Renin Angiotensin System Antagonists and Anesthesia

Renin angiotensin system (RAS) antagonists, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor antagonists are increasingly used to treat cardiovascular and other diseases (1–6). These treatments induce a blockade of the RAS that may affect hemodynamics during anesthesia and surgery. In 1978, Miller et al. (7) reported that the RAS is involved in maintaining normal blood pressure during anesthesia. Although anesthesia is not invariably associated with a deleterious hemodynamic event in RAS-blocked patients (8–10), hemodynamic instability, described as unexpected episodes of hypotension, have been reported (11–13). Otherwise, stresses such as surgery or hypotension stimulate the generation of angiotensin II, which induces vasoconstriction (14) to maintain blood pressure but reduces blood flow to organs such as the kidneys and bowels. Accordingly, an angiotensin II-induced reduction in blood flow may contribute to acute renal failure (15) and splanchnic ischemia (16), which are obvious factors in postoperative morbidity (17). RAS blockade with ACE inhibitors decreases some consequences of the stress response on the regional circulation (9,18,19), which may then contribute to body protection. Much of the information regarding the physiology and pathophysiology of the RAS during anesthesia and surgery is based on the effects of ACE inhibitors. Because ACE inhibitors probably act mostly by blocking the RAS, similar effects should be obtained from angiotensin (AT) receptor antagonists. RAS antagonist pharmacology may help us to understand the hemodynamic risk of anesthesia in RAS-blocked patients, to identify predisposing factors, and to determine the potential benefit of RAS antagonists during anesthesia and surgery. Physiology of the RAS Generation of Angiotensin II The RAS is basically defined as a biochemical cascade (Figure 1) (20). A highly specific proteolytic enzyme, renin, cleaves an ineffective peptide precursor, angiotensinogen, to generate a decapeptide, angiotensin I. Angiotensin I is converted to an octapeptide, angiotensin II, by an nonspecific carboxypeptidase, the ACE. Angiotensin II is considered the effective final product of enzymatic reactions (20–22). The biochemical cascade is self-limited by rapid metabolism of angiotensin II and/or by the negative feedback control of angiotensin II on renin release (20).Figure 1: The renin-angiotensin biochemical cascade.The biochemical cascade originates from different organs. The kidney produces renin, the liver produces angiotensinogen, and plasma and vascular endothelium produce angiotensin. However, almost all angiotensin I and angiotensin II (90% and 64%, respectively) is generated within endothelium, rather than in plasma (22–24). The primary determinant of the rate of angiotensin II formation is the plasma level of renin created by the regulated secretion of renal renin (25). The well known areas that regulate renal renin secretion (renal baroreceptors, neurogenic stimulation, or macula densa-mediated RAS activation) have been confirmed at the cellular and subcellular levels (26). All these mechanisms regulate renin expression by Ca2+, adenosine 3′,5′-cyclic monophosphate, and chemiosmotic forces (K+, Cl−, and water flux coupled to H+ movements). Under favorable conditions, prorenin is then processed to renin, which may be secreted by regulative degranulation or divergence translocation (26). The final activity of angiotensin II depends mostly on the level of renin substrate and the availability of ACE. However, alternative pathways for the conversion of angiotensin I to angiotensin II, originating from masocytes and endothelial cells, have been identified (e.g., cathepsin G, chymase, serine proteases, tonin) (Figure 1). They are thought to be involved in modulating local angiotensin II formation in the heart, specifically under ischemic conditions and for structural remodeling (27,28). Angiotensin Receptors Angiotensin II acts on multiple target organs after binding to specific receptors. Angiotensin II binds at least to two specific receptors, angiotensin I receptor subtypes AT1 and AT2, which are polypeptides containing approximately 360 amino acids that span the cell membrane seven times. Despite their similar affinities for angiotensin II, AT1 and AT2 receptors are functionally distinct, with a sequence homology of only 30%. The gene for the AT1 receptor is located on chromosome 3, and the gene for AT2 receptor is on chromosome X. Specific, high-affinity binding of angiotensin is determined by amino acids located on or near the extracellular surface of the membrane-bound receptor, as well as by sequences in the transmembrane domains (4). The signal-transducing proteins associated with AT receptors is well established for the AT1 receptor. The binding of angiotensin II to the AT1 receptor is coupled to a G protein, which then activates phospholipase C to generate diacylglycerol and inositol trisphosphate. The inositol trisphosphate then releases calcium from intracellular stores. Angiotensin II also increases the entry of calcium into the cell through channels in the cell membrane. Calcium and diacylglycerol activate enzymes, including protein kinase C and calcium-calmodulin kinases, catalyze the phosphorylation of