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General Toxicology Lec.2 Cardiovascular toxicity Cardiac Structure The cardiovascular system consists of the myocardium and vascular vessels which supply the tissues and cells of the body with appropriate nutrients, respiratory gases, hormones, and metabolites and remove the waste products of tissue. In addition to the maintaining of the optimal internal homeostasis of the body as well as for critical regulation of body temperature and maintenance of tissue and cellular pH. Cardiac myocytes are composed of contractile elements known as myofibrils, which consist of a number of thick and thin myofilaments. The thick filaments consist of the protein myosin, whereas the thin filaments primarily consist of the protein actin. Cardiac myocytes are joined end to end by intercalated disks. Within those disks, there are tight gap junctions that facilitate action potential propagation and intercellular communication. Cardiac Electrophysiology Action Potential The ionic movement of action potential can be classified into 4 phases: Phase 0: a phase of rapid depolarization due to a fast inflow of Na + into the cells. Phase 1: a short initial period of rapid repolarization caused mainly by outflow of K+ from the cells. Phase 2: a period of delay in repolarization caused by inflow of Ca +2 into the cells. Phase 3: a second period of rapid repolarization caused mainly by outflow of K+ from the cell . Phase 4: It’s a fully repolarized state during which Na+ and Ca+2 move out of the cell while K+ move back into the cell Electrical Conduction in the Heart Spontaneous depolarization can be found in the sinoatrial (SA) node, the atrioventricular (AV) node, the bundle of His (atrioventricular bundle), and Purkinje fibers. SA nodal cells set the pace of the heart. If the SA node is damaged or inhibited, the next fastest depolarizing cells (AV node) assume the pacemaking activity. The dense fibrous tissue of the AV node causes the electrical impulse to slow down. This delayed transfer of current between the atria and the ventricles allows the atria to complete contraction before depolarization of the ventricles. Electrical cardiac activity is regulated by the autonomic nervous system (ANS). Norepinephrine and similar sympathomimetics stimulate an increase in cardiac rate and the contractility of the myocardium. The major effect of parasympathomimetics is to decrease the rate of depolarization with only a slight decrease in ventricular contractility. Excitation-Contraction Coupling For contraction to occur, both ATP and Ca2 + must be available. Mechanical contraction of cardiac myocytes occurs when Ca2 + binds to the protein troponin C with tropomysin. After a Ca2 +-induced conformational change in troponin C and tropomysin, ATP is hydrolyzed, and subsequently allowing myosin to bind actin, thus producing contraction. 2 Electrocardiogram: The P wave is generated by atrial depolarization, the QRS by ventricular muscle depolarization, and the T wave by ventricular repolarization. The PR interval is a measure of conduction time from atrium to ventricle through AV node, and the QRS duration indicates the time required for all ventricular cells to be activated ( i.e the intraventricular conduction time). The QT interval reflects the duration of the ventricular action potential. Cardiac Output Normal cardiac output at rest is approximately 5 L/min in an average adult human, and that value may increase three- to fourfold during exercise. Toxicants may alter cardiac output Abnormal Heart Rhythm The normal human heart rate at rest is approximately 70 beats per minute. A rapid resting heart rate (i.e., above 100 beats per minute) is known as tachycardia, whereas a slow heart rate (i.e., below 60 beats per minute) is known as bradycardia. Any variation from normal rhythm is termed an arrhythmia, and arrhythmias are often complications secondary to other ongoing disturbances in cardiac function. Supraventricular arrhythmias may be based on defects in AV nodal reentry circuits. Ventricular arrhythmias may arise from muscle injury secondary to 3 ischemia, infarction, or from ventricular hypertrophy. Heart block is due to impairments in the cardiac conducting system. Ischemic Heart Disease Ischemic heart disease (IHD) may be produced by various pathologic conditions and/or xenobiotics that disturb the balance of myocardial perfusion and myocardial oxygen and nutrient demand. A major cause of IHD is coronary artery atherosclerosis and the resulting arterial obstruction. Prolonged ischemia may lead to myocardial infarction, or death of myocardial cells because of lack of blood flow. Areas of the heart that are permanently damaged by myocardial infarction are replaced with scar tissue. The cardiac remodeling process thus includes hypertrophy of remaining myocytes, , and microcirculatory changes within the heart. Cardiac Hypertrophy and Heart