Changes in the Baroreflex Control of Heart Rate Produced by Central Infusion of Selective Angiotensin Antagonists in Hypertensive Rats
Abstract We have recently shown that an angiotensin-(1-7) [Ang-(1-7)] analogue, d-Ala7-Ang-(1-7) (A-779), is a selective Ang-(1-7) antagonist with no significant action on angiotensin type 1 or type 2 receptors. The availability of selective angiotensin antagonists prompted us to evaluate the role of Ang-(1-7) and Ang II on central modulation of the baroreflex control of heart rate in normotensive Wistar rats and spontaneously hypertensive rats (SHR). Blood pressure recording and reflex changes in heart rate elicited by intravenous bolus injections of phenylephrine were made before and within 1 and 3 hours of intracerebroventricular (ICV, lateral ventricle) infusion of saline (8 μL/h), A-779 (4 μg/h), DuP 753 (100 μg/h), or CGP 42112A (50 μg/h) in conscious rats. The slope of the relationship between changes in pulse interval versus changes in mean arterial pressure was used as an index of the baroreflex control of heart rate. ICV infusion of saline or any of the antagonists did not significantly change basal levels of mean arterial pressure and heart rate in SHR (170±6 mm Hg and 360±9 beats per minute, respectively; n=29) or Wistar rats (108±2 mm Hg and 377±6 beats per minute, respectively; n=29). Three hours of ICV infusion of A-779 markedly decreased baroreflex sensitivity in Wistar rats (from a basal slope of 1.09±0.3). In contrast, A-779 did not significantly alter the depressed baroreflex sensitivity of SHR (0.61±0.1). ICV infusion of DuP 753 produced a significant increase (60%) in baroreflex control of heart rate in both Wistar rats and SHR. Saline or CGP 42112A infusions did not significantly alter baroreflex control of heart rate. These results suggest that endogenous Ang II and Ang-(1-7) are differentially affecting central baroreflex modulation, acting probably through distinct receptor subtypes. Although the central Ang II inhibitory effect is mediated by the type 1 receptor subtype, the facilitatory effect of Ang-(1-7) might be mediated by a different, unidentified receptor.
Angiotensin (1-7) [Ang-(1-7)] is an endogenous circulating and tissue product of the renin-angiotensin system that possesses selective actions at peripheral and central sites involved in the control of arterial pressure.1 2 Peripherally, the major known in vivo action of Ang-(1-7) is to produce a potent antidiuretic effect on water-loaded rats.3 Centrally, Ang-(1-7) evokes cardiovascular responses when microinjected into the dorsomedial4 or ventrolateral5 6 medulla of anesthetized rats. In addition, in vitro experiments have shown that Ang-(1-7) has potent vasopressin-releasing1 and prostaglandin-releasing7 activities and that it excites neuronal elements in the hypothalamus and medulla.2 We have recently shown that central Ang-(1-7) differentially modulates baroreceptor reflex sensitivity.8 Although ICV infusion of Ang II or Ang III produced the well-known attenuation, ICV infusion of equal doses of Ang-(1-7) produced a significant facilitation of the baroreflex control of HR in normotensive rats.8
All the cardiovascular and fluid homeostatic actions of Ang II appear to be mediated by the AT1 receptor subtype.9 10 However, there is much evidence for the existence of other angiotensin receptor subtypes,8 10 11 12 and it is possible that distinct angiotensin receptor subtypes exist for the distinct biologically active angiotensin peptides. The recent identification of a specific binding site for Ang-(3-8) (Ang IV) in guinea pig hippocampus12 supports this hypothesis.
More recently, on the basis of in vitro and in vivo studies, we have characterized the peptide d-Ala7-Ang-(1-7) (A-779) as a potent and selective Ang-(1-7) antagonist.13 We have shown that A-779 potently blocked the antidiuretic effect of Ang-(1-7) in water-loaded rats and antagonized the changes in blood pressure produced by Ang-(1-7) injection into dorsomedial and ventrolateral medulla. In addition, A-779 produces a selective blockade of the Ang-(1-7) stimulatory effect on the neuronal activity at the paraventricular nucleus of the hypothalamus.14 In contrast, A-779 did not alter the dipsogenic, pressor, or myotropic effects of Ang II or the effects of other related peptides such as Ang III, vasopressin, bradykinin, or substance P in rats.13 Additionally, A-779 did not compete significantly for the binding of 125I–Ang II to adrenal cortical or medullary membranes at concentrations up to 1 μmol/L.13
The availability of selective angiotensin antagonists allows a more precise evaluation of the role of angiotensin peptides in the modulation of the baroreceptor reflex. In the present study, we attempted to evaluate the role of endogenous angiotensin peptides on the central modulation of the baroreceptor control of HR by determining the effect of central administration of selective antagonists for AT1 (DuP 753) and AT2 (CGP 42112A) receptors and the selective antagonist for Ang-(1-7) (A-779) in normotensive rats and SHR.
