Page 210 - Basic _ Clinical Pharmacology ( PDFDrive )

196 SECTION III Cardiovascular-Renal Drugs

Ca 2+
channel
Ca 2+ – blockers

Ca 2+ K +
Calmodulin ATP
+ β 2 agonists

Ca 2+ – Calmodulin complex
cAMP
+ +

MLCK* Myosin-LC kinase MLCK(PO 4 ) 2
(MLCK)
+ + cGMP
Myosin
light chains Myosin-LC-PO 4 Myosin-LC
(myosin-LC)
Actin
–
Contraction ROCK Relaxation

Vascular smooth muscle cell

FIGURE 12–1 A simplified diagram of smooth muscle contraction and the site of action of calcium channel-blocking drugs. Contraction is
triggered (red arrows) by influx of calcium (which can be blocked by calcium channel blockers) through transmembrane calcium channels. The
*
calcium combines with calmodulin to form a complex that converts the enzyme myosin light-chain kinase to its active form (MLCK ). The latter
phosphorylates the myosin light chains, thereby initiating the interaction of myosin with actin. Other proteins, including calponin and caldes-
2+
mon (not shown), inhibit the ATPase activity of myosin during the relaxation of smooth muscle. Interaction with the Ca -calmodulin complex
reduces their interaction with myosin during the contraction cycle. Beta 2 agonists (and other substances that increase cAMP) may cause relax-
ation in smooth muscle (blue arrows) by accelerating the inactivation of MLCK and by facilitating the expulsion of calcium from the cell (not
shown). cGMP facilitates relaxation by the mechanism shown in Figure 12–2. ROCK, Rho kinase.

2+
2. Decreasing intracellular Ca : Calcium channel blockers inactivation of myosin light chain kinase, the enzyme responsi-
predictably cause vasodilation because they reduce intracellular ble for triggering the interaction of actin with myosin in these
2+
Ca , a major modulator of the activation of myosin light chain cells. This appears to be the mechanism of vasodilation caused
kinase (Figure 12–1) in smooth muscle. Beta blockers and by β agonists, drugs that are not used in angina (because they
2
2+
calcium channel blockers also reduce Ca influx in cardiac cause too much cardiac stimulation), and by fenoldopam, a D
1
muscle fibers, thereby reducing rate, contractility, and oxygen agonist used in hypertensive emergencies.
requirement under most circumstances.
3. Stabilizing or preventing depolarization of the vascular ■ BASIC PHARMACOLOGY OF
smooth muscle cell membrane: The membrane potential of
excitable cells is stabilized near the resting potential by increas- DRUGS USED TO TREAT ANGINA
ing potassium permeability. cGMP may increase permeability
2+
+
of Ca -activated K channels. Potassium channel openers, such Drug Action in Angina
as minoxidil sulfate (see Chapter 11), increase the permeability The three drug groups traditionally used in angina (organic nitrates,
+
+
of K channels, probably ATP-dependent K channels. Certain calcium channel blockers, and β blockers) decrease myocardial oxygen
agents used elsewhere and under investigation in the United requirement by decreasing one or more of the major determinants
States (eg, nicorandil) may act, in part, by this mechanism. of oxygen demand (heart size, heart rate, blood pressure, and
4. Increasing cAMP in vascular smooth muscle cells: As shown contractility). In some patients, the nitrates and the calcium
in Figure 12–1, an increase in cAMP increases the rate of channel blockers may cause a redistribution of coronary flow