Abstract Angiotensin-(1-7) [Ang-(1-7)] was recently recognized to have novel biological functions that are distinct from those of Ang II. In these studies, we determined the vasoactive effects of Ang-(1-7) together with the endothelium-dependent mediator(s) of these responses in canine coronary arteries. Isometric tension was measured in intact canine coronary artery rings suspended in organ chambers perfused with 95% O2/5% CO2 at 37°C. Ang-(1-7) caused significant concentration-dependent vascular relaxation (2.73±0.58 μmol/L, EC50) of rings precontracted with the thromboxane A2 analogue U46,619. Pretreatment with the nitric oxide synthase inhibitor Nω-nitro-l-arginine (1 mol/L) abolished the vasodilator response to Ang-(1-7), whereas treatment with the cyclooxygenase inhibitor indomethacin (10 μmol/L) was without effect. The vasodilator response produced by Ang-(1-7) was blocked by 75% with the bradykinin B2 receptor antagonist Hoe 140 (1 μmol/L) or by 80% with the nonselective Ang II antagonist [Sar1,Thr8]-Ang II (1 μmol/L). In contrast, the selective AT1 or AT2 Ang II antagonists CV 11974 (1 μmol/L) and PD 123319 (1 μmol/L), respectively, were ineffective in inhibiting the Ang-(1-7)–elicited vasodilation. Furthermore, pretreatment of the coronary rings with 2 μmol/L Ang-(1-7) markedly potentiated the bradykinin response. These results suggest that Ang-(1-7) elicits coronary vasodilation that is specifically mediated by the endothelium-dependent release of nitric oxide. These responses involve a B2 bradykinin receptor and a non-AT1, non-AT2 angiotensin receptor. These data suggest that increases in circulating levels of Ang-(1-7) accompanying long-term administration of converting enzyme inhibitors or Ang II receptor blockers may contribute to the cardioprotective actions of these drugs.
- endothelium-derived relaxing factors
- angiotensin peptides
- coronary artery
- nitric oxide
Removal of the carboxyl-terminal phenylalanine from Ang II imparts selective properties to the heptapeptide Ang-(1-7).1 Unlike Ang II, Ang-(1-7) had no dipsogenic2 or aldosterone-stimulating3 effects, but like Ang II it released vasopressin,4 prostaglandins,5 and NO.6 Recent studies have shown that Ang-(1-7) opposes the actions of Ang II under certain circumstances. In transgenic (mRen-2)27 hypertensive rats, cerebroventricular administration of antibodies to Ang-(1-7) caused significant elevation of blood pressure, whereas administration of a monoclonal antibody to Ang II reduced blood pressure.7 Ang-(1-7) produced a long-lasting depressor response in the pithed rat and vasodilation of piglet pial arterioles.8 9 Both of these actions are blocked by the cyclooxygenase inhibitor indomethacin. In perfused mesenteric and hindquarter vascular beds, Osei et al10 reported that Ang-(1-7) produced vasodilation that was due to the release of NO. Infusion of Ang-(1-7) in SHR reduced blood pressure.11 Thus, these studies suggest that Ang-(1-7) may be a counterregulator of the cardiovascular effects of Ang II by acting as a local modulator of vascular tone.
Local production of Ang-(1-7) in the vasculature has been demonstrated. Ang-(1-7) is generated from either Ang I or Ang II by specific peptidases.12 13 ACE inhibition was associated with 5- to 50-fold increases in Ang-(1-7) both in tissues and in the circulation.14 15 16 In bovine, porcine, and human aortic endothelial cells and human umbilical vein endothelial cells, Ang I is processed to Ang-(1-7) by both neutral endopeptidase 24.11 (40% to 50%) and prolyl endopeptidase (25% to 40%).15 In vascular smooth muscle cells from SHR and Wistar-Kyoto rats, Ang-(1-7) was the major product generated from Ang I, and its generation was dependent on metalloendopeptidase 24.15.17 Further metabolism of Ang-(1-7) or Ang II by aminopeptidases and dipeptidases leads to the formation of smaller fragments, Ang-(3-7) and Ang IV, which may also have a biological function.18 19
Because of the local formation of Ang-(1-7) in the vasculature and its potential for conveying cardioprotective effects by opposing the actions of Ang II, we designed these studies to evaluate the role of Ang-(1-7) in the coronary vessels. Thus, we studied the vasoactive effects of Ang-(1-7) together with the endothelium-dependent mediator(s) of these responses in the canine coronary artery. In addition, we determined the angiotensin receptor subtype(s) that mediates the response and evaluated the interactions between Ang-(1-7) and BK.
