Functional aspects of the renin–angiotensin–aldosterone system and angiotensin II receptor AT1 blockers in arterial hypertension

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  Functional aspects of the renin–angiotensin–aldosterone system and angiotensin II receptor AT1 blockers in arterial hypertension
  Functional aspects of the renin–angiotensin– aldosterone system and angiotensin II receptor AT1 blockers in arterial hypertension Freddy Contreras a  , Marı´a Antonia de la Parte a  , Julio Cabrera a  , Nestor Ospino a  , Rafael Herna´ndez  b , Marı´a J. Herna´ndez  b ,Edwin Lezama a  , Manuel Velasco a, * a  Clinical Pharmacology Unit, Vargas Medical School, Central University of Venezuela, Caracas, Venezuela  b Clinical Pharmacology Unit, Universidad Centroccidental ‘‘Lisandro Alvarado’’, Barquisimeto, Venezuela Abstract Hypertension is a very common condition and the most important risk factor for the occurrence of cardiovascular events. The hyperactivity of the renin–angiotensin–aldosterone system (RAAS) has been attributed as cardiovascular risk factor in subjects with essential hypertension; intrinsic vascular abnormalities in which the RAAS is clearly the keystone for the development of the pathologicalchanges in the blood vessel’s wall, have been found to cause hypertension. Many drugs withdifferent therapeutic mechanisms have been used for the treatment of patients with hypertension andvascular complications. Nevertheless, most of the drugs used are sometimes limited due to their adverse effects. Permanent research for new pharmacological agents for the treatment of hypertension has led to the development of angiotensin II AT1 receptor antagonists. The most important functions mediated by receptor AT1 include: vasoconstriction, induction of the productionand release of aldosterone, renal resorption of sodium, cardiac growth, proliferation of vascular smooth muscle, increase of peripheral noradrenergic action and central activity of sympatheticnervous system, stimulation of vasopressin release, and renin from the kidney. Angiotensin II AT1receptor blockers oppose the effect of the inhibition of angiotensin II, thus lowering the blood pressure without producing cough as a side effect, as they do not affect the levels of bradykinin or Psubstance—making these products suitable in treating patients with hypertension whose treatment requires a drug that blocks the effect of the angiotensin converting enzyme (ACE). D  2002 Elsevier Science B.V. All rights reserved.  Keywords:  Renin–angiotensin system; Hypertension; Angiotensin II AT1 receptor blockers0531-5131/02  D  2002 Elsevier Science B.V. All rights reserved.PII: S0531-5131(01)00578-7 * Corresponding author.  E-mail address: (M. Velasco).International Congress Series 1237 (2002) 87–98  1. Introduction Vascular receptors for angiotensin II (AII) not only mediate the normal regulation of  blood circulation but they also play an important role in hypertension and in theundesirable side effects that ensue when this condition is treated. It is known that anexcessive activity of the renin–angiotensin–aldosterone system (RAAS) is a bad prognosis in arterial hypertension. At present, AII is identified as the main cause of vascular complications seen in hypertension—such as intrinsic vascular modifications,hemodynamic changes, and alterations in cardiac structure. In this process, local vascular  paracrine factors and other paracrine circulating substances are also involved. Theintroduction of drugs inhibiting the angiotensin converting enzyme (ACE) and a newclass of blockers for the angiotensin II (AII) receptor has produced a considerable amount of evidence towards the involvement of the renin–angiotensin–aldosterone system(RAAS) in arterial hypertension. In this review, the physiological aspects of the RAASand its influence in most of the cardiovascular organs, as well as the new drugs used asantagonists of angiotensin II AT1 receptors are considered. 