ANGIOTENSIN RECEPTOR AGONISTS are a family of potent agents with notable actions on the cardiovascular system and electrolyte balance, but have many other possible pathophysiological functions, including a putative central neurotransmitter role.

The peptides are normally formed from a precursor molecule — angiotensinogen — an α2-globulin in the blood, by the action of a 340 amino acid glycoprotein called renin, which acts as an aspartyl protease enzyme (see RENIN INHIBITORS). Renin, and its precursor protein, are both stored in the juxtaglomerular cells of the kidney, and release is controlled by three different pathways within the kidney sensitive to Na+-transport, blood vessel stretch and β1-adrenoceptor activation, respectively. Overall, activation of the renin-angiotensin systems is hypertensive, but serves to increase renal perfusion.

The relationships and actions of the members of the angiotensin peptides formed within the body pathways is complex. Cleavage of angiotensinogen initially forms the decapeptide angiotensin I (AI), which has little cardiovascular potency, but is immediately converted to an octapeptide, angiotensin II, through the C-terminal deletion of two residues, by angiotensin-converting enzyme (ACE) (EC, kininase II, dipeptidyl carboxypeptidase A).

This proteolytic enzyme is found in plasma and elsewhere, but is particularly associated with the vascular endothelium within the lungs; and conversion takes place to a major extent on a single passage of blood through the lungs. ACE is a polymorphic enzyme, where genotypic humans variants are thought to be associated with increased propensity to myocardial infarction and certain other disease states. Drugs that are ACE inhibitors are used in the treatment of hypertension and heart failure, and are discussed under another heading, ACE INHIBITORS.

Angiotensin II (AII) is one of the most potent vasoconstrictors known, and accounts for most of the endogenous activity of the angiotensin peptide family, including vasoconstriction in cutaneous, splanchnic and renal beds. It has few actions on other smooth muscle, but increases the rate and force of the heart. It has actions within the CNS that suggest a role in control of thirst and appetite for salt.

Angiotensin HI (AII2-8) is a heptapeptide formed from angiotensin II on N-terminal deletion by blood-borne aminopeptidases. It has a different pharmacological spectrum, notably in stimulating aldosterone secretion, and in effecting some CNS processes.

Angiotensin1-7 (or [des-Phe8]-AII) is formed on C-terminal deletion of AI by endopeptidases (24.15; 24.11; 24.26), has a distinct pharmacology and may have its own receptors. Angiotensin IV (AII3-8) seems to show preferred binding at certain sites.

Angiotensin peptides act at two main receptor types called AT, and AT2. In the rat and mouse, AT1A and AT1B receptors have been cloned and, though the product of different genes, have 94% homology, with small pharmacological and insignificant functional, differences. All these receptors are of the 7-transmembrane G-protein-coupled type.

The AT1 receptors are activated by angiotensin II (AII) at much lower concentrations than AIII. There are no really selective agonists, but there are many selective antagonists — a number in clinical development or use (see ANCIOTENSIN RECEPTOR ANTAGONISTS). Coupling of this receptor type is to the InsP3/DAG system. The main effects of angiotensin II in the body are mediated via this receptor type.

The AT2 receptors have only about 32% homology with AT1 receptors, and much less is known about their function. Here, AIII and AII are approximately equipotent, and the peptide derivative CGP 42112A has a selective agonist action at low concentrations (though it may inhibit at higher concentrations). There are some selective antagonists (e.g. PD 123319) (see angiotensin receptor antagonists). There are peculiarities about the coupling of this receptor that need to be resolved. A number of ion channels can be modulated, and there are some suggestions of effects linked through tyrosine phosphorylation of endogenous proteins. Regarding a role, the receptor is expressed at a very high level in the developing foetus. In the adult, expression is in the adrenals, uterus, ovary, heart and certain nuclei of the brain. The significance of this is not clear.

There appear to be other angiotensin binding sites, including the ‘atypical’ (tentatively named ‘AT3‘) sites in neuroblastoma cells, where it is associated with a nitric oxide-dependent rise in cGMP (these have a high affinity for saralasin, but low affinity for losartan and PD 123177) and also the AIV (AII3_8) binding site (also called AT4) associated with increased renal and cerebral blood flow (the latter possibly enhancing cognition).