Impact of kinins in the treatment of cardiovascular diseases

Pharmacology & Therapeutics 135 (2012) 94–111

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Impact of kinins in the treatment of cardiovascular diseases☆ Domenico Regoli a,⁎, Gerard E. Plante b, Fernand Gobeil jr. a b c

b, c,⁎⁎

Department of Experimental and Clinical Medicine, University of Ferrara, Ferrara, Italy Department of Pharmacology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Canada, J1H 5N4 Institute of Pharmacology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Canada, J1H 5N4

a r t i c l e

i n f o

Keywords: Bradykinin Antihypertensive drugs Cardiovascular diseases Diabetes

a b s t r a c t In recent years, ACE Inhibitors (ACEIs) and Angiotensin II receptor antagonists (also known as AT1 receptor antagonists (AT1-RAs), angiotensin receptor blockers (ARBs), or Sartans), have become the drugs of choice for the treatment of hypertension, heart and renal failure, coronary artery diseases, myocardial infarction and diabetes. By suppressing angiotensin and potentiating bradykinin effects, ACEIs and ARBs activate hemodynamic, metabolic and cellular mechanisms that not only reduce high blood pressure, but also protect the endothelium, the heart, the kidney and the brain, namely the target organs which are at risk in cardiovascular diseases. Major therapeutic benefits of these drugs are the reduction of cardiovascular events and the amelioration of the quality of life and of the patient survival. Results from large clinical trials have established that ACEIs and ARBs are efficient and safe drugs, suitable for the chronic treatments of cardiovascular diseases. Side effects are rare and easily manageable in most cases. The following is a brief review of the basic actions and mechanisms by which two opposing systems, the renin-angiotensin (RAS) and the kallikreinkinin (KKS), interact in the regulation of cardiovascular and fluid homeostasis to keep the balance in healthy life and correct the imbalance in pathological conditions. Here we discuss how and why imbalances created by overactive RAS are best corrected by treatments with ACEI or AT1-RAs. © 2012 Elsevier Inc. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Renin-angiotensin system (RAS) and kallikrein-kinin system (KKS) in physiology and pathology: two regulatory systems with opposite functions. . . . . . . . . . . . . 3. RAS and KKS: enzymes and receptors . . . . . . . . . . . . . . . . . . . . . . . 4. B1R and B2R: similarities and differences . . . . . . . . . . . . . . . . . . . . . 5. Interaction between peptidases and kinin receptors . . . . . . . . . . . . . . . . 6. Pharmacology of ACEIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. ACEIs in the treatment (and prevention) of diabetes . . . . . . . . . . . . . . . . 8. Action of ACEIs on glomerular circulation and the filtering membrane . . . . . . . . 9. Clinical pharmacology of ACEIs . . . . . . . . . . . . . . . . . . . . . . . . . . 10. Is the KKS involved in some pleiotropic actions of Statins? . . . . . . . . . . . . . 11. Miscellaneous new antihypertensive agents . . . . . . . . . . . . . . . . . . . . 12. Kinins and derivatives: possible uses in therapy . . . . . . . . . . . . . . . . . . 13. Proposal for the use of ACEIs in the therapy of cardiovascular diseases (and diabetes) 14. Conclusion and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: RAS, Renin-Angiotensin System; KKS, Kallikreins-Kinins System; ACEIs, Angiotensin Converting Enzyme Inhibitors; ARBs, Angiotensin Receptor Blockers; Ang II, angiotensine II; BK, bradykinin; NO, nitric oxide; PGI2, prostacyclin; VSMC, Vascular smooth muscle cell. ☆ Associate Editor: Paolo Madeddu ⁎ Corresponding author. ⁎⁎ Correspondence to: F. Gobeil, Department of Pharmacology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Canada, J1H 5N4. E-mail addresses: [email protected] (D. Regoli), [email protected] (F. Gobeil). 0163-7258/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.pharmthera.2012.04.002

D. Regoli et al. / Pharmacology & Therapeutics 135 (2012) 94–111

1. Introduction From 1970 to 2000 the mortality from cardiovascular diseases had progressively declined, while that of other diseases (e.g. cancer) remained stable (Janoff, 2010) (Fig. 1). This is indeed one of the most successful therapeutic achievements in modern medicine. Such extraordinary trend has coincided with the actual recognition of the primary role of the Renin-Angiotensin System (RAS) in the pathogenesis of Hypertension and with the introduction of a group of drugs, the Angiotensin Converting Enzyme Inhibitors (ACEIs) that reduce or block many if not all the actions of the RAS (Hansson et al., 1999a,b). In the same period (1979–2000) prescriptions for the ACEIs, progressively increased while those for other antihypertensive drugs, as those directed to decrease the impact of the central nervous system (ganglion blockers, reserpine, guanethidine, α-methyl dopa, clonidine, as well as some vasodilators such as hydralazine) and even for β-blockers, either disappeared from the therapeutic armamentarium or were progressively reduced (Campbell et al., 2003; IMS_Health, 2010; Psaty et al., 2002). Prescriptions declined also for the diuretics from 56% in 1982 to 27% of the total antihypertensives in 1992 (Manolio et al., 1995). The favourable trend of prescription increase, recorded since the late '70s for the ACEIs has later occurred for the Angiotensin II receptor antagonists (also known as AT1 receptor antagonists (AT1-RA), angiotensin receptor blockers (ARBs), or Sartans), another group of agents whose primary action is to reduce the impact of the RAS (Azizi & Menard, 2004; Brenner et al., 2001). Today, ACEIs and ARBs together occupy the first place in the list of prescribed antihypertensive agents (IMS_Health, 2010) and are recommended as a first choice for the treatment of cardiovascular diseases by the Canadian and American guidelines (JNC7, 2004; Rabi et al., 2011). In addition to their success in the treatment of hypertension (Deshmukh et al., 2011; Dzau et al., 1980; Gavras & Gavras, 2001), these drugs reached rapidly a high place in the list of agents utilised for the treatment a) of patients with chronic heart failure and arrhythmias (Hansson et al., 1999a,b) or b) of patients affected by coronary artery diseases or myocardial infarction with or without left ventricular dysfunction (Dahlof et al., 1992; Dickstein & Kjekshus, 2002; Ferrari et al., 2010; Pfeffer et al., 2003) and c) in diabetic patients as well as in patients with diabetic or non diabetic renal insufficiencies (Agodoa et al., 2001; Brenner et al., 2001; Lewis et al., 2001; Marre et al., 1988; The_GISEN_Group, 1997). To our knowledge, no other type of antihypertensive agents has recorded such a rapid and consistent success in

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the treatments of cardiovascular diseases. What has been the main reason for such a success? The answer to that question has to be found in the fact that ACEIs (and the Sartans) not only counteract the actions of the RAS, but also improve the impact of the Kinins, the other endogenous agents that oppose many if not all the actions of the RAS (Carey & Padia, 2008). We will first discuss in the next section the fundamental concept that kinins as a RAS counterregulatory system are common denominators in the salutary actions of the major antihypertensive drugs ACEIs and ARBs and possibly others (e.g. AT2R agonists) and, then go to into the current understandings of the RAS and Kallikreins-Kinins System (KKS) individual components and other general features of the ACEIs research field. 2. Renin-angiotensin system (RAS) and kallikrein-kinin system (KKS) in physiology and pathology: two regulatory systems with opposite functions In Tables 1 and 2, the two systems are compared through a systematic comparison of their major actions. Table 1 contains a list of the numerous actions of the RAS, mediated by the activation of the AT1R. Angiotensin II and its receptor the AT1R, are considered the most potent hormonal-paracrine system implicated in the stimulation of the tissues (heart and vessels) of the cardiovascular system in all their components and functions. In fact, by contracting the vascular smooth muscle cell (VSMC), Ang II causes vasoconstriction and increases the peripheral vascular resistance (Regoli et al., 1974). By acting on the sympathetic nerve terminals, Ang II promotes the release of noradrenaline, which further stimulates VSMC to contract by activating the adrenergic α1 receptor (Regoli et al., 1974). By increasing the release of endothelin, the vasoconstriction induced by Ang II is further increased and is prolonged. By activating the synthesis and the release of aldosterone and of vasopressin, Ang II expands blood volume and increases the cardiac output, thus further contributing to sustain the systemic blood pressure (Carey & Padia, 2008). Blood volume and cardiac output are further increased through the Na + and H2O retention produced by Ang II at the level of the renal tubuli. In the heart, contractility and the size of the muscle fibers are strengthened by Ang II, and similarly the muscular component of the vessel wall undergoes (proliferative and hypertrophic) changes that have been described as “cardiac and vascular remodelling“ (Carey & Padia, 2008). By interfering with some basic functions of the endothelium, the functional unit Ang II/AT1R favours the production of superoxide anions and thus increasing nitric oxide (NO) inactivation. Moreover, by

Fig. 1. Age-adjusted death rates for cancer and coronary disease. Reprinted from Janoff (2010) with permission.

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D. Regoli et al. / Pharmacology & Therapeutics 135 (2012) 94–111

Table 1 Actions of Ang II through the AT1R. 1. Vasoconstriction (e.g. renal efferent arterioles) 2. Activation of the sympathetic nervous system (SNS) 3. Aldosterone, vasopressin and endothelin secretion 4. Cardiac contractility and hypertrophy 5. Na+ and H2O retention through tubular action 6. Cardiac and vascular remodeling 7. Superoxide anion production 8. NO destruction 9. Decreased vascular compliance 10. Thrombosis: platelets aggregation and adhesion 11. Production of cytokines by macrophages and other cells 12. Fibrosis: collagen biosynthesis 13. Inhibition of renin secretion Modified from Carey and Padia (2008), with permission from Elsevier.

facilitating the adhesion and aggregation of platelets (through inhibition of prostacyclin (PGI2) formation), Ang II increases the risks of thrombosis and sclerosis (Carey & Padia, 2008). Finally, Ang II promotes collagen biosynthesis and causes fibrosis, thus worsening the structure and the functions of the heart and the peripheral vessels. The only action that tends to reduce the activity of the RAS is exerted on the juxtaglomerular cells, where the activation of the AT1R inhibits the release of renin (Carey & Padia, 2008). In mammals and in man, the RAS sustains useful functions that are needed for a normal healthy life. However, when the actions of the RAS become overwhelming, particularly in mature age, the high production of Ang II results in high danger for the health of the heart and the circulatory system. When blood pressure increases, heart hypertrophy develops, vasoconstriction increases, and oxygen transport to tissues decreases. At this point, the endothelium starts to fail and progressively loses its protective functions, and this may increase the risks of thrombosis and of atheroma formation (Carey & Padia, 2008). In order to control, modulate and counteract many if not all the actions of the RAS, nature made the KKS, whose numerous functions are listed in Table 2 (see below).

