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Baroreflex Control of Sodium Excretion and Arterial Pressure

Baroreflex regulation of renal sympathetic nerve activity and heart rate in renal wrap hypertensive rats

¹Department of Pharmacology, University of Texas Health Science Center, San Antonio, Texas; and ²Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan

Submitted 13 September 2004 ; accepted in final form 16 December 2004

	ABSTRACT

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Despite its usefulness as a nongenetic model of hypertension, little information is available regarding baroreflex function in the Grollman, renal wrap model of hypertension in the rat. Baroreflex regulation of renal sympathetic nerve activity (RSNA) and heart rate (HR) were studied in male, Sprague-Dawley rats hypertensive (HT) for 1 or 4–6 wk after unilateral nephrectomy and figure-8 ligature around the remaining kidney or normotensive (NT) after sham surgery. Rats were anesthetized with Inactin and RSNA, and HR was recorded during intravenous infusions of sodium nitroprusside or phenylephrine to lower or raise mean arterial pressure (MAP). Response curves were analyzed using a logistic sigmoid function. In 1- and 4-wk HT rats the midpoints of RSNA and HR reflex curves were shifted to the right (P < 0.05). Comparing NT to 1- or 4-wk HT rats, the gain of RSNA-MAP curves was no different; however, gain was reduced in the HR-MAP curves at both 1 and 4 wk in HT rats (P < 0.05). In anesthetized rats the HR range was small; therefore, MAP and HR were measured in conscious rats during intravenous injections of three doses of phenylephrine and three doses of sodium nitroprusside. Linear regressions revealed a reduced slope in both 1- and 4-wk HT rats compared with NT rats (P < 0.05). The results indicate that baroreflex curves are shifted to the right, to higher pressures, in hypertension. After 1–4 wk of hypertension the gain of baroreflex regulation of RSNA is not altered; however, the gain of HR regulation is reduced.

baroreceptor; renal hypertension; cardiovasular regulation

Although the above characteristics are also observed in renal artery clip, or Goldblatt, models of hypertension, comparatively little information is available regarding baroreflex regulation of sympathetic and parasympathetic function in the renal wrap model of hypertension in the rat. Therefore, we examined baroreflex regulation of renal sympathetic nerve activity (RSNA) and heart rate (HR) in anesthetized normotensive (NT) and renal wrap hypertensive (HT) rats at 1 and 4–6 wk after the induction of hypertension. Because the range of HR regulation was severely blunted in the anesthetized and paralyzed rats, we also examined baroreflex-mediated changes in HR in conscious rats. The results indicate that within 1 wk, baroreflex curves relating mean arterial pressure (MAP) to RSNA and HR are shifted to the right and centered on a new, higher midpoint. The gain of baroreflex regulation of RSNA is normal, whereas the gain of HR regulation is reduced. The changes in the reflex curves are no different when examined after 4–6 wk of hypertension.

	METHODS

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General. Successful experiments were performed on adult, male Sprague-Dawley rats (375–500 g, Charles River Labs, Willington, MA). Rats were housed two per cage in a fully accredited American Association for Accreditation of Laboratory Animal Care laboratory animal room with free access to normal rat chow (1% sodium) and water. All rats were given at least 1 wk to acclimate before being used for any procedures and had access to normal rat chow and water ad libitum. The Institutional Animal Care and Use Committee of the University of Texas Health Science Center at San Antonio approved all experimental protocols.

Chronic hypertensive model. Hypertension was induced using a one-kidney renal wrap procedure. Rats were anesthetized with medetomidine (0.5 mg/kg ip; Pfizer, New York, NY) and ketamine (75 mg/kg ip; Fort Dodge Lab., Fort Dodge, IA). A figure-8 Grollman renal wrap and contralateral nephrectomy were performed on these animals (14). Sham-operated animals received unilateral nephrectomy and no contralateral renal wrap. Anesthesia was terminated by atipamezole (1 mg/kg ip; Pfizer) at the conclusion of the surgical procedures.

