System cardiovascular

Cardiovascular toxins are those chemicals that are toxic to the heart, blood vessels, and blood. More than 500 individual chemicals fall into this category. Table 29.1 contains a partial list of these compounds. A more complete list, along with primary references, is contained on the Scorecard web site, t1] 

It is beyond the scope and outside the intended purpose of this book to explore the individual cardiovascular toxicities of these compounds. Following, however, are a few examples of these. 

Arteriosclerosis, commonly called hardening of the arteries, is a hardening and thickening of the arterial walls resulting in loss of elasticity. Atherosclerosis is a form of arteriosclerosis characterized by the deposition of plaques on the innermost layers of large- and medium-sized arteries. 1,3-butadiene, widely used as a monomer in the rubber and plastics industries and a component of cigarette smoke, has been shown to accelerate the development of atherosclerosis by promoting plaque development J2,31 

Intentional inhalation, or huffing, of volatile organic chemicals for the purpose of inducing euphoria can bring on cardiac arrhythmia, ventricular fibrillation, myocardial infarction, cardiac arrest, and dilated cardiomyopathy, a condition in which the heart becomes enlarged and weakened, thereby limiting its ability to pump bloodJ4 15l Table 29.2 contains a list of cardiotoxic chemicals frequently, intentionally inhaled and the common sources of these chemicals. 

The chemicals in Table 29.2 are often inhaled as mixtures. Though there are surely at least additive effects associated with many of these mixtures, there is evidence that each of these alone is toxic to the heart. 

Total pulmonary system 1300 Total systemic vessels 3100  

Structure Diameter (cm) Blood velocity (cm/s) Tube Reynolds number  

Structure Diameter (cm) Total cross-sectional Number area (cm ) Length (cm) Total volume (cm ) Blood velocity (cm/s) Tube Reynolds number  

Includes both main pulmonary artery and lobar pulmonary artery branches. ° Includes both pulmonary veins and large pulmonary veins. 

Tissue Volume (L) Blood flow (mL/min) Blood flow (mL/lOOmL tissue/min) 

C Cardiovascular system COl Cardiac Therapy COIA Cardiac flycosides 

The cardiac glycosides have a bitter taste. They are soluble in alcohol, poorly in water and can be extracted from aqueous solutions with a mixture of chloroform and alcohol, a method that is also used industrially. 

The cardiac glycosides have up to now been isolated from a limited number of plant families Scrophuhridceae (Digitalis lanata), Apocynaceae (Strophanthus gratus, Nerium oleander), Hyacinthaceae (Urginea mar-itima), Convallariaceae (Convallaria majalis), and Ranunculaceae (Adonis vernalis). 

All cardiac glycosides have qualitatively the same effect. Primarily the systolic contraction of the heart muscle is strengthened. The mode of action of the cardiac glycosides, which is not known in all details, depends on rhythmic intracellular liberation of calcium-ions by inhibition of the calciumion outflow and an increase in the inflow of calcium-ions into the cell. This takes place by inhibition of Na+/K-r-activating membrane-ATP-ase. (Digitalis receptor). The concentration of Na+ is increased and that of K-r is decreased intracellularly. In this way the myosin-ATP-ase is activated with improved use of ATP, which gives increased power of contraction by facilitated reaction between actin and myosin. 

The toxic effect arises from too strong a decrease in the intracellular concentration of potassium by inhibition of the uptake of potassium in the cell. 

Section 3.6.5 describes the normal development of the cardiovascular system. 

