Chronic Renal Neuroadrenergic Hypertension Is Associated With Increased Renal Norepinephrine Sensitivity and Volume Contraction
Individuals with essential hypertension have been characterized by increased renal sympathetic vascular tone with decreased plasma volume and normal cardiac output compared with normotensive individuals. We used a servo-controlled intrarenal infusion system to evaluate the hemodynamic, renal excretory, and plasma hormonal responses to 28-day, low-level elevations in the intrarenal adrenergic neurotransmitter norepinephrine. In uninephrectomized dogs (n=6), servo-controlled norepinephrine infusion increased mean arterial pressure from 95.6±3.1 to 115.7±4.9 mm Hg on day 1 without concomitant reductions in renal blood flow. Arterial hypertension was sustained and renal vascular resistance increased during the 28 days of servo-controlled norepinephrine infusion despite significant decreases in the daily dose of intrarenal norepinephrine (1.49±0.23 to 0.47±0.25 mg/d) necessary to maintain renal blood flow constant. Arterial pressure returned to control values with the cessation of servo-controlled norepinephrine, whereas renal blood flow and renal vascular resistance remained slightly decreased and increased, respectively. Cumulative sodium balance exhibited a net 177±37 mmol sodium loss over the 28 days of norepinephrine infusion, indicating that the hypertension did not result from sodium retention or expansion of extracellular fluid volume. Intrarenal norepinephrine did not change plasma epinephrine, norepinephrine, or vasopressin concentrations. Atrial natriuretic factor, however, increased at 7 and 14 days of servo-controlled norepinephrine, and plasma renin activity increased on day 14 of norepinephrine infusion. We conclude that low-level elevation of intrarenal adrenergic neurotransmitter produces sustained arterial hypertension that is independent of expansion in extracellular fluid volume, increases in circulating catecholamines or plasma renin activity, or reductions in renal blood flow. This hypertension may be associated with increased renal vascular sensitivity to norepinephrine and/or other renal vasoactive factors.
The kidney has a preeminent position in body fluid volume homeostasis and thus contributes importantly to blood pressure regulation. Abnormal renal function has been considered an essential component in both experimental models and human essential hypertension. Many reports over the past 20 years indicate that various extrinsic factors such as hormones and the renal nerves may play an important role in the pathogenesis of hypertension. Neurally mediated alterations in renal function may be particularly important because the kidney is one of the most highly innervated peripheral organs, and the endocrine, excretory, and hemodynamic functions of the kidney are directly affected by renal sympathetic nerve activity.
Differences in renal sympathetic outflow between genetically hypertensive and normotensive animals have been reported. SHR exhibit greater renal sympathetic nerve activity than age-matched normotensive Wistar-Kyoto rats in both whole-nerve and single-fiber recordings.1 2 In this regard, renal nerve activity increased over 25 weeks of age in these rats, with nerve activity in the SHR increasing nearly 2.5 times more than in the Wistar-Kyoto rats. Over the same period of time, arterial pressure increased significantly in the SHR, whereas little change in blood pressure was observed in the Wistar-Kyoto rats. These findings provide a strong correlation between increases in renal sympathetic nerve activity and arterial pressure.
Renal denervation also delays the onset or blunts the magnitude of arterial pressure rise in a variety of experimental models of hypertension. Liard3 first demonstrated that bilateral surgical and chemical renal denervation of the kidneys of SHR delayed the onset of hypertension by 2 to 3 weeks. Norman and Dzielak4 found that serial bilateral renal denervations at 3-week intervals prevented full expression of hypertension in SHR. Therefore, persistent renal denervation prevented 30% to 40% of the progressive elevation in arterial pressure that occurs in the SHR with increasing age.
Evidence of elevated renal sympathetic nerve activity manifested as increased RVR and decreased RBF has been demonstrated in human essential hypertension. The increase in RBF in response to intrarenal arterial administration of the α-antagonist phentolamine was significantly greater in human essential hypertensive patients than in normotensive control subjects.5 Intrarenal β-blockade with the nonselective β-antagonist propranolol decreased RBF, suggesting an unmasking of potent α-adrenergic vasoconstrictor tone.6 These results suggest that elevated sympathetic vasoconstrictor influences on the renal vasculature may promote human essential hypertension.
