Catheter-based renal denervation in the treatment of resistant hypertension.

Clinical trials have shown that catheter-based renal denervation (RD), i.e. interruption of afferent and efferent sympathetic nerves supplying the kidney, can reduce systolic blood pressure (BP) by approximately 30 mm Hg. This technology is currently being tested as a therapeutic option for patients with resistant hypertension, a condition in which BP remains elevated despite adherence to a rational medication regimen. This novel treatment approach was developed on the basis of a wealth of animal and human research demonstrating the importance of the sympathorenal axis in the pathogenesis of hypertension. Sympathetic efferent signals to the kidneys raise BP by stimulating sodium retention and renin release, and the kidneys influence central sympathetic drive via afferent nerves. But as is true with many therapeutic advances, RD has shown benefit in clinical studies long before the mechanisms are fully understood. Additional research is needed to understand the contribution of afferent sympathetic nerve interruption to BP reductions observed with RD; to examine the degree and significance of re-innervation following RD; to elucidate factors that may lead to a lack of response to RD in some patients; to determine whether the modulation of the sympathetic nervous system via RD can have beneficial effects independent of BP reduction; and to develop methods to measure the effectiveness of RD in real time.

Micropuncture studies of the recovery phase of myohemoglobinuric acute renal failure in the rat.

Micropuncture studies of the recovery phase of glycerol-induced myohemoglobinuric acute renal failure were performed in rats whose blood urea nitrogen (BUN) had fallen at least 20% below its peak value. The glomerular filtration rate (GFR) of individual nephrons in a single kidney in the recovery period generally either was in the normal range or minimal. Each animal's BUN concentration at the time of the study was inversely related to the proportion of functioning surface nephrons, but did not correlate with individual nephron GFR values. Proximal tubule fractional water absorption was significantly depressed as manifested by both depressed inulin (TF/P) values and supernormal volumes of collections, a finding which, in the absence of a urea-induced osmotic diuresis, suggests impaired sodium transport by the damaged nephron. The mean proximal tubule hydrostatic pressure in recovery was normal and there was little variation in pressure among functioning nephrons. It is concluded that recovery from this model of acute renal failure reflects the progressive recruitment of increasing numbers of functioning nephrons. The recovery of individual nephron glomerular filtration, once begun, was rapid and complete. No evidence could be adduced that the gradual return of renal function towards normal reflects a slow release of tubular obstruction or repair of disrupted tubular epithelium. Rather, recovery appeared to be directly attributable to the return of an adequate effective glomerular filtration pressure. Significant limitation in proximal tubule water absorption persisted after individual nephron GFR had returned to normal or supernormal values in this model of experimental acute renal failure in the rat, a finding which readily accounts for the diuresis associated with the recovery phase of this syndrome.

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.

Combined antioxidant and COMT inhibitor treatment reverses renal abnormalities in diabetic rats.

The development and progression of diabetic nephropathy is dependent on glucose homeostasis and many other contributing factors. In the present study, we examined the effect of nitecapone, an inhibitor of the dopamine-metabolizing enzyme catechol-O-methyl transferase (COMT) and a potent antioxidant, on functional and cellular determinants of renal function in rats with streptozotocin-induced diabetes. Administration of nitecapone to diabetic rats normalized urinary sodium excretion in a manner consistent with the dopamine-dependent inhibition of proximal tubule Na,K-ATPase activity. Hyperfiltration, focal glomerulosclerosis, and albuminuria were also reversed by nitecapone, but in a manner that is more readily attributed to the antioxidant potential of the agent. A pattern of elevated oxidative stress, measured as CuZn superoxide dismutase gene expression and thiobarbituric acid-reactive substance content, was noted in diabetic rats, and both parameters were normalized by nitecapone treatment. In diabetic rats, activation of glomerular protein kinase C (PKC) was confirmed by isoform-specific translocation and Ser23 phosphorylation of the PKC substrate Na,K-ATPase. PKC-dependent changes in Na,K-ATPase phosphorylation were associated with decreased glomerular Na,K-ATPase activity. Nitecapone-treated diabetic rats were protected from these intracellular modifications. The combined results suggest that the COMT-inhibitory and antioxidant properties of nitecapone provide a protective therapy against the development of diabetic nephropathy.