protein, which regulates the cell functions affected by angiotensins. By contrast, little is known about signal transducing by the AT2 receptors, which differs from transduction by AT1 receptors and does not involve phosphoinositides (4). Many actions of angiotensin II involved in blood pressure control (i.e., vasoconstriction, aldosterone secretion, stimulation of catecholamine release, central pressor and dipsogenic stimulations) are mediated through binding to AT1 receptors (29). Angiotensin II also exerts long-term effects on cellular regulation and growth. Both acute and slower responses are mediated by the signal-transduction events, which are complete in seconds or minutes. Role of Angiotensin II Angiotensin II is involved in short-term regulation of blood pressure and in regulation of intravascular fluid volume and regional circulation. All these aspects are major concerns for anesthesiologists. Regulation of Systemic Hemodynamics. RAS activation is mainly dependent on body fluid volume, specifically “effective” blood volume, i.e., the blood volume that allows adequate cardiac output (30,31). Blood pressure thus depends on RAS as a function of extracellular fluid volume and intravascular volume (31). Although there is moderate RAS dependence in normal intravascular volume (31,32) and minimal effects with extracellular fluid volume expansion (31,33), the RAS contribution to blood pressure becomes crucial with hypovolemia (31,32) (Figure 2). Inversely, the final purpose of RAS activation is to increase body fluid volume (31–33): angiotensin II is the primary stimulus to aldosterone secretion (31,33), but it also contributes to sodium regulation directly (34) and, indirectly, to fluid volume regulation (35). Any renin-dependent, volume-independent state therefore tends to be converted into a renin-independent, volume-dependent state by the RAS action itself (Figures 2 and 3). For example, an increased blood pressure in experimental renovascular hypertension or coarctation hypertension (32,36) is initially maintained by direct pressor actions of angiotensin II (renin-dependent state) and is thus sensitive to RAS blockade (37). During a later chronic phase, hypertension is due to an increase in intravascular volume that is the result of angiotensin II activity (32,36) but then becomes insensitive to RAS blockade (renin-independent state) (37,38).Figure 2: Plasma renin activity (PRA)/effective intravascular volume relationship. In physiologic steady state, normotension is maintained without renin-angiotensin system activity, as assessed by minimal PRA. When intravascular volume is at least maintained, arterial blood pressure is thus renin-independent. Inversely, blood pressure becomes renin-dependent when the intravascular volume decreases.Figure 3: Dual action of angiotensin II. The relationship between arterial blood pressure (BP) and intravascular volume (volemia) is influenced by the renin-angiotensin system (RAS). When (effective) intravascular volume decreases, angiotensin first induces an arterial and venous vasoconstriction that sustains blood pressure (shaded area 1). The intravascular volume then tends to be restored by direct, as well as indirect, angiotensin II actions (aldosterone) (area 2). In the case of RAS blockade, BP tends to be closely related to intravascular volume.Fluid volume regulation requires hours to days, but angiotensin II-induced vasoconstriction is quickly activated; therefore, that acute changes in intravascular volume status are initially caused by vasoconstriction. Angiotensin II-induced vasoconstriction is well known for arterioles and contributes to the maintenance of blood pressure by increasing vascular resistance (31–33). As for arterioles, angiotensin II produces constriction of veins either directly (39–41) or by enhancement of the sympathetic nervous system (39), which results in the reduction of vascular capacitance (i.e., in either vascular volume and/or vasoconstriction may also venous cardiac output is from to effective intravascular volume therefore may be maintained a in blood volume Both the arterial and venous actions of angiotensin II venous to the heart, and cardiac output is then the direct actions of angiotensin II, a between angiotensin II and other factors may be involved in blood pressure results from between II, or between angiotensin II and endothelial control of such as are also similar with factors involved in angiotensin body volume may increase angiotensin II-induced aldosterone and aldosterone may increase angiotensin II receptor and angiotensin protein In during RAS activation first results in angiotensin II-induced vasoconstriction. Angiotensin II then fluid volume increase through stimulation of sodium and water When effective intravascular volume is RAS is (Figure Regulation of circulation is the regional circulation with to the of the RAS on regulation of regional vascular the kidney of the first in which in formation of angiotensin II The RAS is involved in the regulation of renal and mainly by angiotensin II-induced vasoconstriction of the of Many other are probably affected by the of RAS in regional but such a in local is In the circulation is sensitive to angiotensin II-induced therefore, are during RAS activation of ACE and AT of and of ACE ACE is an that is involved