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Am J Physiol Heart Circ Physiol 293: H2543-H2549, 2007. First published August 17, 2007; doi:10.1152/ajpheart.01201.2006
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Impairment of sympathetic baroreceptor reflexes in obese Zucker rats

Ann M. Schreihofer,1 Daniel A. Mandel,1 Susan C. Mobley,1 and David W. Stepp1,2

1Department of Physiology and 2Vascular Biology Center, Medical College of Georgia, Augusta, Georgia

Submitted 1 November 2006 ; accepted in final form 15 August 2007


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Adult obese Zucker rats (OZRs) have elevated sympathetic vasomotor tone and arterial pressure (AP) with blunted baroreflex-mediated changes in heart rate (HR) compared with adult lean Zucker rats (LZRs). The present study examined whether compromised cardiac baroreflexes are indicative of attenuated sympathetic responses. In addition, because juvenile OZRs have a normal mean AP, we determined whether baroreflexes are fully functional prior to hypertension. At 13 wk, adult OZRs had an elevated baseline mean AP compared with LZRs (137 ± 3 vs. 123 ± 5 mmHg, P < 0.05) under urethane anesthesia. Phenylephrine-induced increases in AP evoked smaller inhibitions of splanchnic sympathetic nerve activity (SNA) and HR in OZRs compared with LZRs. In addition, sympathoexcitatory responses to nitroprusside-induced hypotension were also blunted in OZRs. Sigmoid analysis revealed a decreased gain, a higher mean AP at the midpoint of the curve (AP50), and a reduced range of changes in SNA in OZRs. In contrast, at 7 wk of age, although juvenile OZRs weighed more than LZRs (313 ± 13 vs. 204 ± 4 g, P < 0.05), mean AP was comparable in both groups (122 ± 5 vs. 121 ± 4 mmHg, not significant). In these rats, rapid changes in AP evoked comparable changes in SNA and HR in OZRs and LZRs. Sigmoid analysis revealed that, although the gain of the reflex was blunted in OZRs (P < 0.05), the mean AP50 and range of changes in SNA were comparable in OZRs and LZRs. Together, these data indicate that in adult OZRs, sympathetic responses to acute changes in AP are smaller than those observed in adult LZRs and that impairment of baroreceptor reflexes in OZR is not limited to the regulation of HR but extends to sympathetic vasomotor control. In addition, most of these deficits in baroreflex control of SNA develop in adulthood long after the onset of obesity and when other deficits in cardiovascular regulation are present.

phenylephrine; nitroprusside; splanchnic; sympathetic; heart rate

OBESITY impairs the regulation of arterial pressure (AP), but the mechanisms linking obesity and cardiovascular dysfunction are not well understood. Obesity is associated with changes in the autonomic regulation of AP and vascular reactivity to sympathetic stimulation. Obese hypertensive patients have elevated resting sympathetic nerve activity (SNA) and peripheral vascular resistance, which likely contributes to the development of hypertension (6, 9, 22). In addition, obese people have reduced sympathetic baroreceptor reflexes that contribute to increased variability of AP and reduced variability of heart rate (HR), which are hallmarks of increased cardiovascular morbidity (6, 7, 10, 17).

The development of suitable animal models that are analogous to the human condition will greatly facilitate invasive examinations of mechanisms underlying altered autonomic control associated with obesity. Obese Zucker rats (OZRs), which display hyperphagia-induced obesity due to a mutation of the leptin receptor (13), may provide such a model. Like obese humans, OZRs have significant deficits in the neural regulation of cardiovascular function. Adult OZRs have higher resting AP compared with age-matched lean Zucker rats (LZRs) (5, 8, 21). In agreement with the notion that SNA contributes more to resting mean AP in OZRs, the resting levels of recorded SNA are higher (15) and autonomic ganglionic blockade produces greater decreases in mean AP in OZRs compared with LZRs (4, 21).

