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1 Department of Veterans Affairs Medical Center and Departments of 2 Internal Medicine and 3 Psychology, University of Iowa, Iowa City, Iowa 52242
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Recent studies suggest that the forebrain contributes to the circulatory derangements leading to heart failure after myocardial injury. We tested that hypothesis by examining the effect of myocardial infarction (MI) or sham MI (MI-s) on neurohumoral regulation in rats with prior anteroventral (AV) third ventricle lesion (AV3V-x) or sham lesion (AV3V-s). AV3V-s/MI rats had higher sodium intake, lower urine volume, and lower urinary sodium excretion than AV3V-s/MI-s rats. AV3V-x/MI rats had lower sodium intake and higher urine volume than AV3V-s/MI or AV3V-s/MI-s rats and urinary sodium excretion comparable to AV3V-s/MI-s rats. AV3V-x had no effect on baseline plasma renin activity (PRA). One week after MI, PRA had increased in AV3V-s but decreased in AV3V-x rats. AV3V-x reduced renal sympathetic nerve activity in MI and MI-s rats. AV3V-x improved baroreflex function in MI rats but diminished it in MI-s rats. Survival beyond 2 wk was lower in the AV3V-x/MI rats than in all other groups. These results confirm a critical role for the forebrain in the neurohumoral adjustments to MI.
anteroventral third ventricle; baroreflex; sympathetic drive; volume regulation; plasma renin activity
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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CONGESTIVE HEART FAILURE (HF) is characterized by fluid accumulation, increased sympathetic drive, and altered baroreflex regulation (31). These homeostatic abnormalities can be mimicked in normal rats by activating forebrain angiotensin (ANG) type 1 receptors. Blood-borne ANG II, acting via ANG type 1 receptors in the circumventricular organs (CVOs) surrounding the anterior third ventricle, stimulates thirst and sodium appetite, initiates the release of the antidiuretic and vasoconstrictor peptide arginine vasopressin, contributes to sympathetic activation (7, 17, 24), and modulates baroreflex regulation (2). These influences of blood-borne ANG II can be blocked by a lesion in the anteroventral (AV) third ventricle (AV3V) region (7), which interrupts the descending pathways from forebrain CVOs and from median preoptic nucleus to critical hypothalamic effector neurons.
In the rat model of ischemia-induced HF, the activity within one of these effector sites, the paraventricular nucleus of the hypothalamus, is increased, suggesting that this region of the brain is either contributing to or reacting to the development of the HF syndrome. Paraventricular nucleus neurons respond to ascending inputs from brain stem regions that process afferent signals from chemosensitive and mechanosensitive receptors in the cardiovascular system and to descending inputs from CVO neurons stimulated by circulating neuropeptides like ANG II. In HF, both the ascending and the descending systems impinging on the forebrain are altered.
The present study examined the effect of a lesion in the AV3V region on neurohumoral mechanisms leading to HF after myocardial infarction (MI) in rats. The hypothesis was that activation of forebrain regions regulating fluid balance and sympathetic drive contributes to the progression of heart failure after MI. In normal rats, the AV3V lesion interrupts the effects of blood-borne ANG II to induce sodium appetite, thirst, and sympathetically mediated increases in arterial pressure (7), and in experimental models it prevents the development of hypertension (6).
