is negligible, but increases notably for pacing periods above 700 ms. Surprisingly, with decreasing INa inactivation time, the percentage of reexcitations does not grow monotonically, but presents vulnerable windows, separated by values of the INa inactivation speed-up where reexcitation does not occur. By increasing the strength of L-type calcium current ICaL above a certain threshold, reexcitation disappears. Finally, we show the formation of reentry in stimulated two-dimensional epicardial tissue with modified INa kinetics and Ito heterogeneity. Thus, we confirm that while Ito dispersion is necessary for phase-2 reentry, altered sodium inactivation kinetics influences the probability of reexcitation in a highly nonlinear fashion.