Neural control of renal function: cardiovascular implications.

The innervation of the kidney serves to function of its component parts, for example, the blood vessels, the nephron (glomerulus, tubule), and the juxtaglomerular apparatus. Alterations in efferent renal sympathetic nerve activity produce significant changes in renal blood flow, glomerular filtration rate, the reabsorption of water, sodium, and other ions, and the release of renin, prostaglandins, and other vasoactive substances. These functional effects contribute significantly to the renal regulation of total body sodium and fluid volumes with important implications for the control of arterial pressure. The renal nerves, both efferent and afferent, are known to be important contributors to the pathogenesis of hypertension. In addition, the efferent renal nerves participate in the mediation of the excessive renal sodium retention, which characterizes edema-forming states such as congestive heart failure. Thus, the renal nerves play an important role in overall cardiovascular homeostasis in both normal and pathological conditions.

Sympathetic neural control of the kidney in hypertension.

Efferent renal sympathetic nerve activity is elevated in human essential hypertension as well as in several forms of experimental hypertension in animals. In addition, bilateral complete renal denervation delays the development and/or attenuates the magnitude of the hypertension in several different forms of experimental hypertension in animals. Efferent renal sympathetic nerve activity is known to have dose-dependent effects on renal blood flow, the glomerular filtration rate, renal tubular sodium and water reabsorption, and the renin secretion rate, which are capable of contributing, singly or in combination, to the development, maintenance, and exacerbation of the hypertensive state. Of the many factors known to influence the central nervous system integrative regulation of efferent renal sympathetic nerve activity, two environmental factors, a high dietary sodium intake and environmental stress, are capable of significant interaction. This resultant increase in efferent renal sympathetic nerve activity and subsequent renal functional alterations can participate in the hypertensive process. This is especially evident in the presence of an underlying genetic predisposition to the development of hypertension. Thus, interactions between environmental and genetic influences can produce alterations in the sympathetic neural control of renal function that play an important role in hypertension.

Stress and sodium intake in neural control of renal function in hypertension.

The interaction between genetic and environmental factors is important in the pathophysiology of hypertension. By examining the effects of two environmental factors--acute psychoemotional stress and dietary sodium intake--in rats with genetic hypertension, an important influence on central neural mechanisms governing the renal sympathetic neural control of renal function has been demonstrated. Additional studies of the central opioid systems have demonstrated an important role of opioid peptides in modulating the renal functional responses to acute psychoemotional stress. The observed renal functional alterations--antidiuresis, antinatriuresis, and renal vasoconstriction--are known to be capable of contributing to the initiation, development, and maintenance of the hypertensive process.

Central adrenergic receptor control of renal function in conscious hypertensive rats.

The role of central nervous system alpha-adrenergic and beta-adrenergic receptors in the increased renal sympathetic nerve activity and antinatriuresis resulting from environmental stress (air stress) in conscious spontaneously hypertensive rats (SHR) was examined. Intracerebroventricular administration of the alpha 2-adrenergic receptor agonist clonidine (1, 5, and 15 micrograms) prevented the effects of air stress on renal sympathetic nerve activity and urinary sodium excretion. Clonidine, 5 and 15 micrograms, lowered baseline mean arterial pressure and renal sympathetic nerve activity and increased baseline urine flow rate and urinary sodium excretion; clonidine, 1 micrograms, had no effect on these baseline levels. Intravenous administration of 5 micrograms, but not 1 microgram of clonidine, abolished the renal responses to air stress. Intracerebroventricular administration of alpha 2-adrenergic receptor antagonists (yohimbine, rauwolscine) reversed the effects of clonidine, alpha 2-adrenergic receptor blockade alone, alpha 1-adrenergic receptor blockade (20 micrograms prazosin), or combined alpha 1-adrenergic and alpha 2-adrenergic receptor blockade (30 micrograms phenoxybenzamine) had no effect on the renal sympathetic nerve activity or antinatriuretic responses to air stress. Intracerebroventricular, but not intravenous, administration of the beta 2-adrenergic receptor antagonist ICI 118551 (30 micrograms) prevented the increased renal sympathetic nerve activity and antinatriuretic responses to air stress. In contrast, intracerebroventricular administration of the beta 1-adrenergic receptor antagonist atenolol (30 micrograms) had no effect on the renal responses to air stress. These results indicate that the increased renal sympathetic nerve activity and antinatriuresis resulting from environmental stress in conscious SHR can be prevented by pharmacological stimulation of central alpha 2-adrenergic receptors or by blockade of central beta 2-adrenergic receptors.