The results demonstrate that an AV3V lesion has both beneficial and detrimental effects after acute MI. It prevents the abnormalities of volume and sympathetic regulation early after MI, but eventuates in reduced survival as early as 3 wk after MI. Instead of blocking the effects of an overly active renin-angiotensin-aldosterone system (RAAS), it prevents activation of RAAS post-MI. These results call attention to the importance of forebrain mechanisms in mediating the neurohumoral changes that lead to HF after MI. A more precise delineation of the specific mechanisms involved will require further study.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals
Adult male Sprague-Dawley rats (3-4 mo old), weighing 300-325 g, were obtained from Harlan Sprague Dawley (Indianapolis, IN). They were housed in temperature-controlled (23 ± 2°C) and light-controlled (lights on between 0500 and 1700 h) animal quarters and were provided with rat chow ad libitum. The experimental procedures were approved by the University of Iowa Institutional Animal Care and Use Committee.Protocols
Rats underwent AV3V lesion (AV3V-x) or sham AV3V lesion (AV3V-s) and 6 wk later underwent coronary artery ligation (CL) to induce MI or sham CL (MI-s). There were two experimental groups. One group was kept in metabolic cages for 2 wk before and for up to 4 wk after MI or MI-s, depending on survival. Consumption of water and an alternative 1.8% sodium chloride solution were monitored and urine samples were collected for measurement of urine sodium and volume. Samples of venous blood were obtained for measurement of plasma renin activity (PRA). Survival data were also gathered for this group. The other group was kept in standard rat cages. Two or three weeks after MI or MI-s, these animals were reanesthetized briefly to implant renal nerve recording electrodes. Four hours after recovery from anesthesia, baseline recordings of sympathetic nerve activity and arterial pressure were obtained and baroreflex testing was performed. These animals then underwent terminal anesthesia for measurements of left ventricular (LV) end-diastolic pressure.Surgical Preparations
All surgical procedures were performed using sterile techniques, and animals were treated for postoperative pain with subcutaneous injection of buprenorphine (0.03 mg/kg, Q 12 h ×2, then as needed).AV3V lesioning. AV3V lesions were performed using methods previously described (3, 4, 8). Rats were anesthetized with an Equithesin-like anesthetic cocktail (0.97 g of pentobarbital sodium and 4.25 g of chloral hydrate per 100 ml distilled water; 0.33 ml/100 g). The animals were secured in a stereotaxic apparatus (Kopf Instruments; Tujunga, CA) with the skull leveled between the bregma and lambda. A monopolar electrode made of 24-gauge nichrome wire (Driver-Harris; Harrison, NJ), insulated except at the tip, was placed in the AV3V region using stereotaxic coordinates (midline; 0.3 mm caudal to bregma; 7.5 mm ventral to dura). Anodal current (2-3 mA for 25-30 s) was passed between the monopolar electrode in the AV3V region and a reference electrode placed in the rectum. In AV3V-s, the brain electrode was placed 1.0 mm above the target coordinates and no current was passed.
AV3V-x were considered successful if the rats were adipsic for the first 24 to 48 h. The AV3V-x animals were given 10% sucrose solution to prevent dehydration, and the concentration of sucrose was gradually tapered over a period of 2 wk until they began drinking regular water. At the end of the study, the brains were examined to verify the location of lesions.Jugular catheterization. After the animals were placed under ketamine and xylazine anesthesia (90 and 10 mg/kg ip, respectively), a midline cervical incision was made and the jugular vein was isolated by blunt dissection. A Silastic catheter (0.025-in. ID and 0.047-in. OD) (Dow Corning; Midland, MI) was inserted into the vein and held in position by sutures. The free end of the catheter was externalized to the base of the skull. The catheter was flushed every other day for the first week and then every day with a mixture of polyvinyl pyrrolidine, bacteriostatic saline, and heparin sodium (100 U/ml), and was sealed with a piece of blunt steel tubing to prevent clogging.
Induction of MI. Six weeks after AV3V surgery, MI was induced by coronary artery ligation. Rats were anesthestized with ketamine and xylazine (90 and 10 mg/kg ip, respectively), endotracheally intubated, and mechanically ventilated (room air, tidal volume 2.5 ml, 50-55 breaths/min). Under sterile conditions, a left thoracotomy was performed to expose the heart. The pericardium was opened and the heart was exteriorized. The left anterior descending coronary artery was ligated between the pulmonary outflow tract and the left atrium with a 6-0 silk suture that passed through the superficial layers of myocardium. The heart was returned to the chest cavity, the lungs were reinflated, and the chest incision was closed. MI-s rats were prepared in the same manner but did not undergo coronary artery ligation. After completion of the surgical procedures, rats were removed from the ventilator and the endotracheal tube was removed. Postsurgical animals were given an intramuscular injection of benzathine penicillin (30,000 units) and four intramuscular injections of lidocaine (2 mg, Q 2 h).