After approval by the Institutional Animal Care and Use Committee, 12 male dogs (body weight, 15 to 25 kg) were injected with ketamine (15 mg/kg IM) and given inhalation anesthesia with 2% halothane. Animals were then given a lethal dose of sodium pentobarbital (50 mg/kg IV); their hearts were removed and kept in ice-cold modified Krebs-Henseleit buffer of the following composition (in mmol/L): NaCl 118.3, KCl 4.7, CaCl2 2.5, MgSO4 1.2, KH2PO4 1.2, NaHCO3 25, CaNaEDTA 0.026, and glucose 11. The LAD was dissected free of fat and adhering connective tissues, cut into 3-mm-wide rings, and mounted in glass organ chambers containing modified Krebs-Henseleit solution. The solution was aerated with 95% O2/5% CO2 at 37°C (pH 7.4). The rings were allowed to equilibrate for 60 minutes at 1 g initial resting tension. Basal tension was raised in steps until an optimal length-tension relation was achieved by repeated exposure to 40 mmol/L KCl. Isometric tension was measured continuously with a polygraph (Grass No. 7). The integrity of the vascular endothelium was confirmed by demonstration of a relaxing response (>90%) during application of a 10−7 mol/L dose of acetylcholine in rings preconstricted with 10 nmol/L of the thromboxane A2 agonist 9,11-dideoxy-11α,9α-epoxy-methanoprostaglandin F2α (U46,619, Sigma Chemical Co). Tension in the vascular rings was increased to between 40% and 50% of the maximal developed tension produced by U46,619. It was ascertained that the addition of 10 nmol/L U46,619 resulted in stable constriction of the rings.
Ang-(1-7) dose-response curves (10−8 to 10−4 mol/L) were obtained before and after removal of the vascular endothelium by gentle mechanical rubbing of the lumen with a stainless steel wire. Removal of endothelium was confirmed by the absence of relaxation to the administration of acetylcholine (10−7 mol/L dose).
The contributions of endothelium-dependent humoral mechanisms and angiotensin receptors participating in the changes in tension produced by Ang-(1-7) were investigated in separate protocols. The contribution of vasodilator prostaglandins was evaluated during administration of the cyclooxygenase inhibitor indomethacin (10−5 mol/L) for 20 minutes, whereas in other experiments, rings were pretreated with the NO synthase inhibitor L-NA (10−3 mol/L) for 20 minutes. Coronary artery rings were also exposed for 20 minutes to the specific BK B2 receptor blocker Hoe 140 (Hoechst-Roussell Inc) at a concentration of 10−6 mol/L to evaluate a potential interaction between Ang-(1-7) and kinins.
In additional studies, the effects of pretreatment of coronary rings with 2×10−6 mol/L Ang-(1-7) on the vascular responsiveness to 1 nmol/L BK were tested. Vessels were allowed to relax to basal tension and then were pretreated with 2×10−6 mol/L Ang-(1-7) for 10 minutes. The rings were then preconstricted with 10 nmol/L U46,619 before the 1 nmol/L BK response was repeated. To test the specificity of the response for BK, responses to acetylcholine (0.5×10−7 mol/L) and sodium nitroprusside (10−7 mol/L) were compared in rings before and after pretreatment with Ang-(1-7).
