(Hypertension. 1997;30:542.)
© 1997 American Heart Association, Inc.
Articles |
Potentiation of the Hypotensive Effect of Bradykinin by Short-term Infusion of Angiotensin-(1-7) in Normotensive and Hypertensive Rats
From the Laboratório de Hipertensão, Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, 31 270-901, Belo Horizonte, MG, Brazil.
Correspondence to Robson A.S. Santos, MD, Departamento de Fisiologia e Biofísica, Av Antônio Carlos, 6627-ICB-UFMG, 31270-901, Belo Horizonte, MG, Brazil. E-mail marrob{at}oraculo.lcc.ufmg.br
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Abstract |
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Abstract In this study we evaluated the effect of angiotensin-(1-7) on the hypotensive action of bradykinin (BK) in normotensive rats, renal hypertensive rats (RHR), and spontaneously hypertensive rats (SHR). In addition, we evaluated the effect of angiotensin-converting enzyme (ACE) inhibition with enalaprilat treatment (10 mg/kg IV) on the BK-potentiating activity of Ang-(1-7). Renal hypertension was produced by aorta coarctation between the origin of renal arteries. Ang-(1-7) (0.3 pmol/min) or saline (0.9% NaCl, 5 µL/min) was infused intravenously in conscious male Wistar rats, adult SHR, or RHR. Intravenous bolus injections of BK (0.1 to 1.6 nmol in RHR and SHR; 0.625 to 5 nmol in Wistar rats) were made before and within 30 and 60 minutes of Ang-(1-7) infusion. Ang-(1-7) infusion did not change mean arterial pressure (MAP) of Wistar rats (MAP=97±3 mm Hg), RHR (MAP=173±3 mm Hg), or SHR (MAP=177±5 mm Hg). In Wistar rats, Ang-(1-7) increased the BK hypotensive effect by 24±6% within 60 minutes of infusion. No significant changes were observed at 30 minutes of infusion. In additional groups of rats, Ang-(1-7) (5 pmol/min, n=5) was infused alone or combined with its selective antagonist D-Ala7-Ang-(1-7) (A-779) (5 pmol/min, n=6). The bradykinin-potentiating activity of Ang-(1-7) was completely abolished by A-779. In SHR and RHR, Ang-(1-7) significantly increased the hypotensive effect of BK by 59±8% and 57±9.8%, respectively, within 60 minutes of infusion. No significant changes were observed with saline infusion. In Wistar rats, enalaprilat treatment increased the BK-potentiating activity of Ang-(1-7) transforming the effect of 0.3 pmol/min into that observed with a rate 16-fold higher (5 pmol/min). On the other hand, in SHR enalaprilat did not change the Ang-(1-7) effect, while it abolished the BK potentiation in RHR. Our data show that the BK-potentiating activity of Ang-(1-7) is preserved and even augmented in hypertensive rats. The finding that the BK-potentiating activity of Ang-(1-7) could be demonstrated at a very low infusion rate suggests that this angiotensin can act as an endogenous modulator of the vascular actions of kinins. ACE inhibition can influence differently the BK-potentiating activity of Ang-(1-7) in normotensive and hypertensive rats.
Key Words: kinins • angiotensin • blood vessels • angiotensin-converting enzyme inhibitors • endothelial cells • rats, inbred SHR
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Introduction |
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The mechanism of action of ACE inhibitors has been thought to include both an interference with circulating or tissue Ang II formation and BK degradation.1 2 3 4 Inhibition of ACE, however, 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 pathway5 8 9 and possesses selective angiotensinergic actions. Ang-(1-7) produces important central and peripheral effects5 ; however, it is essentially devoid of direct vasoconstrictor action5 10 and presents a weak vasodilatory effect in several vascular beds tested.11 12 13 14
We have recently shown that Ang-(1-7) potentiates the hypotensive effect of BK in conscious rats.15 The potentiation was dose-dependent and appears to involve the release of prostaglandins. The BK-potentiating activity of Ang-(1-7) in normotensive Wistar rats was markedly increased by treatment with the ACE inhibitor enalaprilat.15 This finding raises the possibility that the interaction of BK and Ang-(1-7) can contribute to the antihypertensive effects of ACE inhibition. However, there are no data in the literature regarding the influence of Ang-(1-7) on the cardiovascular effects of BK in hypertensive animals. Therefore, in this study we evaluated the BK-potentiating activity of Ang-(1-7) in control and enalaprilat-treated normotensive rats, SHR, and RHR (aorta coarctation). In addition, the possibility that the BK-potentiating activity of Ang-(1-7) is a receptor-mediated event was evaluated using the selective Ang-(1-7) antagonist A-779.16 17 18 19
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Methods |
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Animals
Experiments were performed in 59 unanesthetized male Wistar rats weighing 200 to 280 g and 24 SHR (180 to 220 g, 14 to 16 weeks) bred at the animal facility of the Biological Sciences Institute (CEBIO, UFMG, Brazil). Before and after surgery, the animals were kept in a temperature-controlled room on a 14/10 light/dark cycle.
