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.     

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)     

Effects of complete renal denervation and selective afferent renal denervation on the hypertension induced by intrarenal norepinephrine infusion in conscious rats

To test the hypothesis that continuous intrarenal norepinephrine (NE) infusions produce hypertension via activation of afferent renal nerves (ARN), rats were subjected to complete renal denervation (RN-x), selective renal deafferentation (ARN-x) or sham surgery, prior to infusion of NE. In the pre-infusion period, mean arterial pressure (MAP) was significantly lower in RN-x than in ARN-x or sham-operated rats. Plasma renin concentration (PRC) was significantly reduced following ARN-x, but not RN-x. During 5-day intrarenal infusions of 4, 12 or 36 micrograms NE/kg per h, MAP rose to similar levels in RN-x and sham-RN-x rats. However, RN-x rats exhibited significantly elevated PRC levels, suggesting that denervation supersensitivity masked the possible effects of RN-x. In sham-RN-x rats, MAP increased significantly more during intrarenal infusion of 12 micrograms NE/kg per h than during intravenous infusion of the same amount. In ARN-x rats, MAP rose to a similar degree during intravenous and intrarenal infusions. The pressor responses in the ARN-x rats, however, were not significantly smaller at any point than those in intact rats. PRC rose to comparable levels in ARN-x and intact rats. Thus, in normotensive rats, efferent renal nerves (ERN) but not ARN are of functional significance in maintaining basal blood pressure. ARN may be involved in the control of renin release. Since neither RN-x nor ARN-x attenuated the development of hypertension, renal nerves are not necessary for the full expression of hypertension in this model.     

Role of the renal nerves in one-kidney, one clip hypertension in rats

The effects of renal denervation on the onset and maintenance of one-kidney, one clip Goldblatt (1K1C) hypertension were determined. Renal denervation was performed at the time of 1K1C surgery, and was repeated at 3-week intervals to prevent renal nerve regeneration. Denervation delayed the onset of 1K1C hypertension by about 5 weeks, but the final hypertensive state was unaltered. Mean arterial pressure (MAP) averaged 196 +/- 11.4 mm Hg in six rats at 9 weeks after 1K1C surgery and 194 +/- 11.3 mm Hg in eight renal-denervated rats at this time. The delay in the development of 1K1C hypertension following renal denervation could not be explained by interference with renin release. This delay in the development of hypertension could be prevented, however, in renal-denervated 1K1C rats by substituting saline for the drinking water. Two weeks after 1K1C surgery and a high sodium diet, MAP averaged 164 +/- 6.4 mm Hg in eight rats rats with intact renal nerves and 173 +/- 4.8 mm Hg in nine renal-denervated rats. Intact renal nerves are not necessary for the development or maintenance of 1K1C hypertension. Renal denervation delays development of 1K1C hypertension, possibly by delaying the ability of these rats to retain sodium.     

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)     

Renal Nerves in the Maintenance of Hypertension: A Potential Therapeutic Target

Renal sympathetic efferent and afferent nerves, which lie within and immediately adjacent to the wall of the renal arteries, contribute to the maintenance of hypertension. Because the causative factors of hypertension change over time, denervation of both efferent and afferent renal nerves should result in long-term attenuation of hypertension. The importance of the renal nerves in hypertensive patients can now be defined with the novel development of percutaneous, minimally invasive renal denervation from within the renal artery using radiofrequency energy as a therapeutic strategy. Studies thus far show that catheter-based renal denervation in patients with resistant essential hypertension lowers systolic blood pressure 27 mm Hg by 12 months, with the estimated glomerular filtration rate remaining stable. The decrease in arterial pressure after renal denervation is associated with decreased peripheral sympathetic nervous system activity, suggesting that the kidney is a source of significant central sympathetic outflow via afferent renal nerve activity.     