Successful creation of MI was confirmed by echocardiography performed within 24 h after operation on MI and MI-s rats and by visual inspection of the heart at the conclusion of the study.Implantation of sympathetic nerve recording electrodes. While under pentobarbital anesthesia (50 mg/kg ip), the left femoral artery and vein were cannulated, and the catheters were tunneled to the back of the neck. The left kidney was exposed via a flank incision. One of the nerves to the left kidney was dissected free from surrounding tissue and placed on bipolar silver wire recording electrodes. When an optimal signal-to-noise ratio was achieved, the electrode and the renal nerve were covered with polyvinylsiloxane (President light, Coltene), and the electrodes were sutured to back muscle and then tunneled to the back of neck.
Data Acquisition
Echocardiographic assessment of LV function. Echocardiographic assessment was performed as previously described (12, 13). Echocardiography was performed using an Acuson (Mountain View, CA) Sequoia clinical imager fitted with an 8-MHz sector-array probe, which generates two-dimensional images at a rate of ~100/s. Animals were sedated with ketamine (25 mg/kg ip) to facilitate positioning for echocardiographic study. The anterior chest was shaved and prewarmed acoustic coupling gel was applied. The animal was positioned in the left lateral recumbent position to optimize the windows for echocardiography. The probe was applied gently to the chest. Short-axis images were acquired parallel to the mitral valve plane to obtain the largest cross-sectional image of the left ventricle, which does not contain the mitral valve. Long-axis views were obtained perpendicular to the mitral valve plane and were deemed optimal when the diastolic apex-to-base length was longest and when both mitral and aortic valves were visible. Pulse-wave Doppler tracings were obtained with gates placed so as to interrogate mitral inflow. Images were written to a magnetooptical disk for subsequent off-line analysis.
Analysis of the stored images was performed offline using proprietary software, which was developed specifically for this purpose by the vendor (Acuson). Heart rate (HR) was determined from the Doppler tracings. LV end-diastolic volume (LVEDV), LV end-systolic volume, LV ejection fraction (LVEF), stroke volume, and LV mass (M) were computed using the area length method, which has been validated in rodents (15) and humans (27). The portion of the LV that displayed akinesis was planimetered electronically and was expressed as a percentage of the total LV silhouette to estimate the size of the ischemic zone (%). Only animals with large infarctions (%ischemic zone
35%; range 36-66%) were used in the study.
Metabolic cage assessment of fluid balance. Ingestion of food, water, and 1.8% NaCl, body weight, urine volume, and urinary sodium content were measured over two consecutive 24-h periods each week, and an average daily value for each variable was reported for that time point. Urine sodium was measured using a sodium and potassium analyzer (NOVA Biomedical; Waltham, MA).
Peptide measurements.
A blood sample was collected at baseline 2 days before CL or sham CL
and then at day 7 and day 14 for the measurement
of PRA. Blood samples were centrifuged at 4°C, and the plasma samples were separated and stored at 
70°C until assayed using
radioimmunoassay. After each collection, blood cells were reconstituted
with the same volume of bacteriostatic heparin in 0.9% saline and
reinfused. ANG I was measured and expressed as PRA with the use of an
ANG I radioimmunoassay kit (NEN Life Science; Boston, MA).
Renal sympathetic nerve recording and baroreflex testing. Sympathetic nerve recordings were made in the conscious, freely mobile state 4 h after recovery from anesthesia to implant bipolar electrodes on the renal nerve. The externalized recording electrodes were connected to a Grass P511 AC amplifier to record renal sympathetic nerve activity (RSNA). RSNA was passed to a Paynter filter (20-ms time constant; Bak Electronics; Germantown, MD) to rectify and integrate the raw signal. The externalized femoral artery catheter was connected to a strain gauge transducer to record mean arterial pressure (MAP). HR was derived by computer analysis of the AP pulse frequency. The MAP and rectified integrated RSNA were passed to a CED 1401 Laboratory Interface (Cambridge Electronic Design; Cambridge, UK) linked to a personal computer. The raw RSNA signal and arterial pressures were also recorded on VCR tape with the use of a recording adapter (pulse code modulation, Vetter; Rebersburg, PA) for analysis off-line.