The receptor subtype mediating the effects of Ang-(1-7) in canine coronary artery rings was evaluated by pretreatment of the rings with either selective or nonselective angiotensin receptor antagonists for 30 minutes. The participation of angiotensin receptor subtypes was determined after administration of the selective AT1 (CV 11974, 10−6 mol/L) and AT2 (PD 123319, 10−6 mol/L) receptor antagonists. CV 11974, the active form of the prodrug TCV-116, possesses potent AT1 properties antagonistic to Ang II receptors in vascular smooth muscle and adrenal glomerulosa cells.20 The comparative effect of the nonselective competitive peptide Ang II receptor antagonist [Sar1,Thr8]-Ang II (10−6 mol/L) (Sarthran) was used to determine the possible participation of other subtypes of angiotensin receptor.
In addition, the vasoactive responses produced by Ang II (10−9 to 10−5 mol/L), Ang-(3-8) (Ang IV, 10−9 to 10−5 mol/L), and Ang-(3-7) (10−8 to 10−4 mol/L) were determined in rings also preconstricted with 10 nmol/L U46,619. In studies that established the dose effect of Ang II on canine coronary arteries, one vessel ring was tested for each dose of the peptide to exclude the potential effect of tachyphylaxis from repeated exposure to Ang II.
Drugs and Solutions
Angiotensin peptides were purchased from Bachem. PD 123319 was generously supplied by Warner-Lambert Parke-Davis Inc and CV 11974 by Takeda Chemical Industries, Ltd. Hoe 140 was a gift of Hoechst-Roussell Inc. Other chemicals were purchased from Sigma Chemical Co. Angiotensin peptides were prepared daily in a Krebs-Henseleit buffer solution. Indomethacin and CV 11974 were dissolved in 0.2 mol/L Na2CO3 in stock solution and diluted with Krebs-Henseleit buffer on use. U46,619 was prepared as a stock solution in ethanol and diluted with Krebs-Henseleit buffer. The concentrations of drugs reported in the text are at a final concentration in organ chambers.
Vascular relaxation and constriction were expressed as percentages of isometric tension of rings preconstricted with 10 nmol/L U46,619. The EC50 of peptide was calculated by use of the sigmoid curve-fitting program, PRISM. Results are reported as mean±SEM. One-way ANOVA and Student’s t test for unpaired observations were used for statistical analysis. A value of P<.05 was considered statistically significant.
Ang-(1-7) Causes Endothelium- Dependent Relaxation
The addition of Ang-(1-7) in concentrations ranging from 10−7 to 10−4 mol/L caused relaxation of coronary artery rings preconstricted with 10 nmol/L of the thromboxane A2 analogue U46,619 (Fig 1⇓). The relaxation response produced by Ang-(1-7) was dose dependent (Fig 2⇓), and the calculated EC50 averaged 2.73±0.58 μmol/L.
Removal of the endothelium abolished the response to Ang-(1-7), and preincubation of rings with L-NA (10−3 mol/L) eliminated the endothelium-mediated vascular relaxation of coronary artery rings in response to Ang-(1-7) (Fig 2⇑). Conversely, exposure of vascular rings to the cyclooxygenase inhibitor indomethacin had no effect on the relaxation response produced by Ang-(1-7) (Fig 3⇓). In contrast, administration of the BK antagonist Hoe 140 markedly attenuated the endothelium-mediated relaxation produced by Ang-(1-7), reducing by 75% the maximal vasodilation of Ang-(1-7) [P<.001 compared with Ang-(1-7) at the maximal dose]. There was a residual component (25%) to Ang-(1-7) that was not blocked by Hoe 140 [P<.01, maximal responses of Ang-(1-7) with Hoe 140 versus vehicle alone or endothelium-denuded rings].
