Pacemaker activity

Physiological response glycogen breakdown visual excitation histamine secretion in all allergic reactions slowing of pacemaker activity that controls the rate of the heartbeat... 

Alreja M, Aghajanian G. Pacemaker activity of locus coeruleus neurons whole-cell recordings in brain slices show dependence on cAMP and protein kinase A. Brain Res 1991 556 339—343. Shiekhattar R, Aston-Jones G. Modulation of opiate responses in brain noradrenergic neurons by cAMP cascade changes with chronic morphine. Neuroscience 1993 57 879-885. 

Gordienko D V, Bolton TB, Cannell MB 1998 Variability in spontaneous subcellular Ca2+ release in guinea-pig ileum smooth muscle cells. J Physiol 507 707-720 Ho R, Shao Z 1991 Axial resolution of confocal microscopes revisited. Optiik 88 147—154 Holz GG, Leech CA, Heller RS, Castonguay N, Habener JF 1999 cAMP-dependent mobilization of intracellular Ca2+ stores by activation of ryanodine receptors in pancreatic [j cells. A Ca2+ signaling system stimulated by the insulinotropic hormone glucagon-like peptide-1-(7-37). J Biol Chem 274 14147-14156 Lipsius SL, Hiiser J, Blatter LA 2001 Intracellular Ca2+ release sparks atrial pacemaker activity. News Physiol Sci 16 101-106... 

Pacemaker activity can be blocked by LSD, which produces a hyperpolarization and a decrease in input resistance. Intracellular studies in the brain slice show that an increase in K+ conductance accounts for these changes. However, LSD... 

Ono, K. and Ito, H. (1995) Role of rapidly activating delayed rectifier K+ current in sinoatrial node pacemaker activity. The American Journal of Physiology, 269... 

Neural innervation Conscious control via spinal Intrinsic pacemaker activity Intrinsic activity with diffuse... 

In the cardiovascular system the effect on the heart rate is prominent. The depressive influence of the nervus vagus on the pacemaking activity in the heart is concentration dependently reduced and thereby the heart rate increases. This can be therapeutically useful in various forms of bardycardia, especially if they are caused by a vagus overstimulation, for example in the carotis-sinus syndrom. There is hardly any effect on the vasculature except a vasodilatation in the thoracic region after very high doses of atropine. 

The rate of pacemaker discharge within these specialized myocytes is influenced by the activity of both divisions of the autonomic nervous system. Increased sympathetic nerve activity to the heart, the release of catecholamines from the adrenal medulla, or the exogenous administration of adrenomimetic amines will cause an increase in the rate of pacemaker activity through stimulation of -adrenoceptors on the pacemaker cells (Figure 16.3). 

The associated initial release of catecholamines may result in an excessive pressor response and stimulation of cardiac force and pacemaker activity. The resulting increase in myocardial oxygen consumption in a patient with ischemic heart disease may lead to ischemic pain (angina pectoris). Patients in a state of circulatory shock probably should not be administered bretylium because of its delayed sympatholytic action. 

Pacemaker activity in the sinoatrial node is decreased because of 3-adrenoceptor blockade and a removal of sympathoadrenal influences on spontaneous diastolic depolarization. Sotalol increases the refractory period of atrial muscle. 

Calcium currents in cardiac tissues serve the functions of inotropy, pacemaker activity (sinoatrial (SA) node), and conduction at the atrioventricular (A-V) node. In principle, the blockade of calcium currents should result in decreased function at these sites. In clinical use, how-... 

Tachyarrhythmias (sinus rate more than 100 per minute) are produced by a disturbances of impulse generation or of impulse conduction in the heart. Tachyarrhythmias due to disturbed impulse formation are associated with irregular and rhythmic discharge from ectopic pacemaker activity in areas of the heart other than the SA node. The characteristic of myocardial cells, which enables them to generate spontaneous depolarization, is called automaticity. 

