Impacto del eje angiotensina-(1-7)/receptor 'Mas' en la inflamación y senescencia vasculares

Tesis doctoral inédta leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Farmacología y Terapéutica . Fecha de lectura: 4 de Octubre de 201

Studies on Angiotensin Converting Enzyme Inhibitors

A range of studies are described examining the responses to blockade of the renin angiotensin system with angiotensin converting enzyme inhibition in patients with heart failure and normal volunteers. The common theme of the studies is the definition of response at low doses of drug and differentiation of effects between agents or over time on first administration. First dose response to ACE Inhibitors in heart failure (a) Oral doses of placebo, captopril 6.25mg, enalapril 2.5mg and perindopril 2mg were given in a randomised double blind parallel group study of 48 elderly patients with stable heart failure. Despite diuretic withdrawal considerable falls in supine blood pressure and heart rate were noted with captopril and enalapril. Compared to placebo perindopril produced no significant fall in pressure. Enalapril and perindopril produced similar plasma ACE inhibition. No patient experienced adverse symptoms. (b) Intravenous doses, by slow (6hr) constant rate infusion, of placebo (saline), enalaprilat (1.5mg) or perindoprilat (1mg) were given in a randomised, double blind, parallel group study of 36 elderly patients with stable heart failure. Both diacid ACE inhibitors caused falls in blood pressure and similar though greater inhibition of plasma ACE activity compared to the oral treatments. Five infusions were terminated on a priori criteria because of the degree of blood pressure fall. Termination of infusion effectively controlled the blood pressure fall. Two patients on active treatment had asymptomatic deterioration in biochemical indices of renal function necessitating withdrawal of maintenance ACE inhibitor treatment. Studies of the response to ACE inhibition in volunteers (a) The transpulmonary extraction of perindoprilat (1mg; by constant rate infusion into a peripheral vein over 20minutes) was examined in a novel study in 10 patients undergoing diagnostic cardiac catheterisation predominantly for symptoms suggestive of ischaemic heart disease. A co-infusion strategy employing concurrent indocyanine green as an intravascular marker was used. Concurrent sampling in the ascending aorta and the pulmonary trunk failed to show any significant first pass uptake of the drug into the pulmonary circulation. Pharmacokinetic models designed to incorporate elements describing simple nonlinear kinetics based on "tissue" distribution were not found to be applicable. A variety of procedural problems may have been responsible for the failure of this study to document tissue distribution. (b) Protracted low dose constant rate infusion of perindoprilat (1mg) over 1, 3 or 6hrs or placebo (saline over 3hr) was conducted in a single (subject) blinded randomised study in 10 healthy male volunteers. This predominantly pharmacokinetic study confirmed a blood pressure fall despite the low doses employed in normal volunteers. Despite higher peak drug concentrations the plasma ACE inhibition profile summarised by the area under the curve was greatest following the 6hr infusion where peak drug concentration was lowest. Drug concentration time profiles showed a clear sigmoid accumulation profile during drug infusion. Pharmacokinetic modelling of individual profiles confirmed that from a hierarchy of systems a non linear model with terms to represent tissue and plasma binding of drug provided the best fit to the observed data. (c) A model of activation of the renin angiotensin system was outlined in a double blind randomised study of low dose oral enalapril (5mg) in eight healthy salt depleted normal volunteers. A system of modest dietary salt restriction (40mmol per day) and diuretic therapy (40mg Frusemide BDS) over three prestudy days produced a reliable activation of the renin angiotensin system. Baseline and reactive elevation of renin activity was recorded in response to enalapril with an associated significant fall in supine and erect blood pressure. Conclusions Differential effects on blood pressure are evident between similar ACE inhibitors (enalapril and perindopril) but not with their respective diacid metabolites despite similar circulating enzyme inhibition in controlled circumstances. This may relate to a differential interaction with the tissue based elements of the renin angiotensin system. Although the transpulmonary study did not reveal significant extraction of the diacid ACE inhibitor perindoprilat into the lungs, the subsequent pharmacokinetic studies with low dose infusions of the same drug indicate that an indirect index of the tissue based system may be possible. Studies in heart failure patients may be usefully extended in volunteers whose renin system is activated using the salt depletion protocol as described