Drugs for high blood pressure
Before the development of drugs for hypertension (high blood pressure) in the 1950s, treatments for severe high blood pressure were few and ineffective. The most severe form of hypertension, malignant hypertension, led to the death of 9 in 10 sufferers within 12 months. Annual deaths in the UK from hypertensive disease were approaching 500 per million population. Bed rest, weight loss through a low fat diet, restriction of salt intake, no smoking and the use of sedatives to reduce stress were all recommended, but the drastic treatment of removal of the adrenal glands (which necessitated life-long replacement therapy with the hormone cortisone) was often the only option.
The development of effective drugs to reduce hypertension was a major step forward. The first class of drugs, the ganglionic blockers, arose directly from study of the nervous system in animals. Activation of certain nerves was shown to constrict blood vessels and raise blood pressure. After many experiments, it was shown that chemical messengers from nerves produced this effect. Thus drugs which acted as mimics or blockers of these chemical messengers would modify the nerve activity. The ganglionic blocking drugs are compounds which can block these nerve-to-nerve junctions where they are concentrated, at swellings called ganglia.
The first drug, hexamethonium, was discovered by William Paton and Zaimis in 1948 during development of muscle relaxants using anaesthetised cats and rabbits. Although it was effective in reducing blood pressure (and its knock-on effects such as severe headache and enlargement of the heart), it had undesirable side effects because of its action on many different nerve reflexes. Better ganglionic blocking drugs followed , after they were shown to be effective and relatively safe in various animals including dogs, cats, rats and mice.
The development of beta-blocking drugs using animals in the 1960s was initially aimed at the treatment of angina and cardiac arrhythmias. In 1964, it was observed that pronethalol, the first beta blocker used to treat patients with angina, also reduced blood pressure.Pronethalol was later withdrawn because it was shown to produce tumours in mice, but the beta blocker propranolol was also shown to be effective in reducing blood pressure. This finding was confirmed in tests on rats which naturally suffer from high blood pressure. Of course, had propranolol been tested on these rats before it reached the clinic, its antihypertensive properties would have been discovered earlier.
The third class of drugs to be developed for hypertension were the ACE (angiotensin converting enzyme) inhibitors. These prevent the formation in the blood of a naturally occurring substance, angiotensin II, which raises blood pressure. An ACE inhibitor called bradyknin potentiating factor (BPF), from the venom of snakes, was found to reduce blood pressure in rats. When eventually it could be purified, BPF was also shown to reduce blood pressure in patients. Various synthetic preparations were tested in rats, resulting in the introduction of captopril in 1977.
Further treatments for hypertension may result from the basic studies in animals which are leading to a greater understanding of the role of nitric oxide, a gas released by many tissues in the body.
We now know that the treatment of less severe cases of raised blood pressure can reduce the risk of stroke, coronary heart disease and kidney disease. Antihypertensive drugs have reduced deaths from hypertensive disease from 500 to about 50 per million population in the UK.
- Paton W & Zaimis E (1948) Nature 162, 810
- Dollery C (1987) Br Heart J 58 , 179
- Prichard B (1982) Br J Clin Pharmac 13, 51
- Garvey H & Ram N (1975) L Pharm Exper Ther 194, 220
- Vane J (1992) in Animal Experimentation and the Future of Medical Research, ed Botting J, Portland Press, London