The KKS can reduce and eventually block the actions of RAS at all levels by exerting effects that are opposite to those of the RAS. A comparison between the actions listed in Tables 1 and 2, indicates that the vasodilatory KKS, through its ability to promote the formation and the release of NO and PGI2 and by blocking the production of superoxides, maintains the basic functions of the vascular endothelium, which are needed to insure optimal blood flow to tissues. Indeed, NO and PGI2 are considered the two best endothelial defenders against angiopathies (Gryglewski & Moncada, 1987). The kinins Bradykinin (BK) and Lys-BK (alias Kallidin) are the most potent and efficient vasodilatatory agents, which are particularly active on peripheral and coronary arteries (Cruden & Newby, 2005). Vasodilatation of the vessels by the kinins is brought about by several mechanisms, as a) the release of NO, PGI2 and the so-called endothelium derived-hyperpolarizing factor (EDHF) from the endothelium, b) the inhibition of superoxide anion production, c) the inhibition of catecholamine release from the sympathetic nerve terminals of the arteries and the inhibition of the endothelin release from the endothelium (Feng et al., 1997; Mombouli & Vanhoutte, 1999; Momose et al., 1993). The most efficient vasodilatatory mechanism is sustained by the “NO cascade” which is initiated by the kinins through the activation of the kinin (inducible) B1R and (constitutive) B2R of the endothelium (see Fig. 2). This occurs because the B2R induces an increase of the intracellular Ca 2+, which activates the eNOS and thus promotes the formation of NO (Heitsch, 2003; Linz et al., 1999; Madeddu et al., 2007; Vanhoutte, 2009). The release of NO by the B1R appears to follow another pathway and involves calcium-independent iNOS activation (Fig. 2) (Kuhr et al., 2010). NO diffuses into the VSMC, where it induces the formation of cGMP, the potent relaxant of the VSMC (Regoli, 2004; Vanhoutte, 2009). In other cells, such as the smooth muscle of the veins (Hall, 1997; Regoli & Barabé, 1980), or the cardiac sympathetic terminals (Augustyniak et al., 2007; Feng et al., 1997; Seyedi et al., 1997), or the vasopressin producing cells of the neurohypophysis (Yamamoto et al., 1992), the kinins (through their B2R) mediate stimulatory functions which apparently oppose, but may also

B2/B1 Table 2 Actions of kinins mediated by the B2R and B1R. 1. Vasodilatation of peripheral (e.g. glomerular efferent arterioles) and coronary arteries. Relaxation or contraction of veins 2. Inhibition of peripheral sympathetic, stimulation of cardiac sympathetic terminals 3. Inhibition of endothelin release 4. Natriuresis and diuresis 5. Vascular and cardiac (positive) remodelling, preconditioning and postconditioning 6. Inhibition of superoxide anion production 7. Stimulation of NO, PGI2 and EDHF synthesis and release from endothelia 8. Inhibition of proliferation and growth of VSMC and cardiomyocytes 9. Stimulation of tissue-type plasminogen activator (t-PA) release 10. Inhibition of platelets adhesion and aggregation (antihemostatic, antithrombotic) 11. Inhibition of collagen synthesis and fibrosis 12. Stimulation of cytokines production by macrophages and monocytes 13. Stimulation of white blood cell migration in tissues (proinflammatory actions) 14. Stimulation of sensory nerves (nociceptive actions) 15. Stimulation of reflexes in the airways (pro-asthmatic) and the urinary bladder 1. (Gobeil et al., 1996; Heitsch, 2003; Madeddu et al., 2007; Regoli & Barabé, 1980); 2. (Augustyniak et al., 2007; Feng et al., 1997; Seyedi et al., 1997); 3. (Momose et al., 1993; Yamamoto et al., 1992); 4. (Lortie et al., 1992; Marin-Grez et al., 1972); 5. (Chao et al., 2007; Griol-Charhbili et al., 2005; Madeddu et al., 2007; Manolis et al., 2010; Marketou et al., 2010; Parratt et al., 1995; Sharma, 2008; Xu et al., 2009); 6. (Madeddu et al., 2007); 7. (Alhenc-Gelas et al., 2011; Madeddu et al., 2007; Vanhoutte, 2009); 8. (Chao & Chao, 2005; Chao et al., 2007; Madeddu et al., 2007); 9. (Cruden et al., 2011; Minai et al., 2001; Murphey et al., 2006; Pretorius et al., 2003; Smith et al., 1985); 10. (Labonte et al., 2001; Murphey et al., 2006); 11. (Chao et al., 2007; Imai et al., 2005; Liu et al., 2006; Rhaleb et al., 2011; Schanstra et al., 2002); 12. (Bockmann & Paegelow, 2000; Santos et al., 2003); 13. (Santos et al., 2003); 14. (Couture et al., 2001; Dray & Perkins, 1993; Regoli & Barabé, 1980); 15. (Farmer, 1997; Maggi, 1997).

[Ca2++]

Endothelial Cell

eNOS PLA2

NO

PGI2

? EDHF

IP sGC

cGMP

Relaxation

cAMP [Ca2++]

K+ Hyperpolarization

Vascular Smooth Muscle Fig. 2. Formation of vasorelaxant products from endothelial cells in response to kinin receptor stimulation. BK and Lys-BK (for B2R), and desArg9BK and LysdesArg9BK (for B1R), promote the formation of vasodilatatory agents. This results in the release of NO (from eNOS), PGl2 (from PLA2) and EDHF. These labile substances readily diffuse to smooth muscle cells where they induce relaxation. The pathway leading to NO by the B2R is described above that of the B1R has been recently described and involves calcium-independent iNOS activation (Kuhr et al., 2010). Abreviations: EDHF, endothelial hyperpolarizing factor; cGMP, cyclic guanosine monophosphate; cAMP, cyclic adenosine monophosphate; NO, nitric oxide; eNOS, endothelial nitric oxide synthetase; sGC, soluble guanylyl cyclase; IP, prostacyclin receptor.

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integrate the prominent vasodilatatory and the renal (pro-natriuretic and pro-diuretic) effects of the kinins (Lortie et al., 1992). At the nuclear level, the B2R activates transcriptional processes that regulate proliferation and growth of the VSMC and the cardiomyocytes (Chao & Chao, 2005; Heitsch, 2003; Madeddu et al., 2007). By inhibiting such processes, kinins contribute to reduction of cardiac hypertrophy and arterial wall thickening which occur in hypertension (Chao & Chao, 2005; Rhaleb et al., 2011). Notably, kinins inhibit collagen synthesis, the initial step of fibrosis (Chao et al., 2007; Imai et al., 2005; Liu et al., 2006; Schanstra et al., 2002). In blood, the various actions of the kinins on the endothelium result in the activation of plasminogen, the inhibition of platelets aggregation and adhesion to the endothelium surface. In this way, kinins prevent or reduce the occurrence of thrombosis and may inhibit haemostasis (Cruden et al., 2011; Labonte et al., 2001; Murphey et al., 2006; Smith et al., 1985) (see Table 2). In addition to the beneficial effects above described, kinins are notoriously pro-inflammatory agents which stimulate the migration of blood cells (leucocytes, monocytes) from blood to tissues and promote the synthesis of prostaglandins and of cytokines in a variety of white blood cells (Bockmann & Paegelow, 2000; Santos et al., 2003). On peripheral nerve terminals, kinins activate their receptors of sensory nerves and cause pain (Couture et al., 2001; Dray & Perkins, 1993; Regoli et al., 1981). Kinins can also accentuate defensive reactions, in the airways, the gastrointestinal tract, the gallbladder or the urinary bladder and other viscera (Farmer, 1997; Maggi, 1997; Stadnicki, 2011). When they reach high levels of efficiency, as in severe inflammatory diseases or syndromes, such pathological states require pharmacotherapy with analgesics, or anti-inflammatory drugs and eventually with kinin B1R or B2R antagonists (Marceau & Regoli, 2004, 2008). Such interventions should reduce suffering in patients affected by asthma (Farmer, 1997), intestinal inflammatory syndromes (Marceau & Regoli, 2008) or hyperactive bladder (Maggi, 1997). In the last 20 years, thanks to the work of some prominent investigators (Carretero & Scicli, 1989; Chao & Chao, 2005; Kakoki & Smithies, 2009; Linz et al., 1995; Madeddu et al., 2007; Pesquero & Bader, 2006), the roles of the KKS in physiology and in pathological states have been fairly well clarified. Two major roles have emerged and consistently validated, namely, A) the reactive and inflammatory role in local lesions, when large quantities of kinins are locally produced for the activation and potentiation of pro-inflammatory prostaglandins and cytokines that increase the blood flow (and produce rubor), stimulate the sensory nerves and produce pain, dilate the capillaries and constrict the veins and thus favour the formation of oedemas and cause functional impairments in some organs. B) A defensive and protective role, which is directed to improve the functions of the cardiovascular system in particular at the heart and the endothelium levels. A moderate and continuous production of kinins appears to occur in endothelia to modulate the tonus of the arterioles and maintain an adequate flow of blood to the tissues. At this level, kinins promote the formation and the release of NO, reduce the production of reactive oxygen species (ROS) and thus protect the functions of the heart and the peripheral arterial vessels, reduce the hypertrophy of the heart and of the arterioles, prevent thrombosis as well as the formation of atherosclerotic plaques. In Fig. 2, we describe the sequence of events that lead and sustain the vasodilatatory effects of kinins covered by the general term of “NO cascade”. Activation of the NO cascade is a prominent function of kinins through their receptors which provides the most common and efficient mechanism for vasodilatation. The NO cascade mediates the actions of ACEIs and possibly ARBs (via AT2R stimulation) (see Fig. 5), but not that of other vasodilators, such as Ca 2+ channels blockers (nifedipine)