in the conversion of angiotensin I to angiotensin II and in the in central and a of angiotensin II formation is the of ACE the first of the first specific ACE in in with similar activity have been have from when related to are that be converted by activity in the liver to (e.g., which have than which allows but of ACE activity after ACE the is anesthesia and surgery. However, plasma does not of of and of AT is the first effective antagonist of the AT1 receptor with a of In have confirmed the of that specifically and and without the AT2 responses to all the AT1 actions of angiotensin. A response is in to the of angiotensin II, as well as in renal acute in arterial blood pressure is by a slower reduction the which approximately after These the of or in the action of the major of with a and a of in may be for of the of A increase in plasma renin activity and angiotensin II levels of the negative feedback by angiotensin II on renin secretion In for the pressure response to angiotensin I in a after a of the response to of angiotensin I well in normal and not affect rate or arterial blood pressure AT receptor antagonists are (e.g., All have a similar to that of The potential of of is should not induce the effects of ACE inhibitors such as which in of patients ACE inhibitors. AT receptors should angiotensin II effects than an ACE blockade of the enzyme other pathways to angiotensin II the However, the of such angiotensin II in is not well In reduction by ACE inhibitors also in their AT receptor antagonists may not a similar However, during AT1 receptor blockade, all the AT2 receptors to the increasing levels of angiotensin II, which be a of as AT2 receptors have the effects of AT1 receptors. stimulation of AT2 receptors by increasing levels of angiotensin the effects of AT1 receptor blockade For example, angiotensin II a reduction in arterial blood pressure after AT1 receptor blockade, an probably mediated by AT2 receptors of ACE and AT on Systemic Hemodynamics. Because angiotensin II is involved in short-term regulation of blood pressure the blockade of effects either by of angiotensin II or by of the AT receptor may with blood pressure The effects of ACE inhibitors and AT receptor antagonists on the state and of RAS As blood pressure is not affected by RAS blockade in patients with a normal sodium However, the of ACE inhibitors may the complete blockade of angiotensin II as by blood pressure in i.e., with plasma renin activity A in arterial blood pressure may after a of in with a normal sodium is a result of effects of ACE such as with of or of A blood pressure after RAS blockade is basically the result of a in vascular in normal or (31–33). However, arterial RAS blockade with blood pressure regulation by cardiac output to A in cardiac output been during in patients with an ACE The cardiac output is related to of angiotensin on the a in venous In the blood pressure not associated with which may the maintenance of cardiac is probably due to a of cardiac However, in and have the rate pressure during ACE increased of the response associated with a rather than a of cardiac been Although ACE the of nervous system activity an increased the sympathetic response of the is and of control well in ACE and hypotension does not which may be involved in blood pressure is also maintained during RAS blockade the sympathetic system and may act as to maintain blood pressure during hypovolemia and RAS blockade the control of blood arterial blood pressure is volume-dependent during ACE on and are the regional that may benefit from RAS blockade in renin-dependent In experimental are sensitive to ACE than other regional have renal blood flow and The of an ACE at that not affect blood pressure a complete of renal function in (4). all the angiotensin II-induced renal i.e., vasoconstriction, and increased sodium of the AT1 receptor antagonists arterioles, as ACE inhibitors (4). renal with ACE inhibitors with different increased splanchnic in an experimental of RAS activation or in The potential benefit of such a RAS blockade on splanchnic been in experimental RAS blockade with either AT receptor antagonists or the ACE inhibitors and splanchnic and the formation of after in ACE and AT Many cardiovascular effects are by ACE inhibitors and AT receptor antagonists, and is with to the short-term actions of angiotensin II on blood pressure However, some aspects of regional circulation and cellular or cardiac may be different between ACE inhibitors and AT receptor antagonists. actions of ACE inhibitors on vascular endothelium and cellular or on are mediated through of However, AT1 receptor antagonists angiotensin actions on of and arterial (4). are to a to the of the of these and their these may have little in the of the with of the RAS antagonists. with ACE and with hypertension is related to increased vascular the hemodynamic of treatments is to vasoconstriction ACE initially to obvious renin plasma renin However, ACE inhibitors are considered effective in of the plasma renin activity, vascular be when plasma renin activity The of endothelial angiotensin been for the response of hypertension as well as the with ACE inhibitors AT1 receptor antagonists blood pressure in that have or levels of renin In in patients with AT1 receptor antagonists are approximately as effective