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Abstract Background Renal denervation (RDN) was still performed without any intra-procedural method for nerve mapping. Whether renal nerve stimulation (RNS) is an efficient way to identify renal autonomic innervation and optimize the strategy for RDN remain to be worthy for further exploration. Methods The characteristics of renal autonomic innervation at the sites with different blood pressure (BP) responses to RNS were explored. Then, dogs anatomically eligible for RDN were randomly assigned into elevated BP response ablation group, reduced BP response ablation group, and RNS-control group. The postoperative outcomes were measured at baseline and after 4 weeks follow-up. Results The proportion of afferent sensory nerve was higher at elevated BP response sites (ERS) than reduced BP response sites (RRS) and non-response sites (NRS) (P = 0.012 and P = 0.004). Conversely, the proportion of parasympathetic nerve at RRS was the highest (RRS vs. ERS, P = 0.017; RRS vs. NRS, P = 0.023). More importantly, there was a significant correlation between systolic blood pressure changes and the area ratios of afferent sensory and parasympathetic nerve (R = 0.859; P

Abstract Recent trials have demonstrated the efficacy and safety of percutaneous renal sympathetic denervation (RDN) for blood pressure (BP)‐lowering in patients with uncontrolled hypertension. Nevertheless, major challenges exist, such as the wide variation of BP‐lowering responses following RDN (from strong response to no response) and lack of feasible and reproducible peri‐procedural predictors for patient response. Both animal and human studies have demonstrated different patterns of BP responses following renal nerve stimulation (RNS), possibly related to varied regional proportions of sympathetic and parasympathetic nerve tissues along the renal arteries. Animal studies of RNS have shown that rapid electrical stimulation of the renal arteries caused renal artery vasoconstriction and increased norepinephrine secretion with a concomitant increase in BP, and the responses were attenuated after RDN. Moreover, selective RDN at sites with strong RNS‐induced BP increases led to a more efficient BP‐lowering effect. In human, when RNS was performed before and after RDN, blunted changes in RNS‐induced BP responses were noted after RDN. The systolic BP response induced by RNS before RDN and blunted systolic BP response to RNS after RDN, at the site with maximal RNS‐induced systolic BP response before RDN, both correlated with the 24‐h ambulatory BP reductions 3–12 months following RDN. In summary, RNS‐induced BP changes, before and after RDN, could be used to assess the immediate effect of RDN and predict BP reductions months following RDN. More comprehensive, large‐scale and long term trials are needed to verify these findings.

Background: Renal denervation (RDN) was still performed without any intra-procedural method for nerve mapping. Whether renal nerve stimulation (RNS) is an efficient way to identify renal autonomic innervation and optimize the strategy for RDN remain to be worthy for further exploration. Methods: The characteristics of renal autonomic innervation at the sites with different blood pressure (BP) responses to RNS were explored. Then, dogs anatomically eligible for RDN were randomly assigned into elevated BP response ablation group, reduced BP response ablation group, and RNS-control group. The postoperative outcomes were measured at baseline and after 4 weeks follow-up. Results: The proportion of afferent sensory nerve was higher at elevated BP response sites (ERS) than reduced BP response sites (RRS) and non-response sites (NRS) (P = 0.012 and P = 0.004). Conversely, the proportion of parasympathetic nerve at RRS was the highest (RRS vs. ERS, P = 0.017; RRS vs. NRS, P = 0.023). More importantly, there was a significant correlation between systolic blood pressure changes and the area ratios of afferent sensory and parasympathetic nerve (R = 0.859; P < 0.001). In addition, ablation at BP-elevation sites can result in a significant decrease in BP and plasma norepinephrine (NE) after 4 weeks (P = 0.002; P = 0.008), while ablation at BP-reduction sites can lead to significant increases in BP and plasma NE (P = 0.016; P = 0.033). Conclusions: RNS is an effective method to identify renal autonomic innervation. It could not only help to identify optimal target sites, but also avoid ablation of sympathetic-inhibitory areas during RDN. [ABSTRACT FROM AUTHOR]