After 20 min of stabilization, baseline MAP, HR, and RSNA were recorded for 15 min. A single value for each variable was obtained by averaging the values from five sequential 2-min recording intervals. The integrated RSNA signal was further processed over a 2-min interval to determine burst frequency (reported as bursts per second), using computer identification of the nadirs of the bursts within the signal, and to determine the magnitude of RSNA bursts per cardiac cycle (reported as mV · s), using the peak of the systolic pressure pulse as the trigger for a waveform average. The latter analysis was performed to assess the possibility that differences in HR might account for differences in RSNA among the experimental groups. Baroreflex testing was performed using bolus intravenous injections of phenylephrine (2-10 µg/kg) and sodium nitroprusside (5-20 µg/kg). MAP and RSNA returned to baseline between interventions. Data from baroreflex testing were analyzed in 1-s time bins to generate baroreflex curves comparing responses to phenylephrine and sodium nitroprusside with steady-state control values over the prior 20 s. A nonlinear regression program (SigmaPlot version 4.01, Jandel Scientific; San Rafael, CA) was used to analyze the baroreflex curve using the equation y = y0 + a/{1 + exp[(x x0)/b]}, where x is the
MAP; y is the change in (
) HR or RSNA; a is
the range of HR or RSNA; b is the slope coefficient;
x0 is MAP at the midpoint range of RSNA or
HR; and y0 is the minimum of RSNA or
HR. In each rat, the raw data for MAP, HR, and RSNA were fit
to this logistic function to generate parameters a,
b, x0, and y0.
The maximum gain of the baroreflex curve is defined as
a/4b.
Measurement of LV end-diastolic pressure. After completion of the sympathetic recording, the animals were anesthetized with pentobarbital sodium (50 mg/kg ip), the right carotid artery was exposed, and a polyethylene-50 cannula attached to a pressure transducer was advanced through the carotid artery across the aortic valve into the LV chamber. Pressure was recorded continuously while the cannula was positioned at a site within the left ventricle at which LV pressure could be accurately recorded (i.e., the onset of the rapid rise in LV pressure after atrial contraction could be observed) and LV systolic pressure was not higher than aortic pressure on entering the LV (i.e., there was no evidence of ventricular outflow obstruction by the cannula). LV pressure was then recorded for an interval of 2 min. A single LV end-diastolic pressure value was determined by applying a horizontal cursor across the visually estimated end-diastolic pressure of five sequential LV pressure waveforms.
Statistical Analysis
Changes in salt intake, water intake, urine volume, urinary sodium, and PRA between the four groups were analyzed with the use of a two-way repeated-measures analysis of variance (ANOVA), followed by a post hoc Fisher's least-significant-difference test. Survival data were analyzed using a
2-test of significance. A
nonlinear regression program (SigmaPlot) was used to analyze the
components of the individual sigmoid curve fits of the baroreflex data,
and these values from the individual animals in each group were
averaged to construct representative baroreflex curves relating HR and
RSNA changes to arterial pressure. Baseline values of RSNA, MAP, and
HR, and the maximal gain and range values obtained from the baroreflex
curve fits were analyzed using a one-way ANOVA, followed by a
Student's t-test, with differences considered significant
at P < 0.05. Values are expressed as means ± SE.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Echocardiographic Assessment of HF
Baseline echocardiographic study demonstrated that the AV3V-x/MI rats (n = 14) and AV3V-s/MI rats (n = 14) had a comparable degree of LV injury (ischemic zone as % of LV wall: 49.6 ± 2.6 vs. 47.5 ± 2.5, AV3V-x vs. AV3V-s) [P = not significant (NS)], and comparable LVEF (0.37 ± 0.03 vs. 0.41 ± 0.05; P = NS), LVEDV (697 ± 34 vs. 699 ± 32 µl; P = NS), and LVEDV-to-mass ratios (LVEDV/M: 0.75 ± 0.1 vs. 0.71 ± 0.08; P = NS). The sham MI rats, AV3V-x/MI-s (n = 12) and AV3V-s/MI-s (n = 13), had no ischemic injury. These two groups also had similar values for LVEF (0.78 ± 0.03 vs. 0.80 ± 0.04, AV3V-x vs. AV3V-s; P = NS), LVEDV (341 ± 23 vs. 390 ± 26 µl; P = NS), and LVEDV/M ratio (0.45 ± 0.03 vs. 0.44 ± 0.05; P = NS). The values for LVEF, LVEDV, and LVEDV/M ratio for the MI groups (AV3V-s and AV3V-x) were all significantly (P < 0.05) different from those of the MI-s groups (AV3V-s and AV3V-x). However, HR during echocardiography under sedation was not different across groups.Metabolic Cage Study
Volume regulation.
