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(Hypertension. 1995;26:1154-1159.)
© 1995 American Heart Association, Inc.

Articles

Angiotensin-(1-7) Potentiates the Hypotensive Effect of Bradykinin in Conscious Rats

Renata D. Paula; Celso V. Lima; Mahesh C. Khosla; Robson A.S. Santos

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.

	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

	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 action^{5 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.

	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.

	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).

View larger version (18K): [in this window] [in a new window]   Figure 1. Line graph shows effect of Ang-(1-7) on the hypotensive effect produced by intravenous (, 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.

View larger version (17K): [in this window] [in a new window]   Figure 2. Line graphs show dose-response hypotensive effects of bradykinin in conscious rats before () and within 30 () and 60 () 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).

View larger version (18K): [in this window] [in a new window]   Figure 3. Bar graphs show effect of Ang-(1-7) on the pressor effect of the hypotensive effect of sodium nitroprusside (NP, n=6) (A) or Ang II (n=5) (B). Drugs were injected, alone, or in combination with different doses of Ang-(1-7). Data are expressed as mean±SEM.

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.

View larger version (18K): [in this window] [in a new window]   Figure 4. Line graph shows effect of pretreatment with indomethacin (5 mg/kg IM, n=4) on the bradykinin-potentiating activity of Ang-(1-7) in conscious rats. Indomethacin () or vehicle (20% ethanol in saline, 0.05 mL/100 g IM, n=4) () was administered 30 minutes before intravenous injections of bradykinin alone or in combination with different doses of Ang-(1-7). Data are expressed as mean±SEM. *P<.05 compared with values obtained with bradykinin alone.

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).

View larger version (17K): [in this window] [in a new window]   Figure 5. Line graphs show average changes in MAP produced by injection of bradykinin alone or bradykinin in combination with different doses of Ang-(1-7) in rats treated with enalaprilat (10 mg/kg IV, n=9) (A) or enalaprilat associated with indomethacin (5 mg/kg IM, n=7) (B). Data are expressed as mean±SEM. *P<.05 compared with values obtained with bradykinin alone. In A, indicates 10 pmol IA bradykinin; , 25 pmol IV bradykinin. In B, indicates control; , indomethacin-treated.

	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 peripherally^{5 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 tissues^{11 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 inhibitors^{5 6 7} can contribute to their pharmacological effects by potentiating the cardiovascular actions of bradykinin.

	Selected Abbreviations and Acronyms

 

ACE = angiotensin-converting enzyme Ang I, II = angiotensin I, II Ang-(1-7) = angiotensin-(1-7) HR = heart rate MAP = mean arterial pressure NO = nitric oxide PG = prostaglandin

	Acknowledgments

 
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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