Other investigators have used direct intrarenal norepinephrine infusion to simulate increased renal sympathetic nerve activity in chronically instrumented dogs7 8 9 and rats.10 11 Although these studies used fixed, relatively high doses of intrarenal norepinephrine that may have produced systemic spillover of catecholamines, significant reductions in RBF, increases in PRA, and/or renal ischemia, they categorically resulted in sustained arterial hypertension. Similar doses of norepinephrine administered intravenously were not capable of producing chronic arterial hypertension. These findings imply that selective increases in intrarenal adrenergic neurotransmitter may mediate alterations in renal function and elicit arterial hypertension.
We designed the present experiments to determine whether direct, chronic elevation of intrarenal norepinephrine at nonvasoconstrictor doses produces sustained arterial hypertension. We circumvent marked renal vasoconstriction by using a servo-controlled infusion system that increases intrarenal norepinephrine concentration but keeps it below the threshold that reduces whole-kidney blood flow. The results indicate that chronic, low-level increases in intrarenal neuroadrenergic stimulation produce sustained arterial hypertension in the absence of changes in RBF and extracellular fluid volume expansion.
Experiments were conducted on mongrel dogs of either sex weighing 14 to 17 kg. Dogs were prepared for study within the Medical College of Wisconsin Animal Resource Center by being treated for ectoparasites and endoparasites as well as being immunized for parvovirus, canine distemper, hepatitis, parainfluenza, and coronavirus. All experiments were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and all protocols received prior approval from the institutional animal care and use committee. Dogs were fed a low sodium diet supplemented with sodium chloride to achieve a sodium intake of 40 mmol/d (normal sodium intake). This dietary regimen provided a constant and known level of dietary sodium intake. Throughout the experimental protocol, dogs were allowed water ad libitum.
All surgical procedures in this study were conducted with aseptic technique. With dogs under general anesthesia (1.0% halothane) after sodium thiamylal induction (30 mg/kg IV), the right kidney was removed via a flank incision and retroperitoneal approach. Dogs were allowed at least 3 weeks of surgical recovery and contralateral renal hypertrophy before surgical instrumentation for study.
Via a small suprapubic midline incision, a specially designed, chronic catheter was inserted into the dome of the urinary bladder for urine collection. Catheters were also inserted via the femoral vessels into the aorta for direct arterial pressure measurement and blood collection and into the vena cava for intravenous drug infusion. All catheter lines were tunneled subcutaneously to the midscapular region of the back and exteriorized.
Dogs then were prepared for intrarenal arterial infusion of norepinephrine and measurement of RBF. The left kidney was exposed through a retroperitoneal flank incision. All visible renal nerves were isolated and sectioned to eliminate endogenous nerve activity to the experimental kidney. A nonocclusive catheter was sewn into the media of the renal artery with a technique similar to that described by Herd and Barger.12 An ultrasonic Doppler flow transducer (20 MHz) was placed and anchored approximately 2.0 cm distal to the renal artery and aorta anastomosis for measurement of renal arterial flow (Crystal Biotech). Absolute RBF was obtained at this time with a precalibrated electromagnetic flow probe and calibrated to the Doppler flow signal. All lines were sutured in place and exteriorized at the midscapular region where they were held with a nylon jacket (Mach Designs). Dogs were administered procaine penicillin G and dihydrostreptomycin sulfate (Combiotic, 300 000 U IM), acepromazine maleate (0.3 mg/kg SC) postoperatively, and ampicillin (500 mg BID) as prophylactic antibiotic therapy. All experiments were conducted after at least 1 week of recovery from surgical instrumentation.
Each dog was harnessed in its home cage for chronic study with all lines passing through a large flexible hose anchored to the back of the dog's jacket to allow free movement in the pen. After sodium balance was achieved, a 4-day control period was initiated with intrarenal infusion of vehicle (1 mg/mL ascorbate, 3 U/mL heparin sodium in sterile water, approximately 35 mL/d). Intrarenal norepinephrine infusion began on day 5 and continued for the next 28 consecutive days, followed by a 5-day recovery period with intrarenal infusion of vehicle.