as ACE inhibitors (4). In a of patients, the of for at of and with that of All blood pressure with the the first effective in blood pressure than but blood pressure levels not different on the of which that long-term AT receptor blockade may be as effective as ACE in blood pressure in in the of the which that may to AT1 receptor antagonists have a relationship The of the of is than that associated with an ACE probably of the II mechanisms of ACE inhibitors In volume decreases it is related to changes in and volume and cardiac output by plasma renin activity, increase with in failure sympathetic nervous system and secretion, activation of the RAS increases vascular and with the of the Both ACE inhibitors and AT1 receptor antagonists function in patients with chronic failure but rate in or failure is and is related to structural of the of metabolism and of These effects have the of ACE inhibitors in the of The of to patients with reduces morbidity during an of ACE also been in the after acute expansion is and remodeling is influenced as the result of favorable hemodynamic and responses after ACE ACE inhibitors within a after to patients with of or to patients with and morbidity Although AT receptor antagonists ACE effects on cardiovascular it is not known affect the of failure (4). Both experimental and have that results in an acute activation of the RAS Angiotensin II may a as an in ischemic RAS antagonists In of the actions of ACE inhibitors are not related to of angiotensin formation activity been through and increased of and of function of the is with ACE of or or with ACE inhibitors The of is For example, ACE inhibitors the structural remodeling created by but to after By contrast, AT1 receptor antagonists are of the effects of ACE inhibitors, which may to of function after in a deleterious related to angiotensin action on AT2 receptors In hypertension and ACE is also associated with a of regional which the kidney that episodes are in specific of renal function in or chronic associated or not with hypertension also been with ACE inhibitors. AT1 receptor antagonists have a than ACE inhibitors may contribute to the In there is between the effects of ACE inhibitors and AT1 receptor antagonists on the reduction of and in to RAS and During and Blood Regulation During Blood pressure be by the sympathetic nervous the RAS, and All these act by increasing the intracellular calcium in vascular (Figure with the sympathetic nervous system and the RAS, but an in RAS activation is caused by the in sympathetic nervous may renal sympathetic activity and induce a in renin secretion anesthesia renin release in response to arterial hypotension an by a or are mainly related to their specific effects on the sympathetic nervous the with and/or sympathetic However, during anesthesia and blood pressure may In the of RAS activation does not from that under “effective” intravascular volume activates RAS and blood pressure therefore be maintained intravascular fluid volume changes The reduction in sympathetic on the vascular capacitance results in a effective intravascular volume, and angiotensin II may Accordingly, blood pressure may during anesthesia when angiotensin II action is by an angiotensin II RAS and the sympathetic may be involved in blood pressure regulation during anesthesia through binding to receptors involved in vasoconstriction During anesthesia and of the RAS, the plasma increases anesthesia induces a moderate in blood pressure from system receptors or the RAS, pressor system may therefore act as a other are The RAS contribution to blood pressure is crucial when the sympathetic nervous system is by or anesthesia and when is by a specific receptor antagonist The and in blood pressure with the of RAS blockade and a receptor antagonist in blood pressure different be involved in blood pressure regulation to acts on the i.e., the vascular by an increase in then a cell system is related to the and may act as a and Blood Regulation During in ACE been used to a reduction in the pressor response to but not unexpected deleterious hemodynamic have been described during anesthesia in patients ACE inhibitors In these patients a in blood pressure and rate The of anesthesia reduces the of the sympathetic nervous system on the cardiovascular on venous which results in an acute in effective intravascular volume During ACE angiotensin II and the of anesthesia results in hypotension in the case of which is the only system to maintain blood pressure is effective on vascular than on arterial resistance The intravascular volume dependence of blood pressure in is during anesthesia. In episodes of hypotension have been with intravascular fluid The of of angiotensin II and due to ACE in the of hypotension is regarding AT1 receptor antagonists and anesthesia in patients without cardiovascular have been similar effects should be with ACE inhibitors and AT1 receptor antagonists are mainly related to angiotensin II in The results obtained after short-term RAS in or may not in patients with moderate to chronic of ACE inhibitors blood pressure regulation than short-term activity is after chronic of an ACE with acute in moderate and chronic ACE is with other that also adequate regulation of blood pressure during anesthesia. the of hypertension directly with the of potential