High sodium intake enhances renal nerve and antinatriuretic responses to stress in spontaneously hypertensive rats.

The effects of high sodium intake (drinking 0.9% NaCl for 15 days) on the increased renal sympathetic nerve activity and decreased urinary sodium excretion resulting from stressful environmental stimulation (air jet to head) were examined in conscious spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). On a normal sodium intake in SHR, air stress increased renal sympathetic nerve activity 77% and decreased urinary sodium excretion 28% without altering effective renal plasma flow or glomerular filtration rate. By contrast, in conscious SHR on high sodium intake, the same air stress caused a greater increase in renal sympathetic nerve activity (103%) and a greater antinatriuresis (42%) along with reductions in effective renal plasma flow and glomerular filtration rate. Surgical renal denervation prevented the antinatriuretic responses to air stress in other conscious SHR on high or normal sodium intake. In conscious WKY, air stress had no effect on renal sympathetic nerve activity or urinary sodium excretion, regardless of normal or high sodium intake. We conclude that the enhanced renal sympathetic nerve activity and antinatriuretic responses to air stress in conscious SHR on high sodium intake are dependent on a centrally mediated facilitation of sympathetic neural outflow to the kidney. The greater antinatriuretic response to air stress in conscious SHR than in WKY may reflect a greater genetic predisposition in SHR to increase renal sympathetic nerve activity during air stress.

Role of renal alpha 2-adrenergic receptors in spontaneously hypertensive rats.

To identify a physiological role for renal alpha 2 adrenergic receptors, renal vascular and tubular responses to administration of graded frequencies of renal nerve stimulation or graded doses of adrenergic agonists were determined in anesthetized spontaneously hypertensive, Wistar-Kyoto, and Sprague-Dawley rats. Renal vasoconstrictor responses to renal nerve stimulation and alpha 1-adrenergic receptor agonists (norepinephrine, phenylephrine) were inhibited by an alpha 1-adrenergic receptor antagonist (prazosin) but not by an alpha 2-adrenergic receptor antagonist (rauwolscine). A semilog plot of renal vasoconstrictor responses a fraction of control renal blood flow versus agonist dose (in nanograms) was linear with the slope, k, taken as the fractional decrease in renal blood flow per nanogram. The alpha 2-adrenergic receptor agonists (clonidine, guanabenz) produced minimal renal vasoconstrictor responses (fractional decrease in renal blood flow per nanogram: norepinephrine, 0.011; phenylephrine, 0.003; clonidine, 0.00087; guanabenz, 0.000037). The small renal vasoconstrictor responses to clonidine and guanabenz were more inhibited by rauwolscine than by prazosin. Low frequency renal nerve stimulation produced antidiuresis and antinatriuresis without decreasing glomerular filtration rate or renal blood flow. The antidiuretic and antinatriuretic responses were inhibited by prazosin but unaffected by rauwolscine. The magnitude of the renal vascular and tubular responses and their adrenergic receptor mediation were not different between spontaneously hypertensive, Wistar-Kyoto, and Sprague-Dawley rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Arterial baroreceptor reflex function in borderline hypertensive rats.