Baroreflex curves in anesthetized rats. Either 7–10 days or 4–6 wk after the initial surgery, hypertensive and sham-operated animals were anesthetized with Inactin (100 mg/kg ip) and placed on a thermostatically controlled heating pad. Body temperature was monitored using a rectal probe and maintained at 36–38°C throughout the experiment. After placement of venous catheters in the femoral and jugular veins and cannulation of the trachea, the rat was artificially ventilated with room air supplemented with 100% O₂. Additional anesthetic was given as needed (10 mg iv) to maintain stable arterial pressure and HR at rest and during pinch of the hind paw. Gallamine triethiodide (20 mg·kg^–1·0.5 h^–1, iv) or pancuronium bromide (1 mg/kg iv, supplemented by an iv infusion of 0.5 mg·kg^–1·h^–1) given for paralysis. A femoral artery was cannulated, and arterial pressure was measured using a strain-gauge transducer.

The renal sympathetic nerve was approached retroperitoneally via a flank incision. The nerve was isolated contralaterally to the nephrectomy and placed on bipolar, Teflon-coated platinum wires with the ends bared. RSNA was recorded using a Grass high impedance probe (HIP-511) and amplified (X10K-50K) and filtered between 10 and 3K Hz with a Grass P5 series AC amplifier. The output was rectified and integrated (Coulbourn S76–01) at time constants of 50 and 600 ms. The 50-ms time constant was used to determine the 0 level of RSNA (the baroreceptor-insensitive component of RSNA, including noise) during maximal reductions in RSNA evoked by bolus injections of phenylephrine. Data obtained using the 600-ms time constant was used to construct baroreflex curves. The maximum level of RSNA was that observed during the decrease in MAP evoked by the sodium nitroprusside infusion. Baroreflex curves were obtained during intravenous infusions of phenylephrine HCl (50 µg/ml) to increase MAP and sodium nitroprusside (100 ng/ml) to decrease MAP (Fig. 1, A and B). Infusion rate was adjusted to produce changes in MAP of 1–2 mmHg/s.

View larger version (29K): [in this window] [in a new window]   Fig. 1. Baroreflex curves in a 4 wk HT rat. A, B: changes in (from top to bottom) pulsatile arterial pressure (PAP) and mean arterial pressures (MAP; mmHg), heart rate (HR) in beats per minute (bpm), integrated RSNA (time constant = 600 ms) during phenylephrine (A) and nitroprusside (B) infusions. C, D: curves obtained using logistic fit (solid line) drawn through the binned data (circles) for RSNA normalized between 0 and 100% (C) and HR (D) as a function of MAP.

Data analysis. In both anesthetized and conscious rat studies, HR, RSNA, PAP, and MAP were viewed and saved for off-line analysis using a MacLab A/D system. In anesthetized rat studies, the 0 level of RSNA voltage was subtracted from all subsequent RSNA measurements. RSNA and HR values were averaged over 1-mmHg increments of MAP. Curves relating RSNA to MAP were constructed using two different approaches. In approach 1, the baseline level of RSNA was considered 100% and phenylephrine and sodium nitroprusside-induced deviations were expressed as a percentage of this baseline (22, 36). In approach 2, the resting level of RSNA was normalized between 0% (phenylephrine) and 100%, (sodium nitroprusside). Deviations from this baseline during phenylephrine and sodium nitroprusside infusions were normalized between the 0 and 100% levels of RSNA (35).

In experiments with anesthetized rats, RSNA vs. MAP curves obtained using both approaches and HR-MAP curves were fit as previously described (22, 28, 35, 36) using a sigmoid logistic function of equation: RSNA = P4 + P1/{1 + exp[P2(MAP – P3)]}, where P1 is the range of RSNA, P2 is a coefficient that describes gain as a function of MAP, P3 is the MAP at the midrange of the curve, and P4 is the minimum value of RSNA (Fig. 1, C and D). Maximum gain (Gmax) was calculated using the equation Gmax = (P2 x P1)/4 (28). The numbers of animals in various groups are not equal because in some experiments in which RSNA could not be recorded, it was still possible to obtain HR reflex curves, and in some animals, HR curves were not adequately described by the sigmoidal function. HR-MAP curves obtained from conscious rats were fit using linear regression. Statistical significance was determined using one-way ANOVA with Student-Newman-Keuls used for post hoc comparisons. All values are expressed as means (SD), and significance was accepted at P < 0.05.