2. Hypertension and cardiovascular events Arterial hypertension is a very common condition and represents the most important risk factor for the occurrence of cardiovascular events. In recent years, great efforts have been made to detect and treat patients with hypertension. It is believed that a number of factors are involved in high blood pressure and coronary disease. This association has beenexplained through three important factors: (1) intrinsic vascular alterations, where theRAAS is clearly the keystone for the development of pathological changes in the arterialwall; (2) hereditary risk factors and (3) changes in blood pressure that occur in hyper-tension, which seem to be important in the development of atheromatous disease. Manydrugs with different mechanisms of action have been used in the treatment of individual patients with hypertension and cardiovascular complications but most of these of productsare sometimes unsuitable due to their adverse side effects. Continuous research on drugshas led to the development of new compounds including antagonists of angiotensin II AT1receptors [1].The importance of the renin–angiotensin system in the regulation of blood pressure has been well established. The high activity of this system seems to be a risk factor for subjectswith essential hypertension. Epidemiological studies are currently taking place todetermine if renin by itself is a risk factor for cardiovascular disease or if it is just asignal for other risk factors [2]. 3. Local and systemic angiotensin systems AII actions can be explained by two main events: first, there are two interactingsystems, one local in the tissues and the other in the circulation. In that way, the site of  production of AII could indicate the action of the peptide implied; second, the different   F. Contreras et al. / International Congress Series 1237 (2002) 87–98 88   biological events attributed to AII could be explained through protein G related to AIIreceptors. 4. Circulating system The angiotensin II circulating system produces AII by an enzymatic process by stepsfrom angiotensinogens and the prohormone angiotensin I (AI) mediated by renin andACE, respectively. The reaction occurs during blood circulation when renin is released bythe kidney and produces AI from the angiotensinogen produced by the liver. ACE, boundto the inner endothelial surface of lung and blood vessels, converts AI to AII. AII, produced in blood circulation, reaches its target receptors to produce a biological signalconducted through interstitial fluids. 5. Tissular system It has been demonstrated that the parenchyma of many tissues (blood vessels, heart, brain, and kidney) contains all the necessary components for the local production of AII peptides. The greater amount (90–99%) of angiotensin-converting enzyme (ACE) is present in the tissues. In this case, AII is produced inside the interstitial compartments, inits target receptors, or near them. The heart expresses codification for RNAm correspond-ing to renin, angiotensinogen, and AII subtype AT1 receptor [3]. Similar evidences aredescribed in astrocytes [4,5] and cardiac myocytes [3]. In contrast, it occurs with localsystems in the tissues, which send biological signals with paracrine or autocrine effects [6].The AII produced locally could be limited in its action range due to difficulties in thediffusion of peptide out of the production site because of the presence of proteolyticfactors or absence of specific target receptors. Angiotensin II may be produced in tissues, perhaps through a different ACE-independent pathway (chymase pathway; Fig. 1).Angiotensin II is a potent vasoconstrictor with different other effects on vascular structuresand homeostasis [7].Angiotensin II increases the production of inhibitor type 1 of the plasminogen activator,the primary endogenous inhibitor of t-PA, promotes vascular growth and stimulates the production of other growth factors [8]. Angiotensin II also increases the platelet ag-gregation response to direct platelet agonist and stimulates the production of endothelin,substance which is considered the most potent endogenous vasoconstrictor. Possibleactions of other biologically active components of the system renin–angiotensin–aldoster-one, angiotensin III, also called [des-Asp], or angiotensin-[2–8] that can be formed either  by effect of the aminopeptidase on angiotensin II, or by ACE on angiotensin I are beingstudied recently. Angiotensin II and III produce qualitatively similar effects. AngiotensinIII is almost as potent as angiotensin II when stimulating aldosterone secretion. Notwith-standing, angiotensin III only has between 10% and 25% of the power of angiotensin II toraise the blood pressure values [6]. Angiotensin-[1–7], which is an aminoterminalheptapeptide that can be produced in several tissues in the blood vessels, is produced bythe action of tissular endopeptidases on angiotensin I and angiotensin II [9]. In vascular   F. Contreras et al. / International Congress Series 1237 (2002) 87–98  89  smooth muscles, metaloendopeptidases and propilendopeptidases can be produced fromangiotensin I and II. Findings in several animal studies suggest that angiotensin-[1–7] is avasodilator that could have cardioprotective effects by opposing the actions of angiotensinII on vascular reactivity and growth. In contrast to angiotensin II, angiotensin-[1–7] doesnot produce vasoconstriction, aldosterone release, thirst, or facilitation of noradrenergicneurotransmission. This vasodilatory effect is mediated by the release of endothelial nitricoxide (NO) and endothelial bradykinin [10]. Fig. 1. Renin–angiotensin systemic and tissular systems. Antigiotensin II produced in the tissue plays animportant role in the production of antgiotensin.  