The loss of the vasodilatory action of NO upon combination with02 - may be compensated for by the stimulation of eNOS by H202, which involves a cell 

It is widely assumed that NO is responsible for the pharmacological effects of nitroglycerin, which has been used to treat angina since 1879. However, this has been challenged by Kleschoyov et al. who, using a colloidal iron-dithiocarbamate preparation to trap the radical in vascular segments, showed that the ability of the compound to induce vasorelaxation is not related to its ability to donate NO.289 

NAD(P)H oxidase can also be activated by fluid shear stresses. This is one reason why branched and curved arteries tend to develop atherosclerotic plaques earlier than straight arteries. Using a spin probe to detect 02 , Hwang et al. have demonstrated that monolayer cultures of EC exposed to oscillatory (but not laminar) shear stresses produce the radical using NAD(P)H oxidase.292 A subsequent study showed that XO also responds to oscillatory shear stress.293 Other workers, using BMPO, have detected the flow-induced production of 02 by mitochondria.294 

2 Low-density lipoprotein oxidation. A detailed EPR study of LDL oxidation by HRP has been reported by Pietraforte and colleagues, who reported the direct observation of the a-tocopheroxyl radical and a protein radical (g = 2.003), assigned tentatively to a tyrosyl radical and also trapped with MNP.295 Another study reported the observation of the probucol phenoxyl radical in LDL undergoing oxidation by lipoxygenase. This finding supports the assertion 

A love affair with knowledge will never end in heartbreak. 

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Acrylonitrile is beheved to behave similarly to hydrogen cyanide (enzyme inhibition of cellular metaboHsm) (150) and is befleved to be a potential carcinogen (151). It can also affect the cardiovascular system and kidney and Hver functions (150). Eurther information on the toxicology and human exposure to acrylonitrile is available (152—154) (see Acrylonitrile). 

Histamine in the Cardiovascular System. It has been known for many years that histamine is present in sympathetic nerves and has a distribution within the heart that parallels that of norepinephrine (see Epinephrine and norepinephrine). A physiological role for cardiac histamine as a modulator of sympathetic responses is highly plausible (15). A pool of histamine in rat heart located neither in mast cells nor in sympathetic nerves has been demonstrated. The turnover of this metaboHcaHy active pool of histamine appears to be maintained by normal sympathetic activity. 

Lead is toxic to the kidney, cardiovascular system, developiag red blood cells, and the nervous system. The toxicity of lead to the kidney is manifested by chronic nephropathy and appears to result from long-term, relatively high dose exposure to lead. It appears that the toxicity of lead to the kidney results from effects on the cells lining the proximal tubules. Lead inhibits the metaboHc activation of vitamin D in these cells, and induces the formation of dense lead—protein complexes, causing a progressive destmction of the proximal tubules (13). Lead has been impHcated in causing hypertension as a result of a direct action on vascular smooth muscle as well as the toxic effects on the kidneys (12,13). 

Side Effects and Toxicity. Adverse effects to the tricycHc antidepressants, primarily the result of the actions of these compounds on either the autonomic, cardiovascular, or central nervous systems, are summarized in Table 3. The most serious side effects of the tricycHcs concern the cardiovascular system. Arrhythmias, which are dose-dependent and rarely occur at therapeutic plasma levels, can be life-threatening. In order to prevent adverse effects, as weU as to be certain that the patient has taken enough dmg to be effective, the steady-state semm levels of tricycHc antidepressant dmgs are monitored as a matter of good practice. A comprehensive review of stmcture—activity relationships among the tricycHc antidepressants is available (42). 

The heart, a four-chambered muscular pump has as its primary purpose the propelling of blood throughout the cardiovascular system. The left ventricle is the principal pumping chamber and is therefore the largest of the four chambers in terms of muscle mass. The efficiency of the heart as a pump can be assessed by measuring cardiac output, left ventricular pressure, and the amount of work requHed to accomplish any requHed amount of pumping. 

Methyldopa, through its metaboHte, CX-methyInorepinephrine formed in the brain, acts on the postsynaptic tt2-adrenoceptor in the central nervous system. It reduces the adrenergic outflow to the cardiovascular system, thereby decreasing arterial blood pressure. If the conversion of methyldopa to CX-methyl norepinephrine in the brain is prevented by a dopamine -hydroxylase inhibitor capable of penetrating into the brain, it loses its antihypertensive effects. 

