International Circulation: The renin-angiotensin aldosterone system (RAAS) has a central function in the regulation of blood pressure. What are some of the biggest breakthroughs in understanding the RAAS in the past several years?
　　Prof. Volpe: There have been so many important scientific contributions that it is difficult to make a classification in terms of importance. However， an unexpected major breakthrough has been the widespread use by physicians of all the drugs blocking the renin-angiotensin system. These treated diseases include hypertension， diabetes， atherosclerosis， myocardial infarction， heart failure， renal disease， and stroke. This was a surprise for all the people involved in the understanding of the renin-angiotensin system because many of us have been involved in some of the initial clinical developments of these drugs but we could not have expected such a successful use of these drugs among physicians. Today， we probably have several hundred million people around the world being treated by drugs that block this system and this has been a major achievement in medicine.
　　International Circulation: Aliskiren， the first direct renin inhibitor (DRIs) to be approved for the treatment of hypertension， blocks the RAAS at its point of activation. What is it different from others anti-hypertensive medicines like sartans?
　　Prof. Volpe: What we have now is the possibility of blocking the cascade of the renin-angiotensin system upstream. This is important because you don’t get into any of the potential sideways or shortcuts that the mechanism may take when you use ACE inhibitors or angiotensin receptor blockers. This is a new mechanism and it is independent from the availability of the converting enzyme， the number of receptors to block， or the amount of angiotensin II. Therefore， it is a novelty from the point of view of the mechanism and also a novelty from the point of view of clinical application because this drug is different from the ACEI and ARBs because you do not have a feedback increase in plasma renin activity. With both ACEI and ARBs you have an increase in plasma renin activity and this may be the basis for residual risk that we have in the treatment of hypertension， heart failure， or other cardiovascular renal disease. The expectation with aliskiren is that it may somehow cover the gap of residual risk that we have experienced with the other classes of drugs where the residual risk has overwhelmed the benefits. Another important factor is that the clinical development of aliskiren is based on its use on top of the best standard therapy， including ACEI and ARBs. All of the studies that are planned with aliskiren in diabetes， hypertension， and heart failure are all based on top of the use of the other renin-angiotensin system blockers. As a result， we will learn if it is possible to reduce residual risk by adding aliskiren to the current therapies， including current blockers of the renin-angiotensin system. In addition， there is the potential interference with the prorenin/renin receptor， which to date we do not know if it is an advantage or not. We will probably gain information on that very soon.
　　International Circulation: What do you think of the DRIs combined with other medicines? Do you prefer DRI monotherapy or combination therapy in the management of hypertension?
　　Prof. Volpe:In my opinion， the combination of DRIs with ARBs makes more sense because you combine upstream blockade of the system with downstream blockade. The combination of aliskiren with ACEI is less encouraging because more or less they both act at the level of angiotensin I， either inhibiting the formation of angiotensin I from the angiotensinogen substrate  or inhibiting the transformation of angiotensin I into angiotensin II. Also， you are working on two enzymes whereas in the case of aliskiren plus an ARB you are acting on an enzyme and a receptor binding mechanism From what we know presently， it is clear that in the thousands of patients that have been treated with direct renin inhibition， there is no increase in side when effects when DRIs are used in combination with ARBs and there may be， clinical advantage， particularly in terms of BP reduction. The advantages on some biomarkers such as microalbuminuria， left ventricular hypertrophy， or BNP are already available but we have to want to see the advantages on the hard end points.