Purpose Blood pressure (BP) reduction after renal sympathetic denervation (RDN) is highly variable. Renal nerve stimulation (RNS) can localize sympathetic nerves. The RNS trial aimed to investigate the medium-term BP-lowering effects of the use of RNS during RDN, and explore if RNS can check the completeness of the denervation. Material and methods Forty-four treatment-resistant hypertensive patients were included in the prospective, single-center RNS trial. The primary study endpoint was change in 24-h BP at 6- to 12-month follow-up after RDN. The secondary study endpoints were the acute procedural RNS-induced BP response before and after RDN; number of antihypertensive drugs at follow-up; and the correlation between the RNS-induced BP increase before versus after RDN (delta [Δ] RNS-induced BP). Results Before RDN, the RNS-induced systolic BP rise was 43(±21) mmHg, and decreased to 9(±12) mmHg after RDN (p 0 mmHg residual RNS-induced BP response (126 ± 4 mmHg versus 135 ± 10 mmHg, p = 0.04). 83% of the patients with ≤0 mmHg residual RNS-induced BP response had normal 24-h BP at follow-up, compared to 33% in the patients with >0 mmHg residual RNS-induced BP response (p = 0.023). Conclusion The use of RNS during RDN leads to clinically significant and sustained lowering of 24-h BP with fewer antihypertensive drugs at follow-up. RNS-induced BP changes were correlated with 24-h BP changes at follow-up. Moreover, patients with complete denervation had significant lower BP compared to the patients with incomplete denervation.

Recent trials have demonstrated the efficacy and safety of percutaneous renal sympathetic denervation (RDN) for blood pressure (BP)-lowering in patients with uncontrolled hypertension. Nevertheless, major challenges exist, such as the wide variation of BP-lowering responses following RDN (from strong response to no response) and lack of feasible and reproducible peri-procedural predictors for patient response. Both animal and human studies have demonstrated different patterns of BP responses following renal nerve stimulation (RNS), possibly related to varied regional proportions of sympathetic and parasympathetic nerve tissues along the renal arteries. Animal studies of RNS have shown that rapid electrical stimulation of the renal arteries caused renal artery vasoconstriction and increased norepinephrine secretion with a concomitant increase in BP, and the responses were attenuated after RDN. Moreover, selective RDN at sites with strong RNS-induced BP increases led to a more efficient BP-lowering effect. In human, when RNS was performed before and after RDN, blunted changes in RNS-induced BP responses were noted after RDN. The systolic BP response induced by RNS before RDN and blunted systolic BP response to RNS after RDN, at the site with maximal RNS-induced systolic BP response before RDN, both correlated with the 24-h ambulatory BP reductions 3-12 months following RDN. In summary, RNS-induced BP changes, before and after RDN, could be used to assess the immediate effect of RDN and predict BP reductions months following RDN. More comprehensive, large-scale and long term trials are needed to verify these findings. [ABSTRACT FROM AUTHOR]

Increased sympathetic nervous activity is one of main contributors to pathogenesis and progression of hypertension. Renal denervation (RDN) has been demonstrated as a potential therapy for treatment of hypertension; however, lack of indicators of intra-/post-procedure results in inconsistent clinical outcomes. Renal nerve stimulation (RNS), a simple and promising method, could evoke elevated blood pressure as an intraoperative indicator for RDN. But related researches on patterns of blood pressure responses to RNS are still incomplete. To investigate and categorize the phenotypes of blood pressure response to RNS and heart rate alteration before and after RNS, 24 Chinese Kunming dogs were used to perform RNS from bifurcation to ostium of renal arteries after angiography, and a total of 483 stimulated sites were complete. We identified five different patterns of blood pressure response to RNS in 483 stimulated sites, (1) continuous ascending and finally keeping steady above baseline (26.9%), (2) declining and then rising over baseline (11.8%), (3) declining and then rising but below baseline (14.5%), (4) fluctuating in the vicinity of baseline (39.5%), and (5) continuous declining and finally keeping steady below baseline (7.2%), and found no difference in RR intervals among five blood pressure responses before and after renal nerve stimulation. Renal nerve stimulation could elicit different patterns of blood pressure response, which could potentially assist in distinguishing sympathetic-excitatory sites and sympathetic-inhibitory sites from mixed nerve components, which might help to improve the efficacy of RDN. [ABSTRACT FROM AUTHOR]

