Retardation of the development of hypertension in DOCA-salt rats by renal denervation

To determine the importance of the renal nerves in DOCA-salt hypertension, either renal denervation or a sham-operation was carried out on both DOCA-salt-treated and non-DOCA-treated rats. The systolic blood pressure of the non-DOCA rats remained within normotensive levels, in which the difference in blood pressure levels between the renal denervated and the sham-operated groups was not significant. On the other hand, the blood pressure of the rats treated with DOCA, and having intact renal nerves, began to rise by the end of the first week and rose consistently thereafter, whereas, in the renal denervated DOCA-salt rats, the blood pressure started to rise by the second week and then proceeded to increase gradually. The differences between the sham and the denervated rat groups were significant throughout the four weeks. The mean arterial pressure, directly measured from the caudal artery of conscious rats during the fourth week of this study, was 166 +/- 7 mmHg in the sham-operated and 129 +/- 4 mmHg in the renal-denervated rats (the data having an 1% significant difference). To test the effects of renal denervation on the natriuresis, pentobarbital-anesthetized rats were infused intravenously with physiological saline. The renal denervated rats which had received DOCA excreted more sodium than did the sham-operated rats. When the rats were later anesthetized with urethane to allow intracisternal injections of hypertonic saline, the mean blood pressure in renal denervated rat groups was again lower than that of the sham-denervated rat groups. However, subsequent intracisternal injections of 5% saline produced similar pressor responses as well as tachycardia in both DOCA groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal nerves and the pathogenesis of angiotensin-induced hypertension

The present study examined the role of the renal nerves in the development of hypertension produced by chronic infusion of angiotensin II in the conscious rat. The animals were divided into four groups, and a unilateral nephrectomy was performed. The remaining kidney was denervated in two groups, whereas in the other two groups of animals the nerves were left intact. Four days later either angiotensin II (83 ng/min) or saline infusions were begun through subcutaneously implanted osmotic minipumps. The rats were subsequently studied for 14 days. The results indicate that renal denervation significantly attenuated the pressor response to angiotensin II for approximately 6 days. Following this period, there was no difference in blood pressure between the innervated and denervated rats infused with angiotensin II, as both groups attained a hypertensive level of 170 to 180 mm Hg, which was 60 to 70 mm Hg above the blood pressure of the control rats infused with saline. Kidney norepinephrine content was reduced 95% by the denervation procedure and by 40% following infusion of angiotensin II into rats with intact renal nerves. These data demonstrate that, while the renal nerves appear to play a modulatory role in the development of the hypertension, they are not essential for the pathogenesis to occur nor do they determine the final level of hypertension achieved following chronic infusion of angiotensin II in the rat.     

Renin activity and blood pressure in response to chronic episodic hypoxia.

Previous studies in several strains of rats have demonstrated that 35 days of recurrent episodic hypoxia (EH) (7 hours per day), with a fractional concentration of inspired oxygen that produces desaturation equivalent to the recurrent hypoxemia of sleep apnea, results in an 8 to 13 mm Hg persistent increase in diurnal systemic blood pressure (BP). Carotid chemoreceptors and the sympathetic nervous system have been shown to be necessary for development of this BP increase. Both renal artery denervation and adrenal demedullation block the BP response to chronic EH. The present study was undertaken to define further the role of the kidneys and the renin-angiotensin system in this BP increase. Separate groups of male Sprague-Dawley rats had either (1) bilateral renal artery denervation with EH, (2) sham surgery with EH, (3) sham surgery with sham EH (compressed air), (4) EH with losartan, (5) unhandled with losartan, or (6) unhandled. The experimental period lasted 35 days. Both renal-artery denervated and losartan-treated animals showed no BP change or a lowering of BP in response to EH, whereas the sham-operated EH animals showed a progressive, sustained increase in resting room air BP. BP remained at basal levels or fell in unhandled and unhandled losartan-treated animals. Plasma renin activity was elevated 4-fold versus basal levels in EH animals with renal nerves intact but remained at baseline levels in denervated animals. At the end of the experiment, renal tissue catecholamines confirmed renal denervation in those animals. In conclusion, EH causes a progressive increase in BP, mediated in part through renal sympathetic nerve activity that acts to increase renin-angiotensin system activity through angiotensin II type 1 receptors.     

