Angiotensin

ANGIOTENSIN

Angiotensin-II (AII) is an octapeptide generated in the plasma from a precursor plasma α2 globulin, and is involved in electrolyte, blood volume and pressure homeostasis. Pressor action of kidney extracts was known since the turn of the 19th century. The active material was termed ‘Renin’. In the 1940s renin was shown to be an enzyme which acted indirectly by producing a pressor principle from plasma protein. Subsequently, it became clear that the product of renin action was an inactive decapeptide angiotensinI (AI) which was converted to the active octapeptide AII by an angiotensin converting enzyme (ACE). The renin-angiotensin system (RAS) has attracted considerable attention in the recent years, particularly after the development of ACE inhibitor captopril.

Circulating Renin-Angiotensin System

The generation and metabolism of AII in circulation is depicted in Fig. 36.1. Normally, the amount of renin in plasma acts as the limiting factor for AII generation. The plasma t½ of renin is 15 min. The biological potency of AI is only 1/100 that of AII, but it is rapidly converted into the latter by ACE which is a dipeptidyl carboxypeptidase located primarily on the luminal surface of vascular endothelial cells (especially in lungs). Circulating AII also has a very short t½ (1 min); the first degradation product termed AngiotensinIII (AIII) is 2–10 times less potent than AII, except in stimulating aldosterone secretion, in which it is equipotent. AIII is further acted upon by a variety of peptidases, collectively termed angiotensinases, to inactive fragments.

Tissue (Local) Renin-Angiotensin Systems

Apart from the AII generated in circulation as described above, blood vessels capture circulating renin and angiotensinogen and produce AII within or at the surface of their wall (extrinsic local RAS). Many tissues, especially heart, blood vessels, brain, kidneys, adrenals possess all components of the renin-angiotensin system and generate AII inside their cells (intrinsic local RAS). Thus, local renin-angiotensin systems appear to operate in several organs in addition to the circulating one.

Actions

CVS

The most prominent action of AII is vasoconstriction—produced directly as well as by enhancing Adr/NA release from adrenal medulla/adrenergic nerve endings and by increasing central sympathetic outflow. Vasoconstriction involves arterioles and venules and occurs in all vascular beds. However, it is less marked in cerebral, skeletal muscle, pulmonary and coronary vessels. AII induced vasoconstriction promotes movement of fluid from vascular to extravascular compartment. BP rises acutely. As a pressor agent, AII is much more potent than NA. No tachyphylaxis is seen in the pressor action of AII; rather long-term infusion of low concentration of AII produces sustained rise in BP by its renal effects promoting salt and water reabsorption, as well as by enhancing endothelin generation.

AII increases force of myocardial contraction by promoting Ca²⁺ influx. Though, it can increase heart rate by enhancing sympathetic activity, reflex bradycardia predominates in the intact animal. Cardiac output is often reduced and cardiac work is increased (due to rise in peripheral resistance). In contrast to NA, AII does not activate latent pacemakers—little arrhythmogenic propensity.

AII acting on a chronic basis induces hypertrophy, hyperplasia and increased intercellular matrix production in the myocardium and vascular smooth muscle by direct cellular effects involving expression of protooncogenes and transcription of several growth factors. Indirectly, volume overload and increased t.p.r. caused by AII contributes to the hypertrophy and remodeling (abnormal redistribution of muscle mass) in heart and blood vessels. Long standing hypertension increases vessel wall + intimal thickness and causes ventricular hypertrophy. Fibrosis and dilatation of infarcted area with hypertrophy of the non-infarcted ventricular wall is seen after myocardial infarction. Progressive cardiac myocyte death and fibrotic transformation occurs in CHF. These changes are important risk factors for cardiovascular morbidity and mortality. ACE inhibitor therapy retards/reverses many of these changes imparting a pivotal role to AII in vascular and ventricular hypertrophy, apoptosis and remodeling.

Smooth Muscles

AII contracts many visceral smooth muscles in vitro, but in vivo effects are insignificant.

Adrenal Cortex

AII and AIII are trophic to the zona glomerulosa of the adrenal cortex— enhance synthesis and release of aldosterone which acts on distal tubule to promote Na⁺ reabsorption and K⁺/H⁺ excretion. These effects are exerted at concentrations lower than those required to cause vasoconstriction.

Kidney

In addition to exerting indirect effect on kidney through aldosterone, AII promotes Na⁺/H⁺ exchange in proximal tubule → increased Na⁺, Cl^– and HCO3¯ reabsorption. Further, it reduces renal blood flow and produces intrarenal haemodynamic effects which normally result in Na⁺ and water retention. However, an opposite effect has been observed in cirrhotics and renovascular disease patients.

CNS

It has been noted that systemically administered AII can gain access to certain periventricular areas of the brain to induce drinking behaviour and ADH release—both of which would be conducive to plasma volume expansion. It also increases central sympathetic outflow —contributes to the pressor response.

Peripheral Sympathetic Structures

AII enhances sympathetic activity by peripheral action as well. It releases Adr from adrenal medulla, stimulates autonomic ganglia and increases the output of NA from adrenergic nerve endings.

Angiotensin Receptors And Transducer Mechanisms

Specific angiotensin receptors are present on the surface of target cells. Two subtypes (AT1 and AT2) have been differentiated pharmacologically: Losartan is a selective AT1 antagonist, while PD 123177 is a selective AT2 antagonist. Both subtypes are G-protein coupled receptors. However, all known effects of AII appear to be mediated by AT1 receptor.