The baroreceptor reflex control of autonomic function also appears to be impaired in OZRs compared with LZRs. In conscious rats, phenylephrine (PE)-induced increases in AP produce smaller reflex-mediated decreases in HR in OZRs compared with LZRs, and nitroprusside (NP)-induced decreases in AP produce smaller rises in HR in OZRs (2, 16). These impaired chronotropic responses persist after pharmacological blockade of parasympathetic inputs to the heart with atropine (1). These data suggest that the baroreflex-mediated sympathetic control of the heart is impaired in OZRs, although the cardiac sympathetic responses to changes in AP have not been measured in Zucker rats. In addition, it is not known whether the apparent deficit in baroreceptor reflex-mediated sympathetic control of the heart in OZRs extends to other sympathetic targets such as the vasculature. Indeed, baroreceptor reflex-mediated control of the heart can be altered in the absence of changes in baroreflex control of vascular resistance (11, 12).

An objective of the present study was to examine the hypothesis that baroreflex-mediated changes in SNA are reduced in OZRs compared with LZRs. We sought to determine whether baroreflex-mediated changes in sympathetic vasomotor tone were also impaired in OZRs by measuring changes in splanchnic SNA. In addition, because hypertension appears to develop after the onset of obesity in OZRs (8), we examined whether the normal mean AP observed in juvenile OZRs is associated with fully functional baroreflexes. This experiment also examined whether impaired baroreflexes could be dissociated from the mutation of the leptin receptor.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animals. Experiments used age-matched juvenile (7 wk old) and adult (13 wk old) male OZRs and LZRs (Harlan, Madison, WI) fed standard rat chow and tap water ad libitum. Rats were housed in the animal care facility at the Medical College of Georgia, which is approved by the American Association for the Accreditation of Laboratory Animal Care. The Institutional Animal Care and Use Committee approved all protocols.

Animal preparation and physiological measures. Rats were anesthetized with isoflurane via a nose cone for surgical procedures (initially with 5% and then maintained at 1.9–2.5% in 100% oxygen). Adequacy of anesthesia was verified by the absence of a corneal reflex triggered by lightly touching the eye. A catheter was implanted in a femoral vein for the administration of drugs and in a femoral artery for the measurement of AP. LZRs were artificially ventilated (55–65 strokes/min of 1 ml/100 g LZR body wt, model 683, Harvard Apparatus). After insertion of a tracheal tube, OZRs were initially ventilated at the tidal volume of the age-matched LZRs, and the volume was then adjusted slightly upward to maintain end-tidal CO2 at 3.5–4.0%. The rat was placed in a stereotaxic instrument in the supine position for immobilization. The left greater splanchnic nerve was exposed by a retroperitoneal approach, placed on two Teflon-coated silver wires bared at the tips, and surrounded by dental impression material as previously described (14, 20).

After surgical procedures were completed, isoflurane anesthesia was replaced by urethane. For experiments examining serial doses of PE and NP, OZRs and LZRs were given 1.7 g/kg LZR body wt administered intravenously using 1.7 g/5 ml solution at 50 µl/min. For the experiment examining the sigmoidal relationship between SNA and AP, rats were given 1.2 g/kg LZR body wt using a 1.2 g/5 ml solution. Administering equivalent amounts of urethane intravenously to age-matched LZRs and OZRs (determined by LZR body weight) yielded stable preparations that appeared to be comparably anesthetized. Mean AP was slightly elevated in the adult OZR, as observed in the conscious state, and respiratory status appeared to be comparable, as suggested by end-tidal CO2 levels. Cardiovascular responses to firm toe pinch were minimal (<10 mmHg), and corneal reflexes were absent in both LZRs and OZRs. Once anesthetized with urethane, rats were allowed to recover for 30–45 min. Rectal temperature was maintained at 37°C. Shortly before the beginning of the experiment, the rat was paralyzed (1 mg/kg iv pancuronium, Abbott Labs).