Effect of denervation on the afferent arteriole in the SHR

To study the role the renal nerves may play in the hypertension of the SHR, we conducted a morphometric study of the afferent arteriole of spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) which were subjected to renal denervation (or sham-operation). Methacrylate casts were made of the renal vasculature after perfusion fixation with glutaraldehyde. These vascular casts were then examined and measurements made with the scanning electron microscope (SEM). Afferent arterioles of the denervated SHR were dilated in comparison to the sham-operated SHR, but there was no difference between the afferent arteriolar diameters of the 2 groups of WKYs. However, the afferent arteriolar diameters of the SHR (either group) were smaller than those of the WKY. Renal denervation caused a reduction in systolic blood pressure compared to sham-operated in both strains of rat. We concluded that the dilation changes of afferent arterioles of denervated SHRs may be related to renal autoregulation resulting from the decreased blood pressure. However, the effect of the loss of sympathetic innervation of the arterioles cannot be ruled out.     

Renal denervation inhibits hypothalamo-sympathetic nerve system in normotensive and hypertensive rats

The role of the renal nerve in influencing the hypothalamo-sympathetic nerve system to regulate the cardiovascular system was studied in normotensive Wistar and spontaneously hypertensive rats (SHR). Renal denervation attenuated pressor and sympathetic nerve responses to electrical stimulation of the hypothalamus without lowering the basal blood pressure at 48 hours after denervated operation. These findings suggest that renal denervation could inhibit the hypothalamo-sympathetic nerve system in normotensive rats. The development of hypertension in SHR was completely inhibited by renal denervation during 2 weeks of observation (from 7 to 9 weeks of age) without increasing water intake and urine volume. Pressor responses to intravenous injection of norepinephrine were not affected by renal denervation. The results show that the antihypertensive effect of renal denervation was not due to the changing of vascular reactivity. Pressor and sympathetic nerve responses to hypothalamic stimulation were strongly diminished in renal denervated rats. These results suggest that renal denervation strongly inhibited they hypothalamo-sympathetic nerve system. It is also suggested that the renal afferent nerve may facilitate the hypothalamo-sympathetic nerve system in regulating blood pressure and that this facilitation may contribute to the development of hypertension in SHR.     

Paradoxical structural effects in the unilaterally denervated spontaneously hypertensive rat kidney

OBJECTIVE: To determine the effects of chronic denervation on renal vascular structure and function in young adult spontaneously hypertensive rats (SHRs). DESIGN: Unilateral renal denervation (SHRUDx) or sham-operation (SHRS) was performed in SHRs at 6 weeks of age. At 10 weeks, rats were allocated to one of three procedures designed to examine renal vascular structure and function. A further group underwent bilateral renal denervation. METHODS: In SHRUDx or SHRS groups, either the kidneys were perfusion-fixed for stereological estimates of artery wall and lumen dimensions or for vascular casting to determine arteriole lumen diameters, or the rats were anaesthetized for estimation of glomerular capillary pressure. RESULTS: Chronic unilateral renal denervation had no significant effect on the development of hypertension between 6 and 10 weeks of age, as previously reported, but resulted in luminal narrowing of the interlobular artery (denervated group 52 +/- 2 mum, sham-operated group 64 +/- 1 mum; P < 0.01 for interaction between strain and treatment), without alterations in interlobular or arcuate artery wall dimensions. There were no significant effects on either afferent or efferent arteriole lumen diameters. Estimated glomerular capillary pressure was significantly lower in the denervated kidneys of SHRUDx (47 +/- 1 mmHg) compared with kidneys of the SHRS (50 +/- 1 mmHg; P < 0.04). Mean arterial pressure was approximately 12 mmHg lower in the bilaterally denervated SHRs than in the sham-operated SHRs. CONCLUSIONS: Although bilateral denervation attenuated the development of hypertension in SHRs, unilateral denervation did not, indicating that one neurally intact kidney was sufficient to drive the normal development of SHR hypertension, but only with apparent prohypertensive compensatory changes in the denervated kidney.     