Experiments were performed in 29 male Wistar rats weighing 250 to 300 g and in 29 male SHR 14 to 20 weeks old (SHR/M/EPM) obtained from Escola Paulista de Medicina, São Paulo, Brazil. The SHR were imported from the National Institutes of Health, Bethesda, Md, and bred at Escola Paulista de Medicina. They were kept in a temperature-controlled room on a 14/10-hour light/dark cycle in the animal facility of our university for 1 month on their arrival and before the experiments started.
The rats were anesthetized with thiobarbital (40 to 60 mg/kg IP) and placed in a stereotaxic frame (David Kopf Instruments) with the head in a horizontal position. A metallic cannula made with a 25-gauge butterfly needle (siliconized) bent at a right angle with one end connected to polyethylene tubing (PE-10) and the other end cut obliquely was inserted into the right lateral ventricle (1.5 mm lateral and 1.0 mm posterior to the bregma and 4.5 mm below the skull) through a small hole drilled in the skull, as described previously.8 The cannula was anchored to the skull with dental cement and a jeweler’s screw. The polyethylene tubing, filled with sterile isotonic saline, was driven subcutaneously to the interscapular region of the back and closed by a metallic pin. The total dead space of the cannula was between 2.5 and 3.0 μL, calibrated before cannula implantation. Postoperatively, the rats received a single dose of penicillin (60 000 U IM; Pentabiótico Veterinário, Fontoura-Wyeth). The rats were kept in individual cages for 4 to 7 days, with free access to water and chow. Catheters were then inserted into the femoral artery and vein and tunneled subcutaneously to the back of the neck with rats under ether anesthesia.
ICV Infusion Procedure
The ICV infusion of angiotensin antagonists was carried out with a syringe (10 μL, Hamilton Co) at rates of 100, 50, and 4 μg/8 μL per hour for DuP 753, CGP 42112A, and A-779, respectively, for 3.5 hours. Immediately before the beginning of the infusion, 2.5 to 3.0 μL of the antagonist solution was injected into the ICV cannula over 3 minutes. In the control group, sterile isotonic saline was infused ICV at the same rate (8 μL/h). At the end of the infusion period, 25 ng Ang II was injected through the ICV cannula, and the arterial pressure response and drinking behavior responses were observed.
Antagonist Infusion Rate
The infusion rate of DuP 753 was chosen on the basis of preliminary experiments which showed that this was the minimum effective rate that completely blocked the pressor and drinking responses produced by ICV injection of Ang II. The infusion rate of A-779 was chosen on the basis of preliminary experiments in which this rate was the minimum effective rate that caused a baroreflex change. In addition, to document the effectiveness of A-779 in blocking the effect of Ang-(1-7) on baroreflex sensitivity, we have performed in an extra group of Wistar rats an ICV infusion of Ang-(1-7) (4 μg/h, n=4) or a mixture of A-779 (16 μg/h) and Ang-(1-7) (4 μg/h, n=5) for 1.5 hours. After 1 hour, the Ang-(1-7) infusion produced a significant increase in baroreflex sensitivity (1.28±0.19 versus 0.91±0.18 ms/mm Hg of the period before infusion; P<.05, Student’s paired t test) that was completely blocked by the simultaneous infusion of Ang-(1-7) and A-779 (0.84±0.16 versus 1.08±0.26 ms/mm Hg of the period before infusion; P<.05, Student’s paired t test). The infusion rate of CGP 42112A was chosen to be a 10-fold higher rate, on a molar basis, than the infusion rate of A-779 that was effective in producing a change in baroreflex sensitivity.
