Linda L. Sawin

Renal sympathetic nerve activity and the exaggerated natriuresis of the spontaneous hypertensive rat.

SUMMARY To eraluate the role of altered efferent renal sympathetic nerve actirity in the exaggerated natriuresis of the spontaneous hypertensive rat (SHR), we measured efferent renal sympathetic nerve activity in anesthetized ageand sex-matched SHR and normotensive Wistar Kyoto (WKY) control rats during control and intravenous saline volume expansion. Mean arterial pressure was 40-60 mm Hg higher in SHR than in WKY. During volume expansion, the increment in urinary flow rate (17.5 ± 3.1 vs 42.8 ± 8.0 /J/100 g/min) and sodium excretion (8.1 ± 1.5 vs 15.2 ± 2 3 M Eq/min) were greater in SHR than in WKY. During control, efferent renal sympathetic nerve activity was 12.2 ± 0.4 Hz in WKY and 12.0 ± 0.5 Hz in SHR and fell equally during volume expansion to 5.0 ± 0.6 Hz in WKY and to 4.0 ± 0.8 Hz in SHR. Thus, these studies demonstrate that the exaggerated natriuresis of SHR as compared to WKY cannot be attributed to differences in reflex withdrawal of renal sympathetic nerve activity.

Angiotensin receptor antagonist improves cardiac reflex control of renal sodium handling in heart failure

In rats with congestive heart failure, type 1 angiotensin II receptor antagonist treatment (losartan) decreases basal renal sympathetic nerve activity and improves arterial baroreflex regulation of renal sympathetic nerve activity. This investigation examined the effect of losartan on cardiac baroreflex regulation of renal sympathetic nerve activity and renal sodium handling in rats with congestive heart failure. Losartan treatment decreased arterial pressure from 120 +/- 3 to 93 +/- 5 mmHg and increased the afferent (from 0.95 +/- 0.21 to 2.22 +/- 0.42% delta afferent vagal nerve activity/mmHg mean right atrial pressure, P < 0.05) and overall gain (from -1.14 +/- 0.19 to -4.20 +/- 0.39% delta renal sympathetic nerve activity/mmHg mean right atrial pressure, P < 0.05) of the cardiac baroreflex. During isotonic saline volume loading, urinary sodium excretion increased from 2.4 +/- 0.8 to 10.5 +/- 1.3 mueq/min in vehicle-treated rats (excretion of 52 +/- 3% of the load) and from 3.0 +/- 1.0 to 15.1 +/- 1.8 mu eq/min in losartan-treated rats (excretion of 65 +/- 4% of the load, P < 0.05). When rats were changed from a low- to a high-sodium diet, cumulative sodium balance over 5 days was 7.8 +/- 0.6 meq in vehicle-treated rats and 4.2 +/- 0.4 meq in losartan-treated rats (P < 0.05). In congestive heart failure, losartan treatment improved cardiac baroreflex regulation of renal sympathetic nerve activity, which was associated with improved ability to excrete acute and chronic sodium loads.In rats with congestive heart failure, type 1 angiotensin II receptor antagonist treatment (losartan) decreases basal renal sympathetic nerve activity and improves arterial baroreflex regulation of renal sympathetic nerve activity. This investigation examined the effect of losartan on cardiac baroreflex regulation of renal sympathetic nerve activity and renal sodium handling in rats with congestive heart failure. Losartan treatment decreased arterial pressure from 120 ± 3 to 93 ± 5 mmHg and increased the afferent (from 0.95 ± 0.21 to 2.22 ± 0.42% Δafferent vagal nerve activity/mmHg mean right atrial pressure, P < 0.05) and overall gain (from -1.14 ± 0.19 to -4.20 ± 0.39% Δrenal sympathetic nerve activity/mmHg mean right atrial pressure, P < 0.05) of the cardiac baroreflex. During isotonic saline volume loading, urinary sodium excretion increased from 2.4 ± 0.8 to 10.5 ± 1.3 μeq/min in vehicle-treated rats (excretion of 52 ± 3% of the load) and from 3.0 ± 1.0 to 15.1 ± 1.8 μeq/min in losartan-treated rats (excretion of 65 ± 4% of the load, P < 0.05). When rats were changed from a low- to a high-sodium diet, cumulative sodium balance over 5 days was 7.8 ± 0.6 meq in vehicle-treated rats and 4.2 ± 0.4 meq in losartan-treated rats ( P < 0.05). In congestive heart failure, losartan treatment improved cardiac baroreflex regulation of renal sympathetic nerve activity, which was associated with improved ability to excrete acute and chronic sodium loads.

