Angiotensin II type 2 receptor-mediated vasodilation. Focus on bradykinin, NO and endothelium-derived hyperpolarizing factor(s)

Vascular Pharmacology 42 (2005) 109 – 118 www.elsevier.com/locate/vph

Review

Angiotensin II type 2 receptor-mediated vasodilation. Focus on bradykinin, NO and endothelium-derived hyperpolarizing factor(s) Wendy W. Batenburg, Beril Tom, Martin P. Schuijt, A.H. Jan DanserT Department of Pharmacology, room EE1418b, Erasmus MC, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands

Abstract Angiotensin (Ang) II type 1 (AT1) receptors account for the majority of the cardiovascular effects Ang II, including vasoconstriction and growth stimulation. Recent evidence, mainly obtained in animals, suggests that Ang II type 2 (AT2) receptors counteract some or all of these effects. This review summarizes the current knowledge on the vasodilator effects induced by AT2 receptors in humans and animals, focussing not only on the mediators of this effect, but also on the modulatory role of age, gender, and endothelial function. It is concluded that AT2 receptor-mediated vasodilation most likely depends on the bradykinin–bradykinin type 2 (B2) receptor-NO-cGMP pathway, although evidence for a direct link between AT2 and B2 receptors is currently lacking. If indeed B2 receptors are involved, this would imply that, in addition to NO, also the wide range of non-NO dendothelium-derived hyperpolarizing factorsT (EDHFs) that is released following B2 receptor activation (e.g., K+, cytochrome P450 products from arachidonic acid, H2O2 and S-nitrososothiols), could contribute to AT2 receptor-induced vasodilation. D 2005 Elsevier Inc. All rights reserved. Keywords: Angiotensin; Bradykinin; Receptor; NO; Endothelium–derived hyperpolarizing factor; Nitrosothiol; Gender

Contents 1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. AT2 receptors and vasodilation: results from animal studies . . . . . . . 3. AT2 receptor-mediated effects in humans. . . . . . . . . . . . . . . . . 4. Mediators of AT2 receptor-mediated vasodilation in humans and the role 5. Bradykinin and vasodilatation: role of NO and EDHF . . . . . . . . . . 6. Conclusion and future directions . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction The octapeptide angiotensin (Ang) II mediates its biological actions by activating multiple intracellular pathways following its binding to membrane-bound receptors. Two Ang receptor subtypes are present in humans: Ang II type 1 (AT1) and type 2 (AT2) receptors (Brink et al., 1996; Grone et T Corresponding author. Tel.: +31 10 4087540; fax: +31 10 4089458. E-mail address: [email protected] (A.H.J. Danser). 1537-1891/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.vph.2005.01.005

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al., 1992; Regitz-Zagrosek et al., 1996). Most of the known cardiovascular effects induced by Ang II (e.g., vasoconstriction, water and salt retention, aldosterone synthesis and release, growth and remodelling) are mediated via AT1 receptors. Recent studies emphasize the importance of the AT2 receptor in the cardiovascular system (Carey et al., 2000; Kurisu et al., 2003; Widdop et al., 2002, 2003; Xu et al., 2002; Yang et al., 2002; Zhu et al., 2003). AT2 receptormediated effects will become apparent especially during AT1 receptor blockade, because the increased Ang II levels that

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accompany such blockade will predominantly result in AT2 receptor stimulation. It has even been suggested that this mechanism underlies the beneficial effects of AT1 receptor blockade (Liu et al., 1997; van Kats et al., 2000).