DuP 753, CGP 42112A, and A-779 were dissolved in sterile isotonic saline (0.9% NaCl) immediately before use. A-779 antagonist was synthesized by M.C.K. at the Cleveland Clinic Foundation. DuP 753 and CGP 42112A were obtained from E.I. DuPont de Nemours and CIBA-Geigy, respectively.
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 Khoden) triggered by the arterial pressure wave. All variables were recorded continuously on a direct-writing polygraph (model CP-640G, Nihon Kohden).
Baroreceptor Reflex Test
Twenty-four hours after vascular cannula implantation, baroreflex control of HR was evaluated in conscious rats before and within 1 and 3 hours of ICV infusion of saline or angiotensin antagonists. Baroreceptor reflex control of HR was determined in each rat by recording reflex HR changes in response to MAP changes produced by repeated bolus injections of graded doses of phenylephrine (0.2 to 40 μg/kg). Phenylephrine doses were injected 1 to 2 minutes apart into a femoral vein in 0.1 mL isotonic NaCl. Peak changes in HR occurring during the initial 5 seconds of the corresponding maximum change in MAP produced with phenylephrine were recorded. Pulse interval was calculated by the equation 60 000/HR (in milliseconds per beat per minute). Baroreceptor reflex sensitivity was estimated in each rat by fitting a least-squares regression line for the relationship between changes in pulse interval (milliseconds) and MAP (millimeters of mercury) for each data point obtained with graded injection of phenylephrine. The slope of the line expressing the relationship (milliseconds per millimeter of mercury) that expresses the baroreflex gain was used as an index of baroreceptor sensitivity. The intercept of the line with the y axis was also analyzed for evaluation of the set point.
Verification of ICV Cannula Location
At the end of every experiment, 5 μL Evans blue dye (5%) was injected through the ICV cannula. The brain was removed, and the position of the cannula in the lateral ventricle was confirmed by the diffusion of the dye throughout the ventricular system.
Comparisons among the antagonists or at different time points were assessed by ANOVA followed by the least significant difference test. The criterion for statistical significance was set at a value of P<.05. Numerical values are given as mean±SE.
Effect of ICV Infusion of Angiotensin Antagonists on MAP, HR, and Cardiovascular Responses Evoked by Ang II
As shown in Fig 1⇓, ICV infusion of the angiotensin antagonists did not produce a significant change in baseline values of MAP and HR in normotensive rats (108±2 mm Hg and 377±6 bpm, respectively; n=29) or SHR (170±6 mm Hg and 360±9 bpm). ICV injection of Ang II at the end of ICV infusion of saline produced the expected increase in MAP and decrease in HR and stimulated drinking behavior in normotensive rats (ΔMAP, 24±2 mm Hg; ΔHR,−40±3 bpm; Fig 2⇓) and SHR (ΔMAP, 32±1 mm Hg; ΔHR, −41±1 bpm; Fig 2⇓). ICV infusion of DuP 753 in normotensive rats or SHR abolished the pressor and bradycardic responses and drinking behavior produced by ICV Ang II injection (Fig 2⇓). In contrast, the Ang-(1-7) antagonist A-779 did not significantly change the pressor response (ΔMAP, 24±2 and 29±2 mm Hg in normotensive rats and SHR, respectively; Fig 2⇓), the bradycardic response (ΔHR, −39±1 and −35±3 bpm in normotensive rats and SHR), or drinking behavior produced by ICV injection of Ang II. Similarly, 3 hours of CGP 42112A infusion did not change the pressor response (ΔMAP, 20±1 and 30±2 mm Hg in normotensive rats and SHR; Fig 2⇓), bradycardic response (ΔHR, −31±3.0 and −43±2 bpm in normotensive rats and SHR), or drinking behavior produced by ICV injection of Ang II.
Effect of ICV Infusion of Angiotensin Antagonists on Baroreflex Control of HR in Normotensive Rats
One and 3 hours of ICV infusion of A-779 produced a significant decrease in baroreflex sensitivity (Table⇓ and Fig 3⇓). The sensitivity of the baroreceptor control of HR, taken as the mean of the slopes of individual regression lines for each rat, was significantly lower at 1 hour (0.27±0.1; approximate 70% decrease) and at 3 hours (0.47±0.1; approximate 60% decrease) of infusion compared with values observed before infusion (1.09±0.3) or at 3 hours of saline infusion (1.18±0.1) in other rats (Table⇓). No significant effects were observed for the set point of the baroreflex as determined by the intercept of the line with the y axis (Table⇓).