Baroreceptor reflex tests. On each day, one pair of age-matched LZR and OZR was examined. To elicit a range of rapid rises in AP, multiple doses of PE were administered as bolus intravenous injections (0.2–3.2 µg). The amounts of PE utilized corresponded to doses of 1, 3, and 5 µg/kg. Because age-matched LZRs and OZRs have comparable blood volumes, PE doses were also administered by drug weight (21). Thus, each rat received the three doses prepared for LZRs and OZRs (6 total doses tested/rat) to facilitate a comparison of doses by drug weight. In addition, because juvenile LZRs displayed smaller pressor responses to PE, an additional dose of 10 µg/kg was examined in juvenile rats.

To evoke rapid decreases in AP, multiple doses of sodium NP were administered as bolus intravenous injections (0.4–5.5 µg). The range of NP utilized corresponded to doses of 2, 5, and 10 µg/kg. As with the PE injections, each rat received the three doses of NP prepared for LZRs and OZRs (6 total doses tested/rat).

In each experiment, drugs were administered in ascending order of doses calculated for LZRs followed by doses calculated for OZRs, starting with injections of PE and followed by injections of NP. Between injections, AP, HR, and SNA were allowed to return to within ±5% of baseline. At the end of the experiment, SNA was eliminated by an injection of mecamylamine (10 mg/kg iv for most rats) or clonidine (20 µg/kg iv for some of the adult rats). Baseline values for AP, HR, and SNA were recorded for 30 s immediately preceding each dose, and the initial peak or trough occurring within 30 s after the bolus injection of PE or NP was then recorded.

In another set of age-matched OZRs and LZRs, we examined the gain and range of baroreflex-mediated sympathetic responses to one large decrease in AP evoked by a bolus dose of NP (10 µg/kg OZR body wt) and one large increase in AP evoked by constriction of an abdominal aortic snare, which allowed a slower rate of rise in AP than achieved with bolus doses of PE.

Data analysis and statistics. Amplifiers and filters from the Neurolog system (www.digitimer.com) were used to quantify AP, mean AP, and HR. The HR was triggered from the rising phase of the AP pulse (Spike trigger, Neurolog). The SNA was amplified and filtered (10-Hz to 3-kHz band pass with a 60-Hz notch filter, differential alternating current amplifier 1700, A-M Systems). The raw SNA signal was full wave rectified and averaged into 1-s bins. The baseline SNA (100%) was defined as the activity immediately preceding each stimulus. The voltage due to noise was determined after SNA was silenced by an injection of clonidine or mecamylamine at the end of the experiment (14, 20) and set at 0% SNA. Changes in SNA were expressed as percent changes from baseline utilizing this two-point calibration. All analog physiological variables were converted to digital signals (Micro 1401, Cambridge Electronic Design, www.ced.co.uk) and viewed online (Spike2 software, Cambridge).

All data are expressed as mean ± SE. Significant statistical difference was set at P < 0.05. Baseline values for age, body weight, mean AP, and HR were compared in age-matched OZRs and LZRs by unpaired t-tests. Baroreceptor reflexes were examined in two ways. The magnitudes of changes in SNA and HR evoked by a range of acute changes in AP were assessed as previously reported (1, 16). Following evoked increases or decreases in AP from a series of bolus doses of PE and NP, data were grouped by the amount of change in mean AP in 10-mmHg increments (e.g., 5-14, 15-24, or 25-34). If a rat had more than one response within a grouped range of APs, those values for that animal were averaged to maintain the independence of points within a range of change in mean AP. Responses to PE and NP were analyzed separately. Mean changes in HR or SNA/changes in AP were compared in age-matched OZRs and LZRs by two-way ANOVAs with repeated measures followed by Student-Newman-Kuels post hoc tests (SigmaStat, www.systat.com).

