Excitable cardiac tissue

The Class I agents decrease excitability, slow conduction velocity, inhibit diastoHc depolarization (decrease automaticity), and prolong the refractory period of cardiac tissues (1,2). These agents have anticholinergic effects that may contribute to the observed electrophysiologic effects. Heart rates may become faster by increasing phase 4 diastoHc depolarization in SA and AV nodal cells. This results from inhibition of the action of vagaHy released acetylcholine [S1-84-3] which, allows sympathetically released norepinephrine [51-41-2] (NE) to act on these stmctures (1,2). 

Some cardiac arrhythmias result from many stimuli present in the myocardium. Some of these are weak or of low intensity but are still able to excite myocardial tissue Lidocaine, by raising the threshold of myocardial fibers, reduces the number of stimuli that will pass along these fibers and therefore decreases the pulse rate and corrects the arrhythmia Mexiletine (Mexitil) and tocadnide (Tonocard) are also antiarrhythmic drag s with actions similar to those of lidocaine... 

Shaw RM, Rudy Y The vulnerable window for unidirectional block in cardiac tissue Characterization and dependence on membrane excitability and intercellular coupling. J Cardiovasc Electrophysiol 1995 6 115-131. 

Class I antiarrhythmic drugs are essentially sodium channel blockers.5,27,29 These drugs bind to membrane sodium channels in various excitable tissues, including myocardial cells. In cardiac tissues, class I drugs normalize the rate of sodium entry into cardiac tissues and thereby help control cardiac excitation and conduction.8,27 Certain class I agents (e.g., lidocaine) are also used as local anesthetics the way that these drugs bind to sodium channels is discussed in more detail in Chapter 12. 

Class IV drugs have a selective ability to block calcium entry into myocardial and vascular smooth-muscle cells. These drugs inhibit calcium influx by binding to specific channels in the cell membrane.12,15 As discussed previously, calcium entry plays an important role in the generation of the cardiac action potential, especially during phase 2. By inhibiting calcium influx into myocardial cells, calcium channel blockers can alter the excitability and conduction of cardiac tissues. 

Undoubtedly, the most promising modehng of the cardiac dynamics is associated with the study of the spatial evolution of the cardiac electrical activity. The cardiac tissue is considered to be an excitable medium whose the electrical activity is described both in time and space by reaction-diffusion partial differential equations [519]. This kind of system is able to produce spiral waves, which are the precursors of chaotic behavior. This consideration explains the transition from normal heart rate to tachycardia, which corresponds to the appearance of spiral waves, and the fohowing transition to fibrillation, which corresponds to the chaotic regime after the breaking up of the spiral waves, Figure 11.17. The transition from the spiral waves to chaos is often characterized as electrical turbulence due to its resemblance to the equivalent hydrodynamic phenomenon. 

Calcium performs a variety of cellular functions in muscle and nerve that ultimately result in muscular contraction. Excellent descriptions of calcium s function in muscle and nerve are to be found in the reviews by Hoyle (37), Cohen (38), and Robertson (39). At the neuromuscular junction, the excitable cells are very sensitive to changes in extracellular concentrations of calcium. Curtis (40) and Luttgau (41) described a fall in the resting action potential and electrical resistance when the extracellular calcium concentration fell below 10 M. The action potential and electrical resistance returned to normal following addition of calcium to this vitro preparation. The magnitude of the Initial muscle membrane action potential, that which regulates the propagation of further muscle contraction, is also mediated by the extracellular calcium concentration. While the inward flow of sodium ions from the extracellular space remains the dominant factor in the mechanism of muscle membrane depolarization, calcium ion flux appears to mediate the cell s permeability to sodium ions. This effect is particularly true in cardiac tissue (W). 

Quinidine has direct and indirect, or antimuscarinic, effects on cardiac tissue. Quinidine decreases myocardial excitability, conduction velocity, and contractility. As quinidine concentrations increase, conduction velocity progressively decreases. This is evident in an increase in PR interval, an increase in QRS duration, and an increase in QT interval. The effective refractory period is prolonged by quinidine. The anticholinergic effect on the heart is a decrease in vagal tone. In overdose, sinus node automaticity may be depressed. It is the a-adrenergic blocking properties of quinidine that cause vasodilatation and hypotension. 

Automaticity is the ability of cardiac tissue fibers to depolarize spontaneously. This enables them to contract again without external nerve stimulation. It is not surprising that digitalis affects this ability profoundly. When digitalis causes an increase in the rate of spontaneous depolarization during diastole of the ventricle, automaticity is increased at the pacemaker site. This may result in premature beats that increase as higher doses reduce excitability. 

Tetrandrine, a traditional medicinal alkaloid, has been used in China for the treatment of hypertension, cardiac arrhythmia, and angina pectoris. Recently, it has been shown that tetrandrine blocks voltage activated L-type Ca++ channels in a variety of excitable cells including cardiac tissue. The binding site of tetrandrine is located at the benzothiazepine receptor on the aj-subunit of the channel. It is clear that tetrandrine s actions in the treatment of cardiovascular diseases, including hypertension and supraventricular arrhythmia, are due primarily to its blocking of voltage activated L-type and T-type 08" + channels. 