General Surgical Procedures
Renal hypertension was produced in 10 male Wistar rats by
coarctation of the abdominal aorta between the origin of the renal
arteries, under ether anesthesia. The rats were used 25 to
30 days after the surgery. One day before the experiment, a
polyethylene catheter (PE-10 connected to PE-50) was inserted into the
abdominal aorta through the femoral artery (Wistar rats and SHR) or
carotid artery (RHR) for blood pressure measurements. For
intravenous injections and infusions, polyethylene cannulas
were implanted into the femoral veins. The cannulas, closed by a
metallic pin and filled with isotonic saline, were driven
subcutaneously to the interscapular region of the back of the animals.
All surgical procedures were performed 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.
Arterial Pressure Measurements
The arterial pressure was monitored by a solid-state
strain gauge transducer (model TP-200T, Nihon Kohden) while the 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 Nihon Kohden polygraph
(model CP-640G) or on a computer through a data acquisition system
(CODAS, Dataq Instruments Inc).
Drugs
Bradykinin, Ang-(1-7), D-Ala7-Ang-(1-7) (A-779), and
enalaprilat were dissolved in sterile isotonic saline (0.9% NaCl)
immediately before use. A-779 and Ang-(1-7) were synthesized (by
M.C.K.) at the Cleveland Clinic Foundation (Ohio). Enalaprilat was from
Merck Sharp & Dohme. BK was purchased from Sigma Chemical Co.
Experimental Protocols
Protocol 1: Effect of Ang-(1-7) on the Hypotensive Effect of BK in
Wistar Rats
Intravenous bolus injections of BK (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) (0.3 pmol/min,
n=6) or saline (5 µL/min, n=10). A minimum interval of 3 minutes was
allowed between injections. These two time points were chosen based on
preliminary experiments showing that the degree of change in the BK
effect did not increase further within 2 hours of infusion.
Protocol 2: Effect of A-779 on the BK-Potentiating Activity of
Ang-(1-7) in Wistar Rats
Intravenous bolus injections of BK (0.625,
1.25, 2.5, and 5 nmol) were made before and within 30 and 60 minutes of
intravenous infusion of Ang-(1-7) (5 pmol/min, n=5),
A-779 (12.5 pmol/min, n=6), or Ang-(1-7) combined with A-779 (5
pmol/min of both peptides, n=6).
Protocol 3: Effect of Ang-(1-7) on the Hypotensive Effect of BK
in SHR
Intravenous bolus injections of BK (125, 250, 500,
and 1000 pmol) were made before and within 30 and 60 minutes of
intravenous infusion of Ang-(1-7) (0.3 pmol/min,
n=5) or saline (5 µL/min, n=4).
Protocol 4: Effect of Ang-(1-7) on the Hypotensive Effect of BK
in RHR
Intravenous bolus injections of BK (200, 400, 800,
and 1600 pmol) were made before and within 30 and 60 minutes of
intravenous infusion of Ang-(1-7) (0.3 pmol/min,
n=5).
Protocol 5: Effect of Ang-(1-7) on the Hypotensive Effect of BK in
Enalaprilat-Treated Wistar Rats
Starting 20 minutes after enalaprilat administration (10
mg/kg IV), intravenous bolus injections of BK (15.6
to 250 pmol) were made before and within 30 and 60 minutes of
intravenous infusion of Ang-(1-7) (0.3 pmol/min,
n=10) or saline (5 µL/min, n=6).
Protocol 6: Effect of Ang-(1-7) on the Hypotensive Effect of BK in
Enalaprilat-Treated SHR
Starting 20 minutes after enalaprilat administration (10
mg/kg IV), intravenous bolus injections of BK (15.6,
31.2, 62.5, and 125 pmol) were made before and within 30 and 60 minutes
of intravenous infusion of Ang-(1-7) (0.3 pmol/min,
n=6) or saline (5 µL/min, n=9).