The sensitivity and operating range of the sympathetic baroreflex were also assessed by generating a sigmoid curve fit of a single large increase and decrease in AP for a set of age-matched OZRs and LZRs. We used Origin software (www.originlab.com) and the following Boltzman equation model: y = A2 + (A1 – A2)/{1 + exp[(x – x0/dx)]}, where A1 is the maximum SNA, A2 is the minimum SNA, x0 is the mean AP at the midpoint of the curve (AP50), x is the mean AP, and dx is an estimate of the width of the curve. The maximum gain was calculated as follows: [(A1 – A2)/4]/dx. The mean AP50, gain and maximum and minimum values for SNA were measured for each rat. Group data for juvenile and adult OZRs and LZRs were compared by two-factor ANOVA followed by Student-Newman-Kuels post hoc tests.


   RESULTS
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 RESULTS
DISCUSSION
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Adult OZRs weighed significantly more than age-matched LZRs at 14 wk of age (range: 13.0–14.8 wk old). Under urethane anesthesia, the baseline mean AP of adult OZRs was significantly higher than age-matched LZRs (Table 1). There was a trend for lower baseline HR in OZRs, but this difference did not reach statistical significance (Table 1). Juvenile OZRs weighed significantly more than age-matched LZRs at 8 wk of age (range: 7.6–8.0 wk old; Table 2). In contrast to adult Zucker rats, under urethane anesthesia, the mean AP and HR were comparable in juvenile OZRs and LZRs (Table 2). We and others (4, 12) have previously reported that the decrease in AP after ganglionic blockade in adult OZRs is larger than in LZRs, suggesting an elevated sympathetic vasomotor tone in adult OZRs. In juvenile Zucker rats under urethane anesthesia, the decrease in AP following ganglionic blockade with mecamylamine (10 mg/kg iv) was comparable in LZRs and OZRs (–53 ± 1 vs. –48 ± 5 mmHg, respectively, n = 8 rats/group), suggesting that at this early age the sympathetic support of AP is normal in OZRs.


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  		Table 1. Baseline physiological data in adult Zucker rats

 

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  		Table 2. Baseline physiological data in juvenile Zucker rats

 
Baroreflex-induced changes in SNA and HR in adult Zucker rats. Bolus injections of PE evoked dose-dependent increases in mean AP that were accompanied by decreases in SNA and HR inversely proportional to the amount of change in AP (Fig. 1). The nadirs of SNA and HR occurred within 5 and 20 s, respectively. Analyses of changes in SNA over 10-mmHg increments of changes in AP revealed that adult OZRs had significantly blunted decreases in SNA, particularly with smaller PE-evoked increases in mean AP (Fig. 1A). In contrast, the largest increases in mean AP evoked comparable decreases in SNA in OZRs and LZRs. Although OZRs had blunted decreases in HR at one of the smaller changes in the mean AP range, most of the deficit appeared with large increases in mean AP. Here, OZRs showed significantly blunted bradycardia to PE-evoked increases in AP (Fig. 1B).


Figure 1
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  		Fig. 1. Changes in splanchnic sympathetic nerve activity (SNA) and heart rate [HR; in beats/min (bpm)] elicited by phenylephrine (PE)-evoked increases in arterial pressure (AP) in adult lean Zucker rats (LZRs) and obese Zucker rats (OZRs). A: decreases in SNA in response to 10-mmHg increments of increases in AP in OZRs and LZRs. B: decreases in HR in response to 10-mmHg increments of increases in AP in OZRs and LZRs. ANOVA with repeated measures for SNA revealed a significant effect of rat phenotype (F = 9.65, P = 0.003) and amount of change in AP (F = 55.27, P = 0.001). ANOVA with repeated measures for HR revealed a significant effect of rat phenotype (F = 6.25, P = 0.015) and amount of change in mean AP (MAP; F = 21.57, P = <0.001). *Significantly smaller change in OZRs compared with LZRs with comparable changes in MAP evaluated by Student-Newman-Keuls post hoc tests (P < 0.05).

