03 Sep 2006

Current status of novel antihypertensives Symposium

Dr. Heagerty

Topics: Hypertension
Session number: 164000
Session title: Current status of novel Antihypertensives
Authors: Heagerty, A. Manchester, United Kingdom

You might have thought that the hypertension field was saturated with compounds sufficient to control the blood pressure of even the most difficult of patients. That, plus the development costs of new molecules should deter all except the bravest of innovators. However there is always the drive to find the better drug: one that controls blood pressure with facility, is tolerated perfectly and may carry associated pressure-independent advantages such as the ability to regress atheromatous plaques or improve dyslipidaemia. And so the search continues.

Against this background we were treated to 5 outstanding presentations during this session.

Dr Hayoz (Lausanne) began by telling us about progress in the race to develop a renin inhibitor. The object is to produce a compound that binds to the pocket in renin thereby preventing the attachment of the natural substrate angiotensinogen. Orally active drugs have been difficult to generate but this has been overcome and one agent Aliskiren is now in clinical trial. There is dose-dependent blood pressure lowering activity and synergy with diuretics in combination. A multi-centre outcome study is planned which will recruit large numbers of patients from many countries including India and Sri Lanka. A major advance? We shall see.

Less optimistic was Dr Krum (Melbourne) on the subject of Urotensin antagonists. Urotensin is an 11 amino acid peptide discovered to be a potent vasoconstrictor. Excitement was created when receptors were localised in the heart as well as the vasculature. Studies in vitro suggested that not only could Urotensin vasoconstrict it also influenced myocardial contractility and myocyte hypertrophy. Inhibition was thought could improve diabetes, chronic heart failure and lower blood pressure. However subsequent studies have demonstrated huge variations in response to Urotensin both between species and indeed within the same vascular bed. Reports emerged of no influence on human coronary tone and infusions produced conflicting effects on forearm blood flow. Non-peptide antagonists showed promise in animal models of hypertension but a clinical trial of Palosuran in diabetics demonstrated no effects on blood pressure and no change in albuminuria or glycaemic control.

But spirits rose with news of Rho-kinase inhibitors. Dr Shimokawa (Sendai) documented the description of this intracellular enzyme in1996 and the demonstration of its role in vascular contraction. In Japan a commercially available drug Fasudil is licensed for use in cerebral spasm post-stroke. It is metabolised to hydroxyfasudil which is an inhibitor of Rho-kinase. Also 15 companies are developing inhibitors for a variety of clinical indications. A number of elegant studies have shown that reducing Rho-kinase activity is associated with amelioration of inflammation and perivascular fibrosis. In-vivo gene transfer of a dominant-negative Rho-kinase inhibitor caused regression of constrictive remodelling of the porcine coronary artery suggesting reduction in plaque volume. And Fasudil improved survival in an animal model of pulmonary hypertension with other studies pointing to antihypertensive properties this area perhaps holds promise for a marked advance in cardiovascular disease management.

Professor Macdonald (Dundee) spoke about mineralocorticoid receptor antagonists which are regaining popularity in hypertension management. They work through binding to nuclear receptors so have genomic effects but non-genomic actions are also observed including proarrythmias, and effects on baroreflex sensitivity and vascular tone. The principal activity however is genomically confined to the distal tubule. The two compounds in clinical use are spironolactone and eplerenone. Spironolactone has a short half-life but is metabolised to longer active products therefore it takes 5 half-lives to reach steady state. This explains its slow onset of action. Studies have shown clearly that it is a useful add-on agent lowering blood pressure well and reducing other drug load. However its ability to increase the metabolism of testosterone to oestradiol limits its usefulness due to the development of gynaecomastia. Also it increases plasma levels of digoxin and induces liver enzymes. Eplerenone has no active metabolites and produces less gynaecomastia and a faster onset of action it has gained popularity in consequence.

The last area discussed was that of endothelin antagonism. Professor Ruschitzka (Zurich) took us through the pharmacology of Endothelin type A and B receptors and indicated that antagonists have a greater affinity for type A. Bosentan has been introduced into the management of pulmonary hypertension where it has been shown to prolong life and reduce events. Conclusion In the area of arterial hypertension the agents have not been so effective and negative trials in heart failure have disappointed. A role in resistant hypertension has not been discounted.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.