	RESULTS

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Anesthetized Rat Studies

RSNA expressed as a percentage of baseline. MAP was greater in both HT groups compared with NT rats (P < 0.001). NT rats had a lower MAP (118 mmHg, SD 6, n = 9) than 1 wk HT (132 mmHg, SD 11, n = 7; P = 0.011) and 4 wk HT (135 mmHg, SD 12, n = 9; P = 0.004) rats. There was no difference in resting HRs (NT 373 bpm, SD 36; 1 wk HT 383 bpm, SD 34; 4 wk HT 411 bpm, SD 27, P = 0.057).

Baseline RSNA was considered 100%, and changes in RSNA referenced to this baseline as described in the METHODS. Table 1 contains the averaged curve fit parameters. Curves drawn using the averaged parameters are illustrated in Fig. 2A. There was a significant shift in P3, the midpoint of the curve, comparing NT to both 1 wk (P = 0.037) and 4 wk (P = 0.025) rats. All other parameters were the same comparing NT to 1- and 4-wk HT rats. The relationship between the P2, the gain coefficient, and MAP is illustrated in Fig. 2C. There were no differences in any parameters comparing 1 wk to 4 wk HT rats.

View larger version (30K): [in this window] [in a new window]   Fig. 2. Baroreflex curves relating MAP to RSNA as a percentage of baseline (A) and MAP to RSNA normalized between 0 and 100% (B) in normotensive (), 1 wk HT () and 4 wk HT () anesthetized rats. Curves were generated from the mean values of the curve fit parameters (Tables 1 and 2) for each group. Gray-shaded symbols on curves denote resting level of MAP in each group. C, D: calculated gain vs. MAP using same symbols as above.

Table 2 contains the averaged curve fit parameters. Curves drawn using the averaged parameters are illustrated in Fig. 2B. There was a significant shift in P3 comparing NT to both 1 wk (P = 0.027) and 4 wk (P = 0.025) rats. All other parameters were the same comparing NT to 1 and 4 wk HT rats. The relationship between the P2, the gain coefficient, and MAP is illustrated in Fig. 2D. There were no differences in any parameters comparing 1 wk to 4 wk HT rats.

Table 3 contains the averaged curve fit parameters for baroreflex regulation of HR in anesthetized rats. Curves drawn using the averaged parameters are illustrated in Fig. 3A. There was a significant shift in P3 comparing NT to both 1 wk (P = 0.049) and 4 wk (P = 0.009) HT rats. In contrast to the RSNA curves, P2 was significantly greater in NT compared with 1 wk (P = 0.007) and 4 wk (P = 0.002) HT rats. In addition, the Gmax of the relationship was greater in NT compared with 1 wk (P = 0.009) and 4 wk (P = 0.001) HT rats. There were no differences in any parameters comparing 1 wk to 4 wk HT rats. The relationship between the P2, the gain coefficient, and MAP is illustrated in Fig. 3B.

View larger version (25K): [in this window] [in a new window]   Fig. 3. Baroreflex curves relating MAP to HR (A) in anesthetized normotensive (), 1 wk HT () and 4 wk HT (). Curves were generated from the mean values of the curve fit parameters (Table 3) for each group. Grey filled symbols denote resting level of MAP in each group. B: calculated gain vs. MAP using same symbols as above.

View larger version (20K): [in this window] [in a new window]   Fig. 4. Baroreflex curves relating MAP to HR in conscious normotensive (), 1 wk HT (open circles), and 4 wk HT (). Symbols denote means ± SD. Regression lines are drawn through the points. Grey filled symbols denote resting level of MAP in each group.