Delivery of intrarenal norepinephrine was servo-controlled to RBF as determined by the voltage output from the ultrasonic Doppler flowmeter over the 4 control days. This approach provides simultaneous adjustments in the intrarenal infusion of adrenergic neurotransmitter, which prevents the accumulation of increasing norepinephrine concentrations as total RBF decreases in response to the vasoconstrictor effects of norepinephrine. Thus, the daily servo-controlled norepinephrine dose infused for each dog is the maximum elevation of intrarenal neurotransmitter allowed without causing a reduction in RBF.
Daily sodium balance was determined by 24-hour urine collection via a roller pump (Ismatech, Cole Parmer) connected to the dog's vented bladder catheter. Daily water intake was determined volumetrically. Arterial blood (12 mL) was collected from the aortic catheter on day 3 of control; days 7, 14, and 28 of intrarenal norepinephrine infusion; and day 5 of recovery for determination of plasma hormone and electrolyte concentrations and plasma osmolality. Blood for PRA and arginine vasopressin determinations was collected into chilled tubes containing 7.2 mg EDTA (1.4 mg/mL); blood for ANF determinations was collected into tubes containing 5 mg soybean trypsin inhibitor (1 mg/mL) and 14.5 mg aprotinin (2.9 mg/mL) and was stored at −30°C until assayed. Finally, blood for determination of plasma epinephrine and norepinephrine was collected into chilled tubes containing 0.24 mol/L Na2EGTA and 0.19 mol/L reduced glutathione and stored at −80°C until assayed.
Analytical and Statistical Procedures
Plasma and urinary sodium and potassium concentrations were determined by flame photometry (Corning 480), and osmolality was measured by freezing point depression (Precision Instruments). PRA was determined by radioimmunoassay for Ang I generation after 3 hours of incubation at 37°C.13 Plasma norepinephrine and epinephrine concentrations were measured by high-performance liquid chromatography combined with electrochemical detection (Bioanalytical Systems). ANF and vasopressin concentrations were both measured by radioimmunoassay.
Systemic and renal hemodynamic parameters, including systolic, diastolic, and mean arterial pressures; heart rate; and RBF, were acquired with an Apollo 3500 domain series computer (Apollo Computers). Data were obtained at a frequency of 30 Hz with Significat data-acquisition software (version 2.4). Systemic arterial pressure was measured with a pressure transducer (CDX III, COBE Cardiovascular, Inc). Heart rate was measured by peak height analysis of the pulsatile arterial pressure waveform. RBF was measured with pulsed Doppler flowmetry (Crystal Biotech VF1), using the Doppler shift (in kilohertz) as an index of red blood cell velocity. All Doppler flow probe signals were calibrated in vivo via timed blood collection following completion of the protocol. All hemodynamic parameters were averaged in 1-minute intervals throughout the protocol.
Data were calculated as mean±SE. Continuously recorded data were averaged over the same timed 24-hour intervals as the urine collections. Data was stored on-line (Apollo 3500) and transferred to the laboratory computer systems (IBM-PC) for complete data analysis. Between-animal variation was statistically evaluated by one-way ANOVA and within-animal variation by two-way ANOVA. Post hoc analyses of mean differences were determined by Tukey's least significant difference procedure. The .05 level of probability was used as the criterion of significance for all comparisons.
The effects of long-term, servo-controlled intrarenal norepinephrine infusion on arterial pressure, RBF, and heart rate are shown in Fig 1⇓. Servo-controlled intrarenal norepinephrine infusion increased mean arterial pressure from 95.60±3.10 to 115.68±4.93 mm Hg on day 1 and achieved the maximum value of 119.25±5.12 on day 6. The increase in mean arterial pressure was associated with increased systolic pressure from 132.47±3.80 to 158.90±5.95 mm Hg and diastolic pressure from 65.82±3.39 to 81.55±4.59 mm Hg on day 1 of intrarenal norepinephrine infusion. Systolic pressure achieved its maximum value (166.57±7.96 mm Hg) on day 15, and diastolic pressure peaked (87.40±5.35 mm Hg) on day 14 of intrarenal norepinephrine infusion. Arterial pressure remained elevated throughout the 28-day experimental period. After intrarenal norepinephrine administration was stopped, mean arterial pressure promptly returned to control values (97.90±4.28 mm Hg; day 1 of recovery) and remained stable for the 5-day recovery period.