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or α1R blockers (prazosin), K + channel agonists (cromokalin, minoxidil), or the phosphodiesterase (methylxanthines) or the IP3 (hydralazine) inhibitors. NO does not take part to the hemodynamic and metabolic actions of other important antihypertensive agents as diuretics and adrenergic β- and α1R-blockers. ACEIs exert their beneficial effects by suppressing Ang II formation and by protecting kinin from degradation. The vasodilatation by ACEIs however results more from the protection/potentiation of kinins than from the inhibition of Ang II formation (Kakoki et al., 2007). Until the early '90s and even later, the beneficial effects of ACEIs were almost exclusively attributed to blockade of the RAS (Cravedi et al., 2010; McFarlane et al., 2003). Once again, thanks to the seminal work of Carretero and co-workers and, of others, over the last 30 years (Carretero & Scicli, 1989; Chao & Chao, 2005; Chao et al., 2010; Madeddu et al., 2007; Manolis et al., 2010; Rhaleb et al., 2011), the medical literature concerning the therapy of hypertension, heart failure, myocardial infarction, brain and coronary artery diseases and more recently diabetic nephropathies (Kakoki & Smithies, 2009; Kakoki et al., 2010) and arteriogenesis (Hillmeister et al., 2011) has progressively established and validated the protective, defensive and eventually the reparative role of kinins in therapeutics. The title of the paper of Kraenkel et al. (2008) “Role of kinin B2 receptor signaling in the recruitment of circulating progenitor cells with neovascularization potential” explains itself the meaning of “reparative”, which indicates the reactive angiogenesis that follows the implantation of endothelial-progenitor cells in damaged arterial vessels after ischemic insults. The process of new vessel formation in the heart (and in other major organs) is paramount to enhancing recovery and improve outcome. A recent report by Hillmeister P et al. points to the important role of the B1R in the remodelling of preexisting collateral arteries into functional conductance arteries in mouse and rat models of ischemia (Hillmeister et al., 2011). In Fig. 2, the basic structures of the peripheral resistance arteries, namely the endothelium and the VSMC are represented and their interrelations are analysed in terms of agents (endogenous factors) and effects that contribute to the maintenance of a weak tone (relaxation) of the VSMC thus reducing the peripheral vascular resistance and improving the tissue blood flow. According to literature, all actions of the KKS are exerted through the activation of two genetically encoded, functional G protein-coupled receptor structures, the B2R and B1R, which are expressed in a variety of cells, and in particular in endothelia (Hess et al., 1992; Menke et al., 1994; Regoli & Barabé, 1980). The pharmacology of kinin receptors was carefully studied by D'Orléans-Juste et al. (D'Orleans-Juste et al., 1989), who demonstrated that both B1R and B2R promote the release of NO from isolated endothelial cells from bovine aorta. These results could be extended to other vessels whereby endothelial B1R activation leads to NO or PGI2-dependent vasodilatation. These are the rat aorta (Merino et al., 2008), the dog coronary artery (Su et al., 2000) and the perfused rat coronary artery (McLean et al., 1999). These important findings were recently confirmed with other approaches and particularly with experiments in tissues (mesenteric arteries) from B1R knockout (KO) mice by Loiola et al. (Loiola et al., 2011) and in vivo in B1R and B2R KO mice by Kakoki et al. (Kakoki & Smithies, 2009; Kakoki et al., 2004, 2006, 2007) who described the essential contribution of the B1R in the protection of kidneys from ischemic/reperfusion lesions. Similar results were obtained in ischemia-reperfusion syndromes induced in the heart, the liver and the central nervous circulation (e.g. after stroke) (Kakoki et al., 2007). B1R and B2R are needed for the beneficial and protective actions of the kinins. Both receptor systems activate the formation of NO from L-Arginine and the NO cascade, as illustrated in Fig. 2. NO also diffuses to blood where it contributes to reducing the aggregation of platelets, thus preventing the formation of thrombi. Similarly, NO reduces the adhesion of leucocytes to the vascular endothelium, a process which is considered to be the first step towards the inflammatory lesion that leads to the genesis of atheroma. The

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reduction of the platelets and the leucocytes adhesion to the endothelium is reinforced by PGI2. In addition to the fundamental role of NO (whose half life in blood is 6 s), the NO cascade indicates the contribution of two other endogenous factors, the PGI2 (half life in blood, 4 min) and the EDHF which causes the opening of K + channels and reduces the tonus of the VSMC (Fig. 2). Although cyclooxygenase-1 (COX-1) can play a significant role in contributing to PGI2 production in endothelial cells (Bolego et al., 2009), the biosynthesis of PGI2 from arachidonic acid results predominantly from a “common enzymatic effort” of COX-2 isoform (the endothelial inducible enzyme) and the prostacyclin synthase (Gryglewski, 2008; Ruan et al., 2011). PGI2 is the physiological antagonist of the platelets made thromboxane A2, which is produced by the platelets-constitutive COX-1. PGI2 is a potent vasodilator and an efficient antithrombotic agent (Gryglewski, 2008). EDHF are most probably cytochrome P450-derived metabolites of arachidonic acid refered to as epoxyeicosatrienoic acids (EETs) (Campbell & Fleming, 2010; Golding et al., 2002; Pinto et al., 1986); other potential recently proposed EDHFs may include hydrogen peroxide (H2O2) and hydrogen sulfide (H2S) (Feletou & Vanhoutte, 2009). Indeed, the inhibition of cytochrome P450 mono-oxygenase by 17 ODYA, has been shown to reduce the vasodilator effect of BK in the rat isolated perfused kidney and heart (Fulton et al., 1994; Rapacon et al., 1996). EDHF has been shown to induce hyperpolarisation and relaxation of the VSMC via the opening, possibly directly, of K+ channels (Nagao & Vanhoutte, 1993). The hypotensive effect of BK in normotensive rats is reduced by Aminopyridine (4-AP), a voltage sensitive K+ channel inhibitor (Berg & Koteng, 1997). The considerable contribution of EDHF (mediating K+ channel opening) to the endothelium-dependent relaxation to BK has been validated in humans in ex vivo coronary microarteries from excised hearts of cardiac transplant patients (Nakashima et al., 1993) and in vivo in the forearm microcirculation of healthy normal subjects (Inokuchi et al., 2003). 3. RAS and KKS: enzymes and receptors 3.1. Enzymes The general enzymatic pathways leading to the formation of angiotensins and kinins (bradykinin), their receptors and the sites of actions of ACEIs and ARBs are described in Fig. 3 (modified from

(Wollert & Drexler, 1999)). In circulating blood and in some tissues, renin (an aspartyl protease produced mainly in the kidney) releases the decapeptide Ang I from angiotensinogen, a large protein of hepatic origin. Ang I is mostly converted to the octapeptide Ang II by ACE, a peptidyl dipeptidase that is abundant in the vascular endothelium (de Gasparo et al., 2000; Timmermans et al., 1993). Part of Ang I is converted to Ang (1–7) by neutral endopeptidase (NEP), which is present in vessels and in tissues, particularly the kidney (Gafford et al., 1983). In addition, prolylendopeptidase (PEP) can generate Ang (1–7) directly from Ang I. A portion of Ang (1–7) may derive from the conversion of Ang II to Ang (1–7) by a carboxypeptidase named ACE-2 (Santos et al., 2005) (Fig. 3). Ang (1–7) may also derive from conversion of Ang II by prolylcarboxypeptidases (PCP) and prolylendopeptidase (PEP), or by inhibition of its degradation to Ang (1–5) by ACEIs. Ang II and Ang (1–7) are the biologically active species of the RAS: they stimulate specific and selective receptors, namely AT1R, for Ang II, Mas for Ang (1–7) and a third receptor refered as the AT2R, being common to both peptides (Bosnyak et al., 2011; Santos et al., 2005; Walters et al., 2005). The impact of Ang II on the cardiovascular system is reduced by ACEIs or by ARBs, while that of Ang (1–7) is decreased or abolished by recently developed ACE-2 inhibitors (e.g. DX600, XNT) or by MasR antagonists (e.g. D-Ala7Ang 1–7) (Benter et al., 2011; Hayashi et al., 2010). Some effects of Ang II and of Ang (1–7) are reduced by the AT2R antagonists (PD123319) (de Gasparo et al., 2000; Timmermans et al., 1993) and also by Icatibant, a bradykinin B2R antagonist (Brosnihan et al., 1996; Liu et al., 1997; Wiemer et al., 2002), suggesting that kinins contribute to the vasodilatory action of the Sartans. Indeed, the vascular and cardiac effects of the ARBs have been shown to be reduced by Icatibant in several other studies (Hornig et al., 2003; Jalowy et al., 1998; Sato et al., 2000; Zhu et al., 1999). Such implication of B2R in the protective roles and therapeutic effects of Sartans has been repeatedly demonstrated in hypertensive animals and patients (see review by Su, 2006). The KKS is shown on the left of Fig. 3. BK is released from high molecular weight kininogen (HMWK) by plasma kallikrein, while Lys-BK (alias Kallidin) derives from the action of tissue kallikreins (mainly kallikrein-1; KLK1) on low molecular weight kininogen (LMWK). These two latter natural peptides are substrates for plasma and membrane-bound carboxypeptidases (CPN and CPM; alias Kininases I) which convert them into desArg 9-BK and LysdesArg 9-BK, respectively. These latter peptides are the natural agonists of the B1R in

Fig. 3. General enzymatic pathways for the formation of angiotensins and kinins (bradykinin), their receptors and sites of actions of ACEIs and AT1-RAs (Sartans). Naturally occuring agonist: Ang l, H-Asp1-Arg2-Val3-Tyr4-lle5-His6-Pro7-Phe8-His9-Leu10-OH and BK (representative of kinins), H-Arg− 1-Pro2-Pro3-Gly4Phe5-Ser6-Pro7-Phe8-Arg9-OH. Kinin receptors in man and rat show different sensitivity to peptide agonist. In man, LysBK and LysdesArg9BK are the compounds of choice for the B2R and B1R, respectively, while for the rat receptors, the agonist are BK and DesArg9BK. Modified from Wollert and Drexler (1999). In parentheses are the numbers of amino acid resides for each peptide. ACE = angiotensin-converting enzyme; Ang angiotensin; AT1 = angiotensin II type 1 receptor; AT2 = angiotensin II type 2 receptor; Mas = GPCR encoded by the mas proto-oncogene; PCP = prolylcarboxypeptidase; PEP = prolylendopeptides; NEP = neutral endopeptidase; CPM/N = carboxypeptidases M and N. Modified from Wollert and Drexler (1999), used with permission of Oxford University Press.