Diuretic and Natriuretic Responses to Anf in the Presence and Absence of Renal Nerves in Doca-Salt Hypertensive Rats

To determine if renal nerves contributes in the renal response to atrial natriuretic factor (ANF) in DOCA-salt hypertensive rats, diuretic and natriuretic responses to ANF were measured in Inactin (0.1 g/kg, i.p) anesthetized rats with unilateral renal denervation. Rats were assigned to either a control group (108±6 mmHg), or one of two DOCA-salt groups (injected with deoxycorticosterone acetate, DOCA, 25 mg/week, and given 0.9% saline to drink for 4 weeks); a) DOCA-salt group (137±6 mmHg) and b) DOCA-salt-BPC group (with blood pressure controlled at the level of the femoral artery (102±3 mmHg) by an occluder on the abdominal aorta proximal to the right renal artery). Urine flow and sodium excretion in response to ANF infusion (0.3 μg/min/kg) were measured from intact and denervated kidneys of control and DOCA-salt treated rats.

ANF infusion produced a significant increase in diuresis and natriuresis in all three groups of rats. Urine flow and sodium excretion in response to ANF were significantly less in the intact kidney but not the denervated kidneys of the DOCA-salt rats compared to control rats. These results indicate that renal nerves contribute to the blunted renal responses to ANF in DOCA-salt rats. Renal responses also were significantly smaller in both intact and denervated kidneys of DOCA-salt-BPC rats (in which arterial pressure was reduced) compared to DOCA-salt rats. Overall, these results indicate that both renal nerves and arterial pressure determine the natriuretic and diuretic actions of ANF in DOCA-salt hypertensive rats.     

Effect of Renal Denervation on the Development of Cellophane-Wrap Hypertension in Rabbits

The development of hypertension in rabbits with bilateral cellophane wrapping of the kidneys was studied in animals with and without surgical denervatton of the kidneys. Mean arterial pressure was measured before and 14 and 28 days after surgery. After 14 and 28 days of wrapping, mean arterial pressure had increased 12 ± 3 mmHg and 31 ± 3 mmHg in rabbits with innervated kidneys and 7 ± 2 mmHg and 26 ± 2 mmHg in rabbits with denervated kidneys, respectively. The increases in arterial pressure were significantly less in the denervated animals. In sham wrap animals, renal denervation also resulted in significantly lower arterial pressure than in sham wrap+sham denervated rabbits. Noradrenaline concentration of denervated kidneys averaged only 4% of that measured in kidneys subjected to sham denervation. The results show that renal denervation slightly attenuated the degree of hypertension developed following renal wrapping. Since renal denervation produced a similar small decrease in arterial pressure in normotensive rabbits it is suggested that the effect is non-specific and probably due to loss of efferent renal sympathetic nerves.     

Pathogenesis of hypertension in the sinoaortic-denervated spontaneously hypertensive rat

The present study was performed to examine the relation between the gain of the baroreceptor reflex and the pathogenesis of hypertension in the spontaneously hypertensive rat. Spontaneously hypertensive or Wistar-Kyoto rats underwent either sinoaortic baroreceptor denervation or sham denervation at 28-35 days of age. Four months later these rats were chronically instrumented for measurements of arterial pressure and heart rate. Sixty-minute computerized measurements of arterial pressure showed no difference between spontaneously hypertensive sham (163 +/- 5 mm Hg) and spontaneously hypertensive baroreceptor-denervated (166 +/- 5 mm Hg) rats, or Wistar-Kyoto sham (114 +/- 3 mm Hg) and Wistar-Kyoto baroreceptor-denervated (121 +/- 4 mm Hg) rats. The gain of baroreceptor reflex control of heart rate was assessed by measuring maximal heart rate responses to changes in arterial pressure elicited by bolus injection of phenylephrine and nitroprusside (gain = slope of linear regression equation of change in heart rate versus change in arterial pressure). Baroreceptor reflex gain was significantly higher in Wistar-Kyoto sham rats (-2.10 beats/min/mm Hg) than spontaneously hypertensive sham rats (-0.94 beats/min/mm Hg). Baroreceptor denervation significantly decreased baroreceptor reflex gain in both Wistar-Kyoto (-0.26 mm Hg) and spontaneously hypertensive (-0.22 beats/min/mm Hg) groups. Since baroreceptor denervation did not exacerbate the development of hypertension in adult spontaneously hypertensive rats or lead to hypertension in Wistar-Kyoto rats, we conclude that a primary dysfunction in the baroreceptor reflex alone is not responsible for the development of hypertension in this model.     

