(Hypertension. 1995;26:1154-1159.)
© 1995 American Heart Association, Inc.
Articles |
Angiotensin-(1-7) Potentiates the Hypotensive Effect of Bradykinin in Conscious Rats
From the Laboratório de Hipertensão, Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil, and the Cleveland Clinic Foundation (Ohio) (M.C.K.).
Correspondence to Robson A.S. Santos, MD, Departamento de Fisiologia e Biofísica, Av Antônio Carlos, 6627-ICB-UFMG, 31270-901, Belo Horizonte, MG, Brazil.
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Abstract |
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Abstract Treatment with angiotensin-converting enzyme inhibitors increases the angiotensin-(1-7) [Ang-(1-7)] and bradykinin concentrations in plasma and tissue. In this study we evaluated the interaction between these peptides by determining the effect of Ang-(1-7) on the hypotensive action of bradykinin in conscious rats. Administration of Ang-(1-7) (5 nmol) did not change mean arterial pressure or heart rate. However, the hypotensive effect of bradykinin, produced by an intravenous or intra-arterial route, was potentiated by Ang-(1-7) in a dose-dependent manner. The Ang-(1-7) doses necessary to transform the effect of a single dose of bradykinin into that produced by a double dose (potentiating unit) were 2 nmol IV and 5 nmol IA. The Ang-(1-7) dose used did not change either the pressor effect of Ang II or the hypotensive effect of sodium nitroprusside. The bradykinin-potentiating Ang-(1-7) activity was significantly attenuated by pretreatment with indomethacin (5 mg/kg IM, n=4). In an additional group the bradykinin-potentiating activity of Ang-(1-7) was evaluated 30 minutes after treatment with the angiotensin-converting enzyme inhibitor enalaprilat (10 mg/kg IV, n=9). Under this condition the bradykinin-potentiating activity of Ang-(1-7) was substantially increased, resulting in a potentiating unit of approximately 0.2 nmol IV. Pretreatment with indomethacin (5 mg/kg IM, n=7) also attenuated the bradykinin-potentiating activity of Ang-(1-7) in enalaprilat-treated rats. These results show that Ang-(1-7) is a bradykinin-potentiating peptide in vivo. Furthermore, the data obtained with indomethacin suggest that prostaglandins participate in the mechanism of the bradykinin potentiation by Ang-(1-7). More importantly, these data suggest that the interaction between Ang-(1-7) and bradykinin can contribute to the pharmacological effects of angiotensin-converting enzyme inhibitors.
Key Words: bradykinin • kinins • angiotensin–converting enzyme inhibitors • renin-angiotensin system • prostaglandins
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Introduction |
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Inhibitors of ACE (kininase II, EC 3.4.15.1) have been widely used for the treatment of hypertension and other cardiovascular diseases.1 The mechanism of action of ACE inhibitors has been thought to include both an interference with circulating or tissue Ang II formation and bradykinin degradation.1 2 3 4 However, ACE inhibition also increases markedly the Ang-(1-7) concentration in plasma and tissue.5 6 7 This biologically active heptapeptide5 is particularly interesting because it can be formed by an ACE-independent pathway.5 8 9 Additionally, although Ang-(1-7) possesses important central actions related to cardiovascular control5 and peripheral actions related to hydroelectrolyte balance regulation,5 it is essentially devoid of a direct vasoconstrictor action5 10 and presents a weak vasodilator effect in several vascular beds tested.5 11 12 13 14
Recently, it was reported that the relaxation produced by Ang-(1-7) in porcine coronary arteries was attenuated by the bradykinin B2-receptor antagonist Hoe 140 and augmented by the ACE inhibitor quinoprilat, suggesting an interaction between bradykinin and Ang-(1-7).14 Furthermore, it has been reported that short-term infusion of Ang I or Ang II in rats increased the reactivity to bradykinin.15 These findings together with the observation that both Ang-(1-7) and bradykinin increased during ACE blockade prompted us to evaluate the interaction between these peptides by determining the effect of Ang-(1-7) on the hypotensive effect of bradykinin in freely moving rats. We evaluated the effect of Ang-(1-7) in control and enalaprilat-treated rats. In addition, we also evaluated the participation of prostaglandins in the Ang-(1-7) effects.