Direct effects on the heart are determined largely by Bi receptors, although B2 and to a lesser extent a receptors are also involved, especially in heart failure. Beta-receptor activation results in increased calcium influx in cardiac cells. This has both electrical and mechanical consequences. Pacemaker activity—both normal (sinoatrial node) and abnormal (eg, Purkinje fibers)—is increased (positive chronotropic effect). Conduction velocity in the atrioventricular node is increased (positive dromotropic effect), and the refractory period is decreased. Intrinsic contractility is increased (positive inotropic effect), and relaxation is accelerated. As a result, the twitch response of isolated cardiac muscle is increased in tension but abbreviated in duration. In the intact heart, intraventricular pressure rises and falls more rapidly, and ejection time is decreased. These direct effects are easily demonstrated in the absence of reflexes evoked by changes in blood pressure, eg, in isolated myocardial preparations and in patients with ganglionic blockade. In the presence of normal reflex activity, the direct effects on heart rate may be dominated by a reflex response to blood pressure changes. Physiologic stimulation of the heart by catecholamines tends to increase coronary blood flow. 

Schematic representation of the heart and normal cardiac electrical activity (intracellular recordings from areas indicated and ECG). Sinoatrial (SA) node, atrioventricular (AV) node, and Purkinje cells display pacemaker activity (phase 4 depolarization). The ECG is the body surface manifestation of the depolarization and repolarization waves of the heart. The P wave is generated by atrial depolarization, the QRS by ventricular muscle depolarization, and the T wave by ventricular repolarization. Thus, the PR interval is a measure of conduction time from atrium to ventricle, and the QRS duration indicates the time required for all of the ventricular cells to be activated (ie, the intraventricular conduction time). The QT interval reflects the duration of the ventricular action potential.

Latent pacemakers (cells that show slow phase 4 depolarization even under normal conditions, eg, some Purkinje fibers) are particularly prone to acceleration by the above mechanisms. However, all cardiac cells, including normally quiescent atrial and ventricular cells, may show repetitive pacemaker activity when depolarized under appropriate conditions, especially if hypokalemia is also present. 

Arrhythmias are caused by abnormal pacemaker activity or abnormal impulse propagation. Thus, the aim of therapy of the arrhythmias is to reduce ectopic pacemaker activity and modify conduction or refractoriness in reentry circuits to disable circus movement. The major mechanisms currently available for accomplishing these goals are (1) sodium channel blockade, (2) blockade of sympathetic autonomic effects in the heart, (3) prolongation of the effective refractory period, and (4) calcium channel blockade. 

Drug Block of Sodium Channels Refractory Period Calcium Channel Blockade Effect on Pacemaker Activity Sympatholytic Action... 

By blocking sodium channels, procainamide slows the upstroke of the action potential, slows conduction, and prolongs the QRS duration of the ECG. The drug also prolongs the action potential duration by nonspecific blockade of potassium channels. The drug may be somewhat less effective than quinidine (see below) in suppressing abnormal ectopic pacemaker activity but more effective in blocking sodium channels in depolarized cells. 

The cardiovascular effects of local anesthetics result in part from direct effects of these drugs on the cardiac and smooth muscle membranes and from indirect effects on the autonomic nervous system. As described in Chapter 14, local anesthetics block cardiac sodium channels and thus depress abnormal cardiac pacemaker activity, excitability, and conduction. At extremely high concentrations, local anesthetics can also block calcium channels. With the notable exception of cocaine, local anesthetics also depress myocardial contractility and produce direct arteriolar dilation, leading to systemic hypotension. Cardiovascular collapse is rare, but has been reported after large doses of bupivacaine and ropivacaine have been inadvertently administered into the intravascular space. 

The electrophysiologic effects of procainamide are similar to those of quinidine. The drug may be somewhat less effective in suppressing abnormal ectopic pacemaker activity but more effective in blocking sodium channels in depolarized cells. 

Mangoni ME, Couette B, Marger L, Bourinet E, Striessnig J, Nargeot J (2006) Voltage-dependent calcium channels and cardiac pacemaker activity from ionic currents to genes. Prog Biophys Mol Biol 90 38-63... 

Rushforth, N. B. and Burke, D. S., Behavioral and electrophysiological studies of Hydra. II. Pacemaker activity of isolated tentacles, Biol. Bull., 140, 502, 1971. 

Noble, D., Brown, H. F. and Winslow, R. Propagation of pacemaker activity interaction between pacemaker cells and atrial tissue. In Huizinga JD, ed., Pacemaker activity and intercellular communication. CRC Press, New York, 1995, pp 73-92. 

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