With increased dietary NaCl intake (8% NaCl), the borderline hypertensive rat develops hypertension, thus expressing the phenotype of the spontaneously hypertensive parent. Since arterial baroreceptor reflex function is impaired in the spontaneously hypertensive parent, it was the objective of this study to examine arterial baroreceptor reflex function in the borderline hypertensive rat made hypertensive by increased dietary NaCl intake. Borderline hypertensive rats were fed either 1% or 8% NaCl from age 4 to 16 weeks. Borderline hypertensive rats fed 8% NaCl (n = 10) were hypertensive compared with borderline hypertensive rats fed 1% NaCl (n = 11) (141 +/- 3 versus 120 +/- 4 mm Hg, p less than 0.01). They were chronically instrumented for the recording of arterial pressure, heart rate, and renal sympathetic nerve activity. The percent change from control in heart rate and renal sympathetic nerve activity resulting from increases (phenylephrine) and decreases (nitroglycerine) in arterial pressure were measured in conscious freely moving animals. With respect to arterial baroreceptor reflex control of heart rate, 8% NaCl borderline hypertensive rats had a similar range (75 +/- 4%) and maximal gain (-2.72 +/- 0.24%/mm Hg) as 1% NaCl borderline hypertensive rats (70 +/- 4%; -2.78 +/- 0.50%/mm Hg). With respect to arterial baroreceptor reflex control of renal sympathetic nerve activity, 8% NaCl borderline hypertensive rats had values for range (205 +/- 22%) and maximal gain (-3.92 +/- 0.93%/mm Hg) that were not significantly different from those for 1% NaCl borderline hypertensive rats (167 +/- 33%, -2.76 +/- 0.62%/mm Hg).(ABSTRACT TRUNCATED AT 250 WORDS)

Renal manifestations of NaCl sensitivity in borderline hypertensive rats.

Compared with the normotensive Wistar-Kyoto rat, the spontaneously hypertensive rat exhibits exaggerated alterations in renal sympathetic nerve activity and excretory function during volume expansion (exaggerated natriuresis) and environmental stress (antinatriuresis). The borderline hypertensive rat is the first filial offspring of the spontaneously hypertensive rat and the Wistar-Kyoto rat and develops hypertension with increased dietary NaCl intake. The present investigation sought to determine whether the dietary NaCl intake-induced transition from the normotensive state of the Wistar-Kyoto parent to the hypertensive state of the spontaneously hypertensive parent in the borderline hypertensive rat was accompanied by a similar transition of the renal sympathetic nerve activity and excretory responses to volume expansion and environmental stress. Borderline hypertensive rats fed a 1% NaCl diet remained normotensive and exhibited renal sympathetic nerve activity and excretory responses to volume expansion and environmental stress that were similar to those of their Wistar-Kyoto parent. Borderline hypertensive rats fed an 8% NaCl diet developed hypertension and exhibited responses that were similar to those of their spontaneously hypertensive parent. Thus, the dietary NaCl intake-induced transition from the normotensive state of the Wistar-Kyoto parent to the hypertensive state of the spontaneously hypertensive parent in the borderline hypertensive rat was accompanied by a similar transition of the renal sympathetic nerve activity and excretory responses to volume expansion and environmental stress. The results suggest that increased dietary NaCl intake is able to induce or unmask the capabilities for these responses, which are genetically conveyed to the borderline hypertensive rat by the spontaneously hypertensive rat parent in latent forms.

Ganglionic blockade with tetraethylammonium in conscious rats.

