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BREAKTHROUGHS SUMMARY ARTICLE The Full-length version of this article is also available, published online as http://www.fasebj.org/cgi/content/full/18/3/421e.< /FONT> |
Treatment of hypertension has vastly evolved in the past century, moving from difficult and often ineffective low sodium dietary regimens to an arsenal of modern pharmaceuticals. The current use of diuretics, calcium antagonists, ß blockers, angiotensin converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARB) has restored normal blood pressure levels in nearly all hypertensive patients.
It was more than two centuries following the first measurement of blood pressure before the first trenchant treatment for hypertension was developed. It was serendipitous observation that led to creation of the first diuretics. Clinical researchers noted that the urine of patients treated with the antibiotic sulfanilamide had greater concentrations of various salts, including sodium and potassium. Physiologists exploring this phenomenon, elucidated that sulfanilamide disrupted carbonic anhydrase function. Teams of scientists set to work modifying the structure of sulfanilamide, eventually resulting in chlorothiazide (Diuril), a diuretic shown to have dramatic antihypertensive effects. However, while extremely effective in lowering blood pressure, diuretics are associated with deleterious side effects, including impotence and diabetes.
Although originally marketed as a treatment for angina, ß blockers, such as propranolol (Inderal), were soon observed to decrease blood pressure levels in patients and were approved as an antihypertensive. In a search for new antihypertensives similar to propranolol, verapamil was developed. Later studies revealed that the mechanism of verapamil was not that of a ß blocker, as had been presumed, but rather through disruption of calcium channels on cardiac tissue. Clinical research has shown that calcium antagonists and ß blockers reduce the risk of heart attack and stroke by about one-third. But their effectiveness is often marred by their frequent side effects. Although diuretics, calcium antagonists, and ß blockers were effective antihypertensives, even in combination they were not always efficacious in patients with severe hypertension and the side effects often caused patients to stop taking them.
The renin–angiotensin–aldosterone axis was delineated in a series of fundamental experiments and immediately became the focus in the hunt for targets of hypertension alleviation. The concept of inhibiting ACE, which plays an integral role in blood pressure control by converting angiotensin I into the powerful hypertensive peptide angiotensin II, originated from an unusual source. The toxic effects of venom from a Brazilian viper (Bothrops jararaca) were found to be due to a sudden, massive drop in blood pressure. This piqued the interest of Nobel prize winning scientist, Sir John Vane, under whose auspices it was revealed that the snake venom was a potent inhibitor of ACE. Vane took this discovery to the pharmaceutical company Squibb, where two scientists, David Cushman and Miguel Ondetti, began working on creating a synthetic ACE inhibitor for use in treating hypertension.
The challenges faced by Cushman and Ondetti were manifold. Standard biochemical manipulations to alter the substance to an oral form were unsuccessful. Screening thousands of similar compounds to discover an alternative ACE inhibitor was equally fruitless. The project was nearly abandoned when Cushman and Ondetti stumbled upon a paper by Larry Byers and Richard Wolfenden, describing the creation of a caboxypeptidase A inhibitor using a synthetic structure. Cushman and Ondetti began altering this carboxypeptidase A inhibitor so that it more closely resembled the structure of the ACE inhibitors with which they had been working. This pathway led them to the creation of captopril, the first oral ACE inhibitor. Captopril was a breakthrough not only in management of blood pressure, but also as an early example of structure-based drug design, a revolutionary new approach to pharmacology.
Structure-based drug design again played a role in the development of the next class of antihypertensive drugs, the ARBs. ARBs effectively inhibit angiotensin II from interacting with its receptor. Both ACE inhibitors and ARBs have proven to be remarkably efficacious at lowering blood pressure with few side effects. Additionally, recent studies have shown that ACE inhibitors and ARBs may counter a number of symptoms related to cardiovascular disease, including slowing the progression of arteriosclerotic lesions and cardiomyopathy. These drugs not only decrease the risk of cardiac arrest by greater than 20%, they increase rates of survival following myocardial infarction. Moreover, in combination, ACE inhibitors, ARBs, and calcium channel blockers decrease the risk of stroke by about two-thirds. Auxiliary to their cardioprotective effect, ACE inhibitors and ARBs may also have a role in slowing the progression of renal disease.
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