 
Bolus injections of NP produced dose-dependent decreases in mean AP that were accompanied by increases in SNA and HR that were inversely proportional to the amount of change in AP (Fig. 2). Analyses of increases in SNA over 10-mmHg increments of NP-evoked decreases in mean AP revealed that OZRs and LZRs responded comparably to smaller changes in mean AP. In contrast, when NP-evoked decreases in mean AP were larger, prominent deficits in baroreflex-mediated increases in SNA were present (Fig. 2A). Although there was a trend for a similar deficit in NP-evoked bradycardia with larger decreases in mean AP, this apparent difference did not reach statistical significance (Fig. 2B).


Figure 2
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  		Fig. 2. Changes in splanchnic SNA and HR elicited by nitroprusside (NP)-evoked decreases in AP in adult LZRs and OZRs. A: increases in SNA in response to 10-mmHg increments of decreases in AP in OZRs and LZRs. B: increases in HR in response to 10-mmHg increments of decreases in AP in OZRs and LZRs. ANOVA with repeated measures for SNA revealed a significant effect of rat phenotype (F = 7.36, P = 0.009) and amount of change in AP (F = 7.10, P = 0.001). ANOVA with repeated measures for HR revealed a significant effect for amount of change in MAP (F = 16.31, P = 0.001) but not of rat phenotype (F = 1.57, P = 0.22). *Significantly smaller change in OZRs compared with LZRs with comparable changes in MAP evaluated by Student-Newman-Keuls post hoc tests (P < 0.05).

 
In a separate group of rats, sigmoidal analysis of changes in SNA revealed significant deficits in adult OZRs compared with age-matched LZRs (Fig. 3 and Table 3). Adult OZRs had higher baseline mean AP and AP50 levels. In addition, sympathetic baroreflex sensitivity was reduced (Fig. 3 and Table 3), and changes in SNA to both increases and decreases in AP were blunted (Fig. 3 and Table 3).


Figure 3
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  		Fig. 3. Examples of sigmoidal analyses for juvenile and adult OZRs and LZRs. SNA was altered by raising AP by constriction of an aortic snare and lowering AP with an injection of NP. A–D: sympathetic responses in a juvenile LZR (A), a juvenile OZR (B), an adult LZR (C), and an adult OZR (D).

 

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  		Table 3. Average parameters of sigmoidal baroreflex curves for LZRs and OZRs

 
Baroreflex-induced changes in SNA and HR in juvenile Zucker rats. Bolus injections of PE evoked dose-dependent increases in AP that were accompanied by dose-dependent decreases in SNA and HR in juvenile rats (Fig. 4). Analyses of decreases in SNA over 10-mmHg increments of changes in mean AP in juvenile LZRs and OZRs revealed no differences (Fig. 4A). Likewise, the PE-evoked bradycardia was comparable in OZRs and LZRs at all doses examined (Fig. 4B).


Figure 4
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  		Fig. 4. Changes in splanchnic SNA and HR elicited by PE-evoked increases in AP in juvenile LZRs and OZRs. A: decreases in SNA in response to 10-mmHg increments of increases in AP in OZRs and LZRs. B: decreases in HR in response to 10-mmHg increments of increases in AP in OZRs and LZRs. ANOVA with repeated measures for SNA revealed a significant effect for amount of change in AP (F = 92.10, P < 0.001) but not of rat phenotype (F = 1.07, P = 0.31). ANOVA with repeated measures for HR revealed a significant effect for amount of change in AP (F = 31.16, P = 0.001) but not of rat phenotype (F = 0.27, P = 0.60).

 
Bolus injections of NP evoked dose-dependent decreases in AP that were accompanied by increases in SNA and HR (Fig. 5). Analyses of increases in SNA and HR over 10-mmHg increments of changes in mean AP in juvenile LZRs and OZRs showed no differences at any level of change in mean AP (Fig. 5, A and B).