The AT₂ receptor is abundantly expressed in foetal tissues. In adults, it has been demonstrated in vascular endothelium, adrenal medulla, kidney and some brain areas. The functional role of AT₂ receptor is not clearly defined, but is generally opposite to that of AT₁ receptor. Activation of AT₂ receptor causes NO-dependent vasodilatation, promotes apoptosis, myocardial fibrosis and inhibits cell proliferation.

The AT1 receptor utilizes different transducer mechanisms in different tissues. The phospholipase C–IP3/DAG–intracellular Ca²⁺ release mechanism underlies vascular and visceral smooth muscle contraction by activating myosin light chain kinase (MLCK). In addition, membrane Ca²⁺ channels are activated. Enhanced Ca²⁺ movement also induces aldosterone synthesis/release, cardiac inotropy, depolarization of adrenal medullary/autonomic ganglionic cell resulting in CA release/ sympathetic discharge. DAG activates protein kinase C (PKC) which phosphorylates several intracellular proteins and augments the above responses as well as participates in promotion of cell growth. In liver and kidney, AII inhibits adenylyl cyclase. The intrarenal homeostatic action involves phospholipase A2 activation and PG/LT production.

In many tissues, especially myocardium, vascular smooth muscle and fibroblasts, AT1 receptor also mediates long-term effects of AII on cell growth. AII activates MAP kinase, TAK2 tyrosine protein kinase and PKC which together enhance expression of protooncogenes, transcription factors and growth factors. As a result, cell growth is promoted and more intercellular matrix is synthesized.

Pathophysiological Roles

Mineralocorticoid Secretion

There is no doubt that AII (also AIII) is the physiological stimulus for aldosterone secretion from adrenal cortex. It also exerts trophic influence on the glomerulosa cells so that effects are augmented under conditions which persistently raise AII levels.

Electrolyte, Blood Volume And Pressure Homeostasis

The RAS plays an important role in maintaining electrolyte composition and volume of extracellular fluid (see Fig. 36.1). Changes that lower blood volume or pressure, or decrease Na⁺ content induce renin release by—

1.         Decreasing tension in the afferent glomerular arterioles: the intrarenal baroreceptor pathway: possibly operates through increasing local production of prostaglandins (PGs).

2.          Low Na⁺ concentration in the tubular fluid sensed by macula densa cells: the macula densa pathway. It has been found that COX2 and neuronal nitric oxide synthase (n-NOS) are induced in macula densa cells by Na⁺ depletion → release of PGE2 and PGI2 is enhanced both due to increased amount of COX2 as well as its activation by NO. The locally released PGs act on juxtaglomerular cells to promote renin secretion.

3.         Baroreceptor and other reflexes which increase sympathetic impulses to JG cells— activated through β1 receptors: the β adrenoceptor pathway.

Increased renin is translated into increased plasma AII which produces acute rise in BP by vasoconstriction, and more long-lasting effects by directly as well as indirectly increasing Na⁺ and water reabsorption in the kidney. Rise in BP in turn inhibits renin release : the long-loop negative feedback mechanism. It has been recently shown that AII can be formed within the kidney and exerts important local regulatory effects. A short-loop negative feedback mechanism operates within the kidney : activation of AT1 receptors on JG cells inhibits renin release. Long-term stabilization of BP despite varying salt and water intake appears to be achieved through these mechanisms.

The mechanisms of regulation of renin release have important pharmacological implications:

·      ACE inhibitors and AT1 antagonists enhance renin release by interfering with both the shortloop and longloop negative feedback mechanisms.

·        Vasodilators and diuretics stimulate renin release by lowering BP.

·     Loop diuretics increase renin production by reducing entry of Na⁺ into macula densa cells.

·   Central sympatholytics and β blockers decrease renin release by depressing the β adrenoceptor pathway.

·    NSAIDs, including selective COX2 inhibitors, and nNOS inhibitors decrease renin release by inhibiting PG production → cause Na⁺ and water retention.

Development of Hypertension

The RAS is directly involved in renovascular hypertension: plasma renin activity (PRA) is raised in most patients. In essential hypertension also it appears to have a permissive role, though PRA may be raised or low. Since ACE inhibitors consistently lower BP in hypertensives, the involvement of this system appears to be more widespread. A positive correlation between circulating angiotensinogen levels and essential hypertension has also been found. Several genetic evidences point to causation of pregnancy-induced hypertension (preeclampsia) by production of AT₁ receptor agonistic autoantibodies. The role of AII in hypertrophy/remodeling of heart and blood vessels is now well recognized (see above).

Secondary Hyperaldosteronism

The RAS is instrumental in the development of secondary hyperaldosteronism.

CNS

AII can be formed locally in the brain and may function as transmitter or modulator. Regulation of thirst, hormone release and sympathetic flow may be the responses mediated.

AII is not available commercially, and not used clinically.

Inhibition Of Renin-Angiotensin System

It can be achieved by:

1.    Sympathetic blockers (β blockers, adrenergic neurone blockers, central sympatholytics)— decrease renin release.

2.    Renin inhibitory peptides and renin specific antibodies block renin action—interfere with generation of AI from angiotensinogen (rate limiting step).

3.    Angiotensin converting enzyme inhibitors— prevent generation of the active principle AII.

4.    Angiotensin receptor (AT1) antagonists— block the action of AII on target cells.

5.    Aldosterone antagonists—block mineralocorticoid receptors.