Myocardial contraction/contractility

Mechanism of Action A cardiac inotropic agent that increases the influx of calcium from extracellular to intracellular cytoplasm. Therapeutic Effect Potentiates the activity of the contractile cardiac muscle fibers and increases the force of myocardial contraction. Slows the heart rate by decreasing conduction through the SA and AV nodes. Pharmacokinetics ... 

Cardiac output Digitalis increases the cardiac output in CHF patients by increasing the force of myocardial contraction. It also increases the contractility of normal heart but cardiac output remains unchanged or is slightly decreased. In normal individuals, it increases the tone of arteries as well as that of the veins. 

Beta antagonists are generally administered for their effect on the beta-1 receptors that are located on the heart.31 When stimulated, these receptors mediate an increase in cardiac contractility and rate of contraction. By blocking these receptors, beta antagonists reduce the rate and force of myocardial contractions. Consequently, beta antagonists are frequently used to decrease cardiac workload in conditions such as hypertension and certain types of angina pectoris. Beta blockers may also be used to normalize heart rate in certain forms of cardiac arrhythmias. Specific clinical applications of individual beta blockers are summarized in Table 20-2. 

In the past, beta blockers were considered detrimental in patients with heart failure.60 As indicated in Chapter 20, these drugs decrease heart rate and myocardial contraction force by blocking the effects of epinephrine and norepinephrine on the heart. Common sense dictated that a decrease in myocardial contractility would be counterproductive in heart failure, and beta blockers were therefore contraindicated in heart failure.60,69 It is now recognized that beta blockers are actually beneficial in people with heart failure because these drugs attenuate the excessive sympathetic activity associated with this disease.56,64 As indicated earlier,... 

Decreased myocardial contractility is due to calcium influx into the cell, which results in increased release of calcium from the sarcoplasmic reticulum. The overall effect of this calcium influx and release is the bridging of actin and myosin and subsequent myocardial contraction. The negative inotropic effect of the calcium blockers is due to interference with this process. 

Extravascnlar resistance may decrease coronary blood flow, primarily during systole. This effect is much more pronounced in the left ventricle compared with the right ventricle. When the effect of increased contractility is separated from the effect of ventricular pressure, about 75% of extravascnlar resistance is accounted for by passive stretch in equilibrium with ventricular pressure, whereas only 25% results from active myocardial contraction. 

To better understand certain aspects of the mechanism of digitalis drugs, it would be useful to outline briefly their cardiovascular properties. The increased force of myocardial contraction produced by these glycosides is by far their most dramatic pharmacodynamic property. This positive inotropic (increased contractile force) action translates into increased cardiac output and effects on cardiac size and blood volume through diuresis (i.e., the relief of the edema that accompanies CHF). The rate of tension development is apparently affected, not the length of time during which contraction is maintained by the muscle fiber. Digitalis exerts its effect even in the presence of p-blockers or reserpine. 

The events triggered by hormones and sometimes by cAMP are unidirectional (for example, the stimulation of steroidogenesis in the adrenal) or bidirectional (for example, stimulation of mitosis with low doses of cAMP, and inhibition of mitosis at high doses of cAMP see Chapter 16). A new interpretation of the regulation of the bidirectional events rests on the discovery of cyclic GMP. Again, the stimulation of myocardial contraction by epinephrine or isoproteranol induces a proportionate increase in cAMP levels, and a decrease in cGMP also takes place. The acetylcholine-induced decrease in myocardial contractility is associated with a twofold increase in cGMP and only a small or delayed decrease in cAMP. 

Although blood pressure control follows Ohm s law and seems to be simple, it underlies a complex circuit of interrelated systems. Hence, numerous physiologic systems that have pleiotropic effects and interact in complex fashion have been found to modulate blood pressure. Because of their number and complexity it is beyond the scope of the current account to cover all mechanisms and feedback circuits involved in blood pressure control. Rather, an overview of the clinically most relevant ones is presented. These systems include the heart, the blood vessels, the extracellular volume, the kidneys, the nervous system, a variety of humoral factors, and molecular events at the cellular level. They are intertwined to maintain adequate tissue perfusion and nutrition. Normal blood pressure control can be related to cardiac output and the total peripheral resistance. The stroke volume and the heart rate determine cardiac output. Each cycle of cardiac contraction propels a bolus of about 70 ml blood into the systemic arterial system. As one example of the interaction of these multiple systems, the stroke volume is dependent in part on intravascular volume regulated by the kidneys as well as on myocardial contractility. The latter is, in turn, a complex function involving sympathetic and parasympathetic control of heart rate intrinsic activity of the cardiac conduction system complex membrane transport and cellular events requiring influx of calcium, which lead to myocardial fibre shortening and relaxation and affects the humoral substances (e.g., catecholamines) in stimulation heart rate and myocardial fibre tension. 