	DISCUSSION

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The results of this study show that the sensitivity of baroreflex regulation of RSNA, as described by the gain coefficient (P2) and the Gmax, is unchanged in HT rats with the midpoint of the MAP-RSNA relationship shifted to the right and centered near the new HT level of MAP. At the same time, baroreflex regulation of HR is attenuated in HT rats. The attenuated HR baroreflex in anesthetized rats is not due to the anesthetic, as the same result was found when examined in conscious rats. The changes in baroreflex function are evident within 1 wk of hypertension and persist, with no apparent further alterations, when studied after 4–6 wk of hypertension.

One explanation for this dissociation between baroreflex regulation of sympathetic nerve activity (SNA) and HR in HT rats could be that our analysis of RSNA is based upon recording from the sympathetic nerves innervating the kidney, while HR is a direct measure of the end-organ response. However, our finding of dissociation between baroreflex regulation of RSNA and HR in HT rats is consistent with previous studies in a rabbit model of renal hypertension (17). These authors found that in HT rabbits baroreflex regulation of hindlimb vascular resistance and lumbar SNA was normal and baroreflex regulation of HR was attenuated. Blunted baroreflex regulation of HR in a rat model of renovascular hypertension has also been reported (34); however, sympathetic nerve discharge was not studied. The normal gain of baroreflex regulation of renal and lumbar sympathetic outflows suggests normal regulation of vasomotor tone, albeit around a presumed higher baseline level as discussed below. The reduced gain of the baroreflex regulation of heart rate suggests a blunting of the ability of heart rate to respond to perturbations in blood pressure. This might protect the heart from marked increases and decreases in rate as hypertensive damage to the myocardium progresses.

The dissociation of baroreflex regulation of RSNA and HR is likely the result of alterations within the central pathways regulating RSNA and HR. These alterations could occur during the medullary processing of the baroreceptor afferent input (32) and could be the result of changes at the level of the medullary neurons (31). Alternatively, the alterations in reflex function could be the result of changes in the descending modulation of the medullary neurons in the baroreflex circuit. For example, the paraventricular nucleus plays a critical role in the etiology and maintenance of renal role wrap hypertension (19, 23, 30) and the paraventricular nucleus has been shown to modulate the integration of baroreceptor afferent inputs within the medulla (1, 10, 26).

Absolute level of RSNA. Comparisons of absolute levels of sympathetic discharge between groups of animals are not valid (35, 36). The present analytical procedure normalizes RSNA to a maximum and minimum for each rat and cannot discern alterations in absolute levels of RSNA. Many indirect indices suggest elevated levels of SNA in this and other models of hypertension as previously discussed. More specifically, evidence indicates increased RSNA in human and animal hypertension (see Ref. 7 for a review). Surprisingly, the first direct recordings of RSNA for extended time periods, so that RSNA could be measured before and after the development of hypertension in the same animal, found that during ANG II infusions there was a sustained reduction in RSNA (5), leading the authors to suggest that ANG II-dependent hypertension does not require an increase in the absolute level of RSNA but, rather, an increase in sympathetic outflow relative to the increased MAP (4). The finding of reduced RSNA during chronic ANG II infusions has been subsequently verified (2). However, these findings may be specific for RSNA in ANG II infusion models of hypertension, reflecting reflex and/or direct effects on renal blood flow and/or sodium reabsorption. The neurohumoral response during hypertension is possibly fundamentally different if the renin-angiotensin system is activated after renal dysfunction as opposed to after increases in ANG II due to exogenous administration. It is salient to note that chronic ANG II infusions have been shown to enhance vascular responses to ₁-adrenergic receptor agonists (5). Such sensitization of the vasculature has not been observed in renal wrap hypertension (24).

Although the available evidence suggests that the absolute basal level of sympathetic activity to the kidney is enhanced in renal models of hypertension, our results indicate that the baroreflex is still capable of responding to deviations from the new MAP midpoint in hypertension. Within the normalized range of RSNA, regardless of the absolute level of RSNA within this range in hypertension or the normalization procedure used to curve-fit within this range, the gain of the baroreflex as a function of MAP (P2) and Gmax are not altered in renal wrap HT rats. This presents an interesting paradox; if the gain of the baroreflex is normal, how can sympathetic nerve activity remain elevated? Shouldn't a baroreflex with normal gain be capable of returning sympathetic nerve activity to normal prehypertensive levels? As discussed below, alterations occur in the central integration of baroreceptor inputs that enable normal baroreflex gain despite an elevated sympathetic drive to the kidney.