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the rat (and mouse) and in the man (Marceau et al., 1998; Regoli et al., 1998). Fig. 3 also illustrates the double action of the ACE (alias Kininase II) which, on one side activates the RAS and on the other, degrades active kinins into inactive fragments. The overall result is the formation of Ang II, a potent vasoconstrictor and the inactivation of the kinins, the most potent endogenous peptide vasodilators known and the real motor of the NO cascade shown in Fig. 2 (Vanhoutte et al., 1995). Major effects of ACE through Ang II generation are vasoconstriction, salt and water retention, increase of blood pressure and the promotion of many of the actions of the RAS, described in Table 1. ACE is indeed primarily involved in maintaining blood pressure to the levels required for a safe healthy life. However, under conditions of abnormally elevated RAS activity, the ACE contributes to the development and maintenance of hypertension. In animals models of experimental hypertension and in hypertensive patients, the inhibition of ACE works by a triple mechanism: a) by blockade of the formation of Ang II, which reduces the arterial vascular resistance and decreases salt and water retention and consequently the cardiac output; b) by potentiation of the kinins, which lead to vasodilatation and to increased water and salt excretion and c) by the formation of the vasodilator and cardioprotective Ang (1–7) as well as by the protection of the antifibrotic N-acetyl-seryl-aspartyl-lysylproline (AcSDKP), an acetylated tetrapeptide derived from thymosin β4, which also exerts cardioprotective effect (Rhaleb et al., 2011). Moreover, the blockade of ACE is accompanied by a significant increase of circulating Ang I which favours the formation of Ang (1–7) by the NEP (Chappell et al., 1998; Santos et al., 2005). The overall effect of the ACE inhibition is a marked reduction of the vascular peripheral resistance and consequently of the arterial blood pressure. 3.2. Receptors Five receptors, all belonging to the category of GPCRs, mediate the actions of the RAS (the angiotensin AT1R, AT2R and MasR) and of the KKS (the kinin B1R and B2R). In Tables 1 and 2, all the actions of the RAS have been attributed to the AT1R while those of the KKS derive from the actions of both B1R and B2R. The classical signaling pathway of AT1R is illustrated in Fig. 4. It consists of the Gq protein and of the IP3, which mediate the increase of the intracellular Ca 2+ leading to the activation of several enzymes which, depending on cell effectors lead to smooth muscle contraction, catecholamine and others neurotransmitter release, hormone

Ang II AT1R

[Ca2+]

Gq

G12/13

RhoK

99

synthesis and secretions (vasopressin, endothelin, aldosterone and others) and to nuclear functions involved in cell (VSMC, cardiomyocytes, others) multiplication, hypertrophy and hyperplasia (Carey & Padia, 2008; de Gasparo et al., 2000; Timmermans et al., 1993). B2R are expressed in a variety of smooth muscles, including those in vein wall, in sensory nerves, for mediation of pain and protective reflexes, in endocrine and exocrine glands (e.g. pancreas beta cells, sweat submandibular secretory glands), in white blood cells (e.g. macrophages, eosinophils, others) (Bhoola et al., 1992; Hall, 1992; Leeb-Lundberg et al., 2005; Regoli & Barabé, 1980). The B2R and the B1R work in manner mechanistically similar to AT1R in terms of coupling to Gq proteins for triggering VSMC contraction (see Fig. 4) (Leeb-Lundberg et al., 2005). The B2R and B1R are widely expressed in endothelia where they activates the NO cascade (see Fig. 2) and may contribute to the actions of others vasodilatory systems e.g. the AT2R (Fig. 5) (Su, 2006), MasR (Iwai & Horiuchi, 2009; Pinheiro et al., 2004) and renin inhibitors (Campbell et al., 2011). The B2R are involved in a series of inhibitory actions namely i) the inhibition of the release of endothelins from the vascular endothelium (Brunner & Kukovetz, 1996; Momose et al., 1993), and in particular ii) the reduction of water and salt reabsorption from the renal tubule (Lortie et al., 1992; Marin-Grez et al., 1972) (see Table 2). The G proteins implicated in the above actions and the corresponding pathways remain, in most cases, to be elucidated. Extrareceptorial actions of kinins that depend on the positive polarity and amphipaticity of the peptides and need high doses of these agents to occur, are the release of some prostaglandins (deriving presumably from the direct interaction of BK with the phospholipase A2), or of histamine (Bueb et al., 1993; Gies et al., 1993; Mousli et al., 1990). From the above, we conclude that an essential difference between AT1R and the two kinin receptors is the presence and function of these latter receptors at the endothelium layer and the particular ability of the endothelial cell to use Ca 2+ for the synthesis of NO, PGI2 and EDHF (see Fig. 2). Such synthesis is a prominent function which is important for the homeostasis of the cardiovascular system. The endothelial actions of B2R and B1R are potentiated by ACEIs and by certain other drugs (Sartans) capable of stimulating the synthesis or the release of kinins. The other two functional units shown in Fig. 3, the AT2R and the MasR, are also vasodilatatory and oppose the actions of the functional unit Ang II/AT1R. Two hypothetical mechanisms by which the AT2R activates the NO cascade via kinins or their B2R are illustrated in Fig. 5. In the first mechanism, recently reaffirmed by Zhu et al. (2010), the AT2R activates the cellular KKS of the endothelial cells and promotes the formation of kinins (BK or Lys-BK). The two kinins activate

Ang II

BK

AT2R

B2R

MLCP

KKS

Ca2+/CaM MLC

MLC- P

[Ca2++]

(BK,, LysBK))

eNOS

MLCK

Contraction

NO Endothelial cell

Vascular smooth muscle Fig. 4. Ang II/AT1R signaling pathways leading to contraction of vascular smooth muscle cells. Two independent signaling pathways known to be involved in the contraction mediated by the AT1R are depicted. The first involves Gq and ultimately leads to MLCK activation and acto-myosin-based contraction, whereas the second pathway proceeds through G12/13 and the activation of the kinase RhoK ultimately leading to the inhibation of the phosphate MLCP and the direct phosphorylation of MLC by RhoK. MLC myosin light chain; MLCK, myosin light chain kinase; MLCP, myosin light chain phosphatel Ca2+/CaM, Ca2+-calmodulin; Rho-Kinase.

ACTIONS: antihypertensive, anti-proliferative, anti-remodeling, anti-oxidative, antifibrotic, antiatherosclerotic Fig. 5. Hypothetical mechanism of actions of Ang II mediated by the AT2R in endothelial cells. First mechanism: stimulation of BK release and the activation of the NO cascade, second mechanism: Activation of the B2R through heterodimenrization with the AT2R. Beneficial actions are the same as those described for kinins in Fig. 6.

100

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the B2R of the endothelium and initiate the NO cascade. Diffusion of NO to the VSMC and in blood leads to vasodilatation and mediates the antihypertensive effect and the other favourable or protective actions of the AT2R (e.g. inhibition of leucocyte adherence and of cardiac fibrosis, microvascular disfunction) (Akiyoshi et al., 2006; Kurisu et al., 2003) described in Fig. 5. The other mechanism involves the AT2R and B2R, two receptors that have been shown to be present and active on the plasma membrane of endothelial cells and which may undergo heterodimerization (Abadir et al., 2006), and activate the NO cascade with the same end results (Fig. 5). It should be mentioned that the B2R has also been proposed to physically interacts with cell membrane proteins other than the AT2R, for instance the ACE (Chen et al., 2006; Erdos et al., 1999) (see Section 5), AT1R (AbdAlla et al., 2005), the eNOS (Ju et al., 1998), the phospholipase C (Duchene et al., 2005), the B1R (BarkiHarrington et al., 2003), and the B2R itself, forming homodimers in this case (AbdAlla et al., 1999). The in vivo physiological importance of such multiple interactions is not fully understood and remains debatable (Hansen et al., 2009; Lyngso et al., 2009). We favour the first mechanism illustrated in Fig. 5, which leads to the release of BK and ensuing activation of the NO cascade. The presence and function of the AT2R have been studied during the last 12 years, starting with the papers by Liu et al. (1997) and Tsutsumi et al. (1999), whose findings have been validated by the discovery and uses of both the selective and specific agonists, CGP 42112A and Compound 21 and, the antagonist PD123319 (de Gasparo et al., 2000; Unger & Dahlof, 2010). The AT2R is not usually expressed in adult animals and in man (Jones et al., 2008). However, it appears to be present in the endothelial cells and the kidney of patients affected by cardiovascular diseases (Wharton et al., 1998), especially after treatment with ARBs. Similar to the kinin B1R, the angiotensin AT2R is inducible and its number and activity vary in health and diseases (de Gasparo et al., 2000; Jones et al., 2008; Steckelings et al., 2010; Timmermans et al., 1993). The Mas receptor (MasR) is activated exclusively by Ang (1–7) and exert protective effects on the heart, starting with the reduction of vasoconstriction in failing heart that occur in rats after myocardial infarction (Ferreira et al., 2007; Loot et al., 2002). It also improves cardiac functions in spontaneously hypertensive rats (SHR) treated with L-NAME (Benter et al., 2007) or submitted to myocardial infarct by treatment with isoproterenol (Marques et al., 2011). In other models of experimental hypertension, Ang (1–7) modulates heart remodeling and cell (myocytes, fibroblasts) growth (Grobe et al., 2007; Iwata et al., 2005; Tallant et al., 2005). Early data on the pharmacology and the molecular biology of the Mas receptor are to be found in excellent review articles (Ferrario et al., 2005; Santos et al., 2005). The activation of the MasR leads to an increase of NO and BK synthesis (Iwai & Horiuchi, 2009; Pinheiro et al., 2004) (see Table 3). Recently, Zhu et al. (2010) has proposed a new mechanism by which the activation of the AT2R may lead to generation of kinins in endothelial cells and to the production of NO. They have shown that overexpression of the AT2R in mouse coronary artery endothelial cells is accompanied by an increased expression of Prolylcarboxypeptidase (PRCP),

an endothelial enzyme that activates prekallikreins to release kinins. Indeed, PRCP is present in endothelial cells (Shariat-Madar et al., 2002, 2005), where it may promote the formation of kinins and the release of NO suggested some years ago (Zhao et al., 2001), and thus mediates the vasodilatatory effect of the AT2R. The expression of PRCP appears to be upregulated during the treatment of hypertensive rats with Sartans (Xu et al., 2002). Therefore, the mediation AT2R dependent relaxation by the kinins becomes more and more evident. The five receptors indicated in Fig. 3 mediate the vasoactives effects of the two major antihypertensive drugs, ACEIs and ARBs, and will be implicated in the potential actions of new vasodilators (Table 3). The AT1R is vasoconstrictor, the others four are vasodilators; then, the AT1R has to be antagonised (blocked), the others should be activated. BK and Lys-BK are the “key molecules” which mediate the vasodilatatory actions of B2R, AT2R and possibly also of MasR. The two kinins are also the “precursors” of the B1R agonists, desArg 9-BK and Lys desArg 9BK, through proteolytic cleavage by carboxypeptidases M and N (see Section 5). At this point let us analyse the chains of events that lead to the vasodilatatory effects of two widely used drugs ACEIs and ARBs and, of two new potential vasodilatatory agents Compound 21 and Ang(1–7) and its recent surrogate AVE 0991 (see Table 3). The ACEIs protect from degradation the endogenously generated kinins and in so doing enhance their bioavailability and actions. The ARBs blocks the AT1R and this leads to an increase of Ang II and to the activation of the AT2R, which may promote activation of the kinin/NO system (Campbell et al., 2005; Zhu et al., 2010) (see text above). A similar mechanism of action involving BK formation and ensuing NO release has been suggested for Compound 21 (Jing et al., 2011; Unger & Dahlof, 2010), Ang(1–7) and surrogate AVE 0991 (Pinheiro et al., 2004; Wiemer et al., 2002). Altogether, these highlight the prevalence of kinins as a common denominator for the therapeutic effects of several major antihypertensive drugs. Noteworthy is the apparent complexity of pharmacological actions of ARBs in opposition to ACEIs. Moreover, it is recognized that ACEIs reduce the circulating and tissular Ang II, while the ARBs increase Ang II in circulating blood and in tissues (Csajka et al., 1997). An increase of Ang II in the blood stream is definitely not a protective factor in patients affected by cardiovascular diseases or diabetes, considering that the increase of Ang II that occurs under treatment with ARBs may be scarce and/or variable since antagonists are not maximally effective (to block the entire AT1R population) during the whole time of treatment and equally effective in all the tissues and functions described in Table 1. 4. B1R and B2R: similarities and differences The essential role of kinins as protective and therapeutic agents in cardiovascular diseases and diabetes and especially in kidney failure needs further discussion in order to remove a currently existing dogma in the pharmacology of kinin receptors; that the favourable effects of the KKS are due to the B2R while the negative actions are generally attributed to the B1R (Couture & Girolami, 2004; Manolis

