History of High Blood Pressure Treatment

The use of rational therapy for hypertension did not begin until the middle of the 19th century, following understanding of the significance of raised blood pressure as a disease, and the development of a means by which blood pressure could be measured. Prior to the introduction of antihypertensive therapy, individuals with severe hypertension invariably succumbed to stroke, coronary heart disease, heart failure or renal failure. Since the 1950s, several major clinical studies have established that early treatment of all grades of hypertension reduces morbidity and mortality resulting from end-organ damage. The success of antihypertensive therapy is reflected in the declining incidence of death from coronary artery disease and, in particular, stroke that has occurred in recent decades in industrialised countries.

Sir Henry Dale (1875-1968) showed that acetylcholine is released by the nerve endings that control vasodilatation, while those controlling vasoconstriction secrete an adrenalinelike substance. The original discovery was made in 1914 and Dale received the Nobel prize for his work in 1936.

Understanding of the role of the sympathetic nervous system in the control of blood pressure led to the opportunity to treat hypertension by modifying sympathetic tone. At first, only relatively crude methods were available and, during the 1940s, surgical sympathectomy was introduced as a means of permanently blocking the vasoconstrictor influence on the peripheral arterioles.

In the early 1950s, the rauwolfia compounds were introduced. These drugs caused catecholamine depletion in sympathetic neurones and were effective in reducing blood pressure, although they also had a tendency to cause depression. At around the same time, the vasodilator hydralazine was introduced, although this was soon largely replaced by the alpha-blockers.

This practice originated from the work of Ambard and Beaujard who, in the early 1900s, demonstrated that patients with renal disease experience an elevation of blood pressure if the amount of salt in the body is increased.

The long-term modification of sodium balance became feasible in the late 1950s with the development of the orally active thiazide diuretics. This group of agents was to replace the mercurial diuretics, which had been the major class of diuretic agent since the 1940s and had been effective in lowering blood pressure in a small group of hypertensive patients. However, the toxicity and parenteral route of administration of these agents prevented their widespread use.

In the 1960s, loop diuretics were introduced. These agents have a potent diuretic action but a marked hypokalaemic effect. Subsequently, the potassium-sparing diuretics were developed as a means of circumventing this problem. Following their introduction into clinical medicine, diuretics were widely used in the treatment of hypertension and remain in use today. However, at the high doses used in early diuretic therapy, electrolyte disturbances, such as hypokalaemia, and unwanted metabolic effects, such as lipid changes and glucose intolerance, occurred. In addition, some patients experienced adverse effects on their quality of life, due to side-effects such as polyuria and impotence.

Beta-blockers

In 1948, Alquist attempted to explain the apparently contradictory actions of catecholamines on target tissues by suggesting that catecholamine activity was mediated by two subgroups of receptors, which he named alpha- and beta-receptors. This was the first step towards the development of specific alpha- and beta-receptor blocking agents. Betablockers were developed primarily for the treatment of angina pectoris, but careful observation by Pritchard revealed a reduction in blood pressure following administration of one of the early agents, pronathalol. The first beta-blocker, dichloroisoproterenol, was originated by Powell and Slater in 1958. The utility of this compound has a limited utility due to its partial agonist properties.

During the 1960s, James Black and colleagues produced a range of beta-blocking agents, eventually synthesising propranolol, a competitive beta-antagonist, which was free from agonist activity. This has led to the development of a large number of beta-blocking agents, which may be distinguished by their relative affinities for beta-1 and beta-2 receptors, in addition to other properties. In the treatment of hypertension, a selective action on the beta-1 receptors is desirable, avoiding the effects of beta-2 receptor blockade which include bronchospasm, impaired perfusion of he peripheries and adverse effects on glucose homeostasis.

The first beta-blocker to have a selective action on the beta-1 receptors as metoprolol, which was introduced in 1975. Several other selective agents have subsequently been developed. Several major trials of beta-blockers were reported in the late 1980s.