As shown in Fig. 1A, an AV3V
lesion substantially reduced the increase in sodium appetite associated
with MI. Within 1 wk after MI, rats with a sham AV3V lesion (AV3V-s/MI,
n = 8) demonstrated a dramatic increase in consumption
of 1.8% saline compared with those animals with no AV3V lesion and no
MI (AV3V-s/MI-s, n = 9, the sham/sham group). In
striking contrast, ingestion of the saline solution actually fell below
that of the sham/sham group in the AV3V-x/MI rats (n = 9). The AV3V lesion had no effect on saline ingestion in MI-s rats
(n = 7).
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Plasma renin activity.
At baseline after recovery from AV3V-x or AV3V-s surgery, PRA was
comparable in all four study groups (Fig.
3). After MI-s, PRA did not change from
baseline. PRA increased 1 wk after MI in the AV3V-s rats but returned
to a normal level by week 2. In contrast, in the AV3V-x
rats, PRA fell below baseline week 1 after MI, and was lower
in the AV3V-x/MI group than in the AV3V-s/MI and both of the two MI-s
groups. By week 2, PRA had returned to baseline levels in
the AV3V-x/MI group.
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Sympathetic Nerve Recording Study
Baseline measurements. Baseline recordings of RSNA and arterial pressure were obtained in conscious rats 4 h after recovery from a brief anesthesia to implant arterial and venous cannulas and renal nerve recording electrodes. Thus, although the animals received analgesics for pain, they were undoubtedly under some degree of postoperative stress.
Figure 4 shows fast time-base recordings from two rats with MI, one with (Fig. 4B) and one without (Fig. 4A) an AV3V lesion, illustrating both the nature of the sympathetic discharge in these rats and the manner in which the waveform average of RSNA was generated. In both tracings, the RSNA has a pulsatile quality related to the cardiac cycle, indicating persistent baroreflex modulation of RSNA. However, the magnitude of the sympathetic bursts is greater and less variable in the rat with the AV3V intact. In the AV3V-lesioned rat, the pulsatile quality is less dramatic, suggesting more prominent modulation by other factors (e.g., respiration).
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Baroreflex testing.
Figures 6 and
7 show the logistic curve fits for
baroreflex regulation of RSNA and HR, generated by averaging the values
of the individual rats in each group; the mean values for maximum gain
(Gmax) and range of the baroreflex curves are
shown in Fig. 8. The AV3V-s/MI rats
(n = 6) had blunted baroreflex curves for HR and RSNA
compared with the AV3V-s/MI-s rats (n = 5). In MI-s rats with AV3V-x (n = 5), Gmax
and range of the baroreflex curves for RSNA and HR were reduced
compared with AV3V-s/MI-s rats. In contrast, in MI rats with AV3V-x
(n = 6), the Gmax and range of the baroreflex curves for RSNA and HR were improved compared with AV3V-s/MI rats.
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Measurements of LV end-diastolic pressure. LV end-diastolic pressure (EDP) (mmHg) was higher (P < 0.05) in the MI groups (AV3V-x/MI: 16.49 ± 1.75, n = 6; AV3V-s/MI: 18.64 ± 1.96, n = 6) compared with the MI-s groups (AV3V-x/MI-s: 5.30 ± 0.88, n = 5; AV3V-s/MI-s: 4.39 ± 1.01, n = 5). The presence of an AV3V lesion had no significant effect on LVEDP within the MI-s or the MI groups.