In contrast to the results obtained with A-779, ICV infusion of the AT1 receptor antagonist DuP 753 (100 μg/h) produced a significant increase in baroreflex sensitivity (approximately 70%), taken as the slope of the regression line between HR and MAP (1.83±0.3 at 3 hours compared with 1.1±0.1 before infusion; Table⇑ and Fig 3⇑). In addition, the set point of the baroreflex at 3 hours of DuP 753 infusion changed significantly, as determined by the intercept of the regression line with the y axis (Table⇑).
ICV infusion of CGP 42112A or saline did not significantly alter the slope of the regression line for the relationship between the reflex changes in HR and changes in MAP at either 1 or 3 hours of antagonist infusion (Table⇑). No significant effects were observed for the set point of the baroreflex as determined by the intercept of the line with the y axis (Table⇑).
Effect of ICV Infusion of Angiotensin Antagonists on Baroreflex Control of HR in SHR
The gain of the baroreflex of SHR (slope=0.59±0.05 before infusion, n=29) was significantly attenuated compared with that of normotensive rats (slope=1.17±0.10 before infusion, n=29). The ICV infusion of A-779, CGP 42112A, or saline did not modify the already depressed baroreflex sensitivity of the SHR, as evaluated by the slope of the regression line between changes in HR (as pulse interval) and changes in MAP (Table⇑ and Figs 4⇓ and 5⇓). No significant changes were observed in the intercept of the line with the y axis (Table⇑). In contrast, DuP 753 significantly facilitated the baroreflex sensitivity at 3 hours of infusion (increase of approximately 60%) when the data were taken as the slope of the regression line between changes in HR and changes in MAP (0.82±0.2, compared with 0.49±0.1 before infusion; Table⇑ and Fig 4⇓). The set point of the baroreflex determined by the intercept of the regression line with the y axis was not significantly altered (Table⇑).
The major findings of this study were as follows: (1) In normotensive rats, ICV infusion of A-779, a selective Ang-(1-7) antagonist, significantly blunted the baroreceptor control of HR without interfering with the cardiovascular effects evoked by ICV administration of Ang II. In contrast, the AT1 receptor antagonist DuP 753 produced a complete blockade of the central Ang II pressor response and facilitated the baroreflex. (2) In hypertensive rats, DuP 753 increased and A-779 did not affect the depressed baroreceptor sensitivity of SHR. These data suggest that endogenous Ang II and Ang-(1-7) may differentially modulate the baroreceptor control of HR, probably through distinct angiotensin receptors. Whereas the central effects produced by Ang II are mediated by the AT1 receptor subtype, the Ang-(1-7) effects might be mediated by a different unidentified receptor.
The relevance of our findings is based on the recent demonstration that the peptide d-Ala7-Ang-(1-7) (A-779) is a potent Ang-(1-7) antagonist, without demonstrable intrinsic agonistic activity in several biological preparations examined in concentrations up to 2.5 μmol/L.13 14 Furthermore, our previous data indicated that the antagonistic properties of A-779 are unrelated to AT1 or AT2 receptor subtypes. A-779 was unable to change the pressor (intravenous and ICV), dipsogenic, or myotropic effects of Ang II and did not inhibit the binding of radioiodinated Ang II to adrenocortical membranes, which are rich in AT1 receptors. In addition, A-779 did not compete significantly with Ang II for binding in adrenomedullary membranes, indicating that A-779 does not bind to AT2 receptor subtypes either. In contrast, A-779 abolished the peripheral and central effects of Ang-(1-7).13 14 In addition, in the present study, we were able to completely block the facilitatory effect of Ang-(1-7) on baroreflex modulation when A-779 was infused with Ang-(1-7) at a molar ratio of 4:1. Thus, the use of selective antagonists allowed us to extend our previous observation that central infusion of Ang-(1-7) facilitates the baroreceptor reflex control of HR and to suggest a functional role for endogenous Ang-(1-7) in the central regulation of the HR component of the baroreceptor reflex. The possibility that the central effect of A-779 on baroreflex modulation could be due to interference with other peptides is unlikely because we found that A-779 does not influence the biological activity of several peptides, including Ang III, substance P, vasopressin, and bradykinin, even at a molar ratio of 2500:1.13 The effect of A-779 is also unrelated to hemodynamic effects because we did not observe significant changes in MAP or HR during the 3.5 hours of ICV infusion. In addition, it is also unlikely that A-779 was acting as a partial agonist on the AT1 receptor, first because A-779 does not mimic any of the Ang II effects, even in high concentrations (micromolar),13 and second because A-779 has been shown not to interfere with any of the Ang II actions centrally6 13 14 or in the periphery.13