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Methods |
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Surgical Procedures
Experiments were performed in 56 unanesthetized male Wistar rats (200 to 280 g) bred at the Centro de bioterismo do ICB-UFMG (CEBIO). One day before the experiment a polyethylene catheter (PE-10 connected to PE-50) was inserted into the abdominal aorta through the femoral artery for blood pressure measurements. For intravenous injections or infusions a polyethylene cannula was implanted into the femoral vein, and for intra-arterial injections another catheter was inserted into the ascending aorta through the left carotid artery. The polyethylene cannulas, closed by metallic pins and filled with isotonic saline, were driven subcutaneously to the interscapular region of the backs of the animals. All surgical procedures were performed with rats under ether anesthesia. After recovery from anesthesia the rats were kept in individual cages with free access to water and chow until the end of the experiment.
Drugs
Bradykinin, Ang-(1-7), Ang II, sodium nitroprusside, and
enalaprilat were dissolved in sterile isotonic saline (0.9% NaCl)
immediately before use. Ang-(1-7) was synthesized by one of us (M.C.K.)
at the Cleveland Clinic Foundation. Enalaprilat was from Merck Sharp &
Dohme. Bradykinin and indomethacin were purchased from
Sigma Chemical Co.
Arterial Pressure Measurements
Arterial pressure was monitored by a solid-state
strain-gauge transducer (model TP-200T, Nihon Kohden), and HR was
determined with an HR counter (model AT-601G, Nihon Kohden) triggered
by the arterial pressure wave. All variables were
recorded continuously on a direct-writing polygraph (model
CP-640G, Nihon Kohden) or computer through a data-acquisition
system (CODAS, Dataq Instruments Inc).
Protocols
Protocol 1
Intravenous (1 nmol, n=6) or
intra-arterial (10 pmol, n=5) bolus injections of
bradykinin were made alone and together with different doses of
Ang-(1-7) (0.1, 1.0, 2.0, and 5.0 nmol). The hypotensive effect of 2
nmol IV and 20 pmol IA bradykinin was also determined for evaluation of
the Ang-(1-7) dose necessary to transform the effects of the single
doses (1 nmol and 10 pmol, respectively) into that produced by the
double dose (potentiating unit).16 A minimum period of 3
minutes was allowed between injections. This interval was chosen based
on preliminary experiments showing that the potentiating effect of a
single dose of Ang-(1-7) lasted less than 3 minutes. Each dose of
bradykinin or bradykinin associated with Ang-(1-7) was injected twice
(0.1 mL per injection). The effect obtained with the second injection
was considered for calculations.
Protocol 2
Six rats received intravenous bolus injections of
sodium nitroprusside (3.8 nmol) or sodium nitroprusside associated with
different doses of Ang-(1-7) (0.1, 1.0, 2.0, and 5.0 nmol). The
hypotensive effect of intravenous injection of 7.6 nmol
sodium nitroprusside alone was also determined for comparison. In five
additional rats intravenous bolus injections of Ang II were
made alone (5 and 10 pmol) and together (5 pmol) with different doses
of Ang-(1-7) (2.0 and 5.0 nmol).
Protocol 3
Intravenous bolus injections of bradykinin (0.625,
1.25, 2.5, and 5.0 nmol) were made before and within 30 and 60 minutes
of intravenous infusion of Ang-(1-7) (5 pmol/min, n=5) or
saline (0.005 mL/min, n=5). The total period of infusion was 90
minutes. A minimum interval of 4 minutes was allowed between
injections.
Protocol 4
Intravenous bolus injections of bradykinin were made
alone (1 and 2 nmol) and together (1 nmol) with different doses of
Ang-(1-7) (0.1, 1.0, 2.0, and 5.0 nmol) in four rats pretreated (30
minutes before the experiment) with indomethacin (5
mg/kg IM) or vehicle (20% ethanol in 0.05 mL/100 g saline IM,
n=4).
Protocol 5
Intravenous (25 and 50 pmol, n=9) or
intra-arterial (10 and 20 pmol, n=5) injections of
bradykinin were made alone or in combination (25 pmol IV, 10 pmol IA)
with different doses of Ang-(1-7) (0.01, 0.1, 0.2, and 0.5 nmol) in
rats pretreated with the ACE inhibitor enalaprilat (10
mg/kg IV, 30 minutes before experiment).
Protocol 6
Seven rats received MK-422 (10 mg/kg IV) 20 minutes after
indomethacin (5 mg/kg IM). After 30 minutes of the ACE
inhibitor administration the rats were submitted to bolus
intravenous injections of bradykinin alone (25 and 50 pmol)
and together (25 pmol) with different doses of Ang-(1-7) (0.01, 0.1,
0.2, and 0.5 nmol).
Statistical Analysis
Comparisons were made with ANOVA followed by Student's
t test. The criterion for statistical significance was set
at a value of P<.05. Numerical values are given as
mean±SEM.