Administration of BK at a concentration of 1 nmol/L into coronary artery rings elicited a vasodilator response that was markedly potentiated by preincubation with 2 μmol/L Ang-(1-7) (92% increase over control compared with BK alone) (Fig 4⇓). Pretreatment of Ang-(1-7) for 10 minutes in rings maintained at basal tension had no effect on basal tension and little effect on the preconstricted tension of 10 nmol/L U46,619. The Ang-(1-7) potentiating effect on BK responsiveness was specific for BK, since Ang-(1-7) did not change the endothelium-dependent response to 0.5×10−7 mol/L acetylcholine [49±5.8% versus 52±3.7% relaxation with and without Ang-(1-7) pretreatment, P=NS] or the relaxation response to 10−7 mol/L sodium nitroprusside [40±4% versus 43±4% relaxation with and without Ang-(1-7) pretreatment, P>.05].
Coronary Rings Contracted After Exposure to Ang II and Its C-Terminal Fragment
Fig 5⇓ shows that both Ang II and Ang-(3-8) (Ang IV) elicited dose-related contractions of canine coronary artery rings. In contrast, the carboxy-terminal fragment of Ang-(1-7) [Ang-(3-7)] relaxed coronary artery rings, albeit to a lesser degree than Ang-(1-7). The constrictor activity of Ang-(3-8) and the relaxation produced by Ang-(3-7) were proportionally smaller than those evoked by their corresponding parent peptides.
Angiotensin Receptor Mediating the Relaxation Produced by Ang-(1-7)
Preincubation with either the AT1 or AT2 receptor antagonist (1 μmol/L each of either CV 11974 or PD 123319) did not inhibit the Ang-(1-7) relaxation of coronary vascular rings (Fig 6⇓). Conversely, pretreatment of precontracted rings with the nonselective angiotensin receptor antagonist [Sar1,Thr8]-Ang II markedly attenuated (80%) the vasodilator response induced by administration of Ang-(1-7) [P<.01, maximal relaxation with Sarthran versus Ang-(1-7) alone]. Preincubation of the rings with 1 μmol/L each CV 11974, PD 123319, or [Sar1,Thr8]-Ang II alone did not have any effect on preconstricted tension.
In this study, we showed that Ang-(1-7) caused a dose-dependent relaxation of precontracted coronary artery rings that is mediated by the release of endothelium-derived relaxing factors, possibly through the intermediate release or local accumulation of vasodilator kinins. In canine coronary artery rings, the vasodilator action of Ang-(1-7) did not appear to be associated with the synthesis and release of prostaglandins. Assessment of the angiotensin receptor subtypes mediating the effects of Ang-(1-7) revealed that the endothelium-dependent relaxation response produced by the heptapeptide occurred through activation of a population of receptors that cannot be inhibited by subtype-selective, nonpeptidic AT1 or AT2 receptor antagonists. The concurrent finding that the vasodilator response of coronary artery rings to perfusion with Ang-(1-7) was markedly attenuated by prior exposure to the competitive nonselective Ang II peptide receptor antagonist [Sar1,Thr8]-Ang II indicates the existence of another angiotensin receptor pharmacologically distinct from AT1 and AT2 receptor subtypes. Two other studies from this laboratory suggested that the actions of Ang-(1-7) in blood vessels are mediated by a distinct population of a receptor subtype that is insensitive to nonpeptidic AT1 and AT2 antagonists. [Sar1,Thr8]-Ang II but not losartan or PD 123319 antagonized the depressor response mediated by Ang-(1-7) in areflexic rats8 and the antiproliferative effect of the heptapeptide in isolated vascular smooth muscle cells in culture.21 Although the characteristics of the receptor subtype that mediates the vascular actions of Ang-(1-7) remain to be identified, our data provide conclusive evidence for the presence of angiotensin receptor heterogeneity in blood vessels.