Effect of AV3V Lesion on Survival Post-MI
Survival data were acquired on the animals in the metabolic cage study. Survival immediately after CL was comparable in the AV3V-lesioned rats (10/14, 71%) and the rats with sham AV3V lesions (12/16, 75%). However, the AV3V lesion had a pronounced effect on survival beyond 2 wk after CL. Among the 10 AV3V-lesioned rats surviving CL, only 2 (20%) were still alive 3 wk later, whereas 10 (83%) of 12 rats with sham AV3V lesions were alive. In the other groups, 8 (80%) of 10 AV3V-lesioned rats survived the sham CL surgery, and all of those (100%) were still alive 3 wk later; 7 of 7 (100%) rats with sham AV3V lesion survived the sham CL and all were alive at 3 wk. A2 test of significance indicated that the
week 3 survival was reduced in the AV3V-x/MI rats
(P = 0.0013).
Histology of the AV3V Lesion
The AV3V lesions were histologically verified as described previously. The lesions shared a common area of damage to the periventricular tissue between the anterior commissure and optic chiasm, including the ventral portion of organum vasculosum lamina terminalis (OVLT), the median preoptic nucleus, and anteroventral periventricular nuclei and the preoptic anterior hypothalamic periventricular nuclei. The medial preoptic and anterior hypothalamic nuclei sustained little damage beyond their medial borders with the periventricular nuclei.| |
DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The principal new finding of this study is that a lesion in the AV3V region of the forebrain dramatically alters the autonomic adjustments that seek to compensate for reduced heart function early after MI in the rat. After MI in rats with AV3V lesion, the expected increases in PRA and sympathetic drive (two important markers of neurohumoral excitation) did not occur. Physiological correlates included amelioration of the sodium consumption and renal sodium and water retention associated with the post-MI state. Perhaps as a result of this failure of compensatory autonomic mechanisms, survival was compromised early after MI in the AV3V-lesioned rats. These observations point to a critical role for neurons and/or neural pathways within the AV3V region in mediating the circulatory adjustments to impaired myocardial function after MI.
The AV3V lesion was chosen for this study because the method is well characterized, having been practiced for over 20 years (16), survival is not compromised after recovery from the acute adipsic phase, and there is a substantial literature describing the effects of the lesion on cardiovascular and autonomic regulation in the rat. The AV3V lesion damages ventral midline components of the lamina terminalis, including the OVLT and the median preoptic nucleus, thus eliminating OVLT neurons and fibers involved in osmoregulation (22) and in ANG II-induced sodium appetite and thirst (28) and while blocking fibers of passage from the more rostrally located subfornical organ (25). Thus it is strategically placed to impact on sensory afferent inputs arising from the CVO to the forebrain. On the other hand, afferent inputs from hindbrain also project to the AV3V region (21, 26), and their influences on forebrain mechanisms may also be affected.
The AV3V lesion blocks the cardiovascular and autonomic responses to acute administration of ANG II and the effects of acute dipsogenic stimuli that depend on conversion of ANG I to ANG II at forebrain CVOs: functional evidence that it interrupts descending pathways mediating the effects of the RAAS at forebrain CVOs. These same pathways presumably mediate the influences of other circulating peptides, e.g., endothelin, the natriuretic peptides, that are released in the setting of diminished heart function (20) and may have differing cardiovascular and autonomic consequences. Moreover, it is likely that the AV3V lesion ablates neurons and fiber tracts that are tonically active, not dependent on humoral activation. For example, we recently demonstrated (29) that forebrain directed intracarotid injections of the angiotensin-converting enzyme inhibitor captopril reduces sympathetic drive in normal rats.
In this perspective, perhaps the most intriguing finding of the present study is the observation that the AV3V lesion did indeed affect the renin-angiotensin system but not in the anticipated manner. Instead of blocking the effects of an augmented peripheral renin-angiotensin system after MI, as anticipated, the AV3V lesion actually prevented the expected increase in PRA. Because renin release is the rate-limiting factor in the production of circulating ANG II, it may be inferred that the RAAS response to MI with reduced LV function was impaired in the AV3V-lesioned animal.