Table 3 Mechanism of vasodilatation by receptors and by ACE. Vasodilator

Typical compound

Cascade

AT1RA ACEI AT2R agonist MasR agonist

Losartan Captopril Ang II, CGP 42112A, compound 21 Ang (1–7), AVE 0991,

↑ Ang II➔AT2R➔PRCP➔BK➔ B2R➔NO ↑ BK➔B2R➔NO Ang II➔AT2R➔PRCP➔ ↑ BK➔B2R➔NO Ang(1–7)➔MasR➔ ↑ BK➔B2R➔NO

Note. Localization of vasodilator systems: AT1R (VSMC); ACE, AT2R and MasR (endothelium). CGP 42112A: nicotinic acid-Tyr-(Nα-benzyl-oxycarbonyl-Arg)-Lys-His-Pro-Ile-OH (Sasaoka et al., 2008). Compound 21: N-butyloxycarbonyl-3-(4-imidazol-1-ylmethylphenyl)-5-isobutylthiophene-2-sulphonamide (Unger & Dahlof, 2010). AVE 0991: 5-formyl–4–methoxy–2–phenyl–1-[[4-[2-ethyl-aminocarbonylsulfonamido-5-isobutyl-3-thienyl]-phenyl]-methyl]-imidiazole (Wiemer et al., 2002). Abreviation: PRCP; prolyl-carboxypeptidase.

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et al., 2010; Rhaleb et al., 2011). Hence, the choice of drugs with therapeutic potential in the field of kinins is generally for B1R antagonists and (more and more frequently in recent years) for B2R agonists (Alhenc-Gelas et al., 2011; Bélanger et al., 2009; Marceau & Regoli, 2004). In the present review we intend to challenge this conceptual position, taking advantage of the experimental data that have been published in favour of the beneficial roles of the B1R (Côté et al., 2009), instead of the differences of the effects of the B1R and the B2R in health and disease. Indeed, there is emerging evidence showing that both the B1R and B2R are participating to all the actions of kinins, including those protective and favourable to the cardiovascular system (AlhencGelas et al., 2011; Côté et al., 2009; Duka et al., 2008; Griol-Charhbili et al., 2005; Lagneux et al., 2003; Messadi-Laribi et al., 2008; Tschope et al., 2004; Xi et al., 2008; Xu et al., 2009) as well as those reactive and regenerative in inflammation, pain and oedema and other pathological conditions (Leeb-Lundberg et al., 2005; Marceau & Regoli, 2004, 2008). This concept is illustrated in Fig. 6. Both B2R and B1R are implicated in the physiological beneficial and protective effects and in the pathological actions of the kinins especially in the cardiovascular (Duka et al., 2006) or the renal system (Kakoki et al., 2007). Further, the B1R may participate along with the B2R, in the beneficial effects of ACEIs in the treatment of the cardiac and renal ischemia-reperfusion syndromes (Kakoki et al., 2007; Liu et al., 1996; Yao et al., 2007). These findings lead us to suggest that the B1R is essential for the specific beneficial action of the KKS in the protection and cure of the peripheral circulation and of the heart. Worthy of mention in this context is the fact that an exclusive peculiarity of the KKS and of its receptors is that of being present in the endothelial cells, with the specific and selective function of activating the NO cascade and of mediating the vasodilatations produced by the kinins and by other vasodilatatory receptors (ex. the AT2R) or enzyme inhibitors (e.g. Ramipril (ACEI), Aliskiren (Renin I), AVE7688 (NEP I) and Omapatrilat (dual ACEI/NEPI) (Cuculi & Erne, 2011; Fisher et al., 2008; Quaschning, 2005; Quaschning et al., 2006). Actions of the RAS, mediated by AT1R (Table 1), are absent from these endothelial locations and functions which, we believe, are a prominent feature of the KKS. However, in some vascular beds, the activation of B2R expressed itself predominantly through the NO cascade while that of B1R is fairly active on the prostagladin pathway (McLean et al., 1999; Mehta & Malik, 2006). Other differences between the B2R and the B1R are indicated in Fig. 6. Indeed, the B2R exerts metabolic endocrine functions which are not shared by the B1R.

Physiological actions and beneficial effects

Pathological actions

B2/B1

B2/B1

PGI2

EDHF

NO

5. Interaction between peptidases and kinin receptors Studies in isolated organs, especially isolated vessels or in isolated cells expressing recombinant ACE and the B2R or both, have contributed to elucidating the relationships existing between the enzymes proteases involved in peptide metabolisms and the receptors that mediate their biological actions of the same peptides. In particular, the possible interactions between ACE and the B2R have been investigated by several workers using natural systems expressing native enzymes and receptors (Dendorfer et al., 2001; Gobeil et al., 2002; Tom et al., 2002) or by using different recombinant cellular systems as comparison counterpart cells (Chen et al., 2006; Erdos & Marcic, 2001). Recent similar studies have been performed in order to determine the interactions between CPM and the B1R (Zhang et al., 2008, 2011). Such studies have also contributed to the localisation of the enzyme and the receptor molecules at the plasma membranes of endothelial or the smooth muscle cells. One of these studies is illustrated in Fig. 7 (modified from Regoli & Gobeil, 1999). Two isolated vessels, the rabbit aorta (rbA) and the rabbit jugular vein (rbJV) without endothelium, were used to study CPM/B1R and ACE/B2R, respectively. Specific inhibitors of the enzymes and antagonists for the receptors were used occasionally. Thus, when desendothelized rbA is incubated in vitro for several hours to raise B1R level (induction by post-isolation stress) (Marceau, 1995), the B1R agonist desArg 9-BK (DBK) is a contractor more potent than the B2R agonist BK, which is expected to be inactive in the rbA preparation. Surprisingly, BK showed a weak but consistent contractile activity (left graph of Fig. 7). However, when the application of BK was repeated in the presence of Mergetpa (the inhibitor of CPM), the BK then became inactive. These results were interpreted as due to the rapid, immediate conversion of BK into DBK by the CPM that must be localised very closely to the B1R in order to explain the rapidity (in term of secondes) and efficacy of the effect (Regoli & Barabé, 1980). In separate experiments, the constrictor effect of BK was completely blocked by the B1R antagonist, the [Leu8]-desArg9BK, indicating that indeed it was caused by the activation of the B1R (Regoli & Barabé, 1980). In the desendothelized rbJV, a tissue that expresses B2Rs in the VSMC, BK is a potent constrictor while DBK shows a weak effect only at very high doses (right graph of Fig. 7). Applications of Captopril (SQ14225) (Gobeil et al., 2002; Regoli & Barabé, 1980) or of Ramiprilat (Dendorfer et al., 2001) potentiated the BK-induced contractile responses of the rbJV, while the effect of DesArg 9BK was not affected (not shown). Again, the strong potentiation of BK by ACEIs is extremely rapid after the addition of either inhibitors, suggesting that the ACE of the VSMC must be in close proximity of the B2R in order to permit a very rapid protection of BK by the ACEI and the extremely rapid and consistent increase of the concentration of BK at neihboring sites of B2Rs.

rbA

*T-PA *GLUT-1 &-4

100 K+-cha

cGMP

Plasmin

Glucose

Vasodilation, natriuresis, diuresis, cardiac preconditioning, antihypertrophism, *antithrombosis, *fibrinolysis, *reduction of insuline resistance, *insuline like-action

Pain Inflammation Allergy

M.C. (%)

cAMP

101

75

rbJV

DBK DBK + CPMI BK BK + CPMI

100 75

50

50

25

25

0

0 -10

-8

-6

log (M) Fig. 6. Kinins act through B1R and B2R, which exert the same physiological and pathological actions. Physiological actions occur on target organs, the heart, the kidney and the endothelium. Beneficial effects of both receptors are mediated by several tissue autocoids (PGl2), EDHF, NO), which activate different second messengers (cAMP, potassium, cGMP). Two pathways (hematological and metabolic) indicated by the asterisk are mediated only by the B2R. Modified from Rhaleb et al. (2011), used with permission of John Wiley & Sons Ltd.

BK BK + ACEI DBK

-4

-10

-8

-6

-4

log (M)

Fig. 7. Concentration-contractile response curved to BK and desArg9BK in rabbit aorta (rbA) and jugular vein (rbJV) strips in the absence or presence of peptidase inhibitors. CPMI: carboxypeptidase M inhibitor, mergetpa (10− 6 M); ACEI; angiotensinconverting enzyme inhibitor, SQ 14225 (0.5 × 10− 6 M); Ordinate : maximal contraction (M.C.) in percent. Abcissa: log concentration (M) of agonist. Modified from Regoli and Gobeil (1999), used with permission of IOS Press..