Blood pressure (BP) reduction after renal sympathetic denervation (RDN) is highly variable. Renal nerve stimulation (RNS) can localize sympathetic nerves. The RNS trial aimed to investigate the medium-term BP-lowering effects of the use of RNS during RDN, and explore if RNS can check the completeness of the denervation. Forty-four treatment-resistant hypertensive patients were included in the prospective, single-center RNS trial. The primary study endpoint was change in 24-h BP at 6- to 12-month follow-up after RDN. The secondary study endpoints were the acute procedural RNS-induced BP response before and after RDN; number of antihypertensive drugs at follow-up; and the correlation between the RNS-induced BP increase before versus after RDN (delta [Δ] RNS-induced BP). Before RDN, the RNS-induced systolic BP rise was 43(±21) mmHg, and decreased to 9(±12) mmHg after RDN (p < 0.001). Mean 24-h systolic/diastolic BP decreased from 147(±12)/82(±11) mmHg at baseline to 135(±11)/76(±10) mmHg (p < 0.001/<0.001) at follow-up (10 [6–12] months), with 1 antihypertensive drug less compared to baseline. The Δ RNS-induced BP and the 24-h BP decrease at follow-up were correlated for systolic (R = 0.44, p = 0.004) and diastolic (R = 0.48, p = 0.003) BP. Patients with ≤0 mmHg residual RNS-induced BP response after RDN had a significant lower mean 24-h systolic BP at follow-up compared to the patients with >0 mmHg residual RNS-induced BP response (126 ± 4 mmHg versus 135 ± 10 mmHg, p = 0.04). 83% of the patients with ≤0 mmHg residual RNS-induced BP response had normal 24-h BP at follow-up, compared to 33% in the patients with >0 mmHg residual RNS-induced BP response (p = 0.023). The use of RNS during RDN leads to clinically significant and sustained lowering of 24-h BP with fewer antihypertensive drugs at follow-up. RNS-induced BP changes were correlated with 24-h BP changes at follow-up. Moreover, patients with complete denervation had significant lower BP compared to the patients with incomplete denervation. [ABSTRACT FROM AUTHOR]

Purpose: Recently we reported the use of renal nerve stimulation (RNS) during renal denervation (RDN) procedures. RNS induced changes in blood pressure (BP) and heart rate are not fully delineated yet. We hypothesized that electrical stimulation of the sympathetic nerve tissue in the renal artery would lead to an increase in BP and vagal stimulation would cause a decrease in BP. We report the different patterns of BP and heart rate responses elicited by RNS prior to RDN. Methods: 35 patients with drug-resistant hypertension were included. RNS was performed under general anesthesia at four sites in the right and left renal arteries, both before and immediately after RDN. RNS-induced BP and heart rate changes were monitored. Results: A total of 289 RNS sites in 35 patients were analyzed. An increase in systolic BP of >10 mmHg was regarded as a positive BP response to RNS. This pattern of response was observed in 180 sites (62%). 86 RNS sites (30%) showed an indifferent response with BP changes ≤10 mmHg. At 13 sites (4.5%) RNS elicited a decrease in BP up to −8 mmHg. However, 10 RNS sites (3.5%) showed a pronounced vagal response with hypotension and sinus cycle lengths ranging between 4224–10272 milliseconds. These sites were distributed among two patients. Conclusion: RNS identified sympathetic and parasympathetic nerve tissue in the renal arteries. RNS can be potentially used to map nerve bundles and guide selective ablation of sympathetic nerve fibers and prevent inadvertent ablation of parasympathetic nerve tissue during RDN.

Background: Renal nerve denervation (RDN) is developed as a potential treatment for hypertension. Recently, we reported the use of renal nerve stimulation (RNS) to localize sympathetic nerve tissue for subsequent selective RDN. The effects of RNS on arterial pressure dynamics remain unknown. The current study aimed to describe the acute changes in arterial pressure dynamics response to RNS before and after RDN.Methods and results: Twenty six patients with drug-resistant hypertension referred for RDN were included. RNS was performed under general anesthesia before and after RDN. We continuously monitored heart rate (HR) and invasive femoral blood pressure (BP). Augmentation pressure (AP) and index (Aix), pulse pressure (PP), time to reflected wave, maximum systolic BP and dicrotic notch were calculated. Systolic and diastolic BP at site of maximum response significantly increased in response to RNS (120 ± 16/62 ± 9 to 150 ± 22/75 ± 15 mmHg) (p < 0.001/< 0.001), whereas after RDN no RNS-induced BP change was observed (p > 0.10). RNS increased Aix (29 ± 11 to 32 ± 13%, p = 0.005), PP (59 ± 14 to 75 ± 17 mmHg, p < 0.001), time to reflected wave (63 ± 18 to 71 ± 25 ms, p = 0.004) and time to maximum systolic pressure (167 ± 36 to 181 ± 46 ms, p = 0.004) before RDN, whereas no changes were observed after RDN (p > 0.18). All changes were BP dependent. RNS had no influence on HR or the time to dicrotic notch (p > 0.12).  Conclusion: RNS induces temporary rises in Aix, PP, time to maximum systolic pressure and time to reflected wave. These changes are BP dependent and were completely blunted after RDN. [ABSTRACT FROM AUTHOR]