Failure Cardiac hypertrophy is an important component of cardiac remodeling after IHD. However, cardiac hypertrophy is often a compensatory response of the heart to an increased workload. For example, prolonged hypertension contributes to load-induced left ventricular hypertrophy. hypertrophy of the surviving myocytes may be necessary to sustain cardiac output for life support. At some point in the progression of IHD, however, the hypertrophic myocardium may "decompensate" by unknown mechanisms, resulting in failure. During failure, ventricular contractility and/or compliance are reduced such that cardiac output is diminished. Failure may present as left-or right-sided failure or both. When left-sided failure is the primary pathology, blood pools in the lungs and pulmonary edema develops. When right-sided failure is the primary pathology, blood pools in the extremities and pitting edema is found in the lower legs. Cardiomyopathies The term cardiomyopathy essentially refers to any disease state that alters myocardial function. Therefore, causes of cardiomyopathy include IHD (ischemic cardiomyopathy), cardiac hypertrophy, infectious diseases (e.g., viral cardiomyopathy), drug- or chemical-induced cardiomyopathy, and unknown causes (idiopathic cardiomyopathy). 4 General Mechanisms of Cardiotoxicity 1-Interference with Ion Homeostasis any xenobiotic that disrupts ion movement or homeostasis may induce a cardiotoxic reaction that consists principally of disturbances in heart rhythm. This disruption include: Inhibition of Na+,K+-ATPase Na+,K+-ATPase reduces intracellular Na+ in exchange for extracellular K+. Inhibition of cardiac Na+,K+-ATPase increases resting intracellular Na+ concentrations. This in turn increases intracellular Ca2 + concentrations through Na+/Ca2 + exchange, and the elevated intracellular Ca2 + and Ca2 + stores thus contribute to the inotropic actions of these inhibitors. Na+ Channel Blockade Agents that inhibit Na+ channels in cardiac cells alter cardiac excitability, results in reduction of conduction velocity, prolonged QRS duration, decreased automaticity K+ Channel Blockade Many different K+ channels are expressed in the human heart. Blockade of K+ channels increases the duration of the action potential and increases refractoriness (the cell undergoing repolarization is refractory to depolarization). Ca2+ Channel Blockade The L-type Ca2 + channel contributes to excitation-contraction coupling, whereas the T-type Ca2 + channels contribute to pacemaker potential in the SA node. Blockade of Ca2 + channels in the heart produces a negative inotropic effect. 2-Altered coronary blood flow 1-Coronary Vasoconstriction Xenobiotic-induced constriction of the coronary vasculature induces symptoms consistent with IHD. Epinephrine stimulation of β-adrenergic receptors increases heart rate, contractility, and myocardial oxygen consumption. The direct effect of sympathomimetics on the coronary 5 vasculature includes coronary vasospasm through activation of αadrenergic receptors. When β-adrenergic receptors are blocked or during underlying pathophysiologic conditions of the heart, the direct actions of sympathomimetics may predominate, leading to coronary vasoconstriction. 2-Ischemia-Reperfusion Injury Relief of the cause of ischemia provides reperfusion of the myocardium. Reperfusion of the myocardium leads to subsequent tissue damage that may be reversible or permanent, a phenomenon is known as ischemia-reperfusion (I/R) injury. Mechanisms proposed to account for the reperfusion injury include the generation of toxic oxygen radicals, Ca2+ overload, changes in cellular pH, uncoupling of mitochondrial oxidative phosphorylation, and physical damage to the sarcolemma (the cell membrane of a striated muscle fiber cell). 3-Oxidative Stress Reactive oxygen species are generated during myocardial ischemia and at the time of reperfusion. In patients with atherosclerosis, oxidative alteration of low-density lipoprotein is thought to be involved in the formation of atherosclerotic plaques. Xenobiotics such as doxorubicin and ethanol may induce cardiotoxicity through the generation of reactive oxygen species. 3-Organellar Dysfunction 1- Sarcolemmal Injury, sarcoplasmic reticulum (SR) Dysfunction, and Ca2+ Overload: All cells contain systems for the regulation of intracellular Ca2 +. Because extracellular Ca2 + concentrations are typically higher than resting intracellular free Ca2 +, the sarcolemmal membrane must prevent a rapid influx of Ca2 + and subsequent Ca2 + overload. The principal Ca2 + regulatory organelle in cardiac myocytes is the sarcoplasmic reticulum (SR). Alterations of cardiac Ca2 + homeostasis by toxicants may perturb the regulation of cellular functions. 