Effect of Metoprolol Administration on Renal Sodium Handling in Experimental Congestive Heart Failure

BACKGROUND Long-term metoprolol therapy improves cardiac performance and decreases mortality in patients with chronic congestive heart failure (CHF). This study examined the effect of long-term metoprolol therapy on renal sodium handling in an experimental rat model of CHF. METHODS AND RESULTS Rats with left coronary ligation and myocardial infarction-induced CHF were treated with metoprolol (1.5 mg. kg-1. h-1) or vehicle for 3 weeks by osmotic minipump. They were then evaluated for their ability to excrete a short-term sodium load (5% body weight isotonic saline infusion over 30 minutes) and a long-term sodium load (change from low- to high-sodium diet over 8 days). All CHF rats had left ventricular end-diastolic pressure >10 mm Hg, and heart weight/body weight ratios averaged 0.68+/-0.02% (versus control of approximately 0.40%). Compared with vehicle CHF rats (n=19), metoprolol CHF rats (n=18) had lower basal values of mean arterial pressure (122+/-3 versus 112+/-3 mm Hg) and heart rate (373+/-14 versus 315+/-9 bpm) and decreased heart rate responses to intravenous doses of isoproterenol. During short-term isotonic saline volume loading, metoprolol CHF rats excreted 54+/-4% more of the sodium load than vehicle CHF rats. During long-term dietary sodium loading, metoprolol CHF rats retained 28+/-3% less sodium than vehicle CHF rats. CONCLUSIONS Metoprolol treatment of rats with CHF results in an improved ability to excrete both short- and long-term sodium loads.

Functional significance of the pattern of renal sympathetic nerve activation

To assess the renal functional significance of the pattern of renal sympathetic nerve activation, computer-generated stimulus patterns (delivered at constant integrated voltage) were applied to the decentralized renal sympathetic nerve bundle and renal hemodynamic and excretory responses determined in anesthetized rats. When delivered at the same integrated voltage, stimulus patterns resembling those observed in in vivo multifiber recordings of renal sympathetic nerve activity (diamond-wave patterns) produced greater renal vasoconstrictor responses than conventional square-wave patterns. Within diamond-wave patterns, increasing integrated voltage by increasing amplitude produced twofold greater renal vasoconstrictor responses than by increasing duration. With similar integrated voltages that were subthreshold for renal vasoconstriction, neither diamond- nor square-wave pattern altered glomerular filtration rate, whereas diamond- but not square-wave pattern reversibly decreased urinary sodium excretion by 25 ± 3%. At the same number of pulses per second, intermittent stimulation produced faster and greater renal vasoconstriction than continuous stimulation. At the same number of pulses per second, increases in rest period during intermittent stimulation proportionally augmented the renal vasoconstrictor response compared with that observed with continuous stimulation; the maximum augmentation of 55% occurred at a rest period of 500 ms. These results indicate that the pattern of renal sympathetic nerve stimulation (activity) significantly influences the rapidity, magnitude, and selectivity of the renal vascular and tubular responses.

Exaggerated Natriuresis in Experimental Hypertension

Abstract The exaggerated natriuretic response to intravenous isotonic saline volume expansion in conscious spontaneous hypertensive rats (SHR), compared to normotensive Wistar-Kyoto rats (WKY), is associated with an exaggerated inhibition of renal nerve activity. Following bilateral renal denervation, the natriuresis was significantly attenuated in SHR but unaffected in WKY. Thus, the exaggerated natriuretic response to intravenous isotonic saline in SHR is dependent on their enhanced inhibition of renal nerve activity. Conscious Dahl salt-sensitive rats, on either low or high salt diet, did not exhibit an exaggerated natriuretic response to intravenous isotonic saline volume expansion which may be explained by their known impairment of cardiopulmonary baroreceptor reflex mediated suppression of efferent sympathetic nerve activity during intravenous volume expansion. Conscious hypertensive DOCA-NaCl rats exhibited an exaggerated natriuretic response to oral but not to intravenous isotonic saline volume expansion, suggesting differences in gastrointestinal absorption of isotonic saline. It is concluded that enhanced inhibition of efferent renal sympathetic nerve activity via cardiopulmonary baroreceptor reflex activation contributes to the exaggerated natriuretic response to intravenous isotonic saline volume expansion in certain models of experimental hypertension.

