(1) Mean and phasic flows are reduced in the early activated LAD region by ventricular pacing (RVp, Apexp). (2) Under controlled perfusion pressure and intact vascular tone, ventricular pacing compromises blood flow compared with atrial pacing. (3) This effect disappears when vascular tone is eliminated by intracoronary injection of adenosine, suggesting that the coronary autoregulation is responsible for some of the effects.
The proposed model describes myocyte calcium (Ca++) cycling, emphasizing the kinetics of sarcoplasmic reticulum (SR) Ca++ release channels. The suggested SR channel regulating mechanism includes two types of Ca++ binding sites: (1) low affinity sites with high binding rates, regulating the opening of Ca++ channels and (2) high affinity sites with low binding rates, which regulate their closing. The amount of Ca++ released from the SR and the peak value of Ca++ ion concentration [Ca++] in the cytoplasm were found to depend on the rate of the increase of [Ca++], similar to Ca++ induced Ca++ release experiments. The model describes spontaneous release of Ca++ from overloaded SR. The dependence of the control mechanism on the activating and inactivating sites is substantiated by simulations of ryanodine intervention, providing results similar to experimental results. Simulations under conditions of isolated SR vesicles produced Ca++ release results similar to measured data. Consequently, it is suggested that the recovery of Ca++ release channels represents the rate limiting factor in the process of mechanical restitution.
Because the role of sodium channels in the initiation and maintenance of VF is not fully elucidated, we studied the significance of sodium channel activity in VF using sodium channel blockers. In nonischemic isolated feline hearts, the following electrophysiologic parameters were measured before and after application of tetrodotoxin (5 x 10(-7) M, n = 6) or lidocaine (1 x 10(-5) M, n = 8): (a) during pacing, epicardial conduction time; refractoriness; the fastest rate for 1:1 pacing/response capture, and all tissue resistivity, indirectly reflecting intercellular electrical resistance; (b) during 8 min of electrically induced tachyarrhythmias, all tissue resistivity; peak frequency (to measure average frequency based on fast-Fourier transformation analysis); and normalized entropy (to measure the degree of arrhythmia organization). In nonischemic isolated rabbit hearts (n = 4), three-dimensional mapping was performed before and after application of lidocaine (1 x 10(-5) M). In feline hearts, lidocaine and tetrodotoxin application resulted in: (a) more spontaneous arrhythmia termination (63-67%) than in nontreated hearts (7%); (b) transformation from mainly VF into ventricular tachycardia with increased organization; and (c) prolongation of conduction time (155-248%) (p < 0.01 for all parameters). The ventricular refractory period was slightly prolonged by tetrodotoxin in the right ventricle and exhibited rate-dependent shortening in control and with lidocaine. Tetrodotoxin and lidocaine reduced the pacing rate for 1:1 pacing/response capture, and all tissue resistivity was not significantly affected. Peak frequency was decreased by tetrodotoxin and lidocaine mainly in the left ventricle (p < 0.01). In nontreated left ventricles, peak frequency was increased over time but was attenuated by lidocaine. In isolated rabbit hearts, several simultaneous wave fronts were detected during VF in nontreated hearts and were reduced to only one or two major wavefronts after application of lidocaine. Suppression of sodium channel activity that primarily slowed conduction time and had little or no effect on ventricular refractory period and all tissue resistivity resulted in less stable and more organized arrhythmias and reduced tachyarrhythmia rate compared with nontreated hearts. These results suggest an active role for sodium channels in the maintenance of ventricular fibrillation.
The individual activities of sodium versus calcium channels in the initiation and maintenance of ventricular fibrillation (VF) have not been fully elucidated. Therefore we studied in isolated heart under nonischemic conditions (a) VF characteristics in untreated hearts, (b) initiation and maintenance of VF during attenuation and blockade of slow calcium channel activity by verapamil, (c) the effect of these interventions on the characteristics of the induced arrhythmia, and (d) the impact of heart weight on the observed results. Measurements were carried out in both ventricles of isolated feline hearts during ventricular pacing and 8 min of electrically induced tachyarrhythmias. Measurements during ventricular pacing included epicardial conduction time (CON), refractoriness (VRP), and all tissue resistivity (ATR; an indirect measure of changes in intercellular electrical coupling). Measurements during arrhythmia included ATR, peak frequency [PKF; a measure of the prevailing frequency based on Fast Fourier Transform (FFT) analysis], and normalized entropy (ENTROP; a measure of the degree of arrhythmia organization). Measurements during sinus rhythm and arrhythmia were repeated after blocking of calcium channel activity by verapamil at a high concentration (1.8x10(-4) M; n = 8) and at two low concentrations (1.5 and 3.0x10(-7) M; n = 8). In untreated hearts, mainly VF episodes were induced, exhibiting a low degree of organization with no significant change in this parameter throughout the arrhythmia (8 min). In the left ventricle (LV; and to a much smaller extent in the right ventricle; RV), a gradual increase in PKF was observed throughout the arrhythmia, with no significant change in ATR. Verapamil at a high concentration increased CON, but did not affect VRP. These findings were similar in both ventricles. In lower verapamil concentrations, CON was not affected, and VRP was slightly shortened. After treatment with a high verapamil concentration, VF could not be induced in small hearts but was always inducible in large hearts. Transient arrhythmia episodes appeared in 9% of untreated hearts, in 25% with "high" verapamil, and in 25-37% with "low" verapamil. With all verapamil concentrations, the induced arrhythmia was modulated from a predominantly VF to PVT or MVT type, manifested by a decrease in ENTROP. This effect was less pronounced with increasing heart weight. No significant change in PKF and in ATR was obtained with verapamil throughout the arrhythmia. It is suggested that verapamil modulation of arrhythmia organization is associated mainly with a direct blockade of calcium channel activity (perhaps by causing reduction in the safety factor for conduction), rather than with indirect modulation of electrophysiological parameters.
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