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Hypertension Unit, University of Ottawa Heart Institute, Ottawa, Ontario, Canada K1Y 4W7
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In chronic heart failure (CHF), sympathetic activity increases in parallel with the impairment of left ventricle (LV) function, and sympathetic hyperactivity has been postulated to contribute to the progression of heart failure. In the brain, compounds with ouabain-like activity ("ouabain," for brevity) and the renin-angiotensin system contribute to sympathetic hyperactivity in rats with CHF after myocardial infarction (MI). In the present studies, we assessed whether, in rats, chronic blockade of brain "ouabain" or the brain renin-angiotensin system inhibits the post-MI LV dysfunction. In rats, an MI was induced by acute coronary artery ligation. At either 0.5 or 4 wk post-MI, chronic treatment with Fab fragments for blocking brain "ouabain" or with losartan for blocking brain AT1 receptors was started and continued until 8 wk post-MI using osmotic minipumps connected to intracerebroventricular cannulas. At 8 wk post-MI, in conscious rats, LV pressures were measured at rest and in response to volume and pressure overload, followed by LV passive pressure-volume curves in vitro. At 8 wk post-MI, control MI rats exhibited clear increases in LV end-diastolic pressure (LVEDP) at rest and in response to pressure and volume overload. LV pressure-volume curves in vitro showed a marked shift to the right. Intravenous administration of the Fab fragments or losartan at rates used for central blockade did not affect these parameters. In contrast, chronic central blockade with either Fab fragments or losartan significantly lowered LVEDP at rest (only in 0.5- to 8-wk groups) and particularly in response to pressure or volume overload. LV dilation, as assessed from LV pressure-volume curves, was also significantly inhibited. These results indicate that chronic blockade of brain "ouabain" or brain AT1 receptors substantially inhibits development of LV dilation and dysfunction in rats post-MI.
heart; heart failure; left ventricle dilation; ouabain; renin-angiotensin system
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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IN BOTH ANIMALS AND HUMANS, the progressive remodeling
of the left ventricle (LV) after a myocardial infarction (MI) leads to
increases in LV end-diastolic and end-systolic volume and pressure and
decreases in ejection fraction and cardiac output and clinical chronic
heart failure (CHF), with the extent and time course of the changes
depending on the size of the MI (11, 18, 24). Stimuli for cardiac
remodeling after a MI include increases in diastolic wall stress and
(to a lesser extent) systolic wall stress (2). In addition, progressive
increases in the activity of the circulatory and/or cardiac tissue
renin-angiotensin system (RAS) and in sympathetic activity may further
increase wall stress and may cause direct adverse effects on the heart.
In CHF, parameters of sympathetic activity increase in parallel with
the impairment of cardiac performance (5, 14, 20), and sympathetic
hyperactivity has been postulated to contribute to the progression of
heart failure (15). Studies on the possible role of sympathetic
hyperactivity in disease progression in CHF have used tools such as
-blockers (7, 10), and the results are consistent with the
neurohormonal hypothesis (15).
Recent studies in the putative central mechanisms mediating sympathetic hyperactivity in CHF suggest that, in the brain, both compounds with ouabain-like structure (in this paper called "ouabain") and the RAS play a major role. In the brain, inhibition of the Na+-K+-ATPase enzyme by steroids closely related to ouabain causes sympathoexcitation (8). In rats with post-MI LV dysfunction, ouabain-like activity increases about twofold in the hypothalamus (12), and blockade of brain "ouabain" prevents/reverses sympathetic hyperactivity (12) and the impairment of baroreflex function (9). The brain RAS is also involved in the regulation of sympathetic activity and baroreflex function (19). Recent studies indicate that the brain RAS plays a pivotal role in the sympathetic hyperactivity associated with salt-sensitive hypertension (23) and heart failure. In rats with post-MI LV dysfunction, blockade of the brain RAS reverses sympathetic hyperactivity (4, 25) and impairment of arterial baroreflex function (4, 25).
