The Renin-Angiotensin System and Ramipril, A New Converting Enzyme Inhibitor

Angiotensin converting enzyme (ACE) inhibitors have offered new perspectives in the treatment of hypertension. The development of new ACE inhibitors such as ramipril provides an opportunity to improve the knowledge on this class of drug, and to optimize the benefit/risk ratio for the patient. Ramipril was selected among several analogs because of its unique physicochemical properties. It is a nonsulfhydryl ACE inhibitor, and after oral absorption it is transformed in the liver into its active metabolite ramiprilat. which is at least 23 times more lipophilic than enalaprilat. Furthermore, the in vitro affinity of ramiprilat for the enzyme is 7 times higher than for enalaprilat and 47 times higher than for captopril. The ramiprilat-ACE complex is therefore very stable and dissociates 6 times more slowly than the enalaprilat-ACE complex and 22 times more slowly than the captopril-ACE complex. Ramipril possesses a favorable pharmacokinetic profile as a consequence of its physicochemical properties: its high potency allows the use of very low doses, and the slow dissociation of the ramipril-ACE complex explains the long duration of its action, permitting a once-daily treatment. Dose-finding studies have confirmed that very low doses of ramipril–2.5 mg once a day–can be used as a first-step treatment of hypertension. This dose can be increased up to 5 mg, and if necessary a low dose of a diuretic can be added. Using this therapeutic scheme, ramipril normalized blood pressure, insuring that each patient receives the smallest effective dose. Inhibition of the tissue renin-angiotensin system by ramipril has been described in recent studies on animal models. The effects of ramipril on the target organs of hypertension have been compared to those of other ACE inhibitors: possibly due to its lipophilicity, ramipril inhibits the renin-angiotensin system in the heart, kidney, and vascular wall, and the local production of angiotensin II is decreased by the treatment. In clinical trials, a rapid regression of cardiac hypertrophy was shown in hypertensive patients. Furthermore, ramipril is able to exert an antivaso-constrictor effect during infusion of angiotensin I in the brachial artery of healthy volunteers. Ramipril can also decrease blood pressure in binephrectomized hypertensive patients despite the absence of renin secreted by the kidney. These results provide indirect evidence that ramipril may exert an inhibitory effect on tissue renin-angiotensin systems in humans.