It has been argued that the biological actions of Ang-(1-7) merit little consideration because large doses are presumed to be needed to demonstrate an effect. The fallacy of this interpretation is best illustrated by the present findings. In the concentration range between 10−8 and 10−5 mol/L, both Ang II and Ang-(1-7) were shown unequivocally to effect significant but diametrically opposite changes in the contractile state of coronary artery rings. In addition, over the same dose-response range, the derivative fragments of Ang II and Ang-(1-7) [Ang-(3-8) and Ang-(3-7)] were significantly less potent than the congener peptides in eliciting constriction and relaxation, respectively. The importance of determining the functional outcome of signaling mechanisms activated by different angiotensin peptides was further documented in our studies. Seyedi et al6 recently reported that Ang II was significantly more potent than Ang-(1-7) in stimulating the release of nitrites from canine coronary arteries. In view of our findings, the greater formation of nitrites in response to the application of Ang II may constitute a mechanism for limiting the magnitude of the increase in the contractile state of the coronary vessels. The vasorelaxation induced by Ang-(1-7) would presumably require lesser amounts of NO release.
The vasodilator effects of Ang-(1-7) in canine coronary artery rings extend and confirm previous observations in porcine coronary arteries,22 piglet pial vessels,9 the hindlimb and mesenteric circulation of the cat,10 the systemic circulation of normotensive rats8 and SHR,23 and dogs with renovascular hypertension.24 Ang-(1-7) stimulated the release of vasodilator prostaglandins in piglet pial vessels,9 whereas in intact normotensive rats, the depressor component of the response was inhibited by pretreatment with indomethacin. Conversely, inhibition of NO synthase eliminated the vasodilator response to Ang-(1-7) in coronary arteries,22 the mesenteric circulation,10 and in renovascular hypertensive dogs.24 These data suggest a differential activation of signaling mechanisms by Ang-(1-7) in the control of regional vascular resistance. In agreement with this interpretation, the biphasic effects of Ang-(1-7) on the blood pressure of intact animals or perfused regional circulations are conveyed by separate angiotensin receptors. The short-lasting pressor component of the Ang-(1-7) response in the areflexic rat was inhibited by losartan, whereas the longer-lasting depressor component could be prevented only by the administration of [Sar1,Thr8]-Ang II.8
In the present experiments, the relaxation produced by Ang-(1-7) in precontracted coronary artery rings was abolished after endothelial denudation and after inhibition of NO synthase. In addition, it was markedly attenuated after the administration of a selective BK B2 receptor antagonist or the nonselective Ang II receptor antagonist. These data suggest that Ang-(1-7) stimulates a novel endothelial angiotensin receptor that is linked to a signaling pathway that stimulates the formation of NO via an intermediate rise in the concentration of vascular kinins. Three previous studies6 25 26 have linked the actions of Ang-(1-7) to stimulation of kinins. Hoe 140 inhibited the diuretic and natriuretic responses elicited by Ang-(1-7) in rat kidneys,26 whereas Seyedi et al6 reported that Hoe 140 prevented the production of nitrites from canine coronary vessels by Ang II and Ang-(1-7). Because the production of nitrites by Ang II and Ang-(1-7) was also blocked by inhibitors of the synthesis of kinins, local production of kinins was implicated in the response.6 Recently, Paula et al25 showed that Ang-(1-7) potentiated the hypotensive response elicited by systemic injection of BK, a finding that was duplicated in our experiments in coronary vascular rings. Although our experiments confirmed a link among these effector mechanisms, they shed no light on the characteristics of the receptor or mechanism responsible for this cascade of events. Conversely, the pharmacological probing of the Ang-(1-7) response in the precontracted coronary artery rings suggests a potential signaling pathway mediated through a non-AT1, non-AT2 receptor subtype. We suggest that Ang-(1-7) activates an angiotensin receptor, stimulating the release of endogenous endothelial BK. The release of kinins then stimulates the production or release of NO from endothelial cells. Although further studies will be required to ascertain these possibilities, we do not dismiss the more remote possibility that Ang-(1-7) may facilitate accumulation of BK through direct competition of ACE (References 27 and 28 and unpublished observations).