Reed KC and Bygeave FL (1974b) The inhibition of mitochondrial calcium transport by lanthanides and ruthenium red. Biochem J 140 143-155. Sabbioni F, Nicoiaou GR, Peitea R, Beccaloni F, Coni F, Alimonti A and Caeoli S (1990) Inductively coupled atomic emission spectrometry and neutron activation analysis for the determination of clement reference values in human lung tissue. Biol Trace Flem Res 26-27 757-768. Sanborn WG and Langee GA (1970) Specific uncoupling of excitation and concentration in mammalian cardiac tissue by lanthanum. J Gen Physiol 56 191-217. 

These drugs stabilize excitable membranes, primarily in the CNS. Similarly, they stabilize excitable membranes in cardiac tissue and vascular smooth muscle. In susceptible individuals (e.g., the elderly, patients with existing cardiac dysfunction or hepatic dysfunction), this may lead to hypotension and abnormal cardiac activity. 

These drugs decrease calcium flux in the AV node, and decrease the excitability of cardiac tissue. This class includes Preceptor antagonists (e.g., esmolol) and pan-beta receptor antagonists (e.g., propranolol). 

Phase 2 of the cardiac action potential is prolonged, due to the blockade of potassium flux decreasing the excitability of tissue and thus inhibiting the spontaneous formation of ectopic foci. 

Quinidine blocks open sodium channels, which decreases the rate of repolarization in a dose-dependent manner. Thus, the cardiac tissue may still depolarize normally, and the propensity for cardiac failure is lessened. Amiodarone, conversely, blocks resting channels, preventing depolarization in a dose-dependent manner. This could prevent excitation, particularly if the drug is in excess, leading to cardiac failure. Thus, this drug has a more pronounced cardiodepressant effect, as compared to quinidine, and a smaller margin of safety. 

Ca " is a critical cation necessary for cardiac function in terms of automaticity/ pacemaker activity, conduction of electrical signals, and excitation-contraction coupling of myocytes. Drugs and chemicals that influence Ca flux in cardiac tissue also have a profound effect on the electrical and mechanical function of the heart. The slow Ca " current is mediated, in part, via the voltage-gated L-type Ca channels, one that can be influenced by Ca channel antagonists such as verapamil, D600, and diltiazem. Cardiac toxicity associated with the blockade of this channel can result in the disruption of rhythm and rate, as well as contraction and relaxation, of the heart. 

Cardioversion or defibrillation is the electrical termination of arrhythmias using field stimulation. Unlike pacing, in which cardiac excitation is initiated in and propagates from a small region of tissue near the electrode, cardioversion must arrest electrical activity by simultaneous stimulation of most of the heart. In practice, this means establishing a critical field across a critical mass of cardiac tissue. This requires a compromise between the electrical response of the tissue and the electrical capabilities of the device. The electrical response of cardiac cells is complex, but stimulation mostly depends on the first-order properties of the membrane [6]. Theoretical and experimental studies have shown that the optimum voltage waveform for stimulation of cardiac tissue is a waveform with a characteristic rise time comparable to the cell membrane time constant [7,8]. 

Shaw RM, Rudy Y (1997) Ionic mechanisms of propagation in cardiac tissue. Roles of the sodium and L-type calcium currents during reduced excitability and decreased gap junctimi coupling. Circ Res 81(5) 727-741... 

In this model, e is the ratio of the time scales associated with the reactive dynamics of the two variables u and v, while D and are their diffusion coefficients. The parameters a and p characterize the local reactive dynamics. The FHN model was originally constructed as a simple scheme for describing electrochemical wave propagation in excitable nerve or cardiac tissue. The variable u corresponds to the potential while v represents ion currents in the nerve tissue. It has since been used extensively as a generic model that describes so-called excitable behavior of chemically reacting systems. In fact, as we shall show later in this chapter, it is possible to write a chemical reaction scheme whose rate law is of FUN form. ... 

Targets and spirals have been observed in the CIMA/CDIMA system [13] and also in dilute flames (i.e. flames close to their lean flammability limits) in situations of enlianced heat loss [33]. In such systems, substantial fiiel is left unbumt. Spiral waves have also been implicated in the onset of cardiac arrhytlnnia [32] the nomial contractive events occurring across the atria in the mannnalian heart are, in some sense, equivalent to a wave pulse initiated from the sino-atrial node, which acts as a pacemaker. If this pulse becomes fragmented, perhaps by passing over a region of heart muscle tissue of lower excitability, then spiral structures (in 3D, these are scroll waves) or re-entrant waves may develop. These have the incorrect... 

Ca waves in systems [ike Xenopus laevis oocytes and pancreatic (3 cells fall into this category Electrochemical waves in cardiac and nerve tissue have this origin and the appearance and/or breakup of spiral wave patterns in excitable media are believed to be responsible for various types of arrhythmias in the heart [39, 40]. Figure C3.6.9 shows an excitable spiral wave in dog epicardial muscle [41]. 

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