J. Ross, Jr. and co-workers, in J. B. West, ed.. Best and Taylor s Physiological Basis of Medical Practice Cardiovascular System, Section 2, 12th ed., WiUiams and Wilkins, Baltimore, Md., 1990, p. 109. 

At low levels of COHb (0.5-2.0%) the body burden is measurable, but research has not shown any substantive effects at these low levels. When COHb increases to higher levels the body burden of CO is elevated, producing adverse effects on the cardiovascular system and reducing physical endurance. 

Atrazine 0.003 0.003 Cardiovascular system problems reproductive difficulties Runoff from herbicide used on row crops... 

Recently, much emphasis has been put on the harmful effects of small particles, i.e., particulate matter (PM), on human health. A number of standards have been established to characterize the PM fractions in the air and their effects on human health. A widely used PM standard in force in both Europe and the United States is based on the mass concentration of particles with a diameter of 10 gm or less (PMjo). However, recently the U.S. Environmental Protection Agency (EPA) proposed a new standard that is based on the aerodynamic diameter of 2.5 gm particles. This new standard emphasizes the significant impact of small particles on human health, especially on the respiratory and cardiovascular systems. 4 ... 

Mean arterial pressure and cardiac output, an expression of the amount of blood that the heart pumps each minute, are the key Indicators of the normal functioning of the cardiovascular system. Mean arterial pressure is strictly controlled, but by changing the cardiac output, a person can adapt, e.g., to increased oxygen requirement due to increased workload. Blood flow in vital organs may vary for many reasons, but is usually due to decreased cardiac output. However, there can be very dramatic changes in blood pressure, e.g., blood pressure plummets during an anaphylactic allergic reaction. Also cytotoxic chemicals, such as heavy metals, may decrease the blood pressure. 

There is a high degree of variation in response among individuals in a tyijical population. Generally, sensitive populations include the elderly, children, and individuals with diseases that compromise the respiratory or cardiovascular system. 

Iain lack of specificity for the cardiovascular system has diminished the usefulness of these agents. 

Autonomic nervous system. The portion of the nervous system outside of the brain and spinal cord that is responsible for monitoring and controlling the digestive system, cardiovascular system, and other organs that are not under direct conscious control. 

Compounds which act as antagonists at the receptors for beta sympathetic transmitters (beta blockers) have gained very wide acceptance as antihypertensive agents. It was found subsequent to their introduction that there are two populations of beta receptors the beta-1 receptors are richest in the cardiovascular system whereas beta-2 receptors are mostly found in the bronchi. Lack of receptor-type specificity led to bronchial spasm in some asthmatic individuals on ingestion of the earlier beta blockers. Much of the work outlined below had as its goal the preparation of agents which showed selectivity for beta-1 receptors. 

The majority of endogenous prostaglandins tend to exert undesirable effects on the cardiovascular system. These compounds as a rule tend to cause vasoconstriction and promote platelet aggrega-... 

Angiotensin converting enzyme (ACE) plays a central role in cardiovascular hemostasis. Its major function is the generation of angiotensin (ANG) II from ANGI and the degradation of bradykinin. Both peptides have profound impact on the cardiovascular system and beyond. ACE inhibitors are used to decrease blood pressure in hypertensive patients, to improve cardiac function, and to reduce work load of the heart in patients with cardiac failure. 

The substrate specificity of ACE is low. ACE cleaves a variety of pairs of amino acids from the carboxy-terminal part of several peptide substrates. The conversion of ANGI to ANGII and the degradation of bradykinin to inactive fragments are considered the most important functions of ACE. Both peptides have profound impact on the cardiovascular system and beyond. ACE is thus an important target for ACE inhibitors. These compounds are frequently and efficiently used in the treatment of hypertension and cardiac failure. 

Bazedoxifene is a third generation SERM that displays estrogenic effects in bone and the cardiovascular system, but functions as an antiestrogen in the breast and uterus. 

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. 

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