The sympathetic ganglionic blocking agent tetraethylammonium has been used as a clearance marker for the measurement of renal plasma flow, but the sympathetic ganglionic blocking dose in rats is unknown. In light of differential reflex activation of sympathetic nerve activity to heart and kidney, we compared the effect of tetraethylammonium on renal nerve activity, mean arterial pressure, and heart rate. Conscious rats were infused with either vehicle (isotonic saline) or tetraethylammonium (n = 7 in both groups). Tetraethylammonium was infused cumulatively (35 minutes per dose) in the following doses: 10(-5), 10(-4), 10(-3), 10(-2), and 10(-1) g/kg body wt per hour. Doses for 15% reduction were 10(-1) for mean arterial pressure, 0.55 x 10(-1) for heart rate, and 0.055 x 10(-1) g/kg body wt per hour for renal nerve activity. Renal nerve activity was abolished at 10(-1) g/kg body wt per hour; mean arterial pressure and heart rate were unchanged at doses lower than 10(-1) g/kg body wt per hour. The lethal dose was 1 g/kg body wt per hour. No changes were observed in vehicle-treated animals. Tetraethylammonium at 10(-1) g/kg body wt per hour resulted in an attenuated increase in renal nerve activity during acetylcholine-induced reduction in mean arterial pressure, reflecting arterial baroreceptor inhibition. We conclude that renal nerve activity is 10- and 18-fold more sensitive to sympathetic ganglionic blockade than heart rate and mean arterial pressure, respectively. When tetraethylammonium is used as a clearance marker for measurement of renal plasma flow in rats, it should be administered in doses less than 10(-2) g/kg body wt per hour.

Cardiopulmonary baroreflex in NaCl-induced hypertension in borderline hypertensive rats.

Borderline hypertensive rats fed an 8% NaCl diet develop increased arterial pressure in association with increased cardiopulmonary baroreflex sensitivity compared with rats fed a 1% NaCl diet. We performed experiments to localize the site of sensitization within the cardiopulmonary baroreflex. To determine whether decreased cardiopulmonary baroreflex sensitivity, as seen in other models of NaCl-induced hypertension, develops later in the course of the disease, we studied an older backcross population derived from borderline hypertensive rats and Wistar-Kyoto rats. Anesthetized borderline hypertensive rats fed 1% and 8% NaCl diets were volume-loaded while right atrial pressure, afferent vagal nerve activity, and renal sympathetic nerve activity were recorded. In 28- to 30-week-old backcross rats fed an 8% NaCl diet, renal sympathetic nerve activity, natriuresis, and diuresis were measured before and during volume loading. Renal sympathetic nerve activity was analyzed with the sympathetic peak detection algorithm. Increases in afferent vagal nerve activity and renal sympathoinhibition were similar in borderline hypertensive rats on either diet during a right atrial pressure rise of 3 mm Hg. In backcross rats, correlations between arterial pressure and renal sympathoinhibition, natriuresis, or diuresis were not found. During volume loading, the peak height of synchronized renal sympathetic nerve discharges decreased while their frequency increased. Attenuated renal sympathoinhibition during acute increases in intravascular volume is not involved in the development or maintenance of NaCl-induced hypertension in borderline hypertensive rats. Renal sympathetic nerve activity decreases because of a reduction in the number of active renal sympathetic nerve fibers.

Furosemide elicits nonuniform reflex responses via cardiac sympathetic afferents.

To examine whether furosemide elicits a cardiorenal reflex response via stimulation of cardiac afferents, furosemide was administered intrapericardially in sinoaortic denervated rats. The role of vagal afferents was evaluated by intrapericardial (IPC) administration of furosemide before and after bilateral vagotomy. The role of cardiac sympathetic afferents was examined by IPC administration of furosemide before and after IPC lidocaine blockade in rats with bilateral vagotomy. Low-dose furosemide (10 micrograms) elicited renal sympathoinhibition, whereas high-dose furosemide (1000 micrograms) produced a rapid and transient change in efferent renal sympathetic nerve activity of either inhibitory (19/49, or 39%) or excitatory (30/49, or 61%) nature. The responses were not affected by vagotomy but were abolished by IPC lidocaine blockade. In rats with a renal sympathoinhibitory response to IPC administration of 1000 micrograms furosemide, both the hypotensive and sympathoinhibitory responses were inhibited by indomethacin, whereas indomethacin did not affect reflex responses in rats showing a renal sympathoexcitatory response to IPC injection of 1000 micrograms furosemide. We conclude that furosemide elicits a nonuniform reflex response mediated via cardiac sympathetic afferents of which the renal sympathoinhibitory response is dependent on intact cyclooxygenase function.