Purpose: Recently we reported the use of renal nerve stimulation (RNS) during renal denervation (RDN) procedures. RNS induced changes in blood pressure (BP) and heart rate are not fully delineated yet. We hypothesized that electrical stimulation of the sympathetic nerve tissue in the renal artery would lead to an increase in BP and vagal stimulation would cause a decrease in BP. We report the different patterns of BP and heart rate responses elicited by RNS prior to RDN. Methods: 35 patients with drug-resistant hypertension were included. RNS was performed under general anesthesia at four sites in the right and left renal arteries, both before and immediately after RDN. RNS-induced BP and heart rate changes were monitored. Results: A total of 289 RNS sites in 35 patients were analyzed. An increase in systolic BP of >10 mmHg was regarded as a positive BP response to RNS. This pattern of response was observed in 180 sites (62%). 86 RNS sites (30%) showed an indifferent response with BP changes ≤10 mmHg. At 13 sites (4.5%) RNS elicited a decrease in BP up to −8 mmHg. However, 10 RNS sites (3.5%) showed a pronounced vagal response with hypotension and sinus cycle lengths ranging between 4224-10272 milliseconds. These sites were distributed among two patients. Conclusion: RNS identified sympathetic and parasympathetic nerve tissue in the renal arteries. RNS can be potentially used to map nerve bundles and guide selective ablation of sympathetic nerve fibers and prevent inadvertent ablation of parasympathetic nerve tissue during RDN. [ABSTRACT FROM AUTHOR]

A strong evidence of outcomes for vasovagal syncope is not easily identified. It would seem reasonable that the proposed Mayo Clinic technology would be reserved for cases with severe recurrent or refractory syncope. However, recurrence levels are relatively low, and while some predictive methods have been proposed, recurrence is also influenced by the interaction that occurs during screening and examinations, i.e. recurrence diminishes once an initial diagnosis has been made. Finally, a key factor in being able to identify suitable patients relates to understanding the relative significance of the vasodepression and cardioinhibitory components—the therapy is best suited to patients that have a significant level of both components. It is probably not needed in patients with mainly cardioinhibitory involvement—data from ISSUE 2 and ISSUE 3 studies suggest that this is a relatively large proportion, particularly with asystolic involvement. The challenge remains in having suitable screening tests to identify the best patients. Tilt table testing has questions concerning its ability to replicate clinical syncope—implantable loop recorders (ILRs) may provide more accurate data but their usage is not yet widely accepted given the costs and invasive nature of the monitor. [ABSTRACT FROM AUTHOR]