In the present studies, we assessed whether chronic blockade of brain "ouabain" or the brain RAS can inhibit the progressive remodeling of the LV and the LV dysfunction in rats post-MI. Central infusion of antibody Fab fragments (Digibind) that bind in vivo and in vitro ouabain and related steroids, such as brain "ouabain," with high affinity (1, 12) was employed for chronic blockade of brain "ouabain." For blockade of the brain RAS, central infusions of the AT1 receptor blocker losartan were employed. The results indicate that central blockade by the Fab fragments or losartan indeed can significantly blunt the LV dilation and decrease in cardiac function in rats post-MI.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Male Wistar rats (Charles River Breeding Laboratories, Montreal, Canada), weighing 250-300 g, were housed on a 12:12-h light-dark cycle and were given regular rat chow and tap water. All procedures were carried out according to the guidelines of the University of Ottawa Animal Care Committee for the use and care of laboratory animals. After a 5-day acclimatization period, coronary artery ligation was performed as described by Pfeffer et al. (17). Briefly, after the animals were anesthetized with 1.0% halothane in oxygen and the thorax was opened at the 4th or 5th left intercostal space, the left coronary artery was ligated at 2-3 mm from its origin with a 6-0 silk suture attached to an atraumatic needle (K801H; Ethicon). Buprenorphine (0.03 mg/ml, 0.1 ml/rat, twice daily × 3 days) was used to relieve pain. Sham control rats underwent the same surgical procedure without ligation.
Intracerebroventricular Cannulation and Placement of Minipumps
At 0.5 or 4 wk post-MI, under pentobarbital sodium anesthesia (65 mg/kg ip), an L-shaped, 23-gauge stainless steel cannula was placed in the left lateral ventricle (0.5 mm posterior and 1.4 mm lateral to the bregma). The shorter arm of the L-shaped cannula was inserted in the ventricle (3.8 mm from the dura), and the longer arm was connected with a polyethylene (PE; PE-50 fused to PE-60) catheter to an osmotic minipump (model 2002, 12 µl/day; Alza, Palo Alto, CA). The intracerebroventricular cannula was fixed on the skull with dental cement. The minipumps were filled with antibody Fab fragments (Digibind; Glaxo Wellcome, Toronto, Canada),
-globulins as control
(200 µg/day for both; Sigma Chemical, St. Louis, MO), or the
AT1 receptor blocker losartan (1 mg · kg
1 · day1).
The normalization of parameters of sympathetic hyperactivity in rats
with post-MI CHF by infusion of the Fab fragments or losartan at these
rates has been previously documented (9, 12, 25). The compounds were
all dissolved in artificial cerebrospinal fluid. In two groups of rats
after coronary ligation, instead of placing an L-shaped cannula
intracerebroventricularly, a PE-60 catheter was inserted in the left
jugular vein and was connected to a minipump filled with the same
amount of Fab fragments, or losartan as used for
intracerebroventricular infusion. All of the pumps were implanted subcutaneously on the back of the rats. Penicillin G (30,000 IU, Derapen; Ayerst Laboratories, Montreal, Canada) was given
intramuscularly after the surgery. Every 2 wk under halothane
anesthesia the pumps were replaced with new pumps filled with the same
compounds. At the end of the experiments, methylene blue was injected
intracerebroventricularly to confirm the accuracy of the
intracerebroventricular cannulation.
Protocol for Chronic Treatments
Treatment, 0.5-8 wk post-MI. At 0.5 wk after cardiac surgery, in sham rats, treatment with intracerebroventricular-globulins was started, and rats post-MI
were randomly allocated to treatment with intracerebroventricular
-globulins (MI-glob), intracerebroventricular Fab fragments,
intracerebroventricular losartan, or intravenous losartan. All
assessments were performed at the end of 8 wk of infusion (i.e., from
0.5-8 wk post-MI).