Renal denervation abolishes hypertension in low-birth-weight offspring from pregnant rats with reduced uterine perfusion

Low birth weight is a risk factor for the subsequent development of hypertension in humans. We previously reported that reduced uterine perfusion in the pregnant rat results in growth-restricted offspring predisposed to the development of hypertension. The purpose of this study was to determine whether the sympathetic nervous system plays a role in mediating hypertension in this model of low birth weight. Weight at birth was significantly decreased in male growth-restricted offspring (5.9+/-0.1 grams) as compared with male control offspring (6.5+/-0.2 grams; P<0.05). At 10 weeks of age, growth-restricted offspring and control offspring were randomly assigned to either an intact group (sham-denervated) or a group subjected to bilateral renal denervation. For sham-denervated offspring, mean arterial pressure was significantly elevated in growth-restricted offspring (145+/-4 mm Hg; n=7) as compared with control offspring (134+/-3 mm Hg; P<0.05; n=9) at 12 weeks of age. Bilateral renal denervation resulted in a marked reduction in arterial pressure in growth-restricted offspring (125+/-3 mm Hg; P<0.01; difference of 20 mm Hg versus sham growth-restricted; n=8) but no significant decrease in control offspring (127+/-3 mm Hg; difference of 7 mm Hg versus sham control; n=9). Adequacy of renal denervation was verified by >90% reduction in renal norepinephrine content. Therefore, these findings indicate the renal nerves play an important role in mediating hypertension in adult growth-restricted offspring.     

Pain Sensitivity is not Affected by Sino-Aortic Denervation in Rats

Genetic hypertension in rats appears to be associated with diminished pain sensitivity. Acute stimulation of the baroreceptois has also been reported to decrease responsiveness to a noxious stimulus. In this study the effect of sino-aortic denervation on pain sensitivity, as measured by means of a hot plate and threshold electric footshock method has been investigated. Deafferentation resulted in a labile hypertension and tachycardia. However, hot plate response latency times were not significantly different in the sino-aortic denervated rats as compared to sham operated controls under subchronic conditions. When tested for pain sensitivity three weeks after surgery using both methods on one occasion only, again the responsiveness to noxious stimuli was not different between the two groups. At the end of the experiments, the efficacy of denervation was confirmed by assessing lability of blood pressure and measuring heart rate responses to pharmacological manipulation of blood pressure. It is concluded that surgical interruption of the baroreceptor nerves in rats does not alter pain sensitivity under subchronic conditions.     

The Role of Renal Sympathetic Nerves in Hypertension: Has Percutaneous Renal Denervation Refocused Attention on Their Clinical Significance?

Renal sympathetic efferent and afferent nerves, which lie within and immediately adjacent to the wall of the renal artery, contribute to the pathogenesis of hypertension. Because the causative factors of hypertension change over time, denervation of both efferent and afferent nerves should result in long-term attenuation of the hypertension. The importance of the renal nerves in patients with hypertension can now be defined with the novel development of percutaneous minimally invasive renal denervation from within the renal artery using radiofrequency energy as a therapeutic strategy. Studies thus far show that catheter-based renal denervation in patients with refractory hypertension lowers systolic blood pressure 27 mm Hg by 12 months with estimated glomerular filtration rate remaining stable. An attenuation of hypertension of this magnitude by catheter-based renal sympathetic denervation in combination with pharmacologic therapy is likely to be valuable in decreasing the risks of stroke, left ventricular hypertrophy, heart failure, and chronic renal failure.     