2. AT2 receptors and vasodilation: results from animal studies In vitro experiments in cultured cells and isolated vessels, as well as in vivo studies in rats and mice, including studies in transgenic animals, have shown that AT2 receptor stimulation counteracts some or all of the abovementioned effects mediated via AT1 receptors (Gohlke et al., 1998; Hein et al., 1995; Ichiki et al., 1995; Katada and Majima, 2002; Munzenmaier and Greene, 1996; Siragy et al., 1999; van Kesteren et al., 1997; Widdop et al., 1992, 1993, 2002). The vasodilator effects have been investigated most intensely (Dimitropoulou et al., 2001; Endo et al., 1998; Schuijt et al., 2001a; Tada et al., 1997; Tsutsumi et al., 1999; Widdop et al., 2002), although not all studies agree on this matter (Schuijt et al., 1999; Touyz et al., 1999). AT2 receptors are highly expressed during fetal development (Grady et al., 1991; Grone et al., 1992; Yamada et al., 1999), and re-appear in large numbers under pathological conditions (Schuijt et al., 2001a; Tsutsumi et al., 1998). This does not mean that AT2 receptors are absent in healthy adult animals. In fact, AT2 receptor-induced vasodilation can be observed in normal adult animals (Siragy and Carey, 1997; Widdop et al., 2002; Zhang et al., 2003). AT2 receptors are G-protein-coupled receptors (Zhang and Pratt, 1996), and their stimulation results in the activation of protein phosphatases (Nouet and Nahmias, 2000), thereby directly reversing the effects mediated by protein kinases in response to AT1 receptor stimulation. Alternatively, as AT 1 and AT2 receptors also form heterodimers (AbdAlla et al., 2001), AT2 receptor-mediated effects may occur through a direct interaction with AT1 receptors, possibly even in a ligand-independent manner (Jin et al., 2002). Many studies support a link between AT2 receptor stimulation and the NO-cGMP pathway, either directly or via bradykinin and subsequent B2 receptor activation (Bergaya et al., 2004; Gohlke et al., 1998; Hannan et al., 2003; Siragy and Carey, 1996, 1997; Tsutsumi et al., 1999; Widdop et al., 2002). In support of a role for NO, the AT2 receptor-mediated vasodilator effects of Ang II in the rat heart in vivo (Schuijt et al., 2001a) were reversed by the NO synthase inhibitor l-NAME, but not by the cyclo-oxygenase inhibitor indomethacin (Fig. 1). The exact location of vasodilator AT2 receptors in the vessel wall is still a matter of debate. The most likely site, in view of the stimulation of the bradykinin–B2 receptor-NOcGMP pathway, appears to be the endothelium. Heterodimerization with vasoconstrictor AT1 receptors however would require the presence of AT2 receptors on vascular

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angiotensin II (ng/kg/min) Fig. 1. Effects of 10-min intravenous infusions of angiotensin II on myocardial conductance (=myocardial blood flow/mean arterial pressure) in rats pretreated with saline (open circles), l-NAME (10 mg/kg, followed by a continuous infusion of sodium nitroprusside to restore blood pressure to pre-l-NAME level; squares) or indomethacin (triangles). Data (meanFSEM) are obtained from (Schuijt et al., 2001a,b). Note that the increase in conductance (indicative of vasodilation, and blocked by PD123319 (Schuijt et al., 2001a) is reversed into a decrease by l-NAME ( P=0.06) but not indomethacin.

smooth muscle cells. Thus, perhaps AT2 receptors occur at multiple sites in the vessel wall.

3. AT2 receptor-mediated effects in humans Data on AT2 receptor-mediated effects in humans are scarce. Gene variants of the AT2 receptor are associated with left ventricular mass index in both young hypertensive males (Schmieder et al., 2001) and females with hypertrophic cardiomyopathy (Deinum et al., 2001), thereby supporting the antitrophic effect of AT2 receptors. AT2 receptors are upregulated in the human heart with interstitial fibrosis, and cardiac fibroblasts appear to be the major cell type for their expression (Matsumoto et al., 2000; Tsutsumi et al., 1998). Intrabrachial infusion of the AT2 receptor antagonist PD123319 increased forearm vascular resistance in elderly women treated with the AT1 receptor antagonist candesartan (Phoon and Howes, 2002), whereas Ang II tended to induce vasodilation in the forearm of healthy volunteers during AT1 receptor blockade (Saris et al., 2000). These data indirectly support the concept that AT2 receptors mediate vasodilation in human forearm resistance vessels. In large human coronary arteries (HCAs, diameter c4–5 mm), obtained from subjects who had died of non-cardiovascular causes, Ang II-induced contractile res-

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Fig. 2. Contractions of large human coronary arteries (left panel) and human coronary microarteries (right panel) to angiotensin II in the absence (control, circles) or presence of irbesartan (triangles) or PD123319 (squares). Data (meanFSEM) are expressed as a percentage of the response to 100 mmol/L K+ and have been obtained from (MaassenVanDenBrink et al., 1999) and (Batenburg et al., 2004a). Note the difference in scale. *Pb0.05 vs. control.