Inappropriate sympathetic activation is closely associated with the development and progression of hypertension. Renal denervation (RDN) is a neuromodulation therapy performed using an intraarterial catheter in patients with hypertension. Recent randomized sham-operated controlled trials have shown that RDN has significant antihypertensive effects that last for at least 3 years. Based on this evidence, RDN is nearly ready for general clinical application. On the other hand, there are remaining issues to be addressed, including elucidation of the precise antihypertensive mechanisms of RDN, the appropriate endpoint of RDN during the procedure, and the association between reinnervation after RDN and the long-term effects of RDN. This mini review focuses on studies implicating anatomy of the renal nerves, which consist of afferent or efferent and sympathetic or parasympathetic nerves, the response of blood pressure to renal nerve stimulation, and reinnervation of renal nerves after RDN. A comprehensive understanding of the anatomical and functional aspects of the renal nerves and the antihypertensive mechanisms of RDN, including its long-term effects, will enhance our ability to incorporate RDN into strategies to treat hypertension in clinical practice. This mini review focuses on studies implicating anatomy of the renal nerves, which consist of afferent or efferent and sympathetic or parasympathetic nerves, the response of blood pressure to renal nerve stimulation, and reinnervation of renal nerves after renal denervation. Whether the ablation site is sympathetic dominant or parasympathetic dominant, and afferent dominant or efferent dominant, would in turn determine the final output of renal denervation. BP: blood pressure., (© 2023. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Endovascular Stimulation for Treatment of Hypotension Background We have previously shown that sympathetic ganglia stimulation via the renal vein rapidly increases blood pressure. This study further investigated the optimal target sites and effective energy levels for stimulation of the renal vasculatures and nearby sympathetic ganglia for rapid increase in blood pressure. Methods The pre-study protocol for endovascular stimulations included 2 minutes of stimulation (1-150 V and 10 pulses per second) and at least 2 minutes of rest during poststimulation. If blood pressure and/or heart rate were changed during the stimulation, time to return to baseline was allowed prior to the next stimulation. Results In 11 acute canine studies, we performed 85 renal artery, 30 renal vein, and 8 hepatic vasculature stimulations. The mean arterial pressure (MAP) rapidly increased during stimulation of renal artery (95 ± 18 mmHg vs. 103 ± 15 mmHg; P < 0.0001), renal vein (90 ± 16 mmHg vs. 102 ± 20 mmHg; P = 0.001), and hepatic vasculatures (74 ± 8 mmHg vs. 82 ± 11 mmHg; P = 0.04). Predictors of a significant increase in MAP were energy >10 V focused on the left renal artery, bilateral renal arteries, and bilateral renal veins (especially the mid segment). Overall, heart rate was unchanged, but muscle fasciculation was observed in 22.0% with an output >10 V (range 15-150 V). Analysis after excluding the stimulations that resulted in fasciculation yielded similar results to the main findings. Conclusions Stimulation of intra-abdominal vasculatures promptly increased the MAP and thus may be a potential treatment option for hypotension in autonomic disorders. Predictors of optimal stimulation include energy delivery and the site of stimulation (for the renal vasculatures), which informs the design of subsequent research. [ABSTRACT FROM AUTHOR]

Blood pressure (BP) response to renal denervation (RDN) is highly variable and its effectiveness debated. A procedural end point for RDN may improve consistency of response. The objective of the current analysis was to look for the association between renal nerve stimulation (RNS)-induced BP increase before and after RDN and changes in ambulatory BP monitoring (ABPM) after RDN. Fourteen patients with drug-resistant hypertension referred for RDN were included. RNS was performed under general anesthesia at 4 sites in the right and left renal arteries, both before and immediately after RDN. RNS-induced BP changes were monitored and correlated to changes in ambulatory BP at a follow-up of 3 to 6 months after RDN. RNS resulted in a systolic BP increase of 50±27 mm Hg before RDN and systolic BP increase of 13±16 mm Hg after RDN (P<0.001). Average systolic ABPM was 153±11 mm Hg before RDN and decreased to 137±10 mm Hg at 3- to 6-month follow-up (P=0.003). Changes in RNS-induced BP increase before versus immediately after RDN and changes in ABPM before versus 3 to 6 months after RDN were correlated, both for systolic BP (R=0.77, P=0.001) and diastolic BP (R=0.79, P=0.001). RNS-induced maximum BP increase before RDN had a correlation of R=0.61 (P=0.020) for systolic and R=0.71 (P=0.004) for diastolic ABPM changes. RNS-induced BP changes before versus after RDN were correlated with changes in 24-hour ABPM 3 to 6 months after RDN. RNS should be tested as an acute end point to assess the efficacy of RDN and predict BP response to RDN. [ABSTRACT FROM AUTHOR]

Blood pressure response to renal denervation is highly variable, and the proportion of responders is disappointing. This may be partly because of accessory renal arteries too small for denervation, causing incomplete ablation. Renal nerve stimulation before and after renal denervation is a promising approach to assess completeness of renal denervation and may predict blood pressure response to renal denervation. The objective of the current study was to assess renal nerve stimulation-induced blood pressure increase before and after renal sympathetic denervation in main and accessory renal arteries of anaesthetized patients with drug-resistant hypertension. The study included 21 patients. Nine patients had at least 1 accessory renal artery in which renal denervation was not feasible. Renal nerve stimulation was performed in the main arteries of all patients and in accessory renal arteries of 6 of 9 patients with accessory arteries, both before and after renal sympathetic denervation. Renal nerve stimulation before renal denervation elicited a substantial increase in systolic blood pressure, both in main (25.6±2.9 mm Hg; P<0.001) and accessory (24.3±7.4 mm Hg; P=0.047) renal arteries. After renal denervation, renal nerve stimulation-induced systolic blood pressure increase was blunted in the main renal arteries (Δ systolic blood pressure, 8.6±3.7 mm Hg; P=0.020), but not in the nondenervated renal accessory renal arteries (Δ systolic blood pressure, 27.1±7.6 mm Hg; P=0.917). This residual source of renal sympathetic tone may result in persistent hypertension after ablation and partly account for the large response variability. [ABSTRACT FROM AUTHOR]