Central baroreflex regulation by the renal nerves in anesthetized rats

To determine whether the renal nerves affect central baroreflex regulation, the aortic depressor nerve (ADN) was stimulated electrically, while blood pressure, heart rate, and splanchnic nerve activity were recorded in renal denervated and sham-operated rats anesthetized with urethane. Tail cuff systolic pressure fell 6 days after renal denervation, but mean blood pressure recorded after anesthetizing with urethane did not differ between renal denervated and sham-operated rats. Urinary sodium excretion was greater in renal denervated than in sham-operated rats. ADN stimulation produced frequency-dependent falls in blood pressure accompanied by inhibitions of sympathetic nerve activity and heart rate. Depressor and sympathetic inhibitory responses to ADN stimulation were significantly smaller in renal denervated than in sham-operated rats. These findings suggest that the renal nerves can regulate baroreflexes centrally.     

Selective vasodilation produced by renal denervation in adult spontaneously hypertensive rats

The kidneys of adult male spontaneously hypertensive rats (SHR) were denervated, and systemic and regional blood flows were measured 3 to 5 hours or 5 days after denervation. Arterial pressure was reduced 20 to 27% in denervated SHR during both periods compared with that in sham-operated SHR (iliolumbar blood vessels painted with phenol). This hypotensive response was produced by a 32 to 35% reduction in total peripheral resistance. At 3 to 5 hours and at 5 days, a major decrease in total peripheral resistance was produced by vasodilation in the kidneys and splanchnic organs. Acute urine output, sodium excretion, and plasma renin activity in response to a saline load were not different between sham-operated and denervated SHR. The decreased total peripheral resistance in denervated SHR may have been secondary to a decreased central sympathetic nerve activity revealed by a decreased maximum response to ganglionic blockade. The results suggest that a pathophysiological link may exist between the kidneys and splanchnic organs in genetic hypertension and that specific efferent antiadrenergic or antiafferent nerve therapy, or both, in the kidney may lead to substantial specific decreases not only in renal vascular resistance but also in splanchnic vascular resistance and total peripheral resistance.     

Baroreceptor influences on oxytocin and vasopressin secretion

The objective of these studies was to investigate the role of arterial baroreceptors in the control of neurohypophyseal secretion. The effect of sinoaortic denervation on basal and osmotic-induced release of oxytocin and vasopressin and on blood pressure was determined. Hypertonic or isotonic saline was infused intravenously into sham-operated or denervated rats 3 days after surgery. Plasma oxytocin and vasopressin were measured at 5 and 15 minutes after the infusion. The control levels of oxytocin were increased in the denervated rats, but vasopressin levels were not significantly altered. The vasopressin and oxytocin responses to hypertonic saline were greater after baroreceptor denervation. Plasma oxytocin was increased from 4.7 +/- 0.9 to 72.2 +/- 8.7 pg/ml in the denervated rats and from 1.8 +/- 0.3 to 39.9 +/- 6.7 pg/ml in the sham-operated control group at 5 minutes after the infusion (p less than 0.01). The plasma vasopressin response to hypertonic saline was 7.1 +/- 0.6 pg/ml in the sham-operated versus 11.1 +/- 1.6 pg/ml in the denervated rats (p less than 0.05). There was no difference between sham-operated and denervated rats in the effect of hypertonic saline on plasma sodium and hematocrit. Mean arterial blood pressure was increased after sinoaortic denervation (116.3 +/- 4.2 mm Hg in the sham-operated vs. 138.2 +/- 8.3 mm Hg in the denervated rats, p less than 0.05); however, there was no difference in the pressor response to hypertonic saline. These results show that the baroreceptor system influences the secretion of both oxytocin and vasopressin, with effects on basal secretion as well as the response to an osmotic stimulus.(ABSTRACT TRUNCATED AT 250 WORDS)     

Functional Evidence of Inhibitory Reno-renal Reflexes in Spontaneously Hypertensive Rats