Effect of arterial baroreceptor denervation on sodium balance

Abstract—During chronic increased dietary sodium intake, arterial baroreceptors buffer against sustained increases in arterial pressure, and renal sympathoinhibition contributes importantly to the maintenance of sodium balance by decreasing renal tubular sodium reabsorption and increasing urinary sodium excretion. The present study examined the effect of arterial baroreceptor denervation on sodium balance in conscious rats during low, normal, and high dietary sodium intake. Compared with measurements made before arterial baroreceptor denervation, arterial baroreceptor–denervated rats had similar sodium balance during normal dietary sodium intake but significantly more negative sodium balance during low dietary sodium intake and significantly more positive sodium balance during high dietary sodium intake. At the end of the high dietary sodium intake period, arterial pressure (under anesthesia) was 159±5 mm Hg after arterial baroreceptor denervation and 115±1 mm Hg before arterial baroreceptor denervation. Sham arterial baroreceptor denervation in time control rats had no effect on sodium balance or arterial pressure during the different dietary sodium intakes. These studies indicate that (1) arterial baroreceptor denervation impairs the ability to establish sodium balance during both low and high dietary sodium intake, and (2) arterial baroreceptor denervation leads to the development of increased arterial pressure during high dietary sodium intake in association with increased renal sodium retention.

Renal hemodynamic effects of activation of specific renal sympathetic nerve fiber groups

To examine the effect of activation of a unique population of renal sympathetic nerve fibers on renal blood flow (RBF) dynamics, anesthetized rats were instrumented with a renal sympathetic nerve activity (RSNA) recording electrode and an electromagnetic flow probe on the ipsilateral renal artery. Peripheral thermal receptor stimulation (external heat) was used to activate a unique population of renal sympathetic nerve fibers and to increase total RSNA. Total RSNA was reflexly increased to the same degree with somatic receptor stimulation (tail compression). Arterial pressure and heart rate were increased by both stimuli. Total RSNA was increased to the same degree by both stimuli but external heat produced a greater renal vasoconstrictor response than tail compression. Whereas both stimuli increased spectral density power of RSNA at both cardiac and respiratory frequencies, modulation of RBF variability by fluctuations of RSNA was small at these frequencies, with values for the normalized transfer gain being approximately 0.1 at >0.5 Hz. During tail compression coherent oscillations of RSNA and RBF were found at 0.3-0.4 Hz with normalized transfer gain of 0.33 +/- 0.02. During external heat coherent oscillations of RSNA and RBF were found at both 0.2 and 0.3-0.4 Hz with normalized transfer gains of 0. 63 +/- 0.05 at 0.2 Hz and 0.53 +/- 0.04 to 0.36 +/- 0.02 at 0.3-0.4 Hz. Renal denervation eliminated the oscillations in RBF at both 0.2 and 0.3-0.4 Hz. These findings indicate that despite similar increases in total RSNA, external heat results in a greater renal vasoconstrictor response than tail compression due to the activation of a unique population of renal sympathetic nerve fibers with different frequency-response characteristics of the renal vasculature.To examine the effect of activation of a unique population of renal sympathetic nerve fibers on renal blood flow (RBF) dynamics, anesthetized rats were instrumented with a renal sympathetic nerve activity (RSNA) recording electrode and an electromagnetic flow probe on the ipsilateral renal artery. Peripheral thermal receptor stimulation (external heat) was used to activate a unique population of renal sympathetic nerve fibers and to increase total RSNA. Total RSNA was reflexly increased to the same degree with somatic receptor stimulation (tail compression). Arterial pressure and heart rate were increased by both stimuli. Total RSNA was increased to the same degree by both stimuli but external heat produced a greater renal vasoconstrictor response than tail compression. Whereas both stimuli increased spectral density power of RSNA at both cardiac and respiratory frequencies, modulation of RBF variability by fluctuations of RSNA was small at these frequencies, with values for the normalized transfer gain being ∼0.1 at >0.5 Hz. During tail compression coherent oscillations of RSNA and RBF were found at 0.3-0.4 Hz with normalized transfer gain of 0.33 ± 0.02. During external heat coherent oscillations of RSNA and RBF were found at both 0.2 and 0.3-0.4 Hz with normalized transfer gains of 0.63 ± 0.05 at 0.2 Hz and 0.53 ± 0.04 to 0.36 ± 0.02 at 0.3-0.4 Hz. Renal denervation eliminated the oscillations in RBF at both 0.2 and 0.3-0.4 Hz. These findings indicate that despite similar increases in total RSNA, external heat results in a greater renal vasoconstrictor response than tail compression due to the activation of a unique population of renal sympathetic nerve fibers with different frequency-response characteristics of the renal vasculature.