Treatment, 4-8 wk post-MI. At 4 wk after cardiac surgery, in sham rats, treatment with
intracerebroventricular -globulins was started, and rats post-MI
were randomly allocated to treatment with intracerebroventricular
-globulins (MI-glob), intracerebroventricular Fab fragments,
intravenous Fab fragments, or intracerebroventricular losartan. The
assessments were done at the end of 4 wk of infusion (i.e., from
4-8 wk post-MI).
Survival rates for MI rats were in the 81-90% range in the 0.5-8 wk post-MI studies and in the 80-94% range in the 4-8 wk post-MI experiments. Both the time course of mortality and death rates did not differ significantly between treatments.
Assessment of Central Hemodynamics
Under halothane anesthesia, a PE-50 catheter was inserted in the right jugular vein, and another catheter was inserted in the LV through the right carotid artery. Four hours after the recovery from the anesthesia and surgery, the rat was placed in a cage in which it could move back and forth. The catheters were connected to a transducer connected to a Grass 7E polygraph as well as a Grass 7E44 tachograph for continuous recording of LV end-diastolic pressure (LVEDP), peak systolic pressure (LVPSP), and heart rate.Measurement of cardiac filling
pressures. PRESSURE OVERLOAD. After we
allowed a 30-min rest to obtain resting hemodynamic values,
phenylephrine was infused at 4, 8, 12, 16, and 24 µg · kg1 · min1
with each dose for 1 min.
Determination of Passive Pressure-Volume Relationship
After the assessment of the effects of pressure and volume overload, the rat was killed with 2 M KCl, and the heart was excised. To avoid fluid accumulation and a variable compressive force on the interventricular septum, the right ventricle (RV) was incised. A double-lumen catheter was inserted in the LV with one end connected to the Harvard infusion pump and the other end to a pressure transducer. The LV was isolated by ligation with silk round the atrioventricular groove and was compressed manually to expel blood and create a negative pressure of
5 mmHg, which was taken as zero volume. Saline
(0.9%) was infused in the LV at a constant rate of 0.68 ml/min,
whereas LV pressure was recorded continuously over a pressure range of
5 to 30 mmHg. Two to three reproducible pressure-volume curves
were obtained within 10 min of cardiac arrest (before the onset of
rigor mortis). From the pressure-volume curve, LV volumes were
determined at pressures of 0, 2.5, 5, 10, 15, 20, and 30 mmHg and at
the pressure corresponding to the in vivo LVEDP (6).
Assessment of Infarct Size
After the measurement of the pressure-volume relationship, the RV and the LV were separated and weighed. Infarct size was measured as previously described (12). In brief, four to five incisions were made in the LV so that the LV tissue could be pressed flat. The circumferences of the entire flat LV and the visualized infarcted area, as judged from both epicardial and endocardial sides, were outlined on a clear plastic sheet. The difference in weight between the two marked areas on the sheet was used to determine the infarct size. To only include animals with moderate to severe LV dysfunction, data from rats with infarct size <30% were excluded from the analysis. Specifically, for this reason in the 0.5- to 8-wk experiment, two rats with intracerebroventricular Fab were excluded, and in the 4-8 wk experiment, three rats with intravenous Fab and three with intracerebroventricular Fab were excluded.Statistical Analysis
All values are expressed as means ± SE. Using SAS software (SAS Institute, Cary, NC), one-way ANOVA was performed to determine the effects of treatments and MI on the various parameters. When F ratios were significant, a Duncan's multirange test followed as a post hoc test for locating the differences between means of the groups. Least-squares linear regression was performed to compare the changes in LVEDP in relation to LVPSP induced by phenylephrine infusion and the pressure-volume relationship in vitro. For the latter, exponential transformation of LV pressures was performed to make the data suitable for linear regression analysis (6). Statistical significance was defined as P < 0.05.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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General Characteristics
Infarct size was ~40% of the LV and similar for all MI groups. In MI rats, resting LVPSP was significantly decreased, and resting LVEDP increased (Table 1). LVPSP was not affected by any of the treatments. The increase in LVEDP was significantly attenuated by treatment with intracerebroventricular Fab fragments from 0.5 to 8 wk post-MI and somewhat less [not significant (NS)] by intracerebroventricular losartan. Treatment from 4 to 8 wk post-MI had only minor (NS) effects on resting LVEDP. Heart rate was similar in all groups and was not affected by the treatments.
