Page 244 - Basic _ Clinical Pharmacology ( PDFDrive )

230 SECTION III Cardiovascular-Renal Drugs

where C and C are the extracellular and intracellular ion con- of other factors, including permeant ion concentrations, tissue
e
i
centrations, respectively. Thus, the movement of an ion across metabolic activity, and second messenger signaling pathways.
the membrane of a cell is a function of the difference between Pumps and exchangers that contribute indirectly to the mem-
the transmembrane potential and the equilibrium potential. brane potential by creating ion gradients (as discussed above) can
This is also known as the “electrochemical gradient” or “driving also contribute directly because of the current they generate through
force.” the unequal exchange of charged ions across the membrane. Such
The relative permeability of the membrane to different ions transporters are referred to as being “electrogenic.” An important
determines the transmembrane potential. However, ions contrib- example is the sodium-calcium exchanger (NCX). Throughout
uting to this potential difference are unable to freely diffuse across most of the cardiac action potential, this exchanger couples the
the lipid membrane of a cell. Their permeability relies on aqueous movement of one calcium ion out of the cell for every three sodium
channels (specific pore-forming proteins). The ion channels that ions that move in, thus generating a net inward or depolarizing
are thought to contribute to cardiac action potentials are illus- current. Although this current is typically small during diastole,
trated in Figure 14–2. Most channels are relatively ion-specific, when intracellular calcium levels are low, spontaneous release of
and the current generated by the flux of ions through them is calcium from intracellular storage sites can generate a depolarizing
controlled by “gates” (flexible portions of the peptide chains that current that contributes to pacemaker activity as well as arrhythmo-
make up the channel proteins). Sodium, calcium, and some potas- genic events called delayed afterdepolarizations (see below).
sium channels are thought to have two types of gates—one that
opens or activates the channel and another that closes or inacti- The Active Cell Membrane
vates the channel. For the majority of the channels responsible
for the cardiac action potential, the movement of these gates is In atrial and ventricular cells, the diastolic membrane potential
controlled by voltage changes across the cell membrane; that is, (phase 4) is typically very stable. This is because it is dominated by
they are voltage-sensitive. However, certain channels are primar- a potassium permeability or conductance that is due to the activity
ily ligand- rather than voltage-gated. Furthermore, the activity of of channels that generate an inward-rectifying potassium current
many voltage-gated ion channels can be modulated by a variety (I ). This keeps the membrane potential near the potassium
K1

1
2
inward
outward 0 3
Phase 4 Gene/protein

+
Na current SCN5A/Nav 1.5
Ca 2+ L-type CACNA1/Cav 1.2
current T-type CACNA1G, H/Cav 3.1, 3.2

transient l to,f KCND3/Kv 4.3
outward
current l to,s KCNA4/Kv 1.4
l Ks KCNQ1/KvLQT 1
delayed
rectifiers l Kr KCNH2/hERG
(l K )
l Kur KCNA5/Kv 1.5
l K,ACh KCNJ3, 5/Kir 3.1, 3.4
l Cl CFTR/CFTR

inward rectifier, l K1 KCNJ2/Kir 2.1
pacemaker current, l f HCN2, 4/HCN2, 4
+
2+
Na /Ca exchange SLC8A1/NCX 1
+
+
Na /K -ATPase NKAIN1-4/Na, K-pump
FIGURE 14–2 Schematic diagram of the ion permeability changes and transport processes that occur during an action potential and the
diastolic period following it. Yellow indicates inward (depolarizing) membrane currents; blue indicates outward (repolarizing) membrane currents.
Multiple subtypes of potassium and calcium currents, with different sensitivities to blocking drugs, have been identified. The right side of the
figure lists the genes and proteins responsible for each type of channel or transporter.