Following the publication of the randomized controlled but open-label trial Symplicity HTN-2, catheter-based renal sympathetic denervation was proposed as a novel treatment for drug-resistant hypertension. Thousands of procedures were routinely performed in Europe, Australia and Asia, and many observational studies were published. A sudden shift from overoptimistic views to radical scepticism occurred later, when the large US randomized sham-controlled trial Symplicity HTN-3 failed to meet its primary blood pressure lowering efficacy endpoint. Experts are divided on the reasons accounting for the large discrepancy between the results of initial studies and those of Symplicity HTN-3. Indeed, the blood pressure lowering effect associated with renal denervation was overestimated in initial trials due to various patient and physician-related biases, whereas it could have been underestimated in Symplicity HTN-3, which was well designed but not rigorously executed. Still, there is a large consensus on the need to further study catheter-based renal denervation in more controlled conditions, with particular emphasis on identification of predictors of blood pressure response. US and European experts have recently issued very similar recommendations on design of upcoming trials, procedural aspects, drug treatment, patient population and inclusion–exclusion criteria. Application of these new standards may represent a second chance for renal denervation to demonstrate—or not—its efficacy and safety in various patient populations. With its highly standardized treatment regimen, the French trial DENERHTN paved the way for this new approach and may inspire upcoming studies testing novel renal denervation systems in different populations. [ABSTRACT FROM AUTHOR]

We investigated the renal response to direct renal nerve stimulation, 2 weeks following reversal of 24-h unilateral (left) ureteric obstruction. Renal nerve stimulation caused a 13-15 % fall in renal blood flow, in 4 groups of anesthetized rats following ureteric obstruction (n=9) or a sham operation (n=7) both with (n=9) and without (n=7) treatment with the mixed ETA/B receptor antagonist, bosentan. In the sham-operated rats, renal nerve stimulation did not change glomerular filtration rate but reduced urine flow rate (37±3 %, P<0.001), and absolute (38±4 %, P<0.001) and fractional (35±5 %, P<0.01) sodium excretion. Following unilateral ureteric obstruction, renal nerve stimulation increased glomerular filtration rate by 22±3 % (P<0.01), but reduced urine flow rate (14±2 %, P<0.001) and fractional sodium excretion (23±5 %, P<0.01). Bosentan treatment had no effect on baseline or renal responses to renal nerve stimulation in the sham group but normalized the renal response to renal nerve stimulation in the unilateral ureteric obstruction group. We conclude that 14 days after a 24-h period of unilateral ureteric obstruction there is an increase in GFR in response to direct renal nerve stimulation, which is due, in part, to the actions of endothelin at the time of obstruction. [ABSTRACT FROM AUTHOR]

Renal Vein Stimulation Increases Blood Pressure Background Neurocardiogenic syncope (NCS) is a common and sometimes debilitating disorder, with no consistently effective treatment. NCS is due to a combination of bradycardia and vasodilation leading to syncope. Although pacemaker devices have been tried in treating the bradycardic aspect of NCS, no device-based therapy exists to treat the coexistent vasodilation that occurs. The renal sympathetic innervation has been the target of denervation to treat hypertension. We hypothesized that stimulation of the renal sympathetic nerves can increase blood pressure and counteract vasodilation in NCS. Methods and Results High-frequency stimulation (800-900 pps, 10 V, 30-200 seconds) was performed using a quadripolar catheter in the renal vein of 7 dogs and 1 baboon. A significant increase in blood pressure (BP; mean [SD] systolic BP 117 [±28] vs. 128 [±33], diastolic BP 75 [±19] vs. 87 [±29] mmHg) was noted during the stimulation, which returned to baseline after cessation of stimulation. The mean increase in systolic and diastolic BP was 13.0 (±3.3) (P = 0.006) and 10.2 (±4.6) (P = 0.08), respectively. Conclusion We report the first ever study of feasibility and safety of high-frequency electrical stimulation of the renal sympathetic innervation to increase BP in animal models. This has potential applications in the treatment of hypotensive states such as NCS. [ABSTRACT FROM AUTHOR]