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RV weight was significantly increased in the control (MI-glob) group compared with the sham groups, and these increases were attenuated by both intracerebroventricular losartan and intracerebroventricular Fab fragments.
Hemodynamic Responses to Pressure Overload
Phenylephrine increased LVPSP in a dose-related manner (Fig. 1). Compared with the sham groups, in MI-glob groups, this increase was significantly attenuated. This attenuation was improved by both intracerebroventricular losartan and intracerebroventricular Fab fragments from 0.5 to 8 wk post-MI or from 4 to 8 wk post-MI. Increases of LVEDP by pressure overload were higher in the two control MI-glob groups versus sham groups relative to the increase in LVPSP (P < 0.01). The relationship of increases in LVEDP relative to LVPSP was improved significantly by treatment of MI rats with both intracerebroventricular losartan and intracerebroventricular Fab fragments from 0.5 to 8 wk post-MI or from 4 to 8 wk post-MI (Fig. 1). In contrast, treatment of MI rats with intravenous losartan or intravenous Fab fragments at the same rates did not improve this relationship. The pressor effects of phenylephrine were associated with significant rate-related decreases in heart rate, as expected (9), significantly more in the sham versus MI groups (data not shown).
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Hemodynamic Responses to Volume Overload
LVEDP was increased by volume overload in a dose-related manner (Fig. 2). Relative to sham rats, a further increase (P < 0.05) was observed in the two control MI-glob groups. In both studies, this increase was normalized by treatment of MI rats with intracerebroventricular losartan or intracerebroventricular Fab fragments. However, intravenous losartan or intravenous Fab fragments did not affect this response (Fig. 2).
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Volume overload caused minor increases in LVPSP in sham rats but
decreases in the two control MI-glob groups (Table 2).
In the MI groups treated with intracerebroventricular losartan or intracerebroventricular Fab fragments, changes of LVPSP induced by
volume overload were not different compared with the sham group. In
contrast, treatment of MI rats with intravenous losartan or intravenous
Fab fragments at the same low intracerebroventricular rates did not
attenuate MI-induced changes in LVPSP.
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In Vitro Pressure-Volume Relationship
At each level of LV pressure, LV volumes measured in the potassium-arrested heart were significantly increased in all MI groups compared with the sham group (Fig. 3). In both studies, in the pressure range 5-30 mmHg, LV volumes were significantly decreased in the MI groups treated with intracerebroventricular losartan or intracerebroventricular Fab fragments compared with control MI-glob groups. Treatment of MI rats with intravenous losartan or intravenous Fab fragments at the same rates caused only minor, nonsignificant changes in LV volumes. Left ventricular end-diastolic volume index (LVEDVI) in vitro at the resting LVEDP in vivo was significantly higher in all MI groups (Table 1). This increase in LVEDVI was significantly attenuated by treatment of MI rats with intracerebroventricular Fab fragments or intracerebroventricular losartan in both studies.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The present study provides a major new finding that chronic blockade of either brain "ouabain" or the brain RAS inhibits the development of LV dilation and dysfunction in rats post-MI.