An observation in these studies that may have important clinical ramifications is the potentiation by Ang-(1-7) of the BK-induced vasodilation. These actions of Ang-(1-7) may contribute to the cardioprotective effects found during chronic ACE inhibition, since we and others have previously shown that Ang-(1-7) and BK are increased after ACE inhibition.14 16 29 The potentiating effect of Ang-(1-7) on BK was first described by Paula et al,25 who showed that low concentrations of Ang-(1-7) given intravenously potentiated, by 2-fold to 10-fold, the vasodepressor response elicited by BK. Furthermore, they showed that in the presence of acute ACE inhibition, there was further potentiation of the BK response by Ang-(1-7). To date, the mechanism explaining this potentiation is unknown, but a number of possibilities can be considered.
Sites of action for the Ang-(1-7) potentiation of BK may include activation of autocoid relaxing factors arising from either Ang-(1-7) or BK. The first question to be determined is whether the potentiating response is angiotensin receptor–mediated and whether this receptor is distinct from that mediating vasodilation by Ang-(1-7). Candidates for signaling pathways for the potentiating response may include pathways already demonstrated to be involved in Ang-(1-7)–mediated responses, including prostaglandins,5 8 30 other arachidonic acid metabolites,31 NO,6 or local kinins.32
BK elicits its responses by way of three endothelium-dependent mediators, namely NO, prostaglandin I2, and EDHF.33 34 35 In canine coronary arteries, however, the BK response is mediated by NO and EDHF, with little contribution from prostaglandin I2.36 It has yet to be determined whether prostanoid release by either Ang-(1-7) or BK participates in the potentiating effect. EDHF is an as yet chemically unidentified vascular relaxing factor that hyperpolarizes the underlying smooth muscle cells by opening Ca2+-activated K+ channels and contributes to the NO-independent dilator response of BK in different vascular beds.36 37 38 Recent reports indicate that BK-induced EDHF is a cytochrome P-450–derived arachidonic acid metabolite that acts through phospholipase C–induced activation of phospholipase A2.39 Andreatta-Van Leyen et al31 showed that Ang-(1-7) increased phospholipase A2 activity by 2-fold to 3.5-fold and that Ang I–induced activation was enhanced by captopril. For both Ang-(1-7) and BK, augmented NO release may participate in the potentiating mechanism.
The present studies provide further evidence for a physiological role of Ang-(1-7) in the modulation of cardiac function. Ang-(1-7) has been identified in the venous effluent of the coronary sinus before and after ACE inhibition and acute myocardial ischemia.40 In human vascular endothelium, Ang-(1-7) was the predominant peptide generated from radiolabeled Ang I.15 Furthermore, treatment with ACE inhibitors increased endothelial production of Ang-(1-7) by 30%.15 Similarly, cardiac tissue levels of Ang-(1-7) in the rat increased threefold after administration of an ACE inhibitor.41 These studies suggest that Ang-(1-7) may contribute to the hemodynamic actions of ACE inhibition.
In summary, we provide direct evidence for an important action of Ang-(1-7) in the regulation of the canine coronary vascular tone that is the opposite of that produced by Ang II at equivalent concentrations and that is mediated by an angiotensin receptor insensitive to blockade by nonpeptidic AT1 and AT2 angiotensin receptor antagonists. These studies further suggest the participation of BK as an intermediate signaling mechanism in the vasodilator response produced by Ang-(1-7) in canine coronary artery rings.
Selected Abbreviations and Acronyms
|Ang II||=||angiotensin II|
|EC50||=||concentration of peptide inducing 50% of maximal relaxation|
|EDHF||=||endothelium-derived hyperpolarizing factor|
|LAD||=||left anterior descending coronary artery|
|SHR||=||spontaneously hypertensive rat(s)|
This research was supported in part by grant 1-P01-HL-51952 from the National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, Md. We thank Takeda Chemical Industries, Osaka, Japan, for CV 11974; Hoechst-Roussell, Frankfurt, Germany, for Hoe 140; and Parke-Davis Pharmaceutical of Warner-Lambert Co, Ann Arbor, Mich, for PD 123319. We thank Mark Atkinson and Carol Kiger for their contributions to the study.
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