anesthesia changes For all these acute sympathetic by the of anesthesia and RAS blockade may When ACE inhibitors are maintained the of the of hypotension after the of anesthesia in patients is and mainly related to a in and cardiac output The risk of hypotension is increased with some associated or complete RAS blockade, which mainly depends on the increase the of blood pressure control hypertension with the intravascular volume dependence of blood pressure in Although the of the in blood pressure not with the in plasma enzyme activity, the of hypotension after the of anesthesia when enzyme activity restored by ACE inhibitors the anesthesia However, episodes of hypotension are and by the of fluid and, such as and are effective in Angiotensin II may be an alternative an of restored arterial blood pressure quickly at the of an of function and a increase in stress However, angiotensin II is not and that have potential effects in a hemodynamic have been for hypotension after anesthesia in patients with RAS antagonists. In a vascular patients with ACE or AT receptor antagonists hypertension in a these patients, at least of a arterial blood pressure that not for of or In these patients, a of of and In patients, arterial pressure restored with of in two after the of increased from to and area and of as assessed by not which of of during the In these ACE for at least for and for the other ACE inhibitors, the of hypotension than reported in with is known about anesthesia in patients from failure and with RAS antagonists. In an experimental of failure in a of and in of cardiac output and renal blood flow but effects of and ACE may be deleterious for and and therefore, it is to for anesthesia in RAS-blocked patients with In conditions, the of function by an ACE et al. the of chronic RAS blockade may the hemodynamic of the of anesthesia in patients with In that the hemodynamic of the of anesthesia in patients with after ACE inhibitors the of surgery hypotension after the of anesthesia than in a control The of hypotension arterial blood pressure in However, chronic with ACE inhibitors the hemodynamic after the of anesthesia. ACE patients have a in cardiac probably related to a in sympathetic RAS and Systemic During During cardiac ACE inhibitors are to after either stimulation, such as or surgery is not specifically mediated by RAS However, the ACE may hypertension during cardiac surgery RAS may be during as assessed by either increased plasma renin activity or plasma angiotensin II RAS with an ACE is not associated with deleterious hemodynamic during or surgery but chronic may contribute to increased or after moderate In only for the first in the and not affected of vascular resistance after in patients with ACE have been reported In these anesthesia and but hypotension during and after from only with an angiotensin II ineffective after the of in patients with ACE inhibitors been confirmed By contrast, the of an ACE may the increase of the which are in cardiac with a potential benefit for RAS and During are to renal hemodynamic does the RAS during a deleterious in such is a of renal and is associated with a stimulation of the RAS ACE surgery the reduction in effective renal plasma flow and rate during hemodynamics are not RAS activation be by et al. the of RAS blockade with on and regional and after in a In the control an increase in plasma renin activity and a in renal and liver after The decreases in plasma during but release in in renal and liver plasma renal and increased plasma renin activity during that RAS is involved in the renal hemodynamic associated with surgery However, with in patients for surgery to effective renal plasma flow and rate during the RAS is not such an determinant of the renal vasoconstriction associated with Although renal hemodynamics not during in patients, hemodynamic changes during and renal hemodynamics well and after in the patients with control The effects of ACE inhibitors have been in in which little or deleterious on hemodynamics with an ACE However, renal circulation be in patients with a RAS renal is due to either renal or control of intravascular volume during surgery on experimental RAS antagonists may In patients to surgery and with after anesthesia and ischemia as assessed by plasma of and than control patients Although experimental of of splanchnic circulation with RAS antagonists, the is The of on in However, the in that and control of the level of plasma ACE activity described the long-term regulation of extracellular fluid volume, the RAS an physiologic in maintaining venous and blood pressure during acute hemodynamic RAS antagonists inhibitors and AT may therefore venous and cardiac output regulation during anesthesia and surgery. These effects may be as a of RAS antagonists when other factors with cardiovascular deleterious hemodynamic may therefore when effective intravascular volume is is to when predisposing factors (e.g., risk of However, of RAS control of blood pressure at the of some regional alternative should be not RAS antagonists that intravascular volume is maintained during surgery. regional may then benefit from RAS blockade the RAS antagonist or hypotension may after the of anesthesia in Blood pressure then be restored in by sympathetic In patients with hypotension to sympathetic a may be