Renal Sympathetic Neural Mechanisms as Intermediate Phenotype in Spontaneously Hypertensive Rats

The borderline hypertensive rat, the F1 of a cross between a hypertensive spontaneously hypertensive rat (SHR) and a normotensive Wistar-Kyoto (WKY) rat, is a NaCl-sensitive model of genetic hypertension. In addition to hypertension, borderline hypertensive rats fed 8% NaCl develop characteristic alterations in the regulation of efferent renal sympathetic nerve activity and the neural control of renal function that are similar to those observed in the SHR parent. Like the normotensive WKY rat parent, borderline hypertensive rats fed 1% NaCl remain normotensive and do not exhibit these alterations in renal sympathetic neural mechanisms. These renal sympathetic neural mechanisms constitute a complex quantitative trait that may represent an intermediate phenotype. They have a plausible pathogenetic role in hypertension and are different between SHR and WKY rats. This study evaluated two aspects of this complex quantitative trait, enhanced renal sympathoexcitation with air-jet stress and enhanced renal sympathoinhibition with guanabenz, as a candidate intermediate phenotype. As neither of these aspects was observed in two-kidney, one clip Goldblatt-hypertensive rats, this suggests that the trait is not secondary to hypertension from an acquired cause. In a backcross population (F1 x WKY) fed 8% NaCl for 12 weeks, both enhanced renal sympathoexcitation with air-jet stress and enhanced renal sympathoinhibition with guanabenz cosegregated with the hypertension. These results support renal sympathetic neural mechanisms as an intermediate phenotype in SHR.

Reflex Effects on Renal Nerve Activity Characteristics in Spontaneously Hypertensive Rats

The effects of arterial and cardiac baroreflex activation on the discharge characteristics of renal sympathetic nerve activity were evaluated in conscious spontaneously hypertensive and Wistar-Kyoto rats. In spontaneously hypertensive rats compared with Wistar-Kyoto rats, (1) arterial baroreflex regulation of renal sympathetic nerve activity was reset to a higher arterial pressure and the gain was decreased and (2) cardiac baroreflex regulation of renal sympathetic nerve activity exhibited a lower gain. With the use of sympathetic peak detection analysis, the inhibition of integrated renal sympathetic nerve activity, which occurred during both increased arterial pressure (arterial baroreflex) and right atrial pressure (cardiac baroreflex), was due to parallel decreases in peak height with little change in peak frequency in both spontaneously hypertensive and Wistar-Kyoto rats. Arterial and cardiac baroreflex inhibition of renal sympathetic nerve activity in Wistar-Kyoto and spontaneously hypertensive rats is due to a parallel reduction in the number of active renal sympathetic nerve fibers.

Frequency Response of the Renal Vasculature in Congestive Heart Failure

Background—The renal vasoconstrictor response to renal nerve stimulation is greater in congestive heart failure (CHF) rats than in control rats. This study tested the hypothesis that the enhanced renal vasoconstrictor response to renal nerve stimulation in CHF is a result of an impairment in the low-pass filter function of the renal vasculature. Methods and Results—In response to conventional graded-frequency renal nerve stimulation, the reductions in renal blood flow at each stimulation frequency were greater in CHF rats than control rats. A pseudorandom binary sequence pattern of renal nerve stimulation was used to examine the frequency response of the renal vasculature. Although this did not affect the renal blood flow power spectrum in control rats, there was a 10-fold increase in renal blood flow power over the frequency range of 0.01 to 1.0 Hz in CHF rats. On analysis of transfer function gain, attenuation of the renal nerve stimulation input signal was similar in control and CHF rats over the frequency range of 0.001 to 0.1 Hz. However, over the frequency range of 0.1 to 1.0 Hz, although there was progressive attenuation of the input signal (−30 to −70 dB) in control rats, CHF rats exhibited a flat gain response (−20 dB) without progressive attenuation. Conclusions—The enhanced renal vasoconstrictor response to renal nerve stimulation in CHF rats is caused by an alteration in the low-pass filter function of the renal vasculature, resulting in a greater transfer of input signals into renal blood flow in the 0.1 to 1.0 Hz range.