Aims This study examined the interaction between reactive oxygen species and nitric oxide ( NO) in mediating the decrease in renal blood flow ( RBF) evoked by sympathetic renal nerve stimulation ( RNS). Methods Groups of male Wistar rats were subjected to RNS at different frequencies prior to, and following, an infusion of: (i) tempol, the superoxide dismutase ( SOD) mimetic, (ii) tempol plus the hydrogen peroxide-degrading enzyme catalase (tem + cat), (iii) diethyldithiocarbamic acid ( DETC), a SOD inhibitor, (iv) the nitric oxide synthase ( NOS) inhibitor, L-nitro-arginine methyl ester ( L- NAME) alone, or (v) L- NAME followed by tempol, into the kidney cortico-medullary border ( CMB). Blood perfusion within the cortical ( CBP) and medullary ( MBP) regions of the kidney was measured using Laser-Doppler flowmetry. Results Infusion of tempol CMB significantly attenuated RNS-evoked reductions in CBP (by 22% at 8 Hz; P < 0.05), but not MBP. When tempol and catalase were co-infused to reduce both ROS and hydrogen peroxide (H2O2), respectively, there was a significantly greater attenuation of the RNS-evoked reduction in CBP compared with that of tempol alone. Infusion of either DETC or L- NAME alone did not significantly affect the CBP or MBP responses to RNS. Similarly, RNS following tempol infusion with L- NAME also had no effect on CBP and MBP over and above the group that received tempol alone. Conclusion These results suggest that reactive oxygen species such as superoxide and H2O2 have a direct role in reducing renal vascular compliance in response to RNS, rather than indirectly through scavenging NO. [ABSTRACT FROM AUTHOR]

Rhabdomyolysis is an important cause of acute renal failure (ARF) and renal vasoconstriction is the main mechanism in the pathogenesis of ARF. Lipid peroxidation due to hydroxyl radical ( .OH) formation and redox cycling of myoglobin also have a role. We investigated the disturbance in renal vascular reactivity to reveal the mechanisms leading to ARF. Female Wistar rats ( n == 7) were injected with glycerol (10 mL/kg, 50%% in saline) intramuscularly to induce rhabdomyolysis, and then the kidneys were isolated and perfused. We investigated acetylcholine (ACh)-induced endothelium-dependent and papaverine (PAP)-induced endothelium-independent vasodilation responses and renal nerve stimulation (RNS)-induced vasoconstrictions. These were also investigated both in rats which received either .OH scavenger, dimethylthiourea (DMTU: 500 mg/kg before glycerol injection and 125 mg/kg 8 h after glycerol injection, n == 7), or myoglobin redox cycling inhibitor, acetaminophen (ApAP: 100 mg/kg 2 h before glycerol injection and 100 mg/kg each 4 h, and 22 h after glycerol injection, n == 7). ACh-induced responses in glycerol group were decreased ( p < 0.001), but PAP-induced vasodilation did not change. RNS-induced vasoconstriction in all kidneys was greater ( p < 0.001) in glycerol group. DMTU restored both endothelium-dependent vasodilation and RNS-induced vasoconstriction. ApAP had no effect on vascular responses. Both DMTU and ApAP exerted a partial protective effect in renal histology without restoring serum creatinine and blood urea nitrogen (BUN) levels or creatinine clearance. This study showed that endothelial dysfunction and increased vasoconstriction developed during rhabdomyolysis. .OH plays an important role in the development of these vascular responses. These findings suggest that decreased endothelium-dependent vasodilation and augmented renal sympathetic tonus contribute to the development of renal vasoconstriction during rhabdomyolysis-induced ARF. [ABSTRACT FROM AUTHOR]

