Calcium channels pacemaker activity

In the myocardium, automaticity is the ability of the cardiac muscle to depolarize spontaneously (i.e., without external electrical stimulation from the autonomic nervous system). This spontaneous depolarization is due to the plasma membrane within the heart that has reduced permeability to potassium (K+) but still allows passive transfer of calcium ions, allowing a net charge to build. Automaticity is most often demonstrated in the sinoatrial (SA) node, the so-called pacemaker cells. Abnormalities in automaticity result in rhythm changes. The mechanism of automaticity involves the pacemaker channels of the HCN (Hyperpolarization-activated, Cyclic Nucleotide-gated) family14 (e.g., If, "funny" current). These poorly selective cation channels conduct more current as the membrane potential becomes more negative, or hyperpolarized. They conduct both potassium and sodium ions. The activity of these channels in the SA node cells causes the membrane potential to slowly become more positive (depolarized) until, eventually, calcium channels are activated and an action potential is initiated. 

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... 

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. 

Drug Norma 1 Cells Depolarize d Cells Norma 1 Cells Depolarize d Cells Calcium Channel Blockad e Effect on Pacemake r Activity Sympatholyti c Action... 

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... 

Cyanide also causes endogenous catecholamine release (Kanthasamyeta/., 1991 Kawada eta/., 2000 Schomiget a/., 1995 Inoue et al, 1998). Inoue et al (1998) also point out that cyanide-produced depolarization increases intracellular calcium due to the suppression of the potassium channels and activation of the voltage-dependent calcium channel. Anoxia induces suppression of the sodium pump and activates cation channels due to the decrease in ATP. A further consequence of the presence of cyanide in the tissue is inhibition of the Na+/Ca + exchanger (NCX) (Ju and Allen, 2005). NCX is important for the pacemaker currents. Metabolic inhibition of NCX reduces the firing rate of pacemaker cells. 

Calcium channel blockers inhibit the passage of calcium through the membrane charmels the result in myocardial cells is to depress contractility, and in pacemaker cells to suppress their automatic activity. Members of the group therefore may have negative cardiac inotropic and chronotropic actions. These actions can be separated nifedipine, at therapeutic concentrations, acts almost exclusively on noncardiac ion charmels and has no clinically useful anti-arrhythmic activity whilst verapamil is a useful antiarrhythmic. 

Purkinje cells is demonstrated in Figure 12.1 and, like all cardiac myocytes, can be divided into four phases. Phase 4 (pacemaker potential) involves the slow influx of sodium ions, depolarizing the cell until the threshold potential is reached. Once the threshold potential is reached, the fast sodium current is activated, resulting in a rapid influx of sodium ions causing cell depolarization (phase 0 rapid depolarization). Phase 1 (partial repolarization) involves the inactivation of sodium channels and a transient outward current. Phase 2 (plateau phase) results from the slow influx of calcium ions. Repolarization (phase 3) occurs as a result of outflow of potassium ions from the cell and restores the resting potential. There are variations between the different areas of the heart, specifically the nodal tissues do not possess fast sodium channels and slow L-t5rpe calcium channels generate phase 0 current (Fig. 12.1). Phase 4 activity varies between nodal areas the sinoatrial node depolarizes more rapidly than the atrioventricular (AV) node. Automaticity is under autonomic nervous system control. Parasympathetic neurons... 

The worker heart muscle cells (as opposed to the cells in the conduction system, which are also specialized muscle cells) are peculiar in using both Na and Ca in the depolarization phase of the action potential (Figure 5.8b, bottom). While they do not normally create action potentials themselves, under pathological conditions some of them may show spontaneous discharge. This depolarization may then spread across the entire heart (or parts of it) and interfere with normal and regular activity. While both calcium and sodium channel blockers have their applications in treating heart arrhythmias, the beauty of the sodium channel blockers is that they will not interfere with the activity of the regular pacemakers (since those essentially don t use sodium channels). Another beneficial feature was pointed out above Lidocaine extends the duration of the inacti-... 

Vasoactive intestinal peptide (VIP), a neurotransmitter, is found in extrinsic and intrinsic nerves of the heart. VIP is released by the vagal nerve, and its effect is to increase If and pacemaker rates (Chang etfl/., 1994 Acchi eta/., 1996). VIP release takes place under high-frequency stimulation. As an internal brake, it limits the ability of ACh to excessively suppress the sinus node and other pacemakers. It also has an effect on the calcium-activated potassium channel. 

Many antiarrhythmic drugs have local anaesihciic activity (i.c, block voliagc-dependetu Na channels) or are calcium aniagonisLs. These actions decrease the automaticity of pacemaker cells and increase the effective refrticlory jxrritxl of atrial, ventricular and Purkinje fibres. 

The main experimental use of barium is in electrophysiology where it can be used as a charged probe for metal ion-dependent processes. The isolation and identification of individual ion fluxes which contribute to the electric currents flowing through cell membranes often requires techniques to block specific components of electrical activity. This can sometimes be achieved by the use of the soluble salts of divalent cations such as barium and manganese which may block potassium and calcium and currents in, for example, the cardiac pacemaker [4]. Barium can also be used to identify potassium-conducting channels in isolated membrane vesicles [S,6] or calcium charmels in isolated heart muscle cells, myocytes [7], and adrenal gland chromaffin cells [8]. 

Weisbrod D, Khun SH, Bueno H, Peretz A, Attali B (2016) Mechanisms underlying the cardiac pacemaker the role of SK4 calcium-activated potassium channels. Acta Pharmacol Sin 37 82-97... 

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