4. Mediators of AT2 receptor-mediated vasodilation in humans and the role of age, gender and endothelial function Endothelium removal, NOS blockade and B2 receptor blockade fully prevented the PD123319-induced potentiation of Ang II in HCMAs (Batenburg et al., 2004a). Thus,

AT2 receptor-mediated vasodilation in HCMAs depends on the activation of endothelial B2 receptors and NO, thereby fully supporting the animal data on this subject (Hannan et al., 2003; Kurisu et al., 2003; Tsutsumi et al., 1999). The PD123319-induced effects correlated positively with age (Batenburg et al., 2004a). Since endothelial function 200

endothelial function (% relaxation to substance P)

ponses that were fully blocked by the AT1 receptor antagonist irbesartan (Fig. 2) (MaassenVanDenBrink et al., 1999). PD123319 modestly increased the contractile response to Ang II, but the difference was not significant. In contrast, in human coronary microarteries (HCMAs, diameter c200–300 Am), PD123319 significantly increased the constrictor, AT1 receptor-mediated effects of Ang II (Fig. 2) (Batenburg et al., 2004a). Moreover, Ang II relaxed preconstricted HCMAs in the presence of irbesartan, and this relaxation was prevented by PD123319. To the best of our knowledge, these data are the first to directly demonstrate AT2 receptor-induced vasorelaxation in humans. Radioligand binding studies and RT-PCR support the expression of AT2 receptors in HCMAs, HCAs and human coronary endothelial cells (Batenburg et al., 2004a; Li et al., 1999; Wharton et al., 1998). The presence of AT2 receptors in HCAs, despite the non-significant effect of PD123319 on Ang II-induced vasoconstriction in these vessels, suggests either that their density in these arteries is lower, or that they mediate other (non-dilatory) effects, e.g., effects on vascular growth and remodelling.

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age Fig. 3. Correlation between age and endothelial function (defined as the substance P-induced relaxation of preconstricted vessels) of human coronary arteries (r=0.33, Pb0.05). Data are obtained from (MaassenVanDenBrink et al., 1999; Schuijt et al., 2003; Tom et al., 2003).

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Fig. 4. Contractions of human coronary microarteries obtained from men (left panel, n=12) and women (right panel, n=10) to angiotensin II in the absence (control, circles) or presence of PD123319 (squares). Data (meanFSEM) are expressed as a percentage of the response to 100 mmol/L K+ and have been obtained from Batenburg et al. (2004a). Note that the maximum contraction is larger in women than in men ( P=0.05), but that the effect of PD123319 is observed in both sexes.

decreases with age (Fig. 3), this could point to increased AT2 receptor expression in the face of decreased endothelial function, in agreement with the concept that AT2 receptor density increases under pathological conditions (Tsutsumi et al., 1998). The maximal contractile response (E max) to Ang II was larger in women than in men (Fig. 4), but this did not affect the effect of PD123319. There are at least two explanations for the increased E max in women. Men display higher renin levels (Danser et al., 1998b) and this could result, through increased Ang II levels, in AT1 receptor downregulation. Secondly, estrogens modulate AT1 receptor expression, which will directly affect Ang II-induced vasoconstriction (Silva-Antonialli et al., 2004). A multivariate regression analysis of all (n=43) Ang II concentration–response curves in HCAs (MaassenVanDenBrink et al., 1999; Schuijt et al., 2003; Tom et al., 2003), entering age (range 5–58 years, meanFSEM 43F2.1 years), sex (21 women, 22 men), cause of death (cerebrovascular accident, trauma, hypoxia), maximal contractile response (i.e., the response to 100 mmol/L K+, 49F3 mN) and endothelial function (i.e., substance P-induced relaxation of preconstricted vessels, 53F6%) as variables, confirmed that Ang II efficacy was larger in women than in men (21F3.1 vs. 14F2.1% of the response to 100 mmol/ L K+, Pb0.05), independently of all the above parameters. Ang II potency did not differ between men and women (pEC50 7.8F0.1 vs. 7.7F0.1), and correlated positively with endothelial function ( Pb0.02) independently of age, sex, cause of death and maximal contractile response. Thus, the

more dysfunctional the endothelium, the more Ang II is needed to exert a certain vasoconstrictor effect. This observation is in agreement with a counterbalancing (AT2 receptor-mediated) effect under pathological conditions, even in vessels where the PD123319-induced effect is of modest proportion (Fig. 2).

