Journal of Human Hypertension (2002) 16 (Suppl 1), S93–S99 2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh Angiotensin II receptor antagonists role in arterial hypertension R Herna´ndez-Herna´ndez1, B Sosa-Canache1, M Velasco2, MJ Armas-Herna´ndez1, MC Armas-Padilla1 and R Cammarata1 1Clinical Pharmacology Unit, Center of Biomedical Research, School of Medicine, Universidad Centroccidental Lisandro Alvarado, Barquisimeto, Venezuela; 2Clinical Pharmacology Unit, Vargas Medical School, Central University of Venezuela, Caracas, Venezuela Angiotensin II receptor blockers represent a class of with low incidence of side effects even at long term use. effective and well tolerated orally active antihyperten- Monotherapy in mild-to-moderate hypertension controls sive drugs. Activation of AT1 receptors leads to blood pressure in 40 to 50% of these patients; when a vasoconstriction, stimulation of the release of cat- low dose of thiazide diuretic is added, 60–70% of echolamines and antidiuretic hormone and promote patients are controlled. The efficacy is similar to angio- growth of vascular and cardiac muscle. AT1 receptor tensin-converting enzyme (ACE) inhibitors, diuretics, blockers antagonise all those effects. Losartan was the calcium antagonists and beta-blocking agents. AT1 first drug of this class marketed, shortly followed by val- receptor blockers are specially indicated in patients with sartan, irbesartan, telmisartan, candesartan, eprosartan hypertension who are being treated with ACE inhibitors and others on current investigation. All these drugs and developed side effects such as, cough or angio- have the common properties of blockading the AT1 edema. The final position in the antihypertensive ther- receptor thereby relaxing vascular smooth muscle, apy in this special population and other clinical situ- increase salt excretion, decrease cellular hypertrophy ations, such as left ventricular hypertrophy, heart and induce antihypertensive effect without modifying failure, diabetes mellitus and renal disease, has to be heart rate or cardiac output. Most of the AT1 receptor determined in large prospective clinical trials, some of blockers in use controlled blood pressure during the which are now being conducted and seem promising. 24 h with a once-daily dose, without evidence of produc- Journal of Human Hypertension (2002) 16 (Suppl 1), S93– ing tolerance to the antihypertensive effect and being S99. DOI: 10.1038/sj/jhh/1001352 Keywords: angiotensin II receptor antagonist; AT1 receptor; AT2 receptor; losartan Introduction Salarasin was the first receptor antagonist of angiotensin II available for clinical use more than The renin-angiotensin system is integrally involved 20 years ago.4,5 Salarasin is a peptide analogue of in maintaining the healthy body’s haemodynamic angiotensin II with partial agonist effect, and can status. Angiotensin II is the prime effector molecule only be used intravenously; it has a very short dur- of the renin-angiotensin-aldosterone system, ation of action. When saralasin is used there is an inducing vasoconstriction, promotion of cell growth initial increase in arterial blood pressure due to its in vascular and myocardial tissue, activation of the partial agonist effect, but prevents the increment of sympathetic nervous system and producing sodium blood pressure when angiotensin II is administrated. and fluid retention. Most of these cardiovascular Furukawa et al6 was the first to synthesise an imi- effects of angiotensin II are mediated by AT1 recep- dazole derivative that was found to be a selective tors. Selective blockade of the AT1 receptor not only angiotensin II receptor competitive antagonist, and inhibits vasoconstriction and vascular hypertrophy, after chemical modifications, orally active agent.7 but also could lead to a compensatory increase in Losartan was the first orally active and long-acting angiotensin II levels. These increased concen- receptor antagonist developed and in use in the trations of angiotensin II may confer additional treatment of hypertension,8,9 followed by valsartan, pharmacological benefits by stimulating the AT2 irbesartan, eprosartan, candesartan, telmisartan receptor subtype, which has been reported to and others.10 mediate antiproliferative actions on cardiac and vas- 1–3 Blockade of renin-angiotensin system is effi- cular smooth muscle. cacious and a safe way to reduce blood pressure as treatment of patients with hypertension, mainly by the inhibition of angiotensin-converting enzyme Correspondence: Dr Rafael Herna´ndez-Herna´ndez, Clinical Phar- macology Unit, School of Medicine, Universidad Centroccidental (ACE). The main side effects observed with ACE Lisandro Alvarado. Barquisimeto, Venezuela. PO Box 516 inhibitors are cough and