Protocol 7: Effect of Ang-(1-7) on the Hypotensive Effect of BK in
Enalaprilat-Treated RHR
Starting 20 minutes after enalaprilat administration (10
mg/kg IV), intravenous bolus injections of BK (20,
40, 80, and 160 pmol) were made before and within 30 and 60 minutes of
intravenous infusion of Ang-(1-7) (0.3 pmol/min,
n=5).
Statistical Analysis
Comparisons were made by ANOVA followed by Newman-Keuls test.
The criterion for statistical significance was set at
P<.05. Numerical values are given as mean±SEM.
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Results |
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Effect of Ang-(1-7) Infusion in Normotensive Wistar Rats
Infusion of Ang-(1-7) at a rate of 0.3 pmol/min for 60 minutes significantly increased the hypotensive effect of BK in normotensive Wistar rats (Fig 1A), without significantly changing basal MAP (98±3 mm Hg at 60 minutes versus 97±3 mm Hg, before infusion) or HR (311±18 beats/min at 60 minutes versus 295±14 beats/min, before infusion). At the 60-minute time point, the effect of BK was increased in all animals infused with Ang-(1-7). Within 30 minutes of Ang-(1-7) infusion, at this rate, no significant changes in the hypotensive effect of BK were observed. Isotonic saline infusion did not change the hypotensive effect of BK at any time point (Fig 1A).
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P<.05, 30
minute infusion compared with the period before infusion.As shown in Fig 1B, infusion of Ang-(1-7) in rats pretreated with the ACE inhibitor enalaprilat also produced a significant potentiation of the hypotensive effect of BK despite the marked increase in the hypotensive effect of BK produced by enalaprilat (for instance, in the enalaprilat-treated rats, the dose of BK necessary to produce a hypotensive effect of 20 mm Hg was reduced more than 10-fold). Contrasting with the findings in untreated Wistar rats (Fig 1A), a significant BK potentiation was already present within 30 minutes of Ang-(1-7) infusion (Fig 1B), being similar to that observed in untreated rats infused with a rate 16-fold higher (Fig 2; see also Fig 4).
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1.0). Within 60 minutes of infusion, the
hypotensive effect of BK was doubled. Enalaprilat treatment
significantly increased the BK-potentiating activity of Ang-(1-7).
Under this condition, the ratios observed with 0.3 pmol/min were
similar to those obtained with infusion of 5 pmol/min of Ang-(1-7) in
untreated rats. Bottom, in SHR enalaprilat did not increase the
BK-potentiating activity of Ang-(1-7) infused at a rate of 0.3
pmol/min. *P<.05 compared with untreated rats.
To evaluate whether the BK-potentiating activity of Ang-(1-7) was a receptor-mediated response, we determined the effect of infusion of Ang-(1-7) alone or combined with its selective antagonist A-779 on the hypotensive effect of BK. As seen in Fig 2, infusion of Ang-(1-7) at a rate of 5 pmol/min significantly increased the hypotensive effect of BK within 30 or 60 minutes of infusion. On the other hand, infusion of A-779 combined with Ang-(1-7) (5 pmol/min) abolished the BK-potentiating activity of the heptapeptide. This effect could not be attributed to an influence of A-779 alone on the hypotensive action of BK because no consistent changes in the hypotensive effect of BK were observed even during infusion of a higher rate of A-779 (12.5 pmol/min, Fig 2). A-779 infusion at this rate did not significantly change MAP (111±2 mm Hg at 60 minutes versus 114±1 mm Hg, before infusion) or HR (358±9 beats/min at 60 minutes versus 369±8 beats/min, before infusion).
Effect of Ang-(1-7) Infusion in SHR
As observed in normotensive rats, Ang-(1-7) infusion in SHR
significantly increased the hypotensive effect of BK (Fig 3A). The potentiation was more evident
within 60 minutes of infusion. No significant changes in MAP or HR were
observed during Ang-(1-7) infusion in these animals (MAP: 191±5
mm Hg at 60 minutes versus 177±5 mm Hg, before infusion; HR:
299±7 beats/min at 60 minutes versus 357±11 beats/min, before
infusion).
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Values of MAP and HR at 20 minutes after treatment with enalaprilat were 160±7 mm Hg and 348±2 beats/min, respectively. Enalaprilat treatment did not significantly change the BK-potentiating activity of Ang-(1-7) in SHR (Fig 3B). When comparing the averaged ratios of BK hypotensive effects, obtained with matched doses of BK, after and before infusion (Fig 4), it was clear that conversely to that observed in normotensive rats, these ratios did not differ between enalaprilat-treated and untreated SHR. Ang-(1-7) infusion, at this rate in enalaprilat-treated SHR, did not significantly change MAP or HR (values at 60-minute infusion were 157±2 mm Hg and 351±2 beats/min, respectively).