The explanation for this finding is not immediately obvious. Renin renal release from the kidneys is determined by several factors (9), including renal perfusion, the intensity of RSNA and the levels of circulating ANG II. Our model of ischemia-induced HF involves a sizable area of myocardial injury. We had presumed that the resulting impairment of myocardial function would compromise renal blood flow, leading to renin release on that basis. The contrary finding in the AV3V-lesioned animals suggests that reduced renal blood flow is not the dominant factor determining renin release under conditions of MI and that other possibilities need to be considered. The AV3V lesion also led to reduced sympathetic drive in the sham-MI rats, indicating a tonic influence of neural elements within the AV3V region on sympathetic regulation. Rats with the AV3V lesion had less renal sympathetic nerve activity after MI than rats with the sham-AV3V lesion. It may be that the ambient level of renal sympathetic nerve discharge is the primary factor inducing renal release of renin in our HF model. With the AV3V lesion, we may have interrupted a critical circuit linking the sympathetic nervous system and the renin-angiotensin system: e.g., sympathetic drive emanating from the forebrain drives renin release; ANG II in turn acts at forebrain to elicit further sympathetic drive and at the kidney to prevent further renin production and release.
The improvement in baroreflex function induced by the AV3V lesion provides further insight into the role of this region in regulating circulatory adjustments after MI. Baroreflex blunting is a characteristic of both the post-MI (23) and the HF (31) states. A previous study (2) in normal rats has shown that the AV3V region mediates baroreflex blunting provoked by ANG II infusion, an experimental condition simulating HF. Another study (30) in HF rats has shown normalization of sympathetic hyperactivity and baroreflex dysfunction after central angiotensin type 1 receptor blockade. Our MI rats with sham AV3V lesions had increased PRA, and thus increased circulating ANG II may well have contributed to their blunted baroreflexes. Baroreflex function was better (but still not normal) in the MI rats with an AV3V lesion. As previously discussed, the AV3V lesion in our preparation actually reduced renin release in response to MI and so operated by a somewhat different mechanism than by blocking effects of circulating ANG II. In any case, it would have eliminated any descending inhibitory influence the forebrain might have on baroreflex regulation of RSNA, ANG II mediated or not. Thus our results confirm a role for the AV3V region in the abnormal baroreflex response after MI, but suggest that it is not the only factor involved. In HF, both central (18) and peripheral (10) components of the baroreflex activity are said to be impaired.
Baroreflex function was also impaired in the MI-s rats with the AV3V lesion. This finding is at variance with previous results from normal rats (2). Whereas the explanation for this is uncertain, important factors may be differences in analytical technique (linear regression vs. logistic curve-fit analysis) and in timing of study: 2 to 3 wk post-AV3V lesion and 24 h after recovery from anesthesia in the former study; 8 wk after AV3V lesion, and 4 h after recovery from anesthesia in our study. In any case, this observation suggests that the AV3V region has a complex role with respect to baroreflex regulation. Considering the location and connectivity of the AV3V region, plasticity of neuronal function might occur depending on the nature of the neural and humoral signals impinging on it in particular pathophysiological states (e.g., HF and hypertension).
A particularly striking finding of the present study was that AV3V-x rats had a high mortality after MI compared with AV3V-s controls. Most of the AV3V-x/MI rats were dead at 3 wk, in contrast with the general pattern of survival in the other study groups. Thus, whereas interrupting forebrain mechanisms might theoretically confer long-term benefits by preventing the accumulation and retention of fluid that eventuates in HF, it is apparent that compensatory mechanisms mediated by the forebrain are essential to survival beyond the early post-MI period. Of course, any hypothalamic lesion has the potential to affect the multiple critical homeostatic mechanisms regulated by this region of the brain. On the basis of the known functions of this region of the brain, at least two possible contributing mechanisms might be suggested.