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Attempts have been made to measure BK in circulating blood after acute or chronic administrations of ACEIs in men. Small increases of BK have been reported in some (Campbell, 2001) but not in other (Carretero & Scicli, 1981) studies and this is not surprising because BK is rapidly inactivated by the lung and in blood by a variety of enzymes that are not inhibited by ACEI. Therefore the concentrations of BK in blood cannot be taken as an accurate parameter for estimating the peptide that may be produced in tissues or in blood during the actions of ACEIs. Concentrations of kinins at the tissue levels may well exceed those found in the blood and may conceivably pertain to the antihypertensive and vasodilatory effects of ACEIs in humans (Hornig et al., 1997; Langberg et al., 2002; Parratt et al., 1995). In fact, in rats under ACEI treatments, levels of kinins in vessel, kidney, lung, heart and adipose tissues have been found to be higher than in plasma (Campbell et al., 1994). This indicates that ACEIs are able to protect from degradation large quantities of kinins that can exert potent effects at the vascular levels. The classical metabolic functions of ACE are further supported by evidence obtained with BK analogues selective for the B2R and resistant to degradation by ACE, for instance the peptide [Phe8ψ(CH2-NH)Arg9]-BK (Drapeau et al., 1988; Gobeil et al., 2002). This compound is a potent contractile agonist of several animal vascular and extravascular tissues (Drapeau et al., 1988; Gobeil et al., 2002; Nsa Allogho et al., 1998; Regoli et al., 1990) but rather acts as a weak agonist on the human B2R expressed in the isolated human umbilical veins (Bélanger et al., 2009). It does not undergo degradation by ACE and its potency is not augmented by ACEIs contrary to BK in the isolated rabbit jugular vein preparation (Dendorfer et al., 2001; Gobeil et al., 2002). Results similar to those illustrated in Fig. 7 have been reported in other tissues, as the porcine coronary arteries (Tom et al., 2002), the rat isolated heart (Dendorfer et al., 2000) and others (Allogho et al., 1995; Rouissi et al., 1990a,b). Results obtained in isolated tissues expressing naturally occurring receptors and enzymes using organ bath techniques have been generally interpreted as expressions of classical metabolic actions of peptidases resulting in changes of the concentrations of endogenous peptides in the proximity of the receptors (see above). Other hypotheses have been advanced that ACEI do not only exert metabolic actions, but can also interfere directly with the B2R and the B1R enhancing their signalling and cellular responses. In other words, ACEis have been suggested to act as allosteric enhancers of kinin B1R and B2R functions (Erdos et al., 2010). An accurate analysis of the abundant and often contradictory literature published in recent years on this topics is outside the purpose of the present review and the reader is referred to original papers and reviews, both for the B2R (Dendorfer et al., 2001; Erdos & Marcic, 2001; Erdos et al., 2010; Gobeil et al., 2002; Tom et al., 2002) and the B1R (Fortin et al., 2003; Ignjatovic et al., 2002, 2004; Morissette et al., 2008; Stanisavljevic et al., 2006). 6. Pharmacology of ACEIs Discovered by Skeggs et al. in 1956 (Skeggs et al., 1956), intensively studied and characterized by Erdos in the late '60s (Erdos, 1990), the major functions of ACE were described by Vane and his coworkers (Vane, 1969) with the demonstration that the lung converts Ang I to Ang II (Ng & Vane, 1967) and inactivates BK (Ferreira & Vane, 1967). After the demonstration that the two effects (on Ang I and on BK) were sustained by the same ACE (Erdos, 1990), Vane attributed the same effects to the presence of ACE in the pulmonary and more generally in the vascular endothelium (Vane, 1994). Ferreira and coworkers found the first inhibitor of ACE in the venom of Bothrops jararaka (Ferreira et al., 1970), from which several peptides were isolated and synthesized (Ondetti et al., 1971). Later, Ondetti & Cushman designed and prepared Captopril, the tripeptide inhibitor that rapidly reached worldwide therapeutical applications (Ondetti & Cushman,

1984). Chemically, the numerous compounds belong to 3 categories, the sulfhydryls (captopril), the phosphonates (Fosinopril) and the dicarboxylates (Enalapril); 3 groups of compounds that differ for their pharmacokinetics, particularly their duration of action, which, for an average therapeutic dose of Captopril amounts to 6–8 h and for Enalapril to 12–18 h (Williams, 1988). When injected intravenously in man, ACEI reduce the vasopressor effect of exogenous Ang I, not that of Ang II and, potentiate the hypotension evoked by BK (Brown & Vaughan, 1998). After acute administration of an ACEI, the blood concentrations of Ang II and aldosterone are reduced while those of renin and Ang I are increased (Brown & Vaughan, 1998). These changes are accompanied by a decrease of blood pressure that results from a reduction of the vascular peripheral resistance. This is due primarily to the blockade of Ang II formation and to the paracrine action of kinins in the endothelium. Such fall of blood pressure occurs with little changes of heart rate and cardiac output, in contrast with other vasodilators (e.g. hydralazine, nitrates), which induce tachycardia and may cause orthostatic hypotension (Brown & Vaughan, 1998; Dusing et al., 1987). In the kidney, the ACEIs increase blood flow and decrease the glomerular filtration fraction, by reducing the tonus of the efferent glomerular artery and the intraglomerular pressure (Anderson et al., 1986; Zatz et al., 1986). Chronic administrations (for weeks or months) of ACEIs reduce blood pressure not only in high renin hypertensive patients but also in those with normal or low reninemia (Given et al., 1984; Waeber et al., 1982). In these groups of hypertensive patients and in those suffering of heart failure, the therapeutic favourable effects of ACEI do not correlate with reninemia and depend in large part from the paracrine kinins, since they are significantly reduced by the B2R antagonist Icatibant (Duka et al., 2006; Linz et al., 1995; Su, 2006). Important papers describing the clinical pharmacology of ACEIs were published in the '90s by Williams (1988), by Gavras (1988) and by Brown and Vaughan (1998). Already in the early clinical trials quoted by Brown and Vaughan (1998), several ACEIs (captopril, enalapril, ramipril and others) were found to decrease mortality of patients affected by heart failure and myocardial infarction. These findings were confirmed and extended to include diabetic patients in the HOPE study reported by Yusuf et al. (2000). In a systematic survey of all the clinical trials performed before 2001 by Lamarre-Cliche and Larochelle (2001) in a large part supported the conclusion that ACEIs are valuable and efficient drugs for the treatment of practically all the most common cardiovascular diseases. Dagenais et al. (2006) reported that morbidity (frequency of hospitalisations) and mortality were significantly reduced by treatments with ACEIs in a cohort of patients belonging to HOPE, EUROPA and PEACE studies whose data had been submitted to a (valid) meta-analysis. The numerous (more than 60) studies performed before 2009 have been listed and discussed by Mancia et al. (2009). Worthy of note at this point is the fact that ACEIs and ARBs are the drugs most frequently studied and utilised in the long term treatment of cardiovascular diseases, with an optimal patient compliance and a minimum of side effects. Finally, in the Canadian Guidelines published in 2011, ACEIs and ARBs emerge as the most frequently prescribed drugs for the treatment of cardiovascular diseases. If ACEIs or ARBs are insufficient to control blood pressure, the association of diuretics or of Ca 2+ channels blockers and even β-blockers can be beneficial in one or the other type of cardiovascular diseases. Worthy of note is the report of an increased frequency of tumours in patients treated with ARB (Rabi et al., 2011; Sipahi et al., 2010) and the recommendation that these agents should not be associated to ACEIs (JNC7, 2004). Recently, Cravedi et al. (2010) reviewed the data of old and recent trials, particularly those on nephroprotective antihypertensive drugs and in the highlights of their paper, they point out that “in patients with chronic proteinuric nephropathies, ACEI and ARBs are first line therapy because of the incremental nephroprotective effect over

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other antihypertensive agents. “ACEIs may also confer more effective cardioprotection” (Cravedi et al., 2010). The most common side effects found in patients who take ACEIs are cough (~10%; in white population), skin rashes (1%) and rarely angioedemas (0.1–0.2%) (Brown & Vaughan, 1998). Usually, cough decreases in the weeks that follow the onset of the treatment with the ACEIs (Brown & Vaughan, 1998). If cough persists, the ACEIs are generally replaced by ARBs. Indeed, angioedema and cough under ARBs seem less frequent (but not absent) than those observed under ACEIs (Baker-Smith et al., 2010; Kloth & Lane, 2011; Roskiewicz et al., 2007; Shino et al., 2011). The mechanisms responsible for angioedema (the most serious and unpredictable side effect that does not disappear in chronic treatment) remains poorly defined, but may imply the increase of kinin production via the stimulation of AT2R (Fig. 4), and/or the lack of degradation of kinins via multiple enzymes other than ACE (Roskiewicz et al., 2007). ACEIs are contraindicated in states of severe renal insufficiency or failure, as in patients with renovascular hypertension as well as in extremely advanced renal failure (JNC7, 2004; Rabi et al., 2011). ACEIs are contraindicated in patients with bilateral renal artery stenosis (or unilateral stenosis in patients with one kidney). This is because Ang II-dependent constriction of the efferent arteriole is necessary to maintain glomerular filtration in these patients and ACEIs can worsen renal failure. ACEIs act efficiently in the most angiotensin-sensitive vascular beds of the vital organs, the kidney, the heart and brain (Gavras, 1988). In diabetic patients, ACEIs improve intrarenal hemodynamic and reduce proteinuria (Cooper, 2001b). They preserve cardiac functions and reverse cardiac hypertrophy, but, unlike beta blockers and Ca 2+ channel blockers, they do not affect myocardial contractility and conductivity (Brown & Vaughan, 1998). ACEIs do not cause reflex sympathetic activation or retention of water and salt, unlike other vasodilators (Hydralazine). Finally, ACEIs do not cause fatigue, impotence in hypertensive patients, otherwise healthy and active at work and in life. ACEI are well accepted by patients who comply with the therapy in large number. In patients with heart failure, ACEIs increase cardiac output by decreasing afterload (through vasodilatation) and they also reduce preload (by favouring venoconstriction), thus avoiding reflex tachycardia and oxygen demand in patients with angina. Contrary to other antihypertensive agents very frequently used to treating heart failure such as diuretics, ACEIs suppress the increase of Ang II and of aldosterone that causes the retention of salt and fluids (Couture & Girolami, 2004; Jackson, 2006). ACEIs have long term efficacy, they increase exercise capacity and overall reduce coronary insufficiency, thus improving patient's status and quality of life (Yusuf et al., 2000). Past and recent clinical trials have demonstrated that patients treated with ACEI, (especially for heart failure), show decreased morbidity and significant decrease of mortality (Dagenais et al., 2006; Yusuf et al., 2000). ACEIs are cardioprotective especially because they reduce Ang II, which notoriously worsens myocardial ischemia and remodelling. ACEIs are administered immediately after heart attacks and myocardial infarction, to block the extension of ischemia (of the ischemic area) and prevent the damage that may be caused by the ischemia-reperfusion syndrome (Mancini et al., 1996; Pfeffer, 1995). 7. ACEIs in the treatment (and prevention) of diabetes There is evidence demonstrating that the KKS is indeed a “paracrine” system, which acts where it is activated (Carretero & Scicli, 1989). Thus, the important role of kinins in the regulation of blood flow to tissues and in some fundamental metabolic functions of organs and cells have been established (Couture & Girolami, 2004; Dietze, 1982; Kakoki et al., 2007). One of these functions consists in the beneficial role of kinins in the reduction of insulin resistance, which is a component of the “cardiac-metabolic syndrome” (McFarlane et al., 2003). Early studies in the 80s, by Dietze's group (Rett et al., 1989) in healthy subjects during exercise as well as in patients affected by