Ca2+ is an important intracellular second messenger that controls cellular functions including muscle contraction in smooth and cardiac muscle. Ca2+ channel blockers inhibit depolarization-induced Ca2+ entry into muscle cells in the cardiovascular system causing a decrease in blood pressure, decreased cardiac contractility, and antiarrhythmic effects. Therefore, these drugs are used clinically to treat hypertension, myocardial ischemia, and cardiac arrhythmias. 

Myeloproliferative disorder A group of diseases of the bone marrow in which excess cells, usually lymphocytes, are produced. Myelosuppression A condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets. Myelosuppression is a side effect of some cancer treatments. Myocardial contractility The force of contraction of the heart during systole. 

Changes in heart rate also affect the contractility of the heart. As heart rate increases, so does ventricular contractility. The mechanism of this effect involves the gradual increase of intracellular calcium. When the electrical impulse stimulates the myocardial cell, permeability to calcium is increased and calcium enters the cell, allowing it to contract. Between beats, the calcium is removed from the intracellular fluid and the muscle relaxes. When heart rate is increased, periods of calcium influx occur more frequently and time for calcium removal is reduced. The net effect is an increase in intracellular calcium, an increased number of crossbridges cycling, and an increase in tension development. 

Verapamil possesses antiarrhythmic, antianginal, and hypotensive activity. It reduces the myocardial need for oxygen by reducing contractility of the myocardium and slowing the frequency of cardiac contractions. It causes dilation of coronary arteries and increased coronary blood flow. It reduces tonicity of smooth musculature, peripheral arteries, and overall peripheral vascular resistance. It provides antiarrhythmic action in supraventricular arrhythmia. 

Laager, G.A. Ion fluxes in cardiac excitation and contraction and their relation to myocardial contractility. Physiol. Rev. 48 708-757, 1968. 

Digoxin remains the mainstay of treatment for patients with chronic myocardial failure. Other drugs with inotropic and/or vasodilator properties, including the catecholamines and phosphodiesterase III (PDE) inhibitors, are used in the treatment of acute cardiac failure. The inotropic actions of most of these drugs result from a direct or indirect elevation of [Ca2-i-]i (intracellular Ca2+ concentration). This acts as a trigger for a process which leads to increased contractile state and cardiac contraction (Figures 8.3 and 8.4). Myofilament calcium sensitisers increase the sensitivity of contractile proteins to calcium. Some newer drugs, such as vesnarinone, have multiple mechanisms of action. 

There is a risk of inducing uterine contractions if adrenaline is used in late pregnancy. Increased oxygen demand resulting from increases in heart rate and myocardial contractility may outstrip the myocardial oxygen supply and predispose to ischaemia. 

In acute or chronic ischemia patients, angiogenic potential of transplanted cells is of the greatest importance. The patients with chronic nonviable scar and myocardial dysfunction are more likely to benefit from the cells that, either directly or indirectly (via paracrine effect) (47), improve the contractility of the treated myocardium (9). Autologous skeletal myoblasts have been successfully expanded in vitro and implanted in the myocardia of animals. Although they do not contract synchronously with the rest of the myocardium and do not integrate into it, they have been shown to improve contractility... 

The contractile machinery of the myocardial cell is essentially the same as in striated muscle. The force of contraction of the cardiac muscle is directly related to the concentration of free (unbound) cytosolic calcium. Therefore agents that increase these calcium levels (or increase the sensitivity of the contractile machinery to calcium) result in an increase in the force of contraction (inotropic effect). [Note The inotropic agents increase the contractility of the heart by directly or indirectly altering the mechanisms that control the concentration of intracellular calcium.]... 

The effect of ATP-vesicles after chemical hypoxia on myocardial contractility was also determined. After removal of KCN, 50 pL of calcium chloride (2 mM) was added and the cells were stimulated with 0.5-4 Hz, 8-V electric stimulator in an Ion Optix Fluorescence and Contractility System. The contractility data were analyzed with computer software. With 4 Hz stimulation, the velocity of contraction of the... 

Figure 2. Coronary microembolization causes a progressive perfusion-contraction mismatch, i. e. contractile function is progressively reduced, whereas regional myocardial blood flow remains unaltered (by permission from Dorge39).

Heart failure can result from any disorder that affects the ability of the heart to contract (systolic function) and/or relax (diastolic dysfunction) common causes of heart failure are shown in Table 14—1 Systolic heart failure is the classic, more familiar form of the disorder, but current estimates suggest that 20% to 50% of patients with heart failure have preserved left ventricular systolic function and suffer from diastolic dysfunction. In contrast to systolic heart failure that is usually caused by previous myocardial infarction (Ml), patients with diastolic heart failure typically are elderly, female, and have hypertension and diabetes. However, systolic and diastolic dysfunction frequently coexist. The common cardiovascular diseases such as MI and hypertension can cause both systolic and diastolic dysfunction thus many patients have heart failure as a result of reduced myocardial contractility and abnormal ventricular filling. 

---