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 caldesmon (not shown), inhibit the ATPase activity of myosin during the relaxation of smooth muscle. Interaction with the Ca2+-calmodulin complex reduces their interaction with myosin during the contraction cycle. Beta2 agonists (and other substances that increase cAMP) may cause relaxation 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.
Decreasing intracellular Ca2+: Calcium channel blockers predictably cause vasodilation because they reduce intracellular Ca2+, a major modulator of the activation of myosin light chain kinase (Figure 12–1) in smooth muscle. Beta blockers and calcium channel blockers also reduce Ca2+ influx in cardiac muscle fibers, thereby reducing rate, contractility, and oxygen requirement under most circumstances.
3.
Stabilizing or preventing depolarization of the vascular smooth muscle cell membrane: The membrane potential of excitable cells is stabilized near the resting potential by increasing potassium permeability. cGMP may increase permeability of Ca2+-activated K+ channels. Potassium channel openers, such as minoxidil sulfate (see Chapter 11), increase the permeability of K+ channels, probably ATP-dependent K+ channels. Certain agents used elsewhere and under investigation in the United States (eg, nicorandil) may act, in part, by this mechanism.
4.
Increasing cAMP in vascular smooth muscle cells: As shown in Figure 12–1, an increase in cAMP increases the rate of inactivation of myosin light chain kinase, the enzyme responsible for triggering the interaction of actin with myosin in these cells. This appears to be the mechanism of vasodilation caused by β2 agonists, drugs that are not used in angina (because they cause too much cardiac stimulation), and by fenoldopam, a D1 agonist used in hypertensive emergencies.
The three drug groups traditionally used in angina (organic nitrates, calcium channel blockers, and β blockers) decrease myocardial oxygen requirement by decreasing one or more of the major determinants of oxygen demand (heart size, heart rate, blood pressure, and contractility). In some patients, the nitrates and the calcium channel blockers may cause a redistribution of coronary flow
FIGURE 12–2 Mechanism of action of nitrates, nitrites, and other substances that increase the concentration of nitric oxide (NO) in vascular smooth muscle cells. Steps leading to relaxation are shown with blue arrows. MLCK*, activated myosin light-chain kinase (see Figure 12–1). Nitrosothiols (SNOs) appear to have non-cGMP-dependent effects on potassium channels and Ca2+-ATPase. eNOS, endothelial nitric oxide synthase; GC * , activated guanylyl cyclase; mtALDH2, mitochondrial aldehyde dehydrogenase-2; PDE, phosphodiesterase; ROCK, Rho kinase.
and increase oxygen delivery to ischemic tissue. In variant angina, these two drug groups also increase myocardial oxygen delivery by reversing coronary artery spasm. Newer drugs are discussed later.