It is well established that Ang II exerts an inhibitory influence on baroreceptor reflex control of HR after either intravenous or ICV administration in several species.15 The effect shown in the present study, that DuP 753 enhances baroreflex sensitivity, has extended these observations and provided additional confirmation for a role of endogenous Ang II on the central regulation of the HR component of the baroreceptor reflex. Moreover, it suggests that the central inhibitory effect of Ang II in the baroreflex may be mediated by the AT1 receptor subtype. This observation is consistent with the results showing that the central pressor and dipsogenic responses produced by Ang II are mediated by the AT1 receptor subtype in normotensive rats9 and SHR.16
Interestingly, 3 hours of ICV infusion of DuP 753 did not significantly alter baseline levels of MAP and HR in SHR, although DuP 753 abolished the pressor effect and dipsogenic behavior of exogenous Ang II, as mentioned above. In support, DePasquale et al16 showed that ICV injection of DuP 753 (10 μg) also did not change baseline levels of MAP and HR. These results suggest that the antihypertensive effect of intravenous or oral administration of DuP 753 in SHR may be solely due to peripheral AT1 receptor blockade or the occupancy of central AT1 receptors localized in sites not accessible by ICV administration. In addition, it is important to note that the facilitation of the baroreceptor control of HR produced by DuP 753 in the present study cannot be attributed to changes in baseline levels of MAP or HR.
The specificity of DuP 753 has been questioned.17 18 19 Although DuP 753 was described as a specific AT1 receptor antagonist, recent studies have shown that this compound can bind to non–angiotensin-binding sites18 or may interfere with non–angiotensin-mediated responses.20 Recently, it has been shown that losartan (DuP 753) inhibited the cardiovascular responses evoked by l-glutamate microinjected into the rostral ventrolateral medulla in a dose-dependent manner.20 In addition, it was found that this compound can block the effects produced by Ang-(1-7) in some tissues, including the heart19 and kidney.17 21 Therefore, we cannot completely rule out the possibility that the central actions of DuP 753 on the baroreflex could be the result of a complex interaction of this compound with Ang II, Ang-(1-7), and possibly other receptors.
It is interesting to note that a statistically significant action of DuP 753 on the baroreflex as described in the present study was verified only at the third hour of ICV infusion of this compound. This observation raises the possibility that part of the central effect produced by DuP 753 could be due to leakage of this compound to the periphery. Accordingly, it was recently shown that intravenous administration of DuP 753 facilitated the baroreflex in renal hypertensive rats and this effect was more potent than that produced by the angiotensin-converting enzyme inhibitor captopril.22
Unlike Ang II, Ang-(1-7) is a weak vasoactive peptide in vivo2 8 23 24 25 26 and does not interfere with baroreflex modulation when injected into the periphery.8 Therefore, it is likely that the effects produced by A-779 are mediated by the interaction of this antagonist with sites in the central nervous system related to cardiovascular regulation. To date, no data are available concerning the characteristics and location of the Ang-(1-7) receptor or receptors in the brain or other tissues. However, several areas in the central nervous system were identified pharmacologically as potential sites for Ang-(1-7) actions.1 2 4 5 6 The nucleus tractus solitarii4 in the dorsomedial medulla and the rostral and caudal areas of the ventrolateral medulla5 6 are examples of these sites. In addition, Block et al27 showed the presence of Ang-(1-7) immunoreactivity in several nuclei of the hypothalamus and in the neurohypophysis. However, further studies are necessary for investigation of whether the selective actions of the different angiotensin peptides are exclusively due to different populations of receptors or are influenced by differential localization of distinct receptor subtypes in the central pathways involved in arterial pressure modulation.
