The Cardiovascular System

The cardiovascular system includes the heart, arteries and veins. Disorders of the system are very prevalent and are a major cause of death in developed countries. Arrhythmia is the irregular beating of the heart caused by defects in its electrical conduction system. This leads to inefficiency in the pumping of blood and in some cases may develop into a rapid uncontrolled beating which leads to death. A heart attack or myocardial infarction is caused by the sudden blockage of one of the arteries which supplies the heart itself with blood. This 

Congestive heart failure is treated by two approaches. Diuretics, discussed below, are used to reduce blood volume by increasing urine flow and 

In the UK digoxin is among the 20 most prescribed drugs. A more recent approach to the development of cardiotonic agents is shown by dobutamine (Lilly, 1977) which is a mimic of dopamine, a natural hormone with heart-stimulating properties. 

A more recent approach to the treatment of hypertension with vasodilators is illustrated by captopril (Squibb, 1981). The body has several mechanisms for controlling blood pressure. One involves renin, an enzyme produced in the kidney, which cleaves a polypeptide to produce angiotensin I, a decapeptide. This in turn is cleaved by angiotensin converting enzyme to produce angiotensin II, an octapeptide which has potent vasoconstrictor properties. Captopril is an angiotensin-converting enzyme inhibitor and lowers blood 

There are a few vasodilators such as isoxsuprine (Philips Duphar, 1963) which are used to treat poor blood circulation to peripheral organs. Isoxsuprine is a stimulant of jS2 adrenergic receptors which are situated on blood vessels and which mediate vasodilation. 

Although mild to moderate alcohol consumption has beneficial effects on the mammalian system, high consumption of alcohol for a prolonged period has resulted in alcoholic heart muscle disease (AHMD). AHMD is characterized by dilated cardiomyopathy with concomitant ventricular dysfunction and histopathologic lesions.70,71 

Exposure to allylamine in industries synthesizing pharmaceuticals and other commercial products is a known occurrence. Allylamines are known to cause adverse effects, especially to the liver, kidney, heart and/or blood vascular systems in experimental humans. It has been reported that exposure to methyl-, ethyl-, heptyl-, and allylamines results in severe pathologic lesions of the above-mentioned vital organs in animals and humans.72 High doses of allylamines are always associated with the induction of fatal cardiovascular injury.72,73 

The skin as an organ of protection against the external environment, in Dermatology in General Medicine, 2nd ed., T.B. Fitzpatrick et al., eds., McGraw-Hill, New York, 1979. 

Occupational Dermatology, Grune Stratton, New York, 1983. 

Maibach, Occupational and Industrial Dermatology, 2nd ed., Year Book Medical Publishers, Chicago, 1987. 

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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. 

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. 

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. 

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. 

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

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. 

Biological Fnnctions and Clinical Implications of the Cardiovascular System... 

Older adults taking the sympathomimetic bronchoditatorsare at increased risk for adverse reactions related to the cardiovascular system (tachycardia, arrhythmias palpitations and hypertenson) as well as adverse reactions related to the central nervoussystem (restlessness agitation, insomnia). 

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