The experiments were performed to study the role of the renal nerves and the reno-renal reflexes in the control of water and sodium excretion in spontaneously hypertensive rats (SHR) compared to their normotensive controls, Wistar Kyoto (WKY) rats. Unilateral renal denervation in anaesthetized animals produced a slight, progressive decrease in arterial pressure in both WKY and SHR rats. The glomerular filtration rate temporarily increased in the kidney that underwent the denervation in the SHR group only. After unilateral renal denervation a sharp increase in water and sodium excretion from the ipsilateral kidney was observed in both WKY and SHR. One hour after the denervation, the percent changes in water and sodium excretion were smaller in WKY (+32 ± 19% and +24 ± 17%) than in SHR rats (+84 ± 15% and +93 ± 20%). In the kidney contralateral to the denervation a reduction in water and sodium excretion was observed and this reduction was prompter in SHR than in WKY rats. One hour after the denervation, the percent changes in water and sodium excretion were similar in WKY (-21 ± 8% and -18 ± 7%) and SHR (-19 ± 6% and -19 ± 7%). In control groups, sham denervation did not cause significant changes in glomerular filtration rate, and urinary water and sodium excretion. Arterial pressure slightly and progressively decreased in both control groups. Electrical stimulation of the efferent renal nerves performed in WKY and SHR produced similar decreases in renal blood flow, glomerular filtration rate, and water and sodium excretion in the two groups for the same frequencies of stimulation. As this finding indicates that renal targets in hypertensive rats are normally responsive to the neural drive, our data demonstrate that renal responses to unilateral renal denervation in hypertensive rats are equal to the responses observed in normotensive rats. Our results indicate that tonically active inhibitory reno-renal reflexes normally operate in spontaneously hypertensive rats.     

Cardiopulmonary and sinoaortic baroreceptors and volume expansion in the monkey

Summary Experiments were performed to determine the effect of combined cardiopulmonary and sinoaortic baroreceptor denervation on the renal responses of the anesthetized nonhuman primate to acute intravascular volume expansion. Adult maleMacaca fascicularis monkeys underwent chronic bilateral thoracic sympathectomy (middle cervical ganglion-T₆) or sham surgery performed in two stages. After a 1–3 week recovery period, each animal was anesthetized with sodium pentobarbital and subjected to cervical vagotomy-sinoaortic denervation or further sham denervation. Estimated blood volume was then acutely expanded 20% with 6% dextran in isotonic saline. Control renal excretory function did not differ between the two groups, and both groups had similar increases in urine flow, sodium excretion, osmolar clearance, free water clearance and renal plasma flow after volume expansion. The patterns of the responses showed some group differences in that the increases in renal excretion after volume-loading had an earlier onset in the denervated animals. These results demonstrate that combined ablation of thoracic sympathetic, vagal and sinoaortic neural pathways does not compromise the ability of the nonhuman primate to increase salt and water excretion when blood volume is acutely expanded. Therefore, these neural mechanisms are not necessary for eliciting the renal responses to this hypervolemic stimulus in this species during the anesthetized state.Supported by NIH Grant No. HL31987Recipient of a Research Career Development Award (HL01383) from the National Heart, Lung and Blood Institute     

Renal hemodynamics and development of renal fibrotic lesions during hypertension

Hypertension is frequently associated with the development of renal fibrosis leading to chronic renal failure. The objective of the present study was to evaluate the role of blood pressure and renal hemodynamics on the development of renal lesions during hypertension. To this end, rats were treated with a NO synthase inhibitor, L-NAME, for 4 weeks. At this time point, systolic blood pressure reached 170 mmHg, renal blood flow dropped to 3.3 +/- 0.7 ml/min and kidneys displayed glomerular and tubulo-interstitial lesions as evidenced by histological analysis. Thereafter, L-NAME treatment was combined with an AT1 receptor antagonist, losartan (30 mg/kg/d), for an additional period of 4 weeks. Treatment with losartan for 4 additional weeks did not significantly modify hypertension (168 mmHg) either the degree of tubulo-interstitial lesions; in contrast, a significant regression of ischemic and sclerotic glomerular lesions was observed. In parallel, renal blood flow was significantly improved by losartan (5.2 +/- 0.8 ml/min). In addition a negative correlation was observed between renal blood flow and index of glomerulosclerosis (r = -0.82), whereas tubulo-intarstitial damage was positively correlated to systemic pressure (r = 0.93). In conclusion, inhibition of the local effects of angiotensin II alleviates the fall of renal blood flow consecutive to NO deficiency and reduces the morphological and functional lesions of glomeruli, independently of the changes in blood pressure. In contrast, tubulo-interstitial lesions are not correlated with the levels of renal blood flow and do not regress with the blockade of AT1 receptors when rats remain hypertensive.     