Analysis of renal sympathetic nerve responses to stress.

We studied sympathetic nerve activity responses to acute environmental stress (air jet stress) in conscious Wistar-Kyoto, spontaneously hypertensive, and borderline hypertensive rats. The borderline hypertensive rats were fed either 1% (normotensive) or 8% (hypertensive) NaCl. Renal sympathetic nerve activity responses were analyzed with three methods: mean integrated voltage over time, power spectrum analysis, and sympathetic peak detection analysis. Measurements of mean integrated voltage over time showed that air jet stress increased renal sympathetic nerve activity in spontaneously hypertensive rats and in borderline hypertensive rats on 8% NaCl but not in the other groups. In the NaCl responders, power spectrum analysis of renal sympathetic nerve activity indicated that the increase in relative power was at the heart rate frequency, indicating that it was related to renal sympathetic nerve discharge coupled to the cardiac cycle. Sympathetic peak detection analysis of renal sympathetic nerve activity indicate that there was an increase in frequency of sympathetic peaks of greater height and shorter duration because of sinoaortic baroreceptor deactivation (increased peak frequency) and the recruitment of more active fibers (greater peak height) firing with greater synchronization (shorter peak duration). Additional methods of analysis of renal sympathetic nerve activity provide information in addition to that derived from measurement of mean integrated voltage over time.

Acute sympathoinhibitory actions of metformin in spontaneously hypertensive rats.

Chronic treatment with the antihyperglycemic agent metformin prevents hypertension in spontaneously hypertensive rats. This effect has been ascribed to normalization of plasma insulin levels. However, whether metformin affects arterial pressure via changes in sympathetic nerve activity is unknown. Therefore, the objective of this study was to examine whether acute administration of metformin produces changes in mean arterial pressure, heart rate, or efferent renal sympathetic nerve activity in spontaneously hypertensive rats. Rats were anesthetized with alphaxalone-alphadolone (Saffan), paralyzed with pancuronium, and artificially ventilated. Intravenous administration of metformin (0, 1, 10, 100 mg/kg) produced dose-dependent reversible decreases in mean arterial pressure, heart rate, and efferent renal sympathetic nerve activity that were not affected by arterial or cardiopulmonary baroreceptor denervation, nitric oxide synthase inhibition by N(omega)-nitro-L-arginine methyl ester, or cyclooxygenase inhibition by indomethacin. Metformin given into the lateral cerebral ventricle (250, 500, 1000 microg) produced dose-dependent decreases in mean arterial pressure, heart rate, and efferent renal sympathetic nerve activity in doses that caused no changes when given intravenously. The sympathoinhibitory response to intracerebroventricular administration of metformin was not affected by alpha2-adrenoceptor blockade by intracerebroventricular yohimbine. We conclude that metformin has acute sympathoinhibitory effects (decreased arterial pressure, heart rate, and efferent renal sympathetic nerve activity) that are produced by a direct central nervous system site of action.

Central beta-adrenergic receptors mediate renal nerve activity during stress in conscious spontaneously hypertensive rats.