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cardiac-metabolic syndrome (type 2 diabetics, hypertensives, post surgical interventions) showed that muscular exercise is accompanied by vasodilatation of the muscle vessels, which appears to be sustained by the activation of the muscular KKS. The resulting increase of tissue oxygenation is associated with metabolic changes that increase of glucose uptake and glucose metabolism in the muscle fibers (Dietze, 1982). Similar changes (hemodynamic and metabolic) were obtained in the healthy subjects and in diabetic patients, with the local infusion of small doses of BK that did not produce any measurable changes of blood pressure and kidney functions (Dietze, 1982). In patients with the cardiac-metabolic syndrome, the responses to exercise and to exogenous BK were reduced, but could be in large part restored by the administration of an ACEI (Captopril, 10 mg) (Dietze, 1982). In the following years, the beneficial effects of ACEIs in the treatment of the cardiac-metabolic syndrome were consistently reproduced in several studies summarised and analysed by McFarlane et al. (2003). Worthy of note is the demonstration provided by McFarlane et al. that ACEIs are unique in the sense that other antihypertensive drugs (diuretics, β-blockers, Ca2+ channel blockers) were found to reduce blood pressure but had no metabolic benefits. However, McFarlane et al. only considered the effects of the ACEIs on the RAS and did not take into account the possible contribution of the KKS. Such contribution is today well demonstrated in numerous studies and has been shown to derive from the ability of the kinins to activate the NO cascade, while blockade of the RAS is not directly involved in the activation of that cascade (Alhenc-Gelas et al., 2011; Carretero & Scicli, 1989; Kakoki & Smithies, 2009; Su, 2006). Kinins facilitate the glucose transport and increase the glucose utilisation by the cells. Various mechanisms have been proposed to explain the interaction between BK and insulins: 1) The B2R stimulates insulin secretion from the pancreatic beta cells; 2) B2R increases glucose uptake in the presence or absence of insulin by acting on glucose-transporter-4-translocation; 3) B2R facilitates the phosphorylation of the insulin receptor (Couture & Girolami, 2004; Manolis et al., 2010; McFarlane et al., 2001; Sowers et al., 2001). Clinical data (published before 2003), demonstrating the beneficial effect of ACEIs in diabetic patients in comparison to placebo and other antihypertensive drugs have been reviewed, summarised and discussed by McFarlane et al. (2003). Overall, ACEI have shown definite advantages with respect to diuretics and β-blockers, particularly in reducing the occurrence and aggravation of diabetes in type 2 diabetic and in hypertensive patients. More recent trials have confirmed and expanded these early observations and today the ACEIs are administered to practically all early and established type 2 diabetic patients to treat and to prevent the unfavorable progress of the disease (Cravedi et al., 2010; McFarlane et al., 2003). 8. Action of ACEIs on glomerular circulation and the filtering membrane In addition to reducing blood pressure and preventing the progress of the cardiac metabolic syndrome, ACEIs are very efficient in reducing proteinuria in diabetic and renal insufficient patients (Cravedi et al., 2010; McFarlane et al., 2003). Loss of proteins in urines is generally used for evaluating the degree of the functional impairment of the kidneys in renal insufficient patients. Hemodynamic or pathological changes in glomeruli have been observed and quantified, in particular for the intraglomerular pressure in micropuncture studies (Anderson et al., 1986; Zatz et al., 1986) and for the status of the glomerular filter by measuring albuminuria or proteinurias (Couture & Girolami, 2004). The intraglomerular pressure is the critical parameter whose actual value is modulated by the RAS and the KKS. This value depends on the tonus of the efferent glomerular artery, which result high (because of vasoconstriction) when the RAS becomes overactive and is reduced by the vasodilatatory action of the KKS. In fact, renin released from the juxtaglomerular cells induces a rapid

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and abundant production of Ang I, which is rapidly converted to Ang II by the high density of ACE which is present in the endothelium of the efferent glomerular artery and on the membrane of the VSMC, where also the AT1R is present. The administration of an ACEI (enalapril) prevents the formation of Ang II and increase the concentration of the kinins, which are potent vasorelaxant of efferent glomerular artery through their B1R and B2R which mediate the release of NO and of PGI2. Early studies by group of Brenner (Anderson et al., 1986; Zatz et al., 1986) demonstrated a marked increase in the intraglomerular pressure in kidneys of rats made hypertensive and severely renal insufficient by subtotal nephrectomy, and also in diabetic animals 24 weeks after diabetes induction with streptozotocin. These experimental models were used to compare the effects of an ACEI (enalapril) with that of a cocktail of antihypertensive agents, namely, reserpine, hydrochorothiazide and hydralazine (Anderson et al., 1986; Zatz et al., 1986). Both treatments reduced blood pressure but only the enalapril was found to reduce the intraglomerular pressure to near normal values eliminating the proteinuria and prolonging life of the animals (Anderson et al., 1986; Ravid et al., 1993; Zatz et al., 1986). In recent years, ACEIs and ARBs became the drugs of choice for treating hypertensive or diabetic patients with moderate renal failure. Other antihypertensive agents as diuretics and β-blockers and possibly Ca 2+ channel blockers, which are still used for treating high blood pressure are not the drugs of choice for preventing the progression of renal glomerular sclerosis and proteinuria (Ravid et al., 1993) that occur in diabetes and severe renal failure (Ravid et al., 1993, 1998). The beneficial effects of ACEIs are primarily attributed to the vasodilatatory effects produced by the kinins either directly, by activating their B1R and B2R, or indirectly by promoting the synthesis and release of NO or of other vasodilatatory prostaglandins (e.g. PGI2), two agents that reduce vascular tone and increase blood flow to the kidney, the heart and the brain, eventually without reducing the blood pressure. Thus, the major cause of end stage renal failure in diabetes appears to be a microvascular disturbance of the glomeruli that is responsible for proteinuria. Hence, the prophylactic treatment with ACEIs of normotensive, normalbuminuric type 2 diabetics has been recommended (Ravid et al., 1998). Studies on type 1 diabetics have clearly shown that ACEIs are able to reduce microalbuminuria and to retard the appearance of proteinuria (Cooper, 1998). In association with Atenolol, Captopril has been found to reduce the risk of micro- and macrovascular complications in type 2 diabetics (Cooper, 2001b). Recent studies confirm and substantiate the results and the conclusions of those initial investigations (The_ACE_ Inhibitors_in_Diabetic_Nephropathy_Trialist_Group, 2001). The outcome of several studies have been submitted to a meta-regression analysis that has revealed the superiority of the treatment with ACEIs, compared to diuretics and β-blockers, for reducing proteinuria in diabetics of the type 1 and type 2 categories (Kasiske et al., 1993). An extensive and careful analysis of the results obtained in clinical trials performed in the late 10 years can be found in the recent review paper by Cravedi et al. (2010). In addition to the changes in the hemodynamic of the glomerulus, diabetes nephropathy is associated with important changes in the glomerular filter, which notoriously undergoes morphological lesions that depend (in large part) on mesangial cell proliferation and the accumulation of extracellular matrix (Couture & Girolami, 2004). Such changes are, in large part responsible for the functional alterations of the renal filter, which lead first to albuminuria and then to proteinuria (Cooper, 2001a). The activation of the KKS exerts beneficial effects (similar to those observed in the heart (Tschope et al., 2004) in the diabetic kidney and reduces the evolution of the glomerular lesions towards fibrosis (Bascands et al., 2003). It is through the activation of the kinin receptors (both the B1R and the B2R), which are present in the filter structures that kinins can inhibit or stop the cell proliferation and the hyperproduction of fibronectine and collagen (Duchene et al., 2002).

From the above it is evident that the administration of ACEIs will promote and/or potentiate the effects of the kinins on the glomerulus (on both the hemodynamic and structural aspects) and reduce albuminuria and proteinuria, in accord with the results of experimental and clinical studies (Cooper, 2001b). 9. Clinical pharmacology of ACEIs In the last 30 years the clinical pharmacology of ACEIs has been studied in large trials supported by the pharmaceutical Industries and performed in large numbers of patients, in order to assess the therapeutic values of more than 10 new ACEI compounds which have been approved, introduced in the market and extensively used in the treatment of cardiovascular diseases. Data are available at present on more than 60 trials (according to the list compiled by Mancia et al. (2009), in which an ACEI or an ARB was evaluated for its therapeutic value in various categories of patients (affected by hypertension, heart failure, coronary artery diseases, post-myocardial infarction, diabetes associated or not to hypertension and renal insufficiency of various nature) to assess positive acute effects and long terms therapeutic benefits in terms of reduction of blood pressure and stability of such reduction, tolerability and scarcity of side effects, improvement of the quality of life, reduction of the frequency and the gravity of complications, and especially the decrease of mortality, when compared with placebos or with other antihypertensive agents, namely diuretics, Ca2+ channel blockers and sometimes β-blockers. More recently, the data collected in the trials have been selected, pooled and then submitted to large scale meta-analyses (Genest et al., 2009; Hackam et al., 2010; Mancia et al., 2009) to cover very large numbers of patients (up to 60–100,000) and thus validate (with such large FOUR-PHASE clinical studies) the efficacy and the therapeutical usefulness of ACEI and other drugs. From the above, a picture is emerging in favour of the ACEIs in the therapy of several diseases affecting the cardiovascular system, because: 1) It is by now well established that ACEIs are considered safe, potent and efficient, life saving drugs (Lamarre-Cliche & Larochelle, 2001); 2) Except for most uncommon, unpredictable reactions (angioedema), ACEIs produce a low number of side effects that diminish with chronic treatments (Brown & Vaughan, 1998) and dropout frequency from therapy is not high (Hackam et al., 2010); 3) They are suitable for prolonged treatments, as required for cardiovascular diseases; 4) They are at present the agents of first choice for treatment with a single agent or, when required, with the combination of two drugs, combinations that in general include an ACEI together with a diuretic, a Ca 2+ channel blocker or a β-blocker. Association with an ARB is not recommended (JNC7, 2004; Rabi et al., 2011); 5) Long term treatment with ACEIs does not promote the development of diabetes mellitus, in contrast to thiazide diuretics, β-blockers and specially the combination of the two (Al-Mallah et al., 2010; Hackam et al., 2010; Mancia et al., 2009), and 6) Most importantly, when ACE is inactivated, the kinins are released at the level of the endothelium and contribute to maintain and prolong the function of the NO cascade that protects the endothelium and reduces the risks of thrombosis and atheroma formation (Ferrari et al., 2010; Madeddu, 2010). In the following, we will attract the attention of the reader to a few hemodynamic effects that contribute to make the ACEI particularly indicated for the treatment of patients with hypertension, diabetic nephropathy and especially heart failure. ACEIs are potent and generally long lasting (up to 12–24 h) vasodilators which reduce the peripheral vascular resistance with little, if any, changes of heart rate and perhaps a decrease of the pulmonary venous pressure. Still, in the presence of ACE inhibition, heart