Figure 5
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  		Fig. 5. Changes in splanchnic SNA and HR elicited by NP-evoked decreases in MAP in juvenile LZRs and OZRs. A: increases in SNA in response to 10-mmHg increments of decreases in AP in OZRs and LZRs. B: increases in HR in response to 10-mmHg increments of decreases in AP in OZRs and LZRs. No differences were observed between LZRs and OZRs at any level of change in MAP examined. ANOVA with repeated measures for SNA revealed a significant effect for amount of change in AP (F = 4.25, P = 0.01) but not of rat phenotype (F = 0.20, P = 0.66). ANOVA with repeated measures for HR revealed a significant effect for amount of change in AP (F = 2.70, P = 0.046) but not of rat phenotype (F = 1.90, P = 0.17).

 
In a separate group of rats, a sigmoidal analysis of changes in SNA revealed that juvenile OZRs had minimal differences in baroreflex function compared with age-matched LZRs (Fig. 3 and Table 3). Baseline mean AP and AP50 values were normal. Although the slope of the sympathetic baroreflex was reduced in juvenile OZRs compared with age-matched LZRs, the range of sympathetic responses to evoked changes in AP was normal. Comparisons of juvenile and adult OZRs revealed that mean AP and AP50 values increased with age. In addition, with age, baroreflex function was significantly reduced in OZRs, with blunted baroreflex sensitivity and decreased sympathetic responses to decreased AP (Table 3).


   DISCUSSION
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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 REFERENCES
 
Obesity is a positive risk factor for impaired acute and chronic regulation of AP, but the underlying mechanisms remain unknown. The OZR appears to provide a suitable model for examining altered autonomic control associated with obesity. As seen in humans, OZRs become obese due to excessive intake of calories, and autonomic deficits in cardiovascular control emerge with the progression of the obese state. Because dysfunctional sympathetic control of AP has been identified in both humans and animal models of obesity, the present study hypothesized that obesity reduces baroreflex control of sympathetic function, thus contributing to the reduced ability of obese individuals to control AP. The present study is the first to directly observe impaired sympathetic responses to evoked changes in AP in adult OZRs compared with LZRs and to demonstrate the deficit is not limited to effects upon the heart but extends to the sympathetic regulation of vasomotor tone. Although the gain of the baroreflex was significantly reduced in juvenile OZRs, these animals displayed the normal range of changes in SNA and HR evoked by altering AP. Thus, the full development of impaired baroreflex control of SNA and HR appears to be dissociated with the mutation of the leptin receptor and the onset of obesity.

Baroreflex-mediated changes in HR and SNA in adult OZRs and LZRs. Although anesthesia significantly blunted baroreflex-mediated changes in HR in the present study compared with previous reports (1, 2) in conscious Zucker rats, there was still a clear relationship between induced increases and decreases in AP and reflexive changes in HR. In addition, there were detectable impairments in baroreflex-mediated changes in HR in the adult OZR compared with LZR. The most prominent deficits occurred with bradycardia associated with large increases in AP. Our inability to observe significant reductions in hypotension-induced tachycardia in the adult OZR are likely the result of the anesthetized state. In addition, the rapid time frame of the measures for sympathetic responses to changes in AP may not have allowed for the observation of maximal HR responses. However, despite the suppression of baroreflex-mediated changes in HR, we clearly observed deficits in baroreflex-mediated changes in SNA to the vasculature to both increases and decreases in AP. In agreement with the previous report (1) showing that changes in HR to both increases and decreases in HR persisted after cholinergic blockade, we observed that sympathetic responses to changes in AP in either direction were smaller in adult OZRs compared with LZRs. In contrast to the hypertension-induced decreases in HR, the most prominent deficits in the hypertension-induced reduction in SNA occurred with small increases in AP. If deficits in sympathetic control of the heart parallel those observed in splanchnic SNA, additional mechanisms must underlie the prominent impairment of hypertension-induced bradycardia with large increases in AP. Likely, OZRs have impaired hypertension-induced activation of parasympathetic nerve activity to the heart as well. Indeed, after blockade of the sympathetic influences on the heart with propranolol, hypertension continues to evoke attenuated bradycardia in OZRs compared with LZRs (1). These autonomic deficits in baroreflex control of the circulation are likely to contribute to the changes in variability of AP and HR associated with obesity.