Post-MI LV Remodeling and Dysfunction
LV remodeling defined as "progressive loss of ventricular function along with LV cavitary dilation" (11) post-MI involves a cycle of events extending from the MI to late heart failure (Fig. 4 in Ref. 11). Consistent with many previous studies, in the present experiments, infarct sizes in the 40% range resulted by 8 wk post-MI in a marked shift to the right of LV pressure-volume curves in vitro. RV weight increased, likely related to progressive LV failure resulting in increases in RV systolic and diastolic wall stress. As assessed in conscious, unrestrained animals, LV function decreased post-MI, as reflected by a significantly higher resting LVEDP, larger increases in LVEDP in response to volume overload, and larger increases in LVEDP relative to increases in LVPSP caused by phenylephrine. Initiation of blockade of either brain "ouabain" or brain AT1 receptors early post-MI significantly inhibited the development of LV dysfunction. Thus intracerebroventricular Fab fragments or losartan inhibited ~50% of the post-MI LV dilation, as assessed from the pressure-volume curves. Increases in RV weight tended to be inhibited by either intracerebroventricular treatment. Moreover, in vivo increases in resting LVEDP were blunted, and the enhanced responses of LVEDP to volume or pressure overload were normalized.The first phase of LV remodeling, representing up to 50% of the shift of the pressure-volume curves in vitro, occurs within 4 wk after MI in rats (18). Initiation of blockade of brain "ouabain" or the brain RAS at this stage still caused positive effects on LV size and function. Post-MI LV dilation as assessed by the pressure-volume curves and post-MI increases in RV weight were significantly blunted. In addition, whereas effects on resting LVEDP were only minor, the enhanced responses of LVEDP to pressure and volume overload were still normalized by either intracerebroventricular blockade. This may indicate that central mechanisms particularly contribute to this second component in the LV dilation and dysfunction after MI. Further experiments evaluating effects of treatment during specific phases post-MI are needed to address this aspect.
Peripheral administration of losartan or Fab fragments at the same rate as used for central infusion did not improve any of the parameters of post-MI LV dysfunction. It is obvious from the findings with intracerebroventricular versus intravenous infusion that the pattern of changes caused by the central infusion of losartan or Fab fragments cannot be explained by leakage of centrally administered agents into the peripheral circulation. Whether higher central infusion rates of losartan or Fab fragments would more completely block the brain RAS and brain "ouabain" and induce additional changes in central hemodynamics and LV remodeling cannot be excluded. On the other hand, it is likely that higher intravenous infusion rates of losartan and perhaps the Fab fragments will cause improvements in central hemodynamics and LV remodeling. However, assessment of peripheral actions was not the goal of the present studies.
Sympathetic Activity and Post-MI LV Dysfunction
As reviewed by Capasso et al. (2), Packer (15), and Parmley (16), stimuli for post-MI LV remodeling include increases in diastolic and systolic wall stress and progressive increases in sympathetic activity, renin activity, and other neurohormones. Activation of the sympathetic nervous system, either cardiac specific or in addition to other organs such as the kidneys, can lead directly or indirectly to a negative outcome via many mechanisms (for reviews, see Refs. 3, 15, 16). Sympathetic hyperactivity may contribute to the progression of adverse LV remodeling by either direct cardiac effects or through hemodynamic and renal effects increasing diastolic and systolic wall stress. Clinical trials using-blockers (7, 10) provide evidence for an
adverse role of sympathetic activity in CHF. However, such studies do
not assess whether -receptor-mediated sympathetic activity per se
versus sympathetic hyperactivity plays a role. Also, these studies do
not assess 
-receptor-mediated events.
The present studies indicate that central mechanisms contribute to a substantial degree to the development of post-MI LV dilation and dysfunction. Blockade of brain "ouabain" or the brain RAS can both prevent and reverse sympathetic hyperactivity post-MI, as assessed by measurements of renal sympathetic nerve activity or plasma catecholamines (9, 12, 25). It is therefore tempting to conclude that brain "ouabain" and the brain RAS contribute to post-MI LV remodeling and LV dysfunction by being part of the central pathways leading to sympathetic hyperactivity, specifically renal and generalized sympathetic drive. Considering the extensive evidence for regional control of sympathetic activity in CHF (e.g., Ref. 20), one cannot assume that central control of cardiac sympathetic activity follows a similar pattern. Further studies are needed to assess the effects of chronic blockade of brain "ouabain" or the brain RAS on cardiac sympathetic activity relative to the development of post-MI LV dysfunction. From a mechanisms point of view, one has to consider that the central blockade of brain "ouabain" or AT1 receptors may affect directly or indirectly other mechanisms centrally, such as nitric oxide (13), or peripherally, such as vasopressin release from the pituitary or renin release from the kidneys, which may affect disease progression. The present study therefore demonstrates that brain mechanisms play an important role in the disease progression after MI but does not establish the actual pathways or mechanisms involved.