Renal vascular adjustments to partial renal venous obstruction in dog kidney

Blood flow studies were conducted in neurolept anesthetized dogs to characterize the involvement of renal nerves in ipsilateral renal vasoconstriction seen during acute elevation of renal venous pressure above 30 mm Hg. Renal blood flow was measured electromagnetically. The vasoconstrictor response was almost abolished by acute surgical denervation of the kidney, since renal vascular conductance remained unchanged during renal venous pressure elevation from 30-60 mm Hg. However, following additional alpha-adrenoceptor blockade or chronic renal denervation, renal vascular conductance increased progressively during renal venous pressure elevation to 60 mm Hg. The effect of acute decapsulation of kidney was studied in another group of dogs. Decapsulation induced a vasoconstriction. The decrease in renal vascular conductance observed during renal venous pressure elevation was unaffected by acute surgical denervation of decapsulated kidney, but was almost abolished following additional alpha-adrenoceptor blockade or chronic denervation. In decapsulated chronically denervated kidney, the increase in renal vascular conductance during renal venous pressure elevation to 60 mm Hg was still present but considerably attenuated as compared with the chronically denervated kidney with intact capsule. The renin-angiotensin system did not participate in acute vascular adjustments to renal venous stasis in intact kidney or in decapsulated acutely surgically denervated kidney. The data favor the view that neurogenic and myogenic mechanisms significantly influence the vasoconstrictor response to renal venous pressure elevation in dog kidney. The neurogenic contribution to the vasoconstrictor response comprises intrarenal and extrarenal vasoconstrictor mechanisms evoked reflexively by renal venous pressure elevation, and the myogenic contribution to the vasoconstrictor response comprises opposing vasodilator mechanisms due to increase in renal interstitial tissue pressure during renal venous pressure elevation.     

Renal nerve contribution to NaCl-exacerbated hypertension in spontaneously hypertensive rats

Previous studies demonstrate that bilateral renal denervation enhances urinary sodium excretion and delays the onset of hypertension in young (7-week-old) spontaneously hypertensive rats (SHR) maintained on ordinary laboratory chow. We interpret these data as suggesting that increased renal nerve activity in this model contributes to hypertension by causing excess sodium retention. More recent studies show that dietary NaCl supplementation increases blood pressure and peripheral sympathetic nervous system activity in NaCl-sensitive SHR (SHR-S). The present study tests the hypothesis that the renal nerves contribute to the rise in arterial pressure caused by dietary NaCl supplementation in this model. SHR-S were fed a high (8%) or basal (1%) NaCl diet beginning at age 7 weeks. Bilateral renal denervation was carried out 2 weeks after the initiation of the diets, at which time systolic blood pressure was significantly higher in the high (compared with the basal) NaCl group. Systolic blood pressure was reduced slightly less in denervated SHR-S on the high (compared with basal) NaCl diet during the following 5 weeks. Renal denervation performed 1 week before initiation of the diets attenuated the subsequent development of hypertension equally in both groups. Both renal denervation and the high NaCl diet increased alpha 2-adrenergic receptor numbers in the kidney; renal denervation caused an approximately equal increase in alpha 2-adrenergic receptor binding in SHR-S on high and basal NaCl diets. The high NaCl diet increased plasma noradrenaline concentration, and renal denervation lowered mean arterial pressure but did not decrease circulating catecholamines in either diet group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bilateral Renal Denervation Can Prevent the Development of Stress-Induced Hypertension in the Borderline Hypertensive Rat