Renal denervation decreases blood pressure and renal tyrosine hydroxylase but does not augment the effect of hypotensive drugs

The effect of renal denervation on the efficacy of antihypertensive drugs has not yet been elucidated. Twenty-week-old spontaneously hypertensive rats were treated with metoprolol, losartan, indapamide, or saline (controls) and assigned to renal denervation or a sham procedure. Acute hemodynamic measurements were performed ten days later. Series showing a significant interaction between renal denervation and the drugs were repeated with chronic telemetry measurements. In the saline series, denervated rats showed a significantly lower mean arterial blood pressure (blood pressure) than the sham-operated rats. In contrast, in the metoprolol series denervated rats showed a significantly higher blood pressure than sham rats. There were no differences in blood pressure between denervated and sham rats in the losartan and indapamide series. In chronic studies, a 4-week treatment with metoprolol caused a decrease in blood pressure. Renal denervation and sham denervation performed 10 days after the onset of metoprolol treatment did not affect blood pressure. Denervated rats showed markedly reduced renal nerve tyrosine hydroxylase levels. In conclusion, renal denervation decreases blood pressure in hypertensive rats. The hypotensive action of metoprolol, indapamide, and losartan is not augmented by renal denervation, suggesting the absence of synergy between renal denervation and the drugs investigated in this study.     

The Future of Renal Denervation in Resistant Hypertension

Resistant hypertension, defined as inadequate blood pressure control despite three or more antihypertensive medications at maximally tolerated doses, is strongly linked to increased cardiovascular morbidity and mortality. Increased renal afferent and efferent sympathetic activity carried by nerves which arborize the adventitia of the renal arteries, appears to be central to the pathobiology of resistant hypertension. Historical experience indicates that surgical denervation and/or sympathectomy often dramatically reduced blood pressure in patients with malignant hypertension. Catheter-based radio-frequency renal denervation was developed in the past decade as a percutaneous adaptation of surgical denervation. Percutaneous renal denervation using a variety of systems has demonstrated to date, in non-randomized and unblinded studies, dramatic reductions in office-based blood pressure, but more modest impact on ambulatory blood pressure. The only single, appropriately powered, blinded, sham-controlled study of renal denervation conducted to date, however, failed to meet its primary endpoint, casting doubt on the value of the therapy. Ancillary benefits of renal denervation have been described in such conditions as diabetes mellitus, heart failure, and sleep apnea but require further study. While renal denervation is already widely available outside of the USA for commercial use, its utility in resistant hypertension must be vetted by further rigorous investigation before its use can be routinely recommended.     

Inability of dorsal spinal rhizotomy to prevent renal wrap hypertension in rats

Renal hypertension has been shown to be prevented and reversed by renal denervation. It has been postulated that the afferent nerves from the kidney are responsible for mediating the hypertensive stimulus that activates the sympathetic nervous system and increases arterial pressure. This study was designed to directly test the hypothesis that the afferent renal nerves are necessary for the development and maintenance of renal hypertension. In the first experiment, dorsal spinal rhizotomies or sham rhizotomies were performed in rats between T9 and L1, through which afferent renal nerves have been shown to traverse. After the one-kidney, one-wrap procedure, the increase in systolic arterial pressure and water intake was similar in the two groups of rats. To determine whether the removal of afferent renal nerves reversed the hypertensive process, animals with established renal hypertension were subjected to dorsal rhizotomy or the sham-rhizotomy procedure. Again, there was no significant effect on systolic arterial pressure and water intake. Although combined dorsal and ventral rhizotomy and subdiaphragmatic vagotomy did not affect the onset of hypertension, spinal transection at the level of C8 effectively prevented the rise in arterial pressure. Although efferent neural mechanisms contribute to the hypertensive process, these studies suggest that afferent renal nerves are not directly involved in the development and maintenance of one-kidney, one-wrap renal hypertension.     

Les sténoses artérielles rénales post-dénervation – une problématique préoccupante ?

Renal denervation, an invasive technique indicated in resistant hypertension patients insufficiently controlled by antihypertensive drugs, has a good safety profile. However, an increasing number of post-denervation renal artery stenosis cases has recently been reported. We describe the case of a 49-year-old woman with resistant hypertension who was referred to our university hypertension center for renal sympathetic denervation. Her daily treatment included six antihypertensive drugs. CT angiography prior to denervation showed no renal artery stenosis or vessel wall lesions. A standard renal denervation procedure using the St Jude protocol was performed. After an initial improvement in blood pressure profile, she presented with a blood pressure impairment at 3 months after renal denervation leading to the diagnosis of a severe right renal artery stenosis.     