Limitations of the Present Study
To assess their effects, Fab fragments or losartan were chronically infused in the left lateral cerebral ventricle. The results with the Fab fragments point to a major role for compound(s) with ouabain-like structure in the central control of LV remodeling and LV dysfunction post-MI, and the results with losartan point to a major role for AT1 receptor stimulation. These findings do not address the actual stimuli or the central pathways involved. The use of losartan does not provide insights regarding the components of the brain RAS activated post-MI. Similarly, considering their specificity (1, 21, 22), the use of the Fab fragments establishes that a compound(s) with ouabain-like structure plays a role but does not provide insights into its structure or regulation.In conclusion, the present results demonstrate that, in rats post-MI, chronic blockade of either brain "ouabain" or brain AT1 receptors has a substantial positive impact on the development of LV dysfunction after MI. Based on these findings, one may speculate that post-MI treatment with blockers of the RAS causing blockade of both the peripheral and brain RAS will be more beneficial for outcome than treatment with blockers of RAS "only" blocking the peripheral RAS.
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ACKNOWLEDGEMENTS |
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Digibind and losartan were generous gifts from Glaxo Wellcome, Toronto, Canada, and Merck Research Laboratories, Rahway, NJ.
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FOOTNOTES |
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This work was supported by operating grant MT-13182 from the Medical Research Council of Canada. F. H. H. Leenen is a career investigator of the Heart and Stroke Foundation of Ontario, Canada.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: F. H. H. Leenen, Hypertension Unit, H360, Univ. of Ottawa Heart Institute, 40 Ruskin St., Ottawa, Ontario, Canada K1Y 4W7 (E-mail:fleenen{at}ottawaheart.ca).
Received 3 February 1999; accepted in final form 10 June 1999.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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S. A. Dean, J. Tan, E. R. O'Brien, and F. H. H. Leenen 17{beta}-Estradiol downregulates tissue angiotensin-converting enzyme and ANG II type 1 receptor in female rats Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2005; 288(3): R759 - R766. [Abstract] [Full Text] [PDF]
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J. Francis, S.-G. Wei, R. M. Weiss, and R. B. Felder Brain angiotensin-converting enzyme activity and autonomic regulation in heart failure Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H2138 - H2146. [Abstract] [Full Text] [PDF]
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J. Tan, H. Wang, and F. H. H. Leenen Increases in brain and cardiac AT1 receptor and ACE densities after myocardial infarct in rats Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1665 - H1671. [Abstract] [Full Text] [PDF]
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R. B. Felder, J. Francis, Z.-H. Zhang, S.-G. Wei, R. M. Weiss, and A. K. Johnson Heart failure and the brain: new perspectives Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2003; 284(2): R259 - R276. [Abstract] [Full Text] [PDF]
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 R. I. Dmitrieva and P. A. Doris Cardiotonic Steroids: Potential Endogenous Sodium Pump Ligands with Diverse Function Experimental Biology and Medicine, September 1, 2002; 227(8): 561 - 569. [Abstract] [Full Text] [PDF]
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H. Shigematsu, Y. Hirooka, K. Eshima, M. Shihara, T. Tagawa, and A. Takeshita Endogenous angiotensin II in the NTS contributes to sympathetic activation in rats with aortocaval shunt Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2001; 280(6): R1665 - R1673. [Abstract] [Full Text] [PDF]
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, Sham glob; 
, MI glob; 
, MI icv
Fab; 
, MI icv Los; 
, MI iv Los; 
, MI iv Fab. Values represent
mean ± SE changes in LVEDP relative to change in LVPSP at a given
rate of phenylephrine (see Table 
P < 0.05, MI icv Fab or
icv Los vs. MI glob.