The borderline hypertensive rat (BHR) shows large blood pressure responses to either stress or a high salt diet. Since the renal nerves have been shown to play a role in several animal models of hypertension, the current study sought to determine the effect of bilateral renal denervation on the development of stress-induced hypertension in the BHR. BHR were deprived of renal nerves under ether anesthesia after either 5 or 11 weeks of daily 2-hour stress sessions. Additional BHR received sham surgery. Unstressed BHR, age-matched to stressed groups, received denervation or sham surgery. Following a 3 week recovery period, the protocol (stress or no stress) was continued for 10 additional weeks. Tail cuff systolic blood pressures were obtained weekly. BHR stressed for 5 weeks prior to denervation failed to develop hypertension in response to continued stress. Although BHR stressed for 11 weeks prior to denervation showed a temporary reduction in pressure following denervation, blood pressure returned to the hypertensive levels of sham-operated controls after several weeks. Thus, there may be a critical period during which the renal nerves are necessary for the expression of stress-induced hypertension in the BHR. These observations are discussed in relation to the effects of renal denervation on hypertension in various animal models.     

Renal Nerve-Mediated Proximal Tubule Solute Reabsorption Contributes to Hypertension in Spontaneously Hypertensive Rats

Renal nerve activity increases (Na⁺, K⁺)-ATPase activity and contributes to the development of hypertension in young SHR. The present study was designed to examine the effect of sodium intake on blood pressure and proximal tubule solute reabsorption in sham-operated or renal denervated, 5-week old SHR and WKY. Three-week old SHR and WKY rats underwent sham surgery or renal denervation with 10% phenol and were maintained for 10 days on either a 0.6% or 2.2% NaCl diet. Blood pressure was obtained by indirect tail cuff measurements during this interval. Of the eight groups, only sham-operated SHR on a high sodium diet had hypertension, 122.0 × 4.2 mm Hg vs. 98.7 × 3.3 mm Hg (mean for remaining groups). Renal plasma flow (RPF), glomerular filtration rate (GFR), and the fractional excretion of lithium (FE_Lj) were determined in rats maintained on a 2.2% sodium diet at 5 weeks of age. FE_li was less in sham-operated SHR, 5.3 × 0.7%, compared to WKY, 9.4 × 2.8% (P>0.02). Furthermore, denervation ameliorated the reduced FE_Li in SHR, 10.2 × 1.2%, without affecting FE_Li in WKY. RPF and GFR were similar between sham-operated and renal denervated SHR and WKY. No significant difference could be detected in net sodium balance between WKY and SHR during this period. These findings demonstrate 1) from the basis of FE_Li, young SHR, of this strain, exhibit enhanced proximal tubule solute reabsorption and hypertension while on a high sodium diet and, 2) renal denervation ameliorates both the enhanced proximal tubule solute reabsorption and the early development of hypertension. These data support the concept that renal nerve activity of young SHR is augmented and contributes to the development of hypertension by enhancing salt retention.     

Haemodynamic effects of dual blockade of the renin-angiotensin system in spontaneously hypertensive rats: influence of salt

OBJECTIVE: To elucidate the mechanisms responsible for the adverse renal effects induced by dual blockade of the renin-angiotensin system (RAS) and the role of salt therein. METHODS: The effects of enalapril, losartan and their combination on blood pressure, renal haemodynamics, renal function and RAS were investigated over a wide range of doses in spontaneously hypertensive rats fed either a low-sodium or a high-sodium diet. RESULTS: In rats fed the low-sodium diet, the losartan-enalapril combination induced the same dose-dependent haemodynamic and hormonal changes as did three- to 10-fold greater doses of enalapril or losartan alone. When a strong decrease (> 50%) in blood pressure was achieved (with 10 mg/kg enalapril plus 10 mg/kg losartan, 100 mg/kg enalapril or 100 mg/kg losartan), a massive renal vasoplegia occurred and renal insufficiency developed. In addition, because of the huge release of renin, angiotensinogen concentrations were reduced, leading to a decrease in intrarenal angiotensins. In rats fed the high-sodium diet, those treated with the enalapril 30 mg/kg plus losartan 30 mg/kg combination, despite complete functional RAS blockade, exhibited smaller decreases in blood pressure and renal resistance, lesser release of renin and angiotensinogen consumption, and a normal renal function. These effects were similar to those produced by 100 mg/kg of enalapril or losartan in rats fed the high-salt diet, or by 10 mg/kg of enalapril or of losartan in rats fed the low-salt diet. CONCLUSIONS: Dual RAS blockade could be either beneficial, when sodium intake is unrestricted, or dangerous, when sodium intake is restricted.