Baroreflex function in hypertension. Because the vast majority of fibers in the RSN are post-ganglionic (36) and the majority of these are vasomotor, our results suggest no change in baroreflex regulation of renal vascular resistance in renal wrap hypertension. In renal wrap HT rabbits, baroreflex regulation of lumbar SNA and hindlimb vascular resistance was normal (17), lending support to this interpretation. However, we cannot exclude hypertension-evoked changes in baroreflex regulation of more discrete aspects of renal function where a change in a small number of fibers may not be detected using whole nerve recordings (8, 9). For example, baroreflex regulation of proximal tubule sodium excretion could be altered in hypertension and not detected in RSNA recordings.

Baroreflex regulation of HR does not present the same interpretive challenges as RSNA because one is dealing with an absolute number as opposed to a normalized value. Our results indicate a rightward shift in the reflex curve accompanied by a reduction in reflex gain in renal wrap HT rats. Reductions in gain of the HR reflex were observed in anesthetized, as well as conscious rats.

In the renal wrap model of hypertension, sinoaortic denervation results in increased plasma catecholamines and MAP variability (39), indicating tonic baroreflex inhibition of these parameters in renal wrap hypertension. The present study found that within 1 wk of the onset of hypertension, reflex curves relating MAP to RSNA and HR were shifted rightward to higher MAPs, and the resting level of RSNA and HR is positioned at approximately the same point on the HT curve as on the NT curve. This is consistent with studies of SNA in other models of hypertension (3, 4, 21). This indicates that some component(s) of the reflex adapts, or "resets," to the higher prevailing MAP; otherwise RSNA and HR would remain depressed at the lower, plateau level, as in the NT during acute increases in MAP. Resetting enables baroreflex responses to both increase and decrease in MAP.

The above discussion assumes a passive role of the baroreflex in the response to hypertension. It has been suggested that baroreflex resetting is an active process necessary for maintaining SNA in hypertension (4); otherwise, RSNA and HR would remain depressed at the lower, plateau level, as in the NT rat during acute increases in MAP.

Baroreflex resetting likely reflects some mixture of receptor resetting (25, 29, 40), and alterations in the central nervous system (CNS; 11, 19, 30, 31, 33, 42), including descending modulation of medullary neurons integrating baroreceptor afferent inputs (1, 10, 26). A lack of resetting of the MAP-RSNA relationship has been reported in ANG II-infused HT rabbits (2), so that at resting levels of MAP, further inhibition of RSNA is not possible. This contrasts with previous studies in ANG II-infused HT rabbits where resetting of the MAP-RSNA curve was observed (4). Clearly, in our (Fig. 1) and other studies (3, 4, 17, 21), baroreflex inhibition of RSNA can be evoked in chronic hypertension.

Baroreflex regulation of RSNA remains unchanged in hypertension; however, electrical activation of aortic nerve afferents results in reduced depressor responses in this model of hypertension (16, 38, 42) and spontaneously hypertensive rats (13, 18, 41). Although electrical stimulation of afferent fibers is not directly analogous to natural stimulation of the arterial baroreceptors, electrical stimulation of baroreceptor afferent fibers reveals an attenuated reflex function that is not apparent when one naturally activates the arterial baroreceptors by increasing arterial pressure. To this end, a recent report indicates that baroreflex regulation of hypertension remains depressed after normalization of MAP and the return of baroreceptor discharge to the normal, pre-HT level (12). Electrical stimulation of baroreceptor afferents could reveal altered CNS integration as a result of and in adaptation to increased peripheral baroreceptor afferent inputs (32).

	GRANTS

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This work was supported by HL-56637.

	FOOTNOTES

 

Address for reprint requests and other correspondence: Steve Mifflin, Dept. of Pharmacology, Mail Code 7764, Univ. of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900.mifflin{at}uthscsa.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.

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