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Results |
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The hypotensive effect produced by intravenous or intra-arterial bradykinin administration was potentiated by Ang-(1-7) in a dose-dependent manner (Fig 1). The dose necessary to transform the effect of a single dose of bradykinin into that produced by a double dose (potentiating unit) was approximately 2 nmol IV and 5 nmol IA. Intravenous bolus administration of Ang-(1-7) alone did not change MAP or HR (baseline values, 114±8.5 mm Hg and 326±14.5 beats per minute, respectively). As observed for the single-injection experiments, intravenous infusion of Ang-(1-7) at a rate of 5 pmol/min significantly potentiated the bradykinin hypotensive effect within 30 minutes of infusion (Fig 2). A similar potentiation was observed within 1 hour of infusion. As observed with the bolus administration, intravenous infusion of Ang-(1-7) did not change MAP or HR (values before infusion, 98±1 mm Hg and 339±2 beats per minute, respectively).
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, 1 nmol)
or intra-arterial (
, 10 pmol) injection of
bradykinin in conscious rats. Bradykinin was injected as a bolus alone
or associated with different doses of Ang-(1-7)
(intravenous, n=6; intra-arterial, n=5).
Data are expressed as mean±SEM. *P<.05 compared with
values obtained with bradykinin injection alone.
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) and within 30
(
) minutes of intravenous infusion of
saline (0.9% NaCl, 0.3 mL/h, n=5) (A) or Ang-(1-7) (5 pmol/min, n=5)
(B). Values are expressed as mean±SEM. *P<.05 compared
with the period before infusion.To evaluate whether the Ang-(1-7) effect was due to a nonspecific increase of vascular reactivity, we determined the influence of Ang-(1-7) on the hypotensive effect of sodium nitroprusside and the pressor effect of Ang II in additional experiments. As seen in Fig 3, administration of Ang-(1-7) at doses up to 5 nmol did not change either the hypotensive effect of sodium nitroprusside (Fig 3A) or the hypertensive effect of Ang II (Fig 3B).
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The dependence of the potentiating effect of Ang-(1-7) on the release of cyclooxygenase products was evaluated by pretreatment with indomethacin. As shown in Fig 4 the potentiation of the hypotensive effect of bradykinin in the vehicle-treated rats (baseline MAP, 110±4.1 mm Hg and baseline HR, 338±7 beats per minute) was significantly attenuated compared with the indomethacin-treated rats. The potentiating unit increased from 2 to 5 nmol in the indomethacin-treated rats.
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The bradykinin-potentiating activity of Ang-(1-7) was substantially increased by treatment with the ACE inhibitor enalaprilat (Fig 5A). As expected, ACE inhibition produced a marked increase in the hypotensive effect of bradykinin, reducing the dose necessary to produce a 20 mm Hg decrease in MAP by approximately 40-fold (from 1 nmol to 25 pmol). Even in this condition, Ang-(1-7) potentiated the bradykinin hypotensive effect in a dose-dependent manner either intravenously or intra-arterially (Fig 5A). The potentiating unit was decreased 5 to 10 times, averaging 0.2 and 0.5 nmol for the intravenous and intra-arterial routes, respectively. As observed in control rats treatment with the cyclooxygenase inhibitor indomethacin attenuated the bradykinin-potentiating activity of Ang-(1-7) (Fig 5B), increasing the potentiating unit evaluated with intravenous injections from 0.2 to 0.5 nmol. No significant changes in MAP baseline values were observed in the enalaprilat/indomethacin-treated rats compared with the rats receiving only enalaprilat (104±5.4 mm Hg). Also, no changes in HR were observed (354±54 beats per minute in the enalaprilat-treated rats).
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Discussion |
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In the present study we have found that the heptapeptide Ang-(1-7) potentiates the hypotensive effect of bradykinin in freely moving rats in a dose-dependent manner. More importantly, the bradykinin-potentiating activity of Ang-(1-7) was significantly increased in rats treated acutely with the ACE inhibitor enalaprilat. In addition, we have found that prostaglandins appear to be involved in the potentiation of bradykinin by Ang-(1-7).