Effect of acute NaCl depletion on NaCl-sensitive hypertension in borderline hypertensive rats.

OBJECTIVES: The borderline hypertensive rat (BHR) is the first generation offspring of a mating between a female spontaneously hypertensive rat and a male normotensive Wistar-Kyoto rat. With increased dietary NaCl intake, the BHR develops hypertension and augmented cardiovascular and renal responses to acute environmental stress. This investigation sought to examine the role of extracellular fluid volume (ECFV) in these changes. DESIGN: Three groups of 16-week-old BHR were studied: (1) rats on a 1% NaCl diet for 12 weeks; (2) rats on an 8% NaCl diet for 12 weeks; and (3) rats on an 8% NaCl diet for 12 weeks plus furosemide (50 mg/kg, i.p., twice daily) for the preceding 2 days. METHODS: Rats were chronically instrumented for the measurement of mean arterial pressure (MAP), heart rate and renal hemodynamic, excretory and sympathetic nerve activity responses to acute environmental stress (acute air jet stress). ECFV was measured as inulin space. RESULTS: BHR fed an 8% NaCl diet had increased MAP, urinary sodium excretion and ECFV compared with those fed a 1% NaCl diet; they also exhibited augmented pressor, tachycardic, renal sympathetic nerve excitatory and antinatriuretic responses to acute environmental stress. When 8% NaCl-diet BHR were treated with furosemide for 2 days, arterial pressure, urinary sodium excretion, ECFV and cardiovascular and renal responses to acute environmental stress returned to values seen in 1% NaCl-diet BHR. CONCLUSIONS: The hypertension and increased cardiovascular and renal responses to acute environmental stress produced by increased dietary NaCl intake in BHR derive from a central nervous system site of action via a mechanism(s) related to ECFV and/or sodium.     

Hypertension Produced by a High Sodium Diet in the Borderline Hypertensive Rat (BHR)

The effect of high dietary sodium (8%) on blood pressure in spontaneously hypertensive (SHR), borderline hypertensive (BHR), and normotensive Wistar-Kyoto (WKY) rats was determined weekly by tail cuff plethysmography for one week of baseline and four weeks of diet. After 4 weeks, significant elevations in systolic blood pressure were found in SHR and BHR groups, but not in WKY. BHR studied an additional 4 weeks showed a further progression of hypertension, reaching levels nearly equal to control SHR. Direct measurement of arterial pressure in conscious animals in their home cage confirmed the elevation in pressure in both SHR and BHR groups. Metabolic studies revealed that the high sodium diet reduced body weight in SHR and BHR strains, but not in WKY. Although both urinary volumes and sodium excretion values were significantly lower in SHR and BHR compared with WKY, this effect disappeared when adjustments for body weight were made.

Plasma norepinephrine determinations revealed a significant response to cold stress in all groups. Plasma epinephrine was elevated in all strains in response to cold stress; however, a consistent statistical elevation was seen only in WKY. The BHR is discussed as a model for determining the triggers responsible for environmentally-induced hypertension.     