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responses to postural changes and to exercise are well maintained and orthostatic hypotension does not occur frequently, contrary to what happens with other vasodilators (Brown & Vaughan, 1998; Mancia et al., 1988). This may derive from a permanent vasodilatation maintained by the kinins and by the simultaneous interruption of the high sympathetic tonus that is normally sustained by Ang II in hypertension and heart failure. At the kidney level, ACEIs increase renal blood flow and Na + excretion without changing the glomerular filtration rate: the filtration fraction is reduced, as can be expected by a decrease of tone (vasodilatation) of the efferent glomerular artery. No wonder that ACEIs reduce albuminuria and prevent the evolution from microalbuminuria to proteinuria in patients affected by diabetes or other types of nephropathies. For the treatment of patients affected by heart failure, ACEIs have became the drugs of choice because they reduce afterload as well as preload and eventually increase cardiac output with little or no changes in heart rate (Brown & Vaughan, 1998; Dzau et al., 1980; Gavras & Gavras, 2001). In fact, many clinical trials in which ACEI have been chronically administered to patients with heart failure have demonstrated significant reductions of morbidity (frequency of hospitalisation, or of cardiovascular events) and of mortality (CONSENSUS I and II, AIRE, GISSI-3, TRACE, SMILE, quoted by Brown and Vaughan (1998), I PRESERVE, TRASCEND, ONTARGET and others, quoted by Mancia et al. (2009); and PROFESS, PERTINENT and others, quoted by Ferrari et al. (2010). In conclusion, 40 years of intensive research for safe, efficient and potent drugs for the treatment of cardiovascular diseases and diabetes have been successful and the physician of today has at his disposal a group of agents for the efficient control of high blood pressure, heart failure, and other cardiovascular diseases, as well as for retarding the progression of the dangerous lesions (retinopathy, renal failure, peripheral macro- and microvascular deficiencies) associated with diabetes and hypertension. Positive results have been obtained with the use of ACEIs, a group of agents whose major target is the maintenance of the structural and functional integrity of the endothelium (Battegay et al., 2007; Bovenzi et al., 2010) By protecting kinins from the rapid degradation by their major metabolic enzyme, ACEIs act as endothelioprotectors and vasodilators, reduce blood pressure, improve blood flow to the heart, the brain, and the kidney and generally to all tissues, prevent the occurrence of thromboses and the formation of atheroma and reduce the insulin resistance. These beneficial effects are obtained by a double positive action, the inhibition of the RAS and the potentiation of its natural opposing system, the KKS. Recently, the ACEIs are considered as valid tools for uses as preventive drugs in patients with average-high risks for developing heart infarction, stroke, retinopathy and progressive renal failure. 10. Is the KKS involved in some pleiotropic actions of Statins? Another group of drugs, widely used in the treatment of cardiovascular diseases, the Statins, were initially introduced into therapy for reducing serum cholesterol that notoriously contributes to increasing the risks for atherosclerosis and especially for coronary artery diseases. Later it was found that Statins exert pleiotropic beneficial effects, unrelated to the cholesterol-lowering properties, as anti-inflammatory and endothelium-protecting agents (Mancia et al., 2010). In recent years, a possible implication of the KKS has been suggested, based on in vitro experiments performed in cultures of human coronary artery endothelial cells (Liesmaa et al., 2007). It was shown that Lovastatin induces an important increase of the mRNA for the B1R and the B2R that correspond to an up-regulation of the receptor number: an effect that is inhibited by the selective COX-2 inhibitor NS398. The induced B2R is functional in that it activates the cascade BK-B2R-NO-cGMP and releases NO, but no direct proof has been obtained by the blockade with antagonists. However

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in a recent report (Zhang et al., 2010), Atorvastatin was shown to protect the human umbilical vein endothelial cells from the cytotoxicity of Ang II and this effect was blocked by the B2R antagonist, Icatibant. Thus, the up-regulation of the B2R could be demonstrated in cultured human endothelial cells in experiments of sufficient duration (for several hours), while, in acute experiments in which the contact with the drug was only 15 min, the statin was able to improve the endothelial dysfunction by stimulating the release of NO as did an ACEI, but only the effect of the ACEI was blocked by Icatibant (Tiefenbacher et al., 2004). In a recent clinical trial (PHILLIS) (Mancia et al., 2010), Pravastatin (40 mg/day) did not add any antihypertensive effect to those of Fosinopril (20 mg/day) or Hydrochlorothiazide (25 mg/day) during oral treatments for 3 years. Further studies are therefore needed to elucidate the (BK and BK-independent) mechanisms of the protection of endothelial functions by the Statins. 11. Miscellaneous new antihypertensive agents Search for new agents for the treatment of hypertension and eventually other cardiovascular diseases continues in four directions for obtaining useful compounds that will act as: a) Agonists for the AT2R, as Compound 21, whose major features have been summarized by Unger & Dahlof, 2010 (see Section 3). b) Renin inhibitors, of which ALISKIREN is in clinical use in the USA and in Europe and has already acquired a respectable status as antihypertensive: for results of clinical trials (see (Riccioni et al., 2010) and (Mancia et al., 2009)). Of note, the group of Campbell recently demonstrated that Aliskiren induces an increase of cardiac bradykinin levels and of tissue kallikrein gene expression, unrelated to renin inhibition and changes in bradykinin metabolism (Campbell et al., 2011). More work is needed to clarify the nature of the Aliskiren interaction with the KKS. c) The selective and specific aldosterone receptor antagonist (AldoRA), EPLERENONE, which is expected to replace the non selective traditional Spironolactone. Recent results have been reviewed by Grandi (2005). d) The potent AT1R β-arrestin-biased ligand TRV120027 belonging to a new class of competitive ARBs (DeWire & Violin, 2011) which is capable of simultaneously blocking AngII-mediated blood pressure elevation (through activation of Gαq signalling pathway causing constriction of VSMC (see Fig. 4)) while activating β-arrestin–dependent cardiomyocyte contractility. This compound is now in clinical trial (phase 2A) for the treatment of acute heart failure. All these new drugs have been shown to be active antihypertensive agents, which should protect the endothelium and reduce target organ damages. Such therapeutic profiles make them “new interesting modern tools” to be recommended for the treatment of cardiovascular diseases. 12. Kinins and derivatives: possible uses in therapy Considering the data presented and discussed in this review and from the current state of knowledge regarding the efficacy of some kinin agonists demonstrated in experimental animal (Couture & Girolami, 2004; Heitsch, 2003; Madeddu et al., 2007; Manolis et al., 2010; Marceau & Regoli, 2004; Parratt, 1994; Rodi et al., 2005; Sharma & Thani, 2004; Tonduangu et al., 2004; Yao et al., 2007) and in clinical studies (Leesar et al., 1999; Matsumoto et al., 2001; Minai et al., 2001; Prasad et al., 1999; Pretorius et al., 2003; Wang et al., 2009; Wei et al., 2004), both B1R and B2R agonists, either the naturally occurring agonists BK, Lys-BK and Lys-desArg9BK, their stabilized peptide analogues resistant to degradation (Amblard et al., 1999; Bélanger et al., 2009; Côté et al., 2009; Dendorfer et al., 1999; TarasevicieneStewart et al., 2005; Vavrek et al., 1992) or the non-peptides agonists

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(e.g. FR190997 (Asano et al., 1998; Gobeil et al., 1999)), may find therapeutical applications in the following conditions: 1. Preconditioning in cardiac surgery, postconditioning after myocardial infarct. 2. Acute intervention in cardiology (angioplasty, bypass grafting, coronary (and other arteries) vasospasm), severe pulmonary hypertension (Taraseviciene-Stewart et al., 2005), other troubles in various vascular beds. 3. CNS diseases (Parkinson, viral infections and neurooncology) where kinins (of B2R and B1R) act as i) modulators of selective vascular permeability in the brain to increase the passage of neuropharmaceutical drugs and chemotherapy (Borlongan & Emerich, 2003; Cardoso et al., 2004; Emerich et al., 2001) and as ii) negative modulators of CNS immune T lymphocyte entry (B1R) as in multiple sclerosis (Schulze-Topphoff et al., 2009). 4. Kinins agonists (B2R) can also be used as potent positive modulator of immunity to some protozoan parasites (Monteiro et al., 2006; Scharfstein et al., 2000). In fact, BK stimulates IL-12 TH1-type cytokine production from dendritic cells during Trypanosoma cruzi and Listeria infections, which appears to be important in the development of acquired resistance to some infections. 13. Proposal for the use of ACEIs in the therapy of cardiovascular diseases (and diabetes) 1. Low-average doses of ACEI should be given to healthy people, which are at risk of cardiovascular diseases and diabetes in order to prevent the onset and the progression of the diseases. 2. For the treatment of hypertension, heart failure, other cardiovascular diseases and Type 2 diabetes, the first choice should be an ACEI: in case of intolerance the ACEI should be replaced by an ARB. Association of the ACEI with the ARB is to be avoided because it may increase the risk of cancer (Rabi et al., 2011). 3. In order to achieve maximum therapeutic effect and benefits, in the treatment of heart failure, ACEI should be combined with diuretics (e.g. Chlorthalidone) for short periods (1 week every month), since prolonged non interrupted administration of diuretics may lead to secondary hyperaldosteronism and risky hypokalemia. 4. ACEI could be associated with Ca2+ channels blockers to control tachycardia or other high frequency arrhythmias, or to β-blockers or other antianginal drugs in patients with coronary artery diseases. 14. Conclusion and perspectives In the last 25 years, progress in the field of cardiovascular diseases has been made by the definition of the unfavourable role of an overactive RAS and by the demonstration of the beneficial role of the KKS. Instrumental for this progress has been the success of the ACEIs and the ARBs in the therapy of cardiovascular diseases. In the clinic, the treatment of cardiovascular diseases has progressed towards the use of drugs that not only would reduce high blood pressure, but also will protect the vascular endothelium and retard the degradation of the heart, the kidney and the cerebral circulation. Such an approach has been validated by the results of a large number of clinical trials in which it has been shown that ACEIs in particular, but also ARBs are safe, efficient and well tolerated drugs, suitable not only for the cure of heart failure and diabetes nephropathies (the initial indications) but also for hypertension with high, normal or low reninemias as well as for myocardial infarction and diabetes at all stages of the disease. The clinical trials have definitely demonstrated that ACEIs and ARBs provide a fairly good quality of life, reduce significantly the morbidity of patients with cardiovascular diseases and diabetes and decrease their mortality. It is hoped that this important scientific message will contribute to fertilize the clinical practice and will lead to the development of new

therapeutic agents which will be able to cure the cardiovascular diseases and also to retard the progression of the lesions of the target organs that are at risk in patients affected by the most common cardiovascular diseases and by diabetes.

Acknowledgments We are indebted to Dr. H Gavras for his valuable suggestions and critical reading of the manuscript. We also thank C. Dubuc and M. Savard for their assistance in compiling the bibliography. F. Gobeil is a recipient of a Junior 2 scholarship from the FRSQ, a researcher of the Canada Foundation for Innovation, and a member of the FRSQfunded Centre de recherche clinique Étienne-Le Bel. This study was supported by a grant from the Canadian Institute of Health Research (CIHR). Preference has been given to articles of a review nature and, in most instances, only the more recent investigations have been cited. We therefore apologize to authors whose original works were omitted in this review.

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