The initial arterial pressor response was produced independently of significant alterations in RBF on days 1 through 9 of servo-controlled intrarenal norepinephrine. The chronic intrarenal norepinephrine infusion coupled with sustained arterial hypertension did elicit modest reductions (approximately 18%) in RBF on days 10 through 13, 18 through 20, 23, and 27 through 28 of the experimental period. In contrast to arterial pressure, RBF values remained decreased compared with control values on days 2 through 4 of the 5-day recovery period.
Finally, with the initiation of servo-controlled intrarenal norepinephrine, heart rate decreased from 96.29±4.42 to 82.88±5.02 beats per minute (bpm) on day 1 of norepinephrine concomitant with the increase in mean arterial pressure, suggesting a baroreflex-mediated decrement in heart rate (Fig 1⇑). The decrease in heart rate achieved significance on day 2 (78.75±3.98 bpm, P≤.05) and remained reduced during norepinephrine infusion. Heart rate promptly returned to control values (97.80±4.35 bpm) after intrarenal norepinephrine infusion was terminated.
Circulating vasoactive hormones (epinephrine, norepinephrine, vasopressin, PRA, and ANF) were measured during control and after 1, 2, and 4 weeks of elevated intrarenal norepinephrine, as well as on the fifth day of the recovery period. Throughout the 4 weeks of servo-controlled intrarenal norepinephrine infusion, plasma norepinephrine (213.53±30.22 pg/mL), epinephrine (211.00±77.02 pg/mL), and vasopressin (4.03±0.35 pg/mL) concentrations remained unchanged (Fig 2⇓). PRA increased after 1 week of intrarenal norepinephrine infusion from 0.87±0.08 to 2.99±0.53 ng Ang I/mL per hour and achieved a maximal value of 5.08±1.99 on day 14 of servo-controlled intrarenal norepinephrine infusion (Fig 2⇓). Circulating ANF concentrations also increased in response to servo-controlled intrarenal norepinephrine infusion from 88.27±10.56 to 200.48±40.81 pg/mL on day 7 of norepinephrine infusion, peaking at 237.03±54.03 on day 14 of servo-controlled intrarenal norepinephrine.
Changes in extracellular fluid volume status that may have contributed to the arterial hypertension were indirectly assessed by determination of cumulative sodium balance and arterial hematocrit. Although the experiment was begun in each dog when zero sodium balance was achieved, urinary sodium excretion continually increased during the 28-day servo-controlled intrarenal norepinephrine infusion protocol (Fig 3⇓). By the third day of intrarenal norepinephrine infusion, the dogs achieved a negative sodium balance, which continued over the course of the 28 days. As arterial hypertension was maintained, each dog exhibited natriuresis and diuresis, resulting in a net loss of 176.95±36.77 mmol sodium. The natriuretic state of the dogs reversed when intrarenal norepinephrine was stopped, as evidenced by no further decrement in cumulative sodium balance during the 5-day recovery period.
As an estimate of extracellular fluid volume status, arterial hematocrit was determined in each dog at weekly intervals throughout the norepinephrine infusion protocol. Arterial hematocrit increased from 40.58±1.49% during control to 47.17±1.56% on day 14 of intrarenal norepinephrine infusion, reaching a maximum value of 49.17±2.15% by day 28 (Fig 3⇑). Arterial hematocrit then returned toward control values (43.67±1.95%) by the fifth day of recovery. Thus, these data suggest that sustained natriuresis and diuresis occur in response to chronic low-level elevations in intrarenal norepinephrine and subsequent sustained arterial hypertension.
Plasma sodium, potassium, and osmolality also were determined before, during, and after servo-controlled intrarenal norepinephrine infusion. Plasma sodium concentration began to decrease after 1 week of intrarenal norepinephrine, and this hyponatremia achieved a nadir after 4 weeks of intrarenal norepinephrine infusion (Table⇓). Similarly, plasma potassium values decreased progressively from control (4.61±0.12 mmol/L) throughout the protocol, attaining a minimum value of 3.88±0.11 mmol/L after 4 weeks of servo-controlled intrarenal norepinephrine infusion. Plasma osmolality remained unchanged over the course of the 4-week servo-controlled norepinephrine infusion protocol (Table⇓). The reductions of plasma sodium and potassium concentrations during the 28-day intrarenal norepinephrine–mediated hypertension were reversed during the 5-day recovery period.