The Role of Renal Denervation in the Treatment of Heart Failure

The heart and kidney interact in terms of hemodynamics and neurohumoral regulatory mechanisms, and this helps to maintain circulatory homeostasis under normal conditions. However, the normal regulatory mechanisms become inappropriate in the setting of congestive heart failure (CHF), and significant renal dysfunction often develops in CHF patients. Activation of renal sympathetic efferent nerves causes renin release, sodium and water retention, and reduced renal blood flow, all hallmarks of the renal manifestations of CHF. An increase in plasma levels of angiotensin II that is mediated in part by renal sympathetic activation has an effect on the central nervous system to further increase global sympathetic tone. Renal sympathetic activity can be assessed clinically by renal norepinephrine spillover, and an increase in renal norepinephrine spillover in CHF predicts reduced survival. In addition to efferent sympathetic activation, activation of renal sensory nerves in CHF may cause a reflex increase in sympathetic tone that contributes to elevated peripheral vascular resistance and vascular remodeling as well as left ventricular remodeling and dysfunction. In animal models of heart failure, surgical renal denervation has been shown to improve both renal and ventricular function. Although surgical renal denervation has long been known to lower blood pressure and improve survival in patients with hypertension, the invasive nature of this approach and its associated complications has limited its appeal. However, a novel catheter-based device has recently been introduced that specifically interrupts both efferent and afferent renal nerves, and there is significant interest in the use of this device to treat both hypertension and CHF. Several ongoing clinical trials are investigating the safety and efficacy of renal denervation in patients with CHF.     

经皮经导管去肾神经术治疗难治性高血压的临床规范

经皮经导管去肾神经术作为治疗顽固性高血压的新技术,其安全性和近、中期疗效肯定.但仍存在一些问题,如顽固性高血压的筛查、手术指征的界定、围手术期管理和术后疗效评估等.现对这些问题做一评述,以推动该手术的规范临床应用.     

Efficacy and safety of renal denervation for the management of arterial hypertension: A systematic review and meta‐analysis of randomized,sham‐controlled,catheter‐based trials

Despite the availability of a numerous antihypertensive agents, hypertension treatment and control rates remain low in many countries. The role of the sympathetic nervous system has long been recognized, but recent sham control renal denervation studies demonstrated conflicting results. In this reviewe paper, the authors performed a systematic review and meta‐analysis to examine outcomes of sham‐controlled studies utilizing new technologies and procedures. Six published randomized, sham‐controlled studies were included in this meta‐analysis. Of those, three trials used the first‐generation radiofrequency renal denervation device and technique and the other three used second‐generation devices and techniques. In total, 981 patients with hypertension were randomized in all 6 trials to undergo renal denervation (n = 585) or sham procedure (n = 396). Overall, renal denervation resulted in a decrease of 24‐hours systolic ambulatory blood pressure (ABP) by 3.62 mm Hg (95% CI: −5.28‐−1.96; I² = 0%), compared to sham procedure (GRADE: low). Renal denervation also reduced daytime systolic ABP by 5.51 mm Hg (95% CI: −7.79‐−3.23; I² = 0%), compared to sham procedure but not nighttime systolic ABP. Office systolic blood pressure was reduced by 5.47 mm Hg (95% CI −8.10‐−2.84; I² = 0%), compared to sham control. Further analysis demonstrated that second‐generation devices were effective in reducing blood pressure, whereas the first‐generation devices were not. These results indicate that effective renal denervation can result in significant and clinically meaningful blood pressure reduction. The second‐generation devices provide better renal nerve ablation.     

Renal denervation decreases blood pressure in DOCA-treated miniature swine with established hypertension

The role of renal sympathetic nerve activity (RSNA) in the maintenance phase of essential hypertension has not yet been clearly defined. Renal function and mean arterial pressure (MAP) were studied in four Yucatan miniature swine (YMS) with established DOCA hypertension prior to and for 3 weeks after surgical renal denervation (RDX). During the first week post-RDX, MAP decreased from 141 /+- 6 to 121 +/- 3 mm Hg (P less than .05), while sodium balance increased from 0.32 +/- 0.05 to 0.95 +/- 0.14 mEq/kg/day (P less than .05). By 3 weeks post-RDX, MAP remained below normotensive levels while sodium balance returned to the pre-RDX value. There was no significant change in potassium or water balance after RDX. Thus, in DOCA-YMS the renal nerves are important in the maintenance of hypertension. The reduction in MAP with RDX in the absence of a natriuresis suggests a role for renal afferent nerve activity.     

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.