Blood pressure is the force exerted by blood on the walls of the arteries. When the pressure is too high, the heart is working harder than it should, andthe blood vessels are overstressed. High blood pressure, or hypertension, canrange from mild to severe. Physicians knew for a long time that very high blood pressure was harmful, but it took the results of a long-term study of theresidents of Framingham, Massachusetts, to convince doctors in the early 1960s that all hypertension was dangerous. It can lead to heartattack, stroke, and kidney failure. Researchers also announced in 1998 that high blood pressure could mean a higher risk of developingdementia. Hypertension affects sixty million, or nearly one out of four, Americans.

Attempts to find effective ways to treat hypertension led researchers to uncover the methods by which the body regulates blood pressure; knowledge of thatprocess is still evolving. In 1898 R. Tigerstedt and P. G. Bergman found that an enzyme produced by the kidneys affected blood pressure. Henry Goldblattand colleagues confirmed the role of the kidneys in 1934, producing hypertension in dogs by constricting the kidney arteries. In 1940 Braun-Menendez in Argentina and Irvine Page and Oscar Helmer at the Cleveland Clinic in Ohio found that renin, the kidney enzyme, catalyzed the formation of angiotensin, a very potent vasoconstrictor (a substance that causes blood vessels to contract). In the 1950s researchers discovered that renin causes the production of angiotensin I, which has little physiological effect but is stimulated by angiotensin converting enzyme to produce the vessel-constricting angiotensin II. Inthe 1960s Gross and others further found that angiotensin stimulates production of the hormone aldosterone by the adrenal glands, which in turn promotesretention of sodium and water, boosting the fluid content of the circulatorysystem and thus the pressure on blood vessel walls. Angiotensins were also shown to act on the nervous system, stimulating release of the neurotransmitternorepinephrine, which signals the arterioles to constrict. This complex is called the renin-angiotensin-aldosterone system. Exactly why the system malfunctions to produce hypertension is not yet known, except in the approximately10 percent of cases in which high blood pressure is the result of specific, known physical disorders, particularly of the kidneys and adrenal glands.

Effective drug treatments to control high blood pressure were not developed until after World War II, although some early attempts at drug treatment weremade. The French surgeon Mathieu Jaboulay (1860-1913) in 1900 reported on hisdrastic approach to alleviate severe hypertension: sympathectomy, or the cutting of the nerves that stimulate blood vessel constriction. Two American doctors took a dietary approach; Frederick Allen promoted salt and water restriction in 1920, and Walter Kempner (1903-1997) put patients on a no-salt rice diet in the 1940s.

The modern era of drug treatment for hypertension began with the introductionof reserpine in 1953. Reserpine was first derived from the snakeroot plant,Rauwolfia serpentina, long used by medical practitioners in India, both to lower blood pressure and induce relaxation. Rauwolfia was firstmentioned in Western medical literature in a 1563 Portuguese work, but it wasnot studied seriously by Western-trained Indian physicians until 1931. The results of a clinical trial published by Dr. Rustom Jal Vakil in 1949 caught the attention Dr. Robert Wilkins, director of the hypertension clinic at Massachusetts General Hospital. Wilkins confirmed the hypotensive (anti-hypertensive) effect of Rauwolfia in 1952. The active ingredient was soon isolated and named reserpine; it was synthesized in 1956 by Robert Burns Woodward of Harvard. Reserpine was the first antihypertensive drug to achieve wide clinical use because of its nearly universal effectiveness. (It acts by interfering with transmission of norepinephrine.) It was also widely sold as a tranquilizer.

Other drugs took the place of reserpine as manufacturers and researchers focused their attention on antihypertensives beginning in the 1950s. The discovery of the first thiazide diuretic, benzothiadiazine, was reported in 1957 by the drug company Merck, Sharp and Dohme. Thiazide diuretics, which increase excretion of sodium chloride and water by stimulating the flow of urine,are widely used today to lower blood pressure. They may be taken in combination with methyldopa, an antihypertensive introduced in 1963, or with the beta-blockers, a new class of drugs that came on the market in 1964. JamesBlack, senior pharmacologist at Imperial Chemical Industries of Great Britain, was responsible for the development of the first beta blocker, propranolol. The American biochemist Raymond Ahlquist had suggested that epinephrine andnorepinephrine transmit their signals--which cause an increase in heart rateand stronger contractions of the heart and blood vessels--to beta receptor sites on the heart muscle. In 1957, Black noted reports of a drug that blockedthe stimulating effects of adrenaline on the heart, and set about creating anew chemical compound that would block the effects of epinephrine and norepinephrine at the beta receptor sites. This was accomplished by 1960, with theimproved beta-blocker propranolol appearing in 1964. Beta blockers are now widely used to treat both angina and high blood pressure.

Two other antihypertensives were introduced in the 1980s. Calcium channel blockers work by blocking the channel that carries calcium to muscle cells; since calcium is required for contraction of the muscles in artery walls and affects the rate at which the heart beats, lowering calcium levels in muscle alsolowers blood pressure. ACE (angiotensin converting enzyme) inhibitors interfere with the effect of an enzyme that stimulates angiotensin I to convert tothe powerful vasoconstrictor angiotensin II and that also promotes the destruction of bradykinin, a powerful vasodilator (a substance that promotes the relaxation of blood vessels). Ferreira and his coworkers first found BPFs, factors that intensify the body's reaction to bradykinin, in the venom of pit vipers in the 1960s. The BPFs inhibited the action of an enzyme that Erdos and associates showed was identical to angiotensin converting enzyme. BPFs were then synthesized, and in 1977 Cushman and his colleagues developed the first orally effective ACE inhibitor, captopril. Recently, it has been discovered that ACE inhibitors also reduce the rate of heart failure and progress of heartdisease following heart attack.

Other drug treatments include sympathetic (adrenergic) nervous system blockers, which inhibit the sympathetic nervous system; vasodilators, which lower vascular resistance by dilating the blood vessels; and HMG-CoA reductase inhibitors, which are used with dietary modifications to reduce cholesterol levels.However, drug therapy, which usually includes side effects, isn't the only way to treat hypertension. From the 1970s on, doctors have recommended exercise, weight loss, eliminating smoking, stress reduction, and a diet low in sodium, caffeine, alcohol, and cholesterol as a meansof lowering blood pressure.

Advances are also being made in discovering the biological roots of hypertension. For example, in 1998 researchers reported that glucocorticoid (a specific group of corticoids, or adrenal cortex steroids) abnormalities may play a role in familial disposition to hypertension. Investigators also identified two oncogenes that may be related to sodium-related hypertension by affecting how sodium is released or retained by sodium channels in the kidneys. Variations of an ACE (angiotensin converting enzyme) gene, which encodes for an enzyme that helps regulate blood volume and controls salt and water balance, havealso been linked to hypertension in men but not women.

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