Basic pharmacological considerations

Angiotensin II exerts its effects by stimulating cell membrane receptors—AT₁ and AT₂ receptors. Virtually all of the recognised effects of angiotensin II are mediated by AT₁ receptors, which are blocked by AT₁receptor antagonists. However, these drugs leave the AT₂receptor unblocked and it is a concern that AT₂ receptors may be overstimulated by endogenous angiotensin II when AT₁receptor antagonists are prescribed. However, it seems that AT₂ receptor stimulation in the presence of an AT₁ receptor antagonist may be beneficial, as AT₂ receptors appear to mediate antiproliferative effects and may even attenuate the proliferative effects of AT₁receptor stimulation.1 Clinical trials with AT₁ receptor antagonists have not uncovered any nasty surprises that could be attributed to AT₂ receptor stimulation. Clearly, if AT₂ receptor stimulation is beneficial, then AT₁ receptor antagonists should be better than ACE inhibitors because ACE inhibitors will lead to under stimulation of both AT₁ and AT₂ receptors.

ACE inhibitors not only suppress angiotensin II but they also lead to bradykinin accumulation. This is because the ACE enzyme has a much greater affinity for bradykinin than it does for angiotensin I (bradykinin K_m 0.85–1 μM; angiotensin I K_m30–90 μM).2 The accumulation of bradykinin is a double edged sword. On the debit side, bradykinin is likely to mediate the adverse effects of cough and perhaps angio-oedema; on the credit side bradykinin is likely to stimulate nitric oxide and prostacyclin release, which should improve endothelial function and may even have an antiatherosclerotic effect. However, other harmful effects of bradykinin accumulation have been described and are now attracting interest. The $64 000 question of whether AT₁ receptor antagonists will ever supersede ACE inhibitors may hinge largely, although not exclusively, on the balance between the beneficial and harmful effects of ACE inhibitor induced bradykinin accumulation.

A third issue of pharmacological importance is that angiotensin II can be formed by routes other than angiotensin converting enzyme. Enzymes such as chymase, cathepsin G, and CAGE (chymostatin sensitive angiotensin II generating enzyme) seem able to generate angiotensin II by non-ACE routes.3 We do not really know how big a contribution these non-ACE enzymes make to the production of angiotensin II but clearly ACE inhibitors will not prevent angiotensin II being formed from non-ACE enzymes, whereas AT₁ receptor antagonists will block the effect of angiotensin II, irrespective of which enzyme produced the angiotensin II. In this way, AT₁ receptor antagonists are likely to be able to block the effects of angiotensin II more effectively than ACE inhibitors can (table 1).

AT₁ receptor antagonists in hypertension

These theoretical benefits have led the pharmaceutical industry to develop a large number of AT₁ receptor antagonist drugs. These have initially been developed for the treatment of essential hypertension where they have generally fulfilled their promise of being safe, efficacious, and well tolerated. They appear to be better tolerated than other first line antihypertensive agents, including ACE inhibitors. In particular, the promise of their producing less cough than ACE inhibitors seems to have been fulfilled.4 Indeed the incidence of all side effects of AT₁ receptor antagonist appears to be much the same as placebo, which cannot be said for any other class of antihypertensive drug. As you would expect, drug companies marketing AT₁ receptor antagonists are now trying to distinguish between the various agents. In hypertension, this is likely to focus on differences in antihypertensive efficacy, particularly differences in blood pressure control at trough drug concentrations. We are likely to be bombarded in the near future with data on this subject, but the jury is still out on whether any differences really exist.

AT₁ receptor agonists in heart failure

There are two major constraints in clinical trials with AT₁ receptor antagonists in heart failure. The first is ethical in that ACE inhibitors cannot be withheld from patients for long because of their undoubted clinical benefit. This means that clinical trials with AT₁ receptor antagonists cannot be done in the traditional way comparing the new drug with placebo. The second constraint is a genuine uncertainty about whether the future place of AT₁ receptor antagonists in heart failure will be as a substitute for ACE inhibitors or as an addition. This question remains wide open.

Until recently, clinical trials with AT₁ receptor antagonists in heart failure have in general shown that they exert the expected haemodynamic and neurohormonal effects. DeKocket al showed that single doses of losartan caused vasodilatation and reduced aldosterone and noradrenaline compared with placebo.5 Crozier et al found that, compared with placebo, chronic losartan treatment (12 weeks) reduced pulmonary capillary wedge pressure, systemic vascular resistance, blood pressure, and even heart rate, while cardiac index rose.6 In long term studies comparing losartan with enalapril, both drugs seemed equivalent in terms of exercise capacity, clinical status, neurohormonal activation and adverse effects.7 ,8 Therefore, losartan as the prototype AT₁ receptor antagonist appeared to be as good as an ACE inhibitor, but there were no clear signs in heart failure that it might be any better. All that changed in early 1997 with publication of the ELITE trial results.4

Conclusions

The prospects are therefore good for AT₁ receptor antagonists, but there are more questions about these agents than there are answers. Many trials are underway that will provide these answers and that will tell us whether AT₁ receptor antagonists are likely to eclipse ACE inhibitors or whether they will turn out to be another blind therapeutic alley. The ELITE study suggests that the former is more likely than the latter.