Neurohumoral and Oxidative Influences of Candesartan, Atenolol, Hydrochlorothiazide and Drug Combinations in Essential Hypertensive Patients.

INTRODUCTION.

Three large clinical trials (STOP-2, HOPE, LIFE) {Hansson, Lindholm, et al. 1999}{Dahlof, Devereux, et al. 2002}{Yusuf, Sleight, et al. 2000} have suggested that drugs that specifically inhibit the renin angiotensin system (RAS) such as ACE inhibitors and Angiotensin Receptor Antagonists (ARA) have blood pressure-independant cardiovascular protecting effects. In the most recent of these studies, the LIFE trial, Losartan-based therapy was superior to atenolol-based therapy in hypertensive patients with left ventricular hypertrophy {Dahlof, Devereux, et al. 2002}. Very recently, the ALLHAT mega-trial suggested that diuretics were as good as ACE inhibitors for cardiovascular protection in hypertensive patients {Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT)}. These apparently conflicting results underline that the mechanisms of cardiovascular protections are not well understood.

ARAs {Balt, Mathy, et al. 2001}{Moreau, Richer, et al. 1993} have sympathoinhibitory properties while beta-blockers induce a small counterregulatory activation of the sympathetic system {Lijnen, Amery, et al. 1979}{Sundlof, Wallin, et al. 1983}{van den Meiracker, Man in 't Veld AJ, et al. 1988}.We have shown recently that telmisartan prevents the increase in NE normally associated with a reduction in BP while there are reports that diuretics tend to stimulate the sympathetic system {Fernandez, Snedden, et al. 1987}{Lake, Ziegler, et al. 1979}. It has been suggested that the superiority of ARAs could be due to their unique effects on the autonomic nervous system.

Angiotensin II receptor antagonism also decrease the oxidative stress induced by angiotensin II and aldosterone {de Cavanagh, Ferder, et al. 1999}{Hornig, Landmesser, et al. 2001}{Onozato, Tojo, et al. 2002}.We have also shown that telmisartan decreases plasma aldosterone and should therefore decrease the oxidative stress associated with a reduction in aldosterone Hydrochlorothiazide and beta-blockers have not been shown to have antioxidative properties {Welch & Wilcox 2001}{Taddei, Virdis, et al. 2001}. It is possible that oxidative stress partly explains the differences between pharmacological agents.

Patients included in high blood pressure clinical trials are randomized to a therapeutic strategy meaning that a stepped care approach is taken. Hypertensive patients frequently need more than one drug for appropriate blood pressure control. Consequently, about half of study patients in these trials end up taking more than one drug during the study. First step therapy is by definition prescribed to all study subjects but second or third step therapy are not as well defined. In the HOPE trial, ramipril was added on top of usual treatment. Most of the patients included in HOPE, LIFE, STOP-2 and ALLHAT took at least one other antihypertensive drug, most frequently a thiazide diuretic. Though results were reported as being ACE inhibitor or ARA based, they mostly reflect a mix of single drug and multiple drugs therapy. Whether the beneficial effects of ARAs and beta-blockers are modulated by thiazide diuretics is presently unknown.