Effect of Ang-(1-7) Infusion in RHR
In aorta-coarctated Wistar rats (baseline values: MAP, 173±3
mm Hg; HR, 442±16 beats/min), infusion of Ang-(1-7) produced a higher
degree of BK potentiation compared with that obtained in normotensive
Wistar rats. Within 30 minutes of infusion, an increase of 28±7.5% of
the BK hypotensive effect was observed (Fig 5). A larger potentiation was observed
with 60-minute infusion (57±9.8%, Fig 5). As observed for the other
groups, infusion of Ang-(1-7) at this rate did not change MAP or
HR.
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Conversely to that observed in normotensive Wistar rats and SHR, enalaprilat treatment completely abolished the BK-potentiating activity of Ang-(1-7) in aorta-coarctated rats (Fig 5). No significant changes in MAP and HR were observed during Ang-(1-7) infusion in enalaprilat-treated RHR (baseline values measured 20 minutes after enalaprilat treatment: MAP, 133±5 mm Hg; HR, 485±14 beats/min).
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Discussion |
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The major findings of our study were that short-term low-rate infusion of Ang-(1-7) in normotensive or hypertensive rats significantly increased the hypotensive effect of BK and that this potentiation was differentially influenced by ACE inhibition with enalaprilat. Additionally, our data suggest that the BK-potentiating activity of Ang-(1-7) is a receptor-mediated effect.
Our findings in normotensive rats confirm and extend our previous observation that Ang-(1-7), given in bolus or by infusion, potentiated the hypotensive effect of BK in normotensive Wistar rats.15 As observed in our early study, ACE inhibition did not prevent the BK-potentiating action of Ang-(1-7). Actually, under ACE inhibition the degree of BK potentiation obtained with infusion of 0.3 pmol/min was similar to that observed with a rate 16-fold higher (5 pmol/min, Fig 4) in untreated rats. This finding further suggests that although Ang-(1-7) can act as a weak ACE inhibitor20 (IC50 in the µmol/L range), as predicted by its amino acid sequence, ACE inhibition is not a major mechanism for its BK-potentiating activity in normotensive Wistar rats. Another finding that reinforces this argument is the observation that the Ang-(1-7) analogue A-779 completely abolished the BK potentiation by Ang-(1-7). Our findings contrast with a recent report by Li et al20 in isolated dog coronary artery. In this preparation, the BK-potentiating activity of Ang-(1-7) was abolished by pretreatment with the ACE inhibitor lisinopril, and Ang-(1-7) decreased the metabolism of 125I-[Tyr8]-BK. However, pretreatment with the NO synthase inhibitor L-NA essentially abolished the potentiation, suggesting that the inhibition produced by lisinopril may involve nonenzymatic mechanisms. The absence of BK potentiation in dog coronary arteries by Ang I, which is a good substrate for ACE, also suggests the participation of nonenzymatic mechanisms in the lack of response to Ang-(1-7) in lisinopril-treated coronary artery rings. Also contrasting with our finding in conscious rats,15 indomethacin pretreatment did not change the BK-potentiating activity of Ang-(1-7) in isolated dog coronary arteries. In addition, Ang II (or Ang I) that potentiates BK in conscious rats21 had no BK-potentiating activity in dog coronary arteries. These contrasting findings appear to be related to interspecies or to in vitro versus in vivo differences regarding the mechanism of the vascular effects of angiotensin peptides. Indeed, in pithed rats11 and piglet pial arteries,12 the vasodilation produced by Ang-(1-7) was blunted by pretreatment with cyclooxygenase inhibitors, while in porcine coronary arteries,22 feline vascular beds,13 and dog coronary arteries,14 the Ang-(1-7) vasodilator effect depended upon NO release. In addition to ACE inhibition, NO release, and cyclooxygenase products release, a mechanism involving an allosteric effect of Ang-(1-7) on the BK B2 receptor cannot be ruled out.
The BK-potentiating activity of Ang-(1-7) was completely abolished by its selective antagonist A-779,16 19 suggesting that this action is a receptor-mediated event. In this regard, the early evidence for the existence of angiotensin receptors with selectivity for Ang-(1-7)16 18 23 24 was recently confirmed in bovine endothelial cells.25 As observed for the BK-potentiating activity in our study, the binding of Ang-(1-7) to bovine endothelial cells was completely blocked by A-779.