Several studies have shown that Ang-(1-7) is a weak vasoactive peptide.5 10 11 12 13 14 Ang-(1-7) has little or no vasoconstrictor activity when administered both peripherally5 10 11 12 17 and centrally.17 In vivo weak vasodilator responses to Ang-(1-7) have been reported in the superior mesenteric and hindquarters vascular beds of the cat,13 in piglet pial arterioles,12 and in pithed rats.11 In porcine coronary artery rings Ang-(1-7) elicited a concentration-dependent dilator response, with an ED50 of approximately 2 µmol/L.14 Conversely, in isolated hearts of hamsters Ang-(1-7) induced a weak coronary constrictor effect.18 Our observation that in awake rats Ang-(1-7) did not change MAP in doses up to 5 nmol is in accordance with these previous findings. The weak direct vasoactivity of Ang-(1-7) is probably related to the absence of the carboxy-terminal phenylalanine residue.5 19
The mechanism of the vasodilator activity of Ang-(1-7) appears to involve both prostaglandins and NO.5 However, the degree of dependence of these factors varies according to the species and vascular bed. For instance, in pithed rats11 and piglet pial arteries12 the vasodilatation produced by Ang-(1-7) was abolished by pretreatment with cyclooxygenase inhibitors, whereas in porcine coronary arteries14 and feline vascular beds13 the Ang-(1-7) vasodilator effect depended on NO release. Similarly, the vasodilator actions of bradykinin are multimediated,20 21 22 depending on NO, prostaglandins, cytochrome P-450–derived metabolites of arachidonic acid, and endothelium-derived hyperpolarizing factor.
We have found that the hypotensive action of bradykinin was not
attenuated by indomethacin in control or
enalaprilat-treated rats. However, indomethacin
attenuated the bradykinin-potentiating activity of Ang-(1-7),
suggesting that cyclooxygenase products are
involved in the mechanism of bradykinin potentiation. In this regard,
it should be pointed out that both bradykinin22 and
Ang-(1-7)23 can activate phospholipase
A2, leading to the formation of prostanoid
products. Bradykinin can also increase arachidonic
acid release by activation of other phospholipases.22
Kinins can induce the formation of vasodilator or vasoconstrictor
prostanoids depending on the species and/or vascular bed. In isolated
mesenteric arteries of the rat, for example,
indomethacin potentiates rather than attenuates the
vasodilator effect of bradykinin.24 Thus, Ang-(1-7) could
potentiate bradykinin by facilitating the production of
vasodilator prostanoids5 such as PGI2 or by
limiting the formation of vasoconstrictor prostanoids. The likelihood
for the former possibility is provided by the observation that
Ang-(1-7) has been reported to stimulate the release of
PGE2 and 6-keto-PGF1
, a
metabolite of PGI2, in neural,
endothelial, and vascular smooth muscle
cells5 and that the vasodilator effect of large doses of
Ang-(1-7) can be blocked by cyclooxygenase
inhibitors.5 11 12 Interestingly, the
vasodilator activity of Ang II in piglet pial arterioles12
and rat cerebral arterioles25 can also be blocked by
indomethacin, a finding that is in accordance with the
prostanoid-releasing activity of Ang II.25 26 27
The possibility that at least part of the potentiation of bradykinin by Ang-(1-7) was due to interference with bradykinin metabolism cannot be completely ruled out by our experiments. However, some of our findings argue against a major role for this mechanism. First, because Ang-(1-7) is a substrate for ACE, as can be predicted from its sequence, and the inactivation of bradykinin in the rat pulmonary vascular bed (approximately 98%15 ) is largely due to ACE (approximately 50%),28 we would expect a larger difference between the bradykinin-potentiating activity observed after the intravenous and intra-arterial routes. However, the potentiating unit observed after intravenous administration was only twofold lower than that observed with the intra-arterial route. Second, the bradykinin-potentiating activity was increased in rats treated with enalaprilat, which is also an inhibitor of aminopeptidase P, another important bradykinin-inactivating peptidase.29 The lower potentiating unit observed after intravenous administration in both control and enalaprilat-treated rats could be due to interference of Ang-(1-7) with other peptidases. Another explanation for the lower potentiating unit observed with intravenous administration could be a more pronounced release of vasodilator prostanoids from the pulmonary vascular bed by Ang-(1-7).30
As mentioned above, the bradykinin-potentiating activity of Ang-(1-7) was substantially increased after the administration of the ACE inhibitor enalaprilat. This finding is particularly important when one takes into account the fact that treatment with ACE inhibitors is associated with marked increases in tissue and plasma Ang-(1-7).5 6 7 In addition, although the effect of ACE inhibitors on plasma and tissue bradykinin concentrations is controversial,6 31 32 a recent report6 clearly demonstrated a substantial increase of bradykinin in plasma, blood vessels, and other tissues after administration of perindopril or lisinopril in rats.