5. Bradykinin and vasodilatation: role of NO and EDHF The interaction between AT2 receptors and B2 receptor activation is not yet fully understood. Tsutsumi et al. (1999) proposed that Ang II decreases the intracellular pH in endothelial cells, which subsequently activates kininogenases that cleave bradykinin from intracellularly stored kininogens. It is difficult to conceive how this mechanism explains the AT2 receptor-mediated dilatation of isolated vessels mounted in organ baths, since ACE inhibitors do not induce vasodilation in such vessels, thereby arguing against the presence of endogenous bradykinin in isolated vessels (Danser et al., 2000; Tom et al., 2001, 2002). One possibility is that AT2 receptors and B2 receptors heterodimerize and interact in a bradykinin-independent manner. B2 receptor activation results in NO synthesis by endothelial NOS, and NO relaxes vascular smooth muscle cells through guanylyl cyclase activation and subsequent cGMP generation (Batenburg et al., 2004b,c; Danser et al., 2000). Thus, if B2 receptors are indeed involved in the relaxant effect mediated by AT 2

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receptors, it is not surprising that AT2 receptor activation results in cGMP accumulation. NOS inhibitors however do not completely block bradykinin-induced vasorelaxation, suggesting the existence of either NO-storage sites (Danser et al., 1998a; Davisson et al., 1996) or a nonNO dendothelium-derived hyperpolarizing factorT (EDHF) (Busse et al., 2002). EDHF-mediated responses in different arteries have been linked to K+, cytochrome P450 products from arachidonic acid (epoxyeicosatrienoic acids (EETs), in particular 5,6EET, 11,12-EET and 14,15-EET), prostacyclin and H2O2 (Campbell et al., 1996; Edwards et al., 1998, 2001; Fisslthaler et al., 1999; Matoba et al., 2003; Mombouli and Vanhoutte, 1997). The identity of EDHF and its contribution to overall relaxation appear to differ between species, between vascular beds and between vessels of different sizes (Hwa et al., 1994). In general, de novo synthesized NO is of greater importance in large arteries than in microarteries (Fig. 5). Busse et al. (Busse et al., 2002) recently summarized all currently available data on EDHF and proposed that EDHF-mediated relaxation depends on the activation of endothelial intermediate- and small-conductance Ca2+activated K+ channels (IKCa, SKCa) (Bychkov et al., 2002; Sollini et al., 2002). Such activation results in the release of K+ into the myoendothelial space, which subsequently induces smooth muscle hyperpolarization by activating inwardly rectifying K+ channel (KIR) channels and/or Na+–K+ ATPase (Fig. 6). According to this concept, EETs regulate endothelial hyperpolarization

as well as the spread of this hyperpolarization to the adjacent smooth muscle cells through myoendothelial gap junctions. In addition, EETs directly activate largeconductance Ca 2+-activated K+ channels (BKCa) on smooth muscle cells (Archer et al., 2003). With regard to the latter, it is important to note that NO itself is capable of inducing hyperpolarization via activation of Ca2+-activated K+ channels in vascular smooth muscle cells (Bolotina et al., 1994). Interestingly, AT2 receptorinduced relaxation of rat mesenteric microvessels has also been reported to depend on opening of BKCa channels (Dimitropoulou et al., 2001). Data obtained in human and porcine coronary microarteries fully agree with the unifying EDHF concept proposed by Busse et al. (Batenburg et al., 2004b,c). Bradykinin-induced relaxation of these vessels was found to depend on (1) endothelial IKCa and SKCa channels, and (2) the activation of guanylyl cyclase, KIR channels and Na+/K+ ATPase. Activation of Ca2+-activated K+ channels occurred by a factor other than NO. In HCMAs, this factor was not a cytochrome P450 epoxygenase product or H2O2. Since NO scavengers blocked bradykinin-induced relaxations of coronary arteries to a greater degree than NOS inhibitors (Batenburg et al., 2004c; Danser et al., 2000; Kemp and Cocks, 1997), whereas increasing the concentration of the NOS inhibitor did not yield additional blocking effects (Batenburg et al., 2004d; Kemp and Cocks, 1997), one possibility is that this factor is a NO-containing factor from a source that does not depend on the acute conversion of l-arginine by NOS.