Baroreflex-mediated changes in SNA in juvenile OZRs and LZRs. In contrast to the prominent impairments in baroreflex-mediated changes in HR in adult OZRs, juvenile OZRs appear to have no such deficits compared with age-matched LZRs. Although sigmoidal analysis revealed that the gain of the sympathetic baroreflex was reduced in juvenile OZRs compared with age-matched LZRs, the range of changes in SNA to evoked changes in AP were normal. In addition, the magnitudes of reflexively-mediated changes in SNA and HR were strikingly comparable with LZRs with the full range of doses of PE and NP examined. Juvenile OZRs have a normal mean AP (Table 2) (8, 19) and sympathetic vasomotor tone, suggesting that the altered acute regulation of SNA and AP are associated with the development of attenuated ranges of baroreflex-mediated changes in SNA and HR. In female Zucker rats, the development of impaired baroreflex function appears to precede the development of hypertension (2), suggesting the attenuation of baroreflex function may predispose or contribute to the later development of hypertension in OZRs. In agreement, with sigmoidal analysis we did observe a reduced slope in juvenile OZRs when baseline AP levels were comparable with juvenile LZRs.

The mechanisms leading to impaired baroreflex control of SNA and HR in OZRs are not known. In addition, the dissociation of a reduced gain in the juvenile OZR and later development of blunted magnitudes of sympathetic responses to acute changes in AP may allude to multiple underlying origins. The observation that most of these deficits emerge in the adult OZR suggests they are not a direct consequence of the mutated leptin receptors in OZRs. The onset of obesity and insulin resistance clearly precede the full establishment of impaired baroreflex-mediated responses (8), suggesting these attributes may contribute to the development of autonomic dysfunction in the adult OZR. Indeed, other models of obesity in rats, dogs, and humans also showed analogous deficits in the autonomic control of cardiovascular function (3, 10, 23).

Perspectives Obesity is one of the most important risk factors for cardiovascular disease today. Obesity is commonly associated with increased sympathetic vasomotor tone and diminished ability to maintain a constant AP in animal models and in humans (6). The present study provides the first direct observation that baroreflex control of SNA is impaired in adult OZRs compared with LZRs, analogous to deficits observed in obese humans. In the adult OZR, the reduced baroreflex-mediated changes in SNA combined with impaired adrenergic-mediated constriction of the mesenteric vasculature (18, 21) set the stage for the profoundly diminished autonomic regulation of the vasculature that contributes to the maintenance of AP. In addition, the inability of the baroreflex to fully regulate SNA, HR, and AP appears to develop after the onset of obesity and its related physiological dysfunctions in OZRs, suggesting some mechanisms underlying diminished autonomic control are a consequence of obese state. The onset of hypertension and increased sympathetic vasomotor tone coincide with the development of attenuated baroreflex-mediated changes in SNA and HR, indicating an important role for these reflexes in the long-term regulation of cardiovascular control.


   GRANTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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REFERENCES
 
This work was supported by National Heart, Lung, and Blood Institute Grants HL-075174 (to A. M. Schreihofer) and HL-67303 (to D. W. Stepp).


   FOOTNOTES
 

Address for reprint requests and other correspondence: A. M. Schreihofer, Dept. of Physiology, CA-3132E, Medical College of Georgia, Augusta, GA 30912-3000 (e-mail: aschreihofer{at}mail.mcg.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.


   REFERENCES
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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