The increased bradykinin-potentiating activity of Ang-(1-7) during
ACE inhibition is difficult to explain on the basis of our current
knowledge. It has been reported that in cultured human
endothelial cells the addition of ACE
inhibitors alone increased
[Ca2+]i and facilitated the increase
in [Ca2+]i induced by bradykinin that
is associated with an enhanced production of cGMP and
6-keto-PGF1,3 suggesting
an increased formation of NO and PGI2.3
However, the finding that the B2 receptor
antagonist Hoe 140 prevented both the initial increase
produced by the ACE inhibitors and the
bradykinin-induced increase in cGMP and
PGF1 indicates that bradykinin was involved
in both effects.3 The increase in cGMP in the aorta of
rats chronically treated with the ACE inhibitor ramipril
was also prevented by Hoe 140.33 Yet the possibility that
Hoe 140 could interfere with effects of ACE inhibitors
unrelated to bradykinin, although unlikely, cannot be ruled out. There
is actually evidence for a direct interaction of ACE
inhibitors with bradykinin receptors in the
coronary circulation and rabbit jugular vein.2 As
mentioned above, Ang-(1-7) can be hydrolyzed by ACE, leading to the
formation of Ang-(1-5), which has no demonstrable
bradykinin-potentiating activity (R.D.P., R.A.S.S., unpublished
results, 1995). Thus, one additional factor in the enhancement of the
Ang-(1-7)–potentiating activity in enalaprilat-treated rats could
be the reduction of its "inactivation" by ACE. Ongoing studies in
our laboratory also suggest that part of the
bradykinin-potentiating activity of Ang-(1-7) in control or
enalaprilat-treated rats is related to NO release.
Accumulating evidence indicates that some of the antihypertensive and cardioprotective effects of ACE inhibitors may be due to reduced bradykinin degradation, resulting in an increase of bradykinin levels.1 2 3 6 20 Interestingly, bradykinin antagonists have been shown to attenuate the hypotensive effects of ACE inhibition mainly in high-renin experimental models of hypertension.34 35 36 These observations open an attractive hypothesis that accumulation of plasma and tissue Ang-(1-7) in these situations could account at least in part for the counteracting hypotensive action of kinins in these models of hypertension and could contribute to the effects observed with the bradykinin antagonists. More important, our data suggest that the Ang-(1-7)–bradykinin interaction may contribute to the cardiovascular actions of ACE inhibitors.
We have observed that Ang-(1-7) did not change the pressor effect of Ang II when administered as a bolus in doses up to 5 nmol. It should be pointed out, however, that high doses of an Ang-(1-7) analogue, [Sar1]Ang-(1-7)-amide, have been reported to antagonize the pressor effect of Ang II in anesthetized animals as well as the contractile effect of the octapeptide in isolated rabbit aortic rings.37 More recently, a study using a very similar protocol has described an Ang II antagonistic activity for Ang-(1-7).38 However, the Ang-(1-7) concentration required to attenuate the Ang II contractile effect on isolated rabbit aorta was even higher than that observed with [Sar1]Ang-(1-7) (pA2, 5.5 versus 7.6). A significant attenuation of the Ang II pressor effect in anesthetized rats was achieved only with an infusion rate of 100 µg/kg per minute, which is about 5000-fold higher than the infusion rate necessary to double the bradykinin hypotensive effect in our experiments. Thus, it seems that even though Ang-(1-7) in pharmacological concentrations can antagonize type 1 receptor–mediated effects of Ang II, its actions at more physiological concentrations are possibly linked to interactions with the kinin system. It is interesting to note that when infused, the potency of Ang-(1-7) for bradykinin potentiation was similar or even higher than that observed previously by Salgado and Krieger15 for Ang II and Ang I.
We did not investigate the nature of the angiotensin receptor involved in the bradykinin potentiation by Ang-(1-7) in the present work. It should be pointed out, however, that if this phenomenon is a receptor-mediated event, it probably would be mediated by a receptor distinct from the type 1 or type 2 receptor, as suggested by several studies involving vascular tissues11 12 13 14 or brain sites related to cardiovascular control.39
In summary, we have found that the heptapeptide Ang-(1-7) is a bradykinin-potentiating peptide in vivo acting by a mechanism unrelated to direct ACE inhibition. This effect probably involves amplification of the bradykinin-stimulated release of vasodilator prostaglandins. Furthermore, the bradykinin-potentiating activity of Ang-(1-7) was substantially increased by the ACE inhibitor enalaprilat. These results suggest that the well-documented increase in plasma and tissue Ang-(1-7) observed during long-term treatment with ACE inhibitors5 6 7 can contribute to their pharmacological effects by potentiating the cardiovascular actions of bradykinin.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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Renata D. Paula is a recipient of a scientific undergraduate fellowship from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). The authors are thankful to Dr Maria J. Campagnole-Santos for valuable comments. The technical assistance of José R. Silva is acknowledged.
Received June 19, 1995; first decision August 18, 1995; accepted September 16, 1995.
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