In HF, stroke volume is supported in part by increased filling of the dilated left ventricle. Thus one hypothesis might be that failure of the central mechanisms favoring sodium consumption and renal sodium and water conservation, as occurred after MI in the AV3V lesioned rats in the present study, compromises the ability of the animal to maintain adequate LV filling pressure. Insufficient LV filling associated with low ejection fraction and compromised sympathetic regulation of blood flow distribution to vital tissues may lead to hypotension, acidosis, accumulation of toxic metabolites, and ultimately tissue damage and death. Arguing against that hypothesis is the finding that the LV filling pressures were not low in AV3V-x/MI rats compared with the AV3V-s/MI rats studied 2 wk post-MI. Unfortunately, however, these LVEDP measurements were not obtained from the metabolic study group whose survival was assessed, but rather from the sympathetic nerve recording study group that was not maintained in metabolic cages. Thus a direct assessment of this parameter in animals in declining health was not available in this study.
An alternative hypothesis to explain the poor prognosis associated with
superimposing coronary ligation on a background of the AV3V lesion is
that other stress-related forebrain regulatory mechanisms activated by
MI might be blocked by the AV3V lesion. For example, MI induces the
release of proinflammatory cytokines (1), including tumor
necrosis factor-
, which is increased in our experimental model of MI
(14), and these agents signal the brain to augment the
activity of the hypothalamic-pituitary-adrenal axis via increased
production of corticotropin-releasing hormone in the paraventricular
nucleus of the hypothalamus (19). Interference with this
stress modulating process might well contribute to poor survival in the
post-MI period. However, previous work has demonstrated that
corticotropin-releasing hormone neurons are activated by cytokines
(e.g., interleukin-1) over pathways not affected by interrupting the
descending projections from CVOs of the lamina terminalis
(11), and that cortiocosterone levels are actually increased and respond to stressors such as volume depletion in an
exaggerated rather than a blunted manner after an AV3V lesion (5). Thus, although corticosterone levels were not
measured in these studies, there is no precedent to suggest that
insufficiency of the hypothalamic-pituitary-adrenal axis accounts
for the poor survival of the AV3V-x/MI rats. Indeed, the normal
survival of the AV3V-x/MI-s rats, and the time course (>2 wk) to death
in the AV3V-x/MI rats would seem to argue strongly against a failure of
the AV3V-lesioned rats to tolerate stress.
Perspectives
Our results support the general hypothesis that the forebrain is a critical component of the neural circuitry mediating the early adaptive responses to MI. The AV3V region is specifically implicated in the abnormalities of sympathetic drive and of volume regulation after MI with reduced LV function. Because the AV3V region can be affected by ascending inputs from the hindbrain regions that monitor cardiovascular afferent inputs and by descending inputs from forebrain CVOs that monitor humoral influences, the signal engaging this region of the brain after myocardial injury remains to be determined.One clear message that emerges from this study, however, is that abrogating adaptive forebrain mechanisms has an adverse effect on survival after MI. Whereas these mechanisms may ultimately prove detrimental, eventuating in the excessive volume accumulation and augmented sympathetic drive that characterize end-stage HF, they appear to be essential to the early efforts of the body to compensate for reduced LV function. An important goal for future research will be to determine the best way to introduce a feedback signal indicating that optimal compensation for LV dysfunction has been achieved, thus interrupting the progression to overt HF.
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ACKNOWLEDGEMENTS |
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The authors thank Kathy Zimmerman for diligent and expert assistance in the performance of the echocardiograms.
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FOOTNOTES |
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This study was supported by a Veterans' Affairs Merit Review Award, National Heart, Lung, and Blood Institute (NHLBI) Grant HL-63915 (both to R. B. Felder), American Heart Association Grant-in-Aid 96-010430 (to R. M. Weiss), and NHLBI Cardiovascular Interdisciplinary Research Fellowship HL-07121 (to J. Francis).
Address for reprint requests and other correspondence: R. B. Felder, Univ. of Iowa College of Medicine, E318-GH, 200 Hawkins Dr., Iowa City, IA 52242 (E-mail: robert-felder{at}uiowa.edu).
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. Section 1734 solely to indicate this fact.
10.1152/ajpheart.00488.2001
Received 5 June 2001; accepted in final form 7 January 2002.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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P < 0.05, AV3V-x/MI vs. AV3V-s/MI.