The introduction of calcium antagonists

The importance of calcium in the cellular processes of cardiac muscle contraction was first noted by Sidney Ringer (1835-1910). The discovery of agents that could affect the cardiovascular actions of the calcium ion happened by chance in 1964. The German physiologist, Albrecht Fleckenstein, was approached by two pharmaceutical companies and asked to evaluate two newly synthesised coronary vasodilators, prenylamine and verapamil, which had been found to possess unexplained cardiodepressant effects. Fleckenstein subsequently found that both compounds mimicked the effects of calcium deficiency on the heart. He later found that these agents inhibited the movement of calcium through specific ion channels in myocardial cells. Soon, Fleckenstein found a range of agents with similar properties and he named this group the calcium antagonists. In 1972, Grun and Fleckenstein showed that the smooth muscle in peripheral arterioles, like cardiac muscle, is dependent on the influx of calcium ions for contraction. The calcium antagonists were subsequently shown to reverse arterial constriction and arterial spasm in the coronary, cerebral, mesenteric and renal circulations, in addition to opposing the constriction of peripheral resistance vessels. This latter property led to the widespread use of calcium antagonists in the treatment of hypertension, including the management of acute hypertensive crises.

Discovery and development of ACE inhibitors

In 1898, Tigerstedt and Bergman found that extracts of the kidney contain a chemical that raises the blood pressure, which they called renin. Some 40 years later, in 1940, Braun-Menendez and co-workers reported that renin is an enzyme that acts on a protein substrate, present in the plasma, to form an active substance which produces a rise in blood pressure. This substance was originally called hypertensin and later renamed angiotonin. Finally, the pressor substance was named angiotensin, and its plasma precursor was called angiotensinogen. Further understanding of the hormonal control of blood pressure came in 1952 when Simpson and coworkers outlined the physiological role of aldosterone. This was followed, in 1958, by the suggestion by Gross that the renin-angiotensin system regulated the secretion of aldosterone. A year later, Kagawa described the first aldosterone antagonist agent, spironolactone. These discoveries led, eventually, to the development of the ACE inhibitors for the treatment of hypertension in the late 1970s.

Pit viper venom contains substances that can potentiate the actions of bradykinin

Targeting the angiotensin II receptor

ACE is a non-specific enzyme that acts on other substrates in addition to angiotensin I. These substrates include bradykinin, substance P, neurokinins and luteinising hormone-releasing hormone, some of which have been implicated in the adverse effects of ACE inhibition. For example, the most commonly reported side-effect of ACE inhibitors, cough, is thought to result from the accumulation of bradykinin in the tissues. Furthermore, several pathways exist for the formation of angiotensin II that are not blocked by ACE inhibitors, for example, the pathway involving the enzyme cardiac chymase. Thus, inhibition of the renin-angiotensin system by ACE inhibitors is incomplete. Because angiotensin II is the end-product of the bioenzymatic cascade of the renin-angiotensin system, it is the level of angiotensin II, and not the activity of the regulating enzymes, that is important in the control of hypertension. The first attempts to develop a therapeutically useful angiotensin II receptor antagonist began in the early 1970s with the peptide compound, saralasin, being introduced in 1971 by Pals and co-workers. Although this substance is an effective angiotensin II receptor antagonist, it is of limited clinical value because of its lack of oral bioavailability, in addition to its unacceptable partial agonist activity. In 1982, researchers in Japan were successful in synthesising a non-peptide angiotensin II receptor antagonist, although this agent had only weak antihypertensive properties. The 1990s saw the development of several non-peptide angiotensin II receptor antagonists with good oral bioavailability and marked antihypertensive effects, the first of which was losartan. Among newer agents that have been clinically evaluated are candesartan, valsartan and irbesartan. Studies have demonstrated the antihypertensive efficacy and good tolerability of this new group of agents.

Development of antihypertensive drugs