2- Mitochondrial Injury: ATP is the immediate energy source required for work in most biological systems and is obtained mainly through the oxidative phosphorylation of adenine diphosphate (ADP) in the mitochondria. Oxidative phosphorylation can be affected at various sites along the respiratory chain through the use of different chemical inhibitors, such as rotenone, cyanide, and antimycin A. Conversely, uncouplers such as 2,4-dinitrophenol prevent the formation of ATP. 6 3- Apoptosis (programmed cell death) In the early periods after myocardial infarction, ishemic injury, I/R injury, or toxicant-induced injury, cardiac myocyte death probably occurs through apoptotic pathways. Xenobiotics that are associated with the induction of cardiac myocyte apoptosis in vitro include cocaine, daunorubicin, doxorubicin, isoproterenol, and norepinephrine. Cardiotoxicants: Pharmaceutical Agents The cardiotoxicity of a cardiovascular drug often represents an overexpression of its principal pharmacologic effect on the heart. For example, digitalis, quinidine, and procainamide may induce cardiac arrhythmias as an exaggerated pharmacologic action of those drugs. In contrast, drugs may produce cardiotoxicity by actions that are not necessarily related to their intended therapeutic use. 1-Alcohol The acute toxicity of ethanol includes reduced conductivity. Chronic consumption of ethanol by humans has been associated with myocardial abnormalities, arrhythmias, and a condition known as alcoholic cardiomyopathy. Metabolites from the metabolism of ethanol eg. acetaldehyde may lead to lipid peroxidation of cardiac myocytes and inhibition of protein synthesis. 2-Antiarrhythmic and Inotropic Agents -Cardiac Glycosides Cardiac glycosides (digoxin and digitoxin) used for the treatment of congestive heart failure inhibit Na+,K+-ATPase, elevate intracellular Na+, activate Na+/Ca2 + exchange, and increase the availability of intracellular Ca2 + for contraction. Cardiotoxicity may result from Ca2 + overload, and arrhythmias may occur. -Catecholamines and Sympathomimetics Catecholamine-induced cardiotoxicity includes increased heart rate, enhanced myocardial oxygen demand, and an overall increase in systolic arterial blood pressure. 7 -Anthracyclines and Other Antineoplastic Agents Doxorubicin and daunorubicin are antineoplastic agents whose clinical usefulness is limited because of cardiotoxicity. The acute effects mimic anaphylactic-type responses such as tachycardia and various arrhythmias. These effects are usually manageable and most likely are due to the potent release of histamine from mast cells that sometimes is observed in acute dosing. Long-term exposure to anthracyclines often results in the development of cardiomyopathies and, in severe stages, congestive heart failure. 3- Centrally Acting Drugs -Tricyclic Antidepressants: Standard tricyclic antidepressants have significant cardiotoxic actions, particularly in cases of overdose, that include ECG abnormalities and sudden cardiac death. As a result of peripheral α-adrenergic blockade, postural hypotension is a prevalent cardiovascular effect. The tricyclics also may have direct cardiotoxic actions on cardiac myocytes and Purkinje fibers, depressing inward Na+ and Ca2 + and outward K+ currents. -Antipsychotic Agents The adverse cardiovascular effect of antipsychotic agents is orthostatic hypotension. Direct effects on the myocardium include negative inotropic actions. 4- General Anesthetics Inhalational general anesthetics may reduce cardiac output by 20 to 50 percent, depress contractility, and produce arrhythmias. Halothane, as a prototype, may block Ca2 + channels, disrupt Ca2 + homeostasis associated with the SR, and modify the responsiveness of contractile proteins to activation by Ca2 +. 5- Local Anesthetics Local anesthetics interfere with the transmission of nerve impulses in other excitable organs, including the heart and the circulatory system. 8 6- Cocaine The cardiotoxicity of cocaine includes its ability to act as a local anesthetic and block nerve conduction by reversibly inhibiting Na + channels. In the heart, cocaine decreases the rate of depolarization and the amplitude of the action potential, slows conduction speed, and increases the effective refractory period. 7- Androgens Anabolic steroids increase low-density lipoprotein (LDL) and decrease high-density lipoprotein (HDL) cholesterol. high-dose has been associated with cardiac hypertrophy and myocardial infarction. 8- Glucocorticoids Chronic glucocorticoid therapy often results in elevated total, LDL, and HDL cholesterols. Furthermore, glucocorticoids are known to cause Na+ and water retention which could produce hypertension during chronic therapy. Glucocorticoids may induce hypertrophic growth and alter the expression of several ion transporters. 