The BK-potentiating activity of Ang-(1-7) was preserved and even augmented in the hypertensive rats used in our study (SHR and aorta-coarctated rats). It is interesting to note that both SHR and RHR presented an increased reactivity to BK by itself. A similar finding was described before in SHR26 and RHR.21 The parallel increase in BK reactivity and the BK-potentiating activity of Ang-(1-7) suggests that the mechanisms involved in both effects may be similar or share common elements, such as phospholipase A2 activation.27 28
Different from that observed in normotensive rats, the BK-potentiating activity of Ang-(1-7) was not augmented by ACE inhibition in SHR. A more pronounced difference was obtained in RHR, in which the high BK-potentiating activity observed in basal conditions was abolished by treatment with the ACE inhibitor enalaprilat. We have observed that in SHR treated with enalaprilat, infusion of high rates of Ang-(1-7) (50 pmol/min) did not increase the hypotensive effect of BK (C.V.L. and R.A.S.S., unpublished results, 1996). This observation suggests that at least part of the blunted response to Ang-(1-7) in RHR treated with enalaprilat could be due to high local levels of the heptapeptide achieved by the combination of a marked increase in Ang I and a decrease in the metabolism of Ang-(1-7) as a consequence of ACE inhibition. At high local levels Ang-(1-7) could release, for example, vasoconstrictive prostanoids (PGH2),29 the release of which from endothelial cells is particularly facilitated in hypertension.30 Another possible explanation for the observed differences is that in hypertensive animals the ACE inhibitory activity of Ang-(1-7)20 31 could play a more important role than in normotensive animals. Although the higher pulmonary metabolism of BK in hypertension32 would favor such differences, the low ACE inhibitory activity of Ang-(1-7) together with the low infusion rate used in our study that would result at most in nmol/L concentrations in plasma does not support this possibility. Further studies are obviously needed to clarify the mechanism of the blunted BK-Ang-(1-7) interaction in ACE inhibitor–treated hypertensive rats.
It should be pointed out that the BK-potentiating activity of Ang-(1-7) differs significantly from that observed for peptides that act as ACE inhibitors. Although the BK potentiation starts at a very low infusion rate of the peptide, increasing the rate by 16-fold did not increase further the magnitude of the potentiation. Only the time required to reach the maximum potentiation (approximately 30% in normotensive rats) was shortened. In contrast, "pure" ACE inhibitors are able to increase the BK hypotensive effect 10- to 40-fold. This difference further suggests that Ang-(1-7) increases the BK hypotensive effect by modulating membrane and/or intracellular events associated with BK vasodilation rather than by preventing BK metabolism.
Taken together, the data available in the literature suggest that the endothelial cells are the sites where Ang-(1-7) exerts its endocrine/paracrine BK-potentiating effect. First of all, the heptapeptide can be locally formed.9 Second, it is capable of releasing NO14 15 20 and vasodilatory prostaglandins (and probably other autacoids).5 33 34 Third, endothelial cells appear to be the primary sites for the vascular effects of BK.27 35 Finally, as pointed out above, a selective Ang-(1-7) receptor has been described in these cells.25
In summary, we have found that the BK-potentiating activity of Ang-(1-7) is preserved and even augmented in conscious hypertensive rats. BK potentiation could be demonstrated with a very low infusion rate (300 fmol/min), suggesting that Ang-(1-7) can be an endogenous modulator of the vascular kinin effects. The BK potentiation appears to be a receptor-mediated response since the Ang-(1-7) selective antagonist A-779 completely abolished the Ang-(1-7) action. Contrasting with the findings in normotensive rats, the BK-potentiating activity of Ang-(1-7) was not augmented by ACE inhibition in SHR and was even reduced in RHR. Our results suggest that Ang-(1-7) can favor the counteracting hypotensive effect of BK in hypertension. The possible contribution of BK potentiation by Ang-(1-7) to the pharmacological effects of ACE inhibitors remains to be elucidated.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by FAPEMIG (Fundação de Amparo à Pesquisa do Estado de Minas Gerais) and CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico). C.V. Lima, R.D. Paula, and F.L. Resende are recipients of CNPq fellowships. We are thankful to Jose R. Silva and Soraia S. Silva for technical assistance.
Received March 17, 1997; first decision April 15, 1997; accepted May 8, 1997.
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