The effects of intracerebroventricular (i.c.v.) administration of beta-adrenergic receptor antagonists (d,l-propranolol or timolol, 30 micrograms in 2 microL of isotonic saline) on the increased renal sympathetic nerve activity and decreased urinary sodium excretion (UNaV) responses to stressful environmental stimulation (air jet to head) in conscious spontaneously hypertensive rats (SHR) were examined. Before i.c.v. d,l-propranolol or timolol, air stress increased renal activity (68% from 10.6 +/- 2.1 and 63% from 8.2 +/- 0.9 integrator resets/min respectively). In contrast, after i.c.v. d,l-propranolol or timolol in the same conscious SHR, air stress had no effect on renal sympathetic nerve activity (+7% from 8.1 +/- 1.7 and +7% from 5.5 +/- 1.0 integrator resets/min respectively). Air stress decreased UNaV in conscious SHR given i.c.v. saline vehicle (25% from 2.8 +/- 0.5 microEq/min/100 g body weight), but had no effect on effective renal plasma flow or glomerular filtration rate. In contrast, after i.c.v. d,l-propranolol or timolol, air stress had no effect on UNaV (0% from 2.8 +/- 0.5 and +9% from 3.3 +/- 0.3 microEq/min/100 g body weight respectively). Mean arterial pressure increased similarly during air stress with i.c.v. saline-vehicle or beta-adrenergic receptor antagonists. Intravenous administration of the same doses of d,l-propranolol or timolol did not prevent the increased renal sympathetic nerve activity or decreased UNaV responses resulting from air stress. These results suggest that central nervous system beta-adrenergic receptors mediate the increased renal sympathetic nerve activity and decreased UNaV responses resulting from stressful environmental stimulation in conscious SHR.

Cardiac volume receptor reflex in borderline hypertensive rats.

With increased dietary NaCl intake (8% NaCl), borderline hypertensive rats (BHR) develop hypertension and exhibit an exaggerated natriuresis in response to intravenous isotonic saline volume expansion. The exaggerated natriuresis is mediated by the concurrent exaggerated withdrawal of efferent renal sympathetic nerve activity since prior renal denervation eliminates the exaggerated natriuretic response. It was the objective of the present study to examine cardiac volume receptor reflex control of efferent renal sympathetic nerve activity in BHR made hypertensive by increased dietary NaCl intake. BHR were fed either 1% or 8% NaCl from age 4 to 16 weeks. BHR fed 8% NaCl were hypertensive (148 +/- 9 mmHg) compared with BHR fed 1% NaCl (115 +/- 6 mm Hg, p < 0.05). In one protocol, measurements of right atrial pressure and efferent renal sympathetic nerve activity were made in sinoaortic-denervated BHR before and during a 10% body weight intravenous isotonic saline volume load. Compared with 1% NaCl BHR, 8% NaCl BHR showed both a greater maximal inhibition of efferent renal sympathetic nerve activity (-67 +/- 4% versus -31 +/- 3% of control, p < 0.05) and gain (-22.0 +/- 2.3 versus -9.7 +/- 1.7%/mm Hg, p < 0.05). In a second protocol, measurements of efferent renal sympathetic nerve activity were made in sinoaortic-denervated BHR before and during graded frequency stimulation of the central portion of the sectioned vagus nerve.(ABSTRACT TRUNCATED AT 250 WORDS)

Sodium responsiveness of central alpha 2-adrenergic receptors in spontaneously hypertensive rats.

The responsiveness of central nervous system alpha 2-adrenergic receptors in the neural control of renal function was compared in conscious spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) on normal or high sodium intake (3-4 weeks of 1% NaCl for drinking). The responsiveness of central alpha 2-adrenergic receptors was determined by comparing among groups the dose-response curves for the effects of cumulative intracerebroventricular injections of guanabenz (5, 25, and 125 micrograms) on changes in mean arterial pressure, renal sympathetic nerve activity, and urinary sodium excretion. Guanabenz altered mean arterial pressure similarly in SHR on normal or high sodium intake and in WKY on normal or high sodium intake. High sodium intake shifted the guanabenz-renal sympathetic nerve activity and guanabenz-urinary sodium excretion dose-response curves to the left in SHR and to the right in WKY. The dose-response curves between SHR and WKY on normal sodium intake were similar. Surgical renal denervation or pretreatment with an alpha 2-adrenergic receptor antagonist (rauwolscine, 30 micrograms i.c.v.) attenuated the ability of guanabenz to inhibit renal sympathetic nerve activity or increase urinary sodium excretion in SHR and WKY on either normal or high sodium intake. We conclude that the responsiveness of central nervous system alpha 2-adrenergic receptors regarding the neural control of renal function is increased by high sodium intake in conscious SHR, but not in conscious normotensive WKY.