9- Thyroid Hormones Hypothyroid states are associated with decreased heart rate, contractility, and cardiac output, whereas hyperthyroid states are associated with increased heart rate, contractility, cardiac output, ejection fraction. Vascular system toxicity The vascular system delivers oxygen and nutrients to tissues throughout the body and removes the waste products of cellular metabolism. Disturbances of Vascular Structure and Function: Atherosclerosis involves focal intimal thickenings formed after the migration of smooth muscle cells to the intima and uncontrolled proliferation with collagen and elastin, intra- and extracellular lipids, complex carbohydrates, blood products, and calcium accumulate to 9 varying degrees as the lesion advances. The plaque also contains inflammatory cells, such as monocytes and leukocytes, that leads to a restricted blood supply to distal sites. Oxidative metabolism of plasma lipoproteins is critical in the initiation and progression of atherosclerosis. LDLs are oxidized by oxygen free radicals that are released by arterial cells. Modified LDLs attract macrophages and prevent their migration from the tissues. Oxidation of LDLs generates activated oxygen species, which can directly injure endothelial cells and increase adherence and the migration of monocytes and T lymphocytes into the subendothelial space. Subsequent release of growth modulators from endothelial cells and/or macrophages can promote smooth muscle cell proliferation and the secretion of extracellular matrix proteins. Hypotension, a sustained reduction in systemic arterial pressure, is common in poisonings with CNS depressants or antihypertensive agents. Postural hypotension, can be induced by agents such as drugs that lower cardiac output or decrease blood volume. Hypertension may result from an increased concentration of circulating vasoconstrictors such as angiotensin II and catecholamines. Sustained hypertension is the most important risk factor that predisposes a person to coronary and cerebral atherosclerosis. Thrombosis, is the formation of a semisolid mass from blood constituents in the circulation, can occur in both arteries and veins as a result of exposure to toxicants. thrombosis occurs by means of induction of platelet aggregation, an increase in their adhesiveness, or the creation of a state of hypercoagulability through an increase in or activation of clotting factors. Portions of a thrombus may be released and travel in the vascular system until they are arrested as an embolus in a vessel with a caliber even smaller than that of its origin. The consequence depends on the site of arrest, but a thrombus can result in death. General Biochemical Mechanisms of Vascular Toxicity Chemicals absorbed through the gastrointestinal, respiratory, cutaneous, and intravenous routes contact vascular cells before reaching other sites in the body. This property alone puts the vascular system at increased risk of toxic insult. Many target organ toxicities have a significant microvascular component. Chemicals can produce degenerative or 10 inflammatory changes in blood vessels as a direct consequence of an excessive pharmacologic effect or secondary to the interaction of chemicals or their metabolites with components of the vessel wall. Common mechanisms of vascular toxicity include membrane structure and function. (1) alterations in (2) redox stress leading to disruption of gene regulatory mechanisms, compromised antioxidant defenses, and generalized loss of homeostasis, (3) vessel-specific bioactivation of protoxicants. (4) Accumulation of the active toxin in vascular cells. (5) deficiencies in the capacity of target cells to detoxify the active toxin. Agents: Nicotine Nicotine at pharmacologic doses increases heart rate and blood pressure as a result of stimulation of sympathetic ganglia and the adrenal medulla. Cocaine It causes increase in circulating levels of catecholamines and a generalized state of vasoconstriction. Hypertension and cerebral strokes are notable vascular complications. Oral Contraceptives can produce thromboembolic disorders such as deep vein phlebitis and pulmonary embolism. Intracranial venous thrombosis and secondary increases in the risk of stroke. Natural Products Bacterial Endotoxins 11 Bacterial Endotoxins produce various toxic effects to the liver causes endothelial swelling. In the lung, endotoxins increase vascular permeability and pulmonary hypertension. Vitamin D Vitamin D hypervitaminosis causes degeneration, calcification of the coronary arteries. Industrial Agents Heavy Metals: lead, has direct vasoconstrictor effect. Inorganic mercury produces vasoconstriction of preglomerular vessels and disrupts the integrity of the blood-brain barrier. Acute arsenic poisoning causes capillary dilation, which contributes to transudation of plasma and decreased intravascular volume. Gases -Carbon Monoxide The toxic effects of carbon monoxide have been attributed to the formation of carboxyhemoglobin because carboxyhemoglobin decreases the oxygen-carrying capacity of blood, causing functional anemia. -Oxygen The administration of oxygen to a premature newborn can cause irreversible vasoconstriction and blindness. 12