angioedema, which are E-mail: rhernanȰcantv.net seen in 5 to 10% of patients treated with this drug Angiotensin II receptor antagonists role in arterial hypertension R Herna´ndez-Herna´ndez et al S94 11 21–24 class. AT1 receptor blockers have the advantage in AT2 receptor. The effect of the AT1 receptor having a very low incidence of such side effects. antagonists might be a result of the blockade of the However the place of this class of antihypertensive AT1 receptor and stimulation of the AT2 receptor, action remains to be defined. because increased angiotensins might act preferen- tially on the AT2 receptor when the AT1 receptor is 25 Angiotensin II receptors blocked. It may be possible that the AT2 receptor plays a role in the pathogenesis and remodelling of Angiotensin II (AII) exerts its effects by stimulating cardiovascular diseases, further understanding of some specific receptors on the membrane of several AT2 receptors could contribute to new therapeutic organs. Radioligand studies have characterised sev- strategies for cardiovascular disease and hyperten- eral angiotensin II receptors, mainly type I and type sion. II (AT1 and AT2 receptors). Activation of AT1 recep- Actions mediated by AT1 and AT2 receptors are tors leads to vasoconstriction, stimulation of the summarised in Table 1. Other angiotensin II recep- 26 release of catecholamines and antidiuretic hormone tors have been described such as AT3 and AT4 in and production of thirst; also promoting growth rats and mice; AT1 receptor is also composed of two 12 27 effects in vascular and cardiac muscle, all these subtypes: AT1A and AT1B; these receptors have to effects are blocked by AT1 antagonists. Several AT1 be characterised pharmacologically and in patho- receptor antagonists are now available for clinical physiological conditions. use. Experimental studies have shown interesting differences in their binding properties and the AT receptor antagonists pattern of inhibition of contractile responses to 1 13–15 angiotensin II in isolated blood vessels. In The first chemically useful, orally active AT1 recep- human subcutaneous resistance arteries the AT1 tor antagonist was losartan, followed by other agents receptor antagonists, candesartan, losartan and los- currently in clinical use or under investigation.8,9 artan’s metabolite EXP-3174, reduce the maximal They have a high affinity of AT1 receptor subtype contractile response to AII suggestive of non-com- without exerting agonistic effects and do not bind to petitive antagonism. In the case of losartan the con- the AT2 receptor when given at the recommended centration-response curve also appears to be dis- clinical doses. Likewise, specific inhibitors of the 28,29 placed by higher concentrations of AII, giving the AT2 receptor do not bind to the AT1 receptor. overall appearance of mixed competitive and non- Table 2 summarises the AT1 receptor antagonists competitive antagonism.13 These observations differ either in clinical use or under development. from those obtained in rabbit and rat vessels where The AT1 receptor antagonist reduce blood press- losartan appears to behave as a competitive antagon- ure by decreasing systemic vascular resistance; heart ist16,17 in contrast with candesartan which acts in a rate and cardiac output are not modified.30–32 non-competitive manner.18 Eprosartan differs from Reduction in systemic vascular resistance are due other agents in its class in that it is a non-biphenyl, to inhibition of the direct vasoconstrictive effect of non-tetrazole, competitive angiotensin II receptor antagonist with a high affinity for AT subtype. In 1 Table 1 Actions mediated by AT and AT receptor addition, eprosartan also differs from other angio- 1 2 tensin II receptor antagonists by providing com- Angiotensin II Angiotensin II bined inhibition of both the renin-angiotensin sys- AT1 Receptor AT2 Receptor tem and the sympathetic nervous system, as 19,20 demonstrated in pithed rats. Vasoconstriction Vasodilatation via bradykinin In contrast to the AT1 subtype, the physiological and nitric oxide role of the AT2 receptor has long remained an Aldosterone production and Antiproliferative effect enigma. This subtype is highly expressed in fetal release tissues, whereas its expression is dramatically Sodium tubular reabsortion Embriogenic differentiation and decrease after birth, being restricted to a few organs development such as brain, adrenal, heart, myometrium and Hypertrophy of heart Stimulation of apoptosis ovary. The AT receptors are re-expressed during 2 Proliferation of smooth muscle Endothelial cells growing stressful situations in the adult animal, after cardiac in vascular tree and vascular injury (such as myocardial infarction, Catecholamines secretion and left ventricular