Since the dose of intrarenal norepinephrine was servo-controlled rather than fixed, the possibility exists that an altered dose of intrarenal norepinephrine being infused provided for the chronic arterial hypertension. We studied renal vascular adrenergic sensitivity by examining the relationship between RVR and calculation of the daily servo-controlled dose of intrarenal norepinephrine (Fig 4⇓). RVR was increased by intrarenal norepinephrine on day 1 from 0.763±0.085 to 1.099±0.124 mm Hg/mL per minute and remained elevated for the entire 28 days of norepinephrine infusion. Cessation of intrarenal norepinephrine decreased RVR, although it did not return completely to control values after the 5-day recovery period. The dose of servo-controlled intrarenal norepinephrine progressively decreased over the 28-day infusion period from 1.49±0.23 mg/d on day 1 to 0.47±0.25 by day 21 (Fig 4⇓). Thus, a sustained increase in RVR and arterial pressure occurred during intrarenal norepinephrine infusion despite significant decreases in the daily dose of intrarenal norepinephrine administered by the servo-controlled pump.
Increased renal vascular tone via increased renal sympathetic nerve activity has been implicated in the pathogenesis of human essential hypertension. This viewpoint is substantiated by the fact that one of the most consistently noted abnormalities in individuals with essential hypertension is increased RVR and reduced RBF.14 15 16 In addition, the increase in RVR in individuals with recently acquired essential hypertension may be the result of sympathetically mediated dysfunction,15 17 indicated by the increase in RBF and reversal of renal angiographic abnormalities by intrarenal α-adrenergic blockade with phentolamine.18 Further evidence implicating a selective elevation in renal sympathetic nerve activity in human essential hypertension is derived from elevated renal norepinephrine release in essential hypertensive patients compared with normotensive control subjects as well as significantly greater renal than cardiac norepinephrine release in essential hypertensive patients.19 These findings indicate that human essential hypertension may be mediated in part by a selective or exaggerated elevation in renal sympathetic nerve activity.
In the present study, we evaluated the role of chronic, low-level elevations in intrarenal adrenergic neurotransmitter in the arterial pressure regulation and renal excretory function of conscious dogs. The confounding effects of substantial reductions in RBF noted in previous reports were avoided by servo-controlling the intrarenal norepinephrine dose infused to values of continuously monitored RBF. Chronic intrarenal elevation of adrenergic neurotransmitter promptly produced sustained arterial hypertension for the duration of intrarenal norepinephrine infusion. Since plasma catecholamines did not increase during this low-level intrarenal norepinephrine infusion (Fig 2⇑), the arterial hypertension was mediated by factors unrelated to systemic catecholamine spillover. These findings agree with those of other investigators who have demonstrated that when norepinephrine doses even greater than those used in the present study are administered intravenously, either no pressor response8 or only a transient pressor response7 occurs.
This is the first study that continuously measures RBF in the face of chronic increases in intrarenal adrenergic stimulation associated with arterial hypertension. Since the set point for servo-controlled intrarenal norepinephrine infusion was below threshold for producing measurable vasoconstriction, hypertension was produced and maintained for the initial 9 days of the elevated intrarenal neurotransmitter in the absence of changes in whole-kidney hemodynamics. However, during 10 of the final 19 days of intrarenal norepinephrine infusion, maintenance of RBF during norepinephrine infusion combined with chronic hypertension resulted in an approximate 18% reduction in whole-kidney blood flow. Over the course of the study, a reduction in the norepinephrine concentration in the infusate was required to prevent further elevations in RVR (Fig 4⇑). Thus, under the conditions of servo-controlled norepinephrine infusion, only modest reductions in RBF were achieved during chronic hypertension in the presence of rapidly decreasing amounts of intrarenal norepinephrine infused. As the intrarenal norepinephrine infusion protocol was maintained, the apparent renal vasoconstrictor response to intrarenally infused norepinephrine increased. This assertion is supported by the progressive and sustained increase in RVR despite significant reductions in the daily servo-controlled norepinephrine dose (Fig 4⇑). These findings suggest that changes in the hemodynamic function or demands of the renal vasculature produced an alteration in renal adrenergic vasoconstrictor activity.
