Angiotensin converting enzyme inhibition: from viper to patient.

The story of angiotensin converting enzyme (ACE) inhibitors started approximately 50 years ago, when it was discovered that human plasma incubated with the venom of the Brazilian viper, Bothrops Jararaca, generated a hypotensive compound. This discovery quickly led to the characterisation of the active principle of the venom by Fereira and Greene as a family of peptides, which were named bradykinin potentiating factors as they selectively improved the biological eVects of bradykinin. The observation was then made by Vane that these peptides could also block the conversion of angiotensin I into angiotensin II via the angiotensin converting enzyme. The active peptides were isolated and teprotide became the first ACE inhibitor to be evaluated clinically. The search for an orally active compound that was suYciently potent to be developed as an antihypertensive drug resulted in the design and development of captopril, which entered first phase clinical studies in 1977. ACE has a key role in two diVerent physiological pathways (fig 1). One is in the synthesis of angiotensin II, which has vasoconstrictive properties, promotes retention of sodium and water, and promotes cell growth. The second is in the breakdown of bradykinin into inactive peptides. Bradykinin is a potent vasodilator through the synthesis of nitric oxide and vasodilatory prostaglandins. Importantly, alternative pathways exist such as the kinase pathway, which bypass ACE in the generation of angiotensin II. Also, the renin-angiotensin system (RAS) is not only found in the circulation, but also in tissues. All components of the cascade are found in a series of tissues, including the heart and the vascular wall. With the widespread actions of RAS, it is not surprising that many potential beneficial eVects have been ascribed to ACE inhibitors including improvement of endothelial function, an antihypertensive eVect, and a reduction in left ventricular mass. There are currently 11 diVerent ACE inhibitors available and, interestingly, there are still a further five molecules under investigation. These agents diVer considerably in terms of their pharmacological properties (table 1). ACE inhibitors can be used in the following areas: x hypertension; x heart failure/asymptomatic left ventricular dysfunction; x acute/post-myocardial infarction; x diabetic complications, including nephropathy and retinopathy; x non-diabetic nephropathy. It is very likely that, following the results of the HOPE study, a new indication for coronary or vascular primary prevention in high risk patients will be introduced.