F. Contreras et al. / International Congress Series 1237 (2002) 87–98 90  Angiotensin II has several physiological actions—it elevates extracellular volume, peripheral vascular resistance, and blood pressure and it also participates in cellular growthand differentiation. Molecular cloning and pharmacological studies have defined two maintypes of receptors for angiotensin: AT1 and AT2. Many effects of the angiotensin are produced by its binding to receptor AT1 in cellular membranes. AT1 receptors subtype for AII are predominantly placed in vascular tissue and myocardium and also in the brain,kidney, and glomerular cells of adrenal glands, those which produce aldosterone [11]. Themost important actions mediated by AT1 receptor include: vasoconstriction, stimulation of the synthesis and release of aldosterone, sodium reabsorption from the renal tubule, cardiacgrowth, proliferation of vascular smooth muscle, increase in peripheral noradrenergicactivity and central activity of sympathetic nervous system, stimulation of the release of vasopressin, and inhibition of renal renin. On the other hand, receptors AT2 are placed inadrenal medulla and probably in the central nervous system and have large distribution onfetal tissues [12]. At present, their action on cardiovascular homeostasis is unknown but there are evidences suggesting that AT2 receptors take part in embryonic development anddifferentiation, stimulation of apoptosis, and regeneration of several tissues, taking part inendothelial, antiproliferative effects and vasodilatation. From the previous statements, wecan appreciate that AT1 and AT2 receptors seem to have opposite actions on cellular growthand differentiation, vascular tone and release of arginine–vasopressin. In each case, AT2receptors seem to modulate downwards, the action mediated by AT1 receptors by loweringcellular proliferation, circulating levels of arginine–vasopressin, or the vasoconstrictionresponse. Also, in neuronal cellular line receptors, AT2 receptors have antiproliferativeeffects and promote the neuronal overgrowth, showing significant changes in the patterns of genetic expression for growth and differentiation related to genes [13]. Furthermore, to theimmediate responses, AT1 receptors stimulate growth in vascular and cardiac cells; thisaction has genetic expression [14].The selectivity of the antagonists available for clinical use for this AT1 non-peptidicreceptor subtype shows some promise as they do not seem to have any therapeuticdisadvantage.Antagonists for the renin–angiotensin system are imidazol derivatives recognised ashighly effective drugs for the treatment of hypertension in all its grades and cardiac failure.This is possible for the antagonism of the effects of angiotensin II blocking its receptors ina selective manner. Therefore, they interfere with the binding of AII to its AT1 receptor [15,16]. As a result of this blockade, there are higher levels of circulating AII, the free AIIis ready to bind with another AII receptor [14]. In this case, AII binds preferably to thereceptor AT2. Despite most of the actions mediated by AT2 receptor, it seems to be beneficial and its stimulation could be positive, although there could be undesirable sideeffects after long-term use mediated by this or other AII receptors.Antagonists to the AII receptors have been classified in three pharmacological groups:the selective blockers for AT1 receptors, those selectively blocking AT2 receptors, andthose blocking both types of AII receptors.Six antagonists for AII AT1 receptors have been approved to be use in the treatment of hypertension in its different grades: Losartan, Valsartan, Irbesartan, Candesartan,Telmisartan, and Eprosartan (see Table 1). These new drugs are highly selective to block AT1 receptors and induce dose-dependent inhibition of the response to exogenous  F. Contreras et al. / International Congress Series 1237 (2002) 87–98  91
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