These changes in arterial pressure and renal vascular reactivity must have resulted from infused neurotransmitter. The norepinephrine concentration of innervated control kidneys at the time of unilateral nephrectomy averaged 351.2±32.8 pg/mg tissue, whereas denervated experimental kidneys averaged 15.0±8.3. Thus, pressor and renal hemodynamic responses occurred entirely because of servo-controlled norepinephrine infusion rather than reflexly mediated changes in renal sympathetic outflow.
Several factors have been suggested that may modify the sensitivity of vascular smooth muscle to pharmacological agents, including vascular distention20 or smooth muscle length21 22 and resting membrane potentials.23 For example, previous work by Lombard et al24 has demonstrated augmented adrenergic vascular sensitivity as a function of increasing perfusion pressure in small canine kidney vessels in vitro. These investigators noted that as perfusion pressure was increased, the EC50 for norepinephrine decreased by nearly an order of magnitude for each step increase in perfusion pressure. Therefore, the increase in apparent renal adrenergic vasoconstrictor sensitivity in the present study may have occurred secondary to hypertension and increased renal perfusion pressure initiated by the servo-controlled intrarenal norepinephrine infusion.
An alternative explanation for the increase in adrenergically mediated vasoconstrictor activity is that chronic exposure to elevated neuroadrenergic stimulation and/or arterial pressure produced structural changes in the renal vasculature. Folkow25 developed the concept that increases in transmural pressure elicit structural changes in both the vascular wall and lumen, thereby normalizing wall tension per unit of wall thickness. In response to hypertension, the thickened vascular media becomes an “amplifying lever” such that a similar degree of smooth muscle shortening produces a geometric enhancement of vascular resistance. In addition, several investigators26 27 have consistently demonstrated increased flow resistance in hypertensive humans and animal models compared with normotensive controls. In the current experiments, postcontrol elevation of RVR is consistent with these structural adaptations to chronic vascular pressure overload.
Although the mechanisms for vascular hypertrophy are unknown, neurally derived norepinephrine does exert trophic effects on vascular smooth muscle growth.28 Given the fact that humorally delivered norepinephrine produces hemodynamic and tubular effects similar to those produced via neurally mediated norepinephrine, it is reasonable to suspect that the trophic effects may also be similar. In addition, intrarenal norepinephrine stimulates renin release, with the consequent production of Ang II, which is a known mitogen and growth factor.29 In the present study, the intrarenal hemodynamic and neurohumoral characteristics may promote vascular hypertrophy and alterations in the wall-to-lumen ratio, which may underlie both the increase in vasoconstrictor responsiveness and the persistent increase in RVR.
Heart rate decreased from control levels and remained suppressed in response to arterial hypertension induced by intrarenal norepinephrine infusion. Consideration of the heart rate data along with the plasma catecholamine concentrations suggests that the hypertension is not the result of a generalized increase in sympathetic outflow or systemic spillover of norepinephrine from the renal circulation. On the contrary, the reduction in heart rate suggests an inhibition of cardiovascular sympathetic tone likely caused by continuous baroreceptor stimulation. Significant hemoconcentration in the presence of unaltered arterial catecholamine concentrations also suggests that systemic sympathetic outflow may be generally suppressed. The heart rate response is appropriate in light of findings by Chapleau et al,30 who demonstrated that in contrast to constant pressure perfusion, pulsatile pressure elevation at the carotid sinus attenuated acute baroreceptor resetting. Other investigators7 10 31 also have reported persistent decreases in heart rate during chronic hypertension for up to 12 days.
The systemic pressor response could have been related to changes in two basic renal mechanisms for control of blood pressure: the renin-angiotensin system and the renal pressure natriuresis-diuresis relationship.32 Reinhardt et al9 recently demonstrated that fixing plasma Ang II concentration by simultaneous infusion of captopril and Ang II prevented the development of hypertension during continuous intrarenal norepinephrine infusion. However, our own preliminary report indicates that development of hypertension during 5-day servo-controlled intrarenal norepinephrine infusion does not depend on intact Ang II synthesis.33 In this study, captopril treatment sufficient to block the pressor response to exogenously administered Ang I did not prevent the development or maintenance of intrarenal neurogenic hypertension.33 The discrepancy in these findings is probably due to the nature of the intrarenal norepinephrine delivery. In the current study, it is unlikely that the increase in mean arterial pressure of 25 mm Hg would be caused by such a modest elevation in PRA (Fig 2⇑) after 7 days of servo-controlled intrarenal norepinephrine infusion.