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Fig. 5. Relaxations of large porcine coronary arteries (left panel) and porcine coronary microarteries (right panel), following preconstriction with prostaglandin F2a or U46619, to bradykinin in the absence (control) or presence of 100 Amol/L l-NAME and/or 100 nmol/L charybdotoxin (char)+100 nmol/L apamin (apa). Data (meanFSEM) are expressed as a percentage of preconstriction and have been obtained from (Danser et al., 2000) and (Batenburg et al., 2004c). Note that the rightward shift induced by l-NAME is much larger in large coronary arteries, supporting a more important role for NO in these arteries.

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Fig. 6. Unifying scheme linking AT2 receptors to bradykinin, B2 receptors, NO and the EDHF pathway. Modified according to Busse et al. (2002). AA— arachidonic acid; BKCa, IKCa and SKCa—Ca2+-activated K+-channels of large, intermediate and small conductance; EET—epoxyeicosatrienoic acid; KIR— inwardly rectifying K+ channel; NOS—NO synthase; PL—phospholipase. See text for explanation.

NO-containing factors are thought to mediate lightinduced photorelaxation of vascular smooth muscle cells (Lovren and Triggle, 1998; Megson et al., 2000). Nitro-

sothiol-depleting agents reduce photorelaxation responses (Lovren and Triggle, 1998), and S-nitrosothiols have therefore been proposed to mediate this phenomenon. S-nitro-

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Fig. 7. Relaxations of large porcine coronary arteries (left panel) and porcine coronary microarteries (right panel), following preconstriction with U46619, to the S-nitrosothiol l-S-nitrosocysteine (l-SNC) in the absence (control, circles) or presence of 100 nmol/L charybdotoxin+100 nmol/L apamin (squares). Data (meanFSEM) are expressed as a percentage of preconstriction and have been obtained from (Batenburg et al., 2004c,d).

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Fig. 8. Relaxations of human coronary microarteries, following preconstriction with U46619, to bradykinin in men (left panel, n=8) and women (right panel, n=12) in the presence (control, circles) or absence of NO (triangles). Data (meanFSEM) are expressed as a percentage of preconstriction and have been obtained from (Batenburg et al., 2004b). Note that the rightward shift induced by NO removal (with either l-NAME or hydroxocobalamin) is larger in men ( P=0.003) than in women ( P=0.01).

sothiols induce relaxation not only through their decomposition to NO (Rafikova et al., 2002), but also by activating stereoselective recognition sites (Davisson et al., 1996). Recently, the cysteine residues within the a subunit of the BKCa channel were identified as a S-nitrosothiol binding site (Lang et al., 2003). In support of the concept that Snitrosothiols mediate bradykinin-induced, EDHF-dependent relaxations, the nitrosothiol-depleting agent p-hydroxymercurobenzoic acid reduced the relaxant effects of bradykinin in porcine coronary arteries (Batenburg et al., 2004d). Furthermore, the S-nitrosothiol l-S-nitrosocysteine activated endothelial IKCa and SKCa channels (Fig. 7) and hyperpolarized smooth muscle cells (Batenburg et al., 2004c). The effect of NO blockade on bradykinin-induced relaxation of HCMAs was larger in men than in women (Fig. 8). This suggests that the contribution of EDHF is larger in women. Similar observations were made in rat arteries, where it was simultaneously demonstrated that estrogens directly upregulate the EDHF pathway, without altering NOS expression (Liu et al., 2002; Sakuma et al., 2002). The reduced efficacy of Ang II in coronary arteries of men compared to women (Fig. 4) may also relate to this phenomenon.

6. Conclusion and future directions Animal studies from many groups around the world support the idea that AT2 receptors mediate vasodilation. Recent in vitro data suggest that such vasodilation also occurs in humans. Although most studies agree that this effect is NO-dependent, the role of bradykinin and B2

receptors as mediators of AT2 receptor-induced vasodilation is less well established. Future studies should investigate the exact mechanism resulting in kininogenase activation and bradykinin release following AT2 receptor stimulation. Alternatively, AT2 receptor–B2 receptor interaction in a ligand-independent manner might be considered. If indeed B2 receptors are involved in AT2 receptorinduced vasodilation, this would imply that a range of inhibitors of the EDHF pathway (e.g., blockers of Ca2+activated K+ channels) will also, at least in part, inhibit AT2 receptor-induced vasodilation. Confounding factors in this regard are the upregulation of AT2 receptors and the EDHF pathway under pathological conditions, the existence of AT1 receptor–AT2 receptor heterodimers, and the gender-related differences in the expression of components of the renin–angiotensin system and the EDHF pathway. These aspects should therefore be taken into consideration when designing new studies.

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