The ICV infusion of the AT2 receptor antagonist CGP 42112A did not significantly alter the gain (slope) of the baroreceptor control of HR in normotensive or hypertensive rats. However, there was a tendency for a decrease in the baroreflex. This result indicates that the AT2 receptor subtype may not be importantly involved in central baroreflex modulation. The tendency for a decrease in the baroreflex produced by CGP 42112A may be unrelated to the AT2 receptor subtype. One possibility is that CGP 42112A would interact with the Ang-(1-7) receptor and the magnitude of the effect would be related to the dose of the compound used. Actually, AT2 receptor antagonists have been shown to block some of the Ang-(1-7) actions in the brain28 and periphery.19 Another possibility is that although CGP 42112A was described as a selective AT2 receptor antagonist, this compound may behave as a partial agonist on AT1 receptors, especially because of its peptide characteristics.9
In the present study, ICV infusion of CGP 42112A did not alter the cardiovascular effects produced by Ang II. The effects of AT2 receptor antagonists on central Ang II responses are very controversial.9 29 30 The AT2 receptor antagonist PD 123177 has been shown to inhibit the ICV effects evoked by Ang II.29 Conversely, other authors have not observed any effect of PD 123177 on the effect of ICV or subcutaneous Ang II injection.30 Our results are more in accordance with these investigators.
Anatomic and functional studies have provided evidence that brain Ang II may play an important role in the pathogenesis of hypertension in SHR.31 32 33 34 ICV administration of saralasin (a nonspecific Ang II receptor antagonist) or captopril markedly lowered blood pressure in adult SHR or attenuated the development of hypertension in young SHR.35 36 Moreover, it has been reported that lifetime oral captopril treatment37 or ICV [Sar1,Thr8]Ang II infusion34 increased baroreflex sensitivity in SHR. Our results showing that DuP 753 enhances the baroreceptor control of HR in SHR extend these observations and show that the AT1 receptor subtype is at least in part involved in the depressed baroreflex sensitivity observed in these rats. It was also possible to show that the effect on baroreflex sensitivity was independent of any antihypertensive effect because ICV infusion of DuP 753 did not alter baseline levels of MAP. This observation is similar to that of Berecek et al34 that showed an increase in baroreflex modulation without changes in MAP of SHR after infusion with [Sar1,Thr8]Ang II. Unexpectedly, ICV infusion of the selective Ang-(1-7) antagonist A-779 did not significantly alter the baroreceptor control of HR in SHR. This result is intriguing, especially when compared with the pronounced effect produced by A-779 in normotensive rats. Furthermore, the lack of A-779 antagonism in SHR suggests that the reduced baroreflex sensitivity of these rats could be related at least in part to an alteration in the metabolism and/or action of Ang-(1-7) at central sites involved in the control of blood pressure.
In summary, the present results show that central infusion of an AT1 receptor antagonist facilitated the sensitivity of the baroreceptor control of HR in normotensive rats and SHR, whereas central infusion of an Ang-(1-7) antagonist blunted the baroreflex sensitivity only in normotensive rats. These data suggest that central endogenous Ang II and Ang-(1-7) are differentially modulating the baroreflex, probably through distinct receptors or receptor subtypes. In addition, our data suggest that site-specific imbalances of angiotensin peptide formation and/or action may be responsible for the depressed baroreceptor reflex sensitivity in SHR.
Selected Abbreviations and Acronyms
|AT1, AT2||=||angiotensin type 1, type 2|
|bpm||=||beats per minute|
|MAP||=||mean arterial pressure|
|SHR||=||spontaneously hypertensive rat(s)|
This work was partially supported by Fundação de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG), Pró-reitoria de Pesquisa (PRPq-UFMG), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and the National Institutes of Health (grant to M.C.K.). D.R.O. was a recipient of a fellowship from Coordenadoria de Aperfeiçoamento de Pessoal (CAPES). We are thankful to Jose Roberto da Silva and Katia Marques for their skillful technical assistance. We also thank E.I. DuPont de Nemours & Co and CIBA-Geigy Ltd for kindly providing DuP 753 and CGP 42112A, respectively, and Dr Miriam Geraldini at Escola Paulista de Medicina (São Paulo, Brazil) for providing the SHR.
- Received January 5, 1996.
- Revision received February 9, 1996.
- Accepted February 9, 1996.
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