Neurogenic stimuli influence renal function34 ; therefore, intrarenal norepinephrine infusion may interfere with the normal relationship between arterial pressure and urine output. Elevated renal sympathetic nerve activity increases tubular sodium reabsorption35 36 and RVR.37 Such alterations in renal function could lead to extracellular fluid volume retention and increased cardiac output and total peripheral resistance via whole-body autoregulation.32 In these dogs, however, renal neurogenic hypertension was associated with a net sodium and water loss over the entire 28-day experimental period. The observed natriuresis was also associated with progressive reductions in plasma sodium and potassium concentrations over the 4-week intrarenal norepinephrine infusion (Table⇑). Thus, despite elevated intrarenal adrenergic stimuli to stimulate sodium reabsorption, the hypertension caused sustained pressure natriuresis for 28 days.
Further evidence of volume contraction is provided by the increase in arterial hematocrit during the experimental period. The mass of sodium lost represents an approximate 20% reduction in extracellular fluid volume combined with a 21% increase in arterial hematocrit. Although we did not measure plasma volume in the present study, it is possible that the modest reduction in hypertension during the last 7 days of the intrarenal norepinephrine infusion is due to the significant extracellular fluid volume contraction rather than the decrease in the daily dose of servo-controlled intrarenal norepinephrine infused. Thus, the exaggerated natriuresis may serve as a compensatory mechanism to attenuate the intrarenal adrenergically mediated increase in arterial pressure.
The total mechanism surrounding the reduction in extracellular fluid volume is unclear; however, chronic hypertension was associated with increased plasma ANF concentration. ANF concentrations increase in many models of hypertension, including human essential hypertension38 and deoxycorticosterone acetate–salt hypertension.39 In addition, the natriuretic response to ANF infusion is enhanced with elevations in renal perfusion pressure in anesthetized, uninephrectomized dogs.40 Therefore, it is possible that increased ANF enhanced sodium and water excretion in the current experiments because of the elevation in arterial pressure.
In conclusion, the present findings indicate that long-term, low-level increases in intrarenal neuroadrenergic stimulation modify renal function and produce chronic arterial hypertension in the absence of marked decreases in RBF. The results suggest that the development and maintenance of arterial hypertension in the current model does not depend on either expansion of extracellular fluid volume or increases in circulating catecholamine, Ang II, or vasopressin concentrations. Moreover, the present findings suggest that under conditions of low-level elevations in intrarenal neuroadrenergic stimulation, hypertension increases the adrenergic vasoconstrictor activity of the renal vasculature to subsequent intrarenal adrenergic stimulation. The long-term neuroadrenergic stimulation in the presence of arterial hypertension may alter vascular structure to chronically increase RVR. Thus, the current model of neuroadrenergic hypertension is characterized by increased RVR and extracellular fluid volume contraction, which are analogous to clinical findings in human essential hypertension.
Selected Abbreviations and Acronyms
|ANF||=||atrial natriuretic factor|
|Ang I, II||=||angiotensin I, II|
|PRA||=||plasma renin activity|
|RBF||=||renal blood flow|
|RVR||=||renal vascular resistance|
|SHR||=||spontaneously hypertensive rat(s)|
This work was supported by National Heart, Lung, and Blood Institute Grant PO-29587 and a Grant-in-Aid from the American Heart Association, Wisconsin Affiliate (AHA/WI). Portions of this work were conducted during the tenure of an AHA/WI Fellowship awarded to C.F. Plato. The authors wish to thank Lisa Henderson, Camille Torres, and Kelly Zanoni for their efforts in performing the biochemical and hormonal assays. The technical assistance and computer expertise of Erez Gordin is also gratefully appreciated.
Reprint requests to Jeffrey L. Osborn, PhD, Department of Physiology, Medical College of Wisconsin, 8701 W Watertown Plank Rd, Milwaukee, WI 53226.
- Received April 2, 1996.
- Revision received April 29, 1996.
- Revision received May 24, 1996.
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