The role of renal sympathetic nerves in the pathogenesis of ischemic acute renal failure (ARF) and the immediate changes in the renal excretory functions following renal ischemia were investigated. Two groups of male Sprague Dawley (SD) rats were anesthetized (pentobarbitone sodium, 60 mg kg−1 i.p.) and subjected to unilateral renal ischemia by clamping the left renal artery for 30 min followed by reperfusion. In group 1, the renal nerves were electrically stimulated and the responses in the renal blood flow (RBF) and renal vascular resistance (RVR) were recorded, while group 2 was used to study the early changes in the renal functions following renal ischemia. In post-ischemic animals, basal RBF and the renal vasoconstrictor reperfusion to renal nerve stimulation (RNS) were significantly lower (all p < 0.05 vs. control). Mean arterial pressure (MAP), basal RVR, urine flow rate (UFR), absolute and fractional excretions of sodium (UNaV and FENa), and potassium (UKV and FEK) were higher in ARF rats (all p < 0.05 vs. control). Post-ischemic animals showed markedly lower glomerular filtration rate (GFR) ( p < 0.05 vs. control). No appreciable differences were observed in urinary sodium to potassium ratio (UNa/UK) during the early reperfusion phase of renal ischemia ( p > 0.05 vs. control). The data suggest an immediate involvement of renal sympathetic nerve action in the pathogenesis of ischemic ARF primarily through altered renal hemodynamics. Diuresis, natriuresis, and kaliuresis due to impaired renal tubular functions are typical responses to renal ischemia and of comparable magnitudes. [ABSTRACT FROM AUTHOR]

Renal nerves play an important role in the setting of the sensitivity of the tubuloglomerular feedback (TGF) mechanism. We recently reported a time-dependent resetting of TGF to a lower sensitivity 3–4 h after acute unilateral renal denervation (aDNX). This effect persisted after 1 week, but was then less pronounced. To determine whether normal TGF sensitivity could be restored in aDNX kidneys by low-frequency renal nerve stimulation (RNS), the following experiments were performed. Rats with aDNX were prepared for micropuncture. In one experimental group proximal tubular free flow (Pt) and stop flow pressures (Psf) were measured during RNS at frequencies of 2, 4 and 6 Hz. In another series of experiments the TGF sensitivity was evaluated from the Psf responses at different loop perfusion rates after 20 min of RNS at a frequency of 2 Hz. The maximal drop in Psf (ΔPsf) and the tubular flow rate at which half the maximal response in ΔPsf was observed (turning point, TP), were recorded. At RNS frequencies of 2, 4 and 6 Hz, Pt decreased from the control level of 14.1 ± 0.8–13.1 ± 1.0, 12.4 ± 1.1 and 11.2 ± 0.8 mmHg (decrease 21%, P < 0.05), respectively, while at zero perfusion and during RNS at 2 and 4 Hz Psf decreased from 42.5 ± 1.6 to 38.2 ± 1.4 and 32.8 ± 4.3 mmHg (decrease 23%, P < 0.05), respectively. The TGF characteristics were found to be reset from the normal sensitivity with TP of 19.0 ± 1.1 nL min–1 and ΔPsf of 8.7 ± 0.9 mmHg to TP of 28.3 ± 2.4 nL min–1 (increase 49%, P < 0.05) and ΔPsf of 5.8 ± 1.2 mmHg (decrease 33%) after aDNX. After 20 min of RNS at 2 Hz TP was normalized and ΔPsf was 33% higher. Thus the present findings indicate that the resetting of the TGF sensitivity that occurred 2–3 h after aDNX could be partially restored by 20 min of RNS at a frequency of 2 Hz. These results imply that renal nerves have an important impact on the setting of the sensitivity of the TGF mechanism. [ABSTRACT FROM AUTHOR]

The role of prostaglandins in the renin release response to renal nerve stimulation (RNS) at different intensities was examined in the anaesthetized dog. The animals were divided into two groups receiving either low or high level RNS, defined by the frequencies of stimulation producing reduction in renal blood flow by 5% or less and 50%. Indomethacin or diclofenac sodium (5 mg/kg i.v.), prostaglandin synthesis inhibitors, did not affect the renin release response to high level RNS by 31±8% ( P<0.01). Addition of metoprolol, (0.5 mg/kg i.v.) beta-1-adrenoceptor antagonist, to indomethacin or diclofenac sodium resulted in a greater reduction (68±6% P<0.01) of the renin release response to high level RNS compared to that produced by either drug alone. Metoprolol, alone, reduced the renin release response to high level RNS by 37±14% ( P<0.05). Phenoxybenzamine (0.6 μg·kg·min), alphaadrenoceptor antagonist, into the renal artery practically abolished the renal vasoconstrictor response to high level RNS and reduced the renin release response by 50±7% ( P<0.01). Addition of metoprolol to phenoxybenzamine practically abolished the renal vasoconstrictor response and the renin release response to high level RNS; 94±4% ( P<0.01). Addition of phenoxybenzamine to indomethacin or diclofenac sodium practically abolished the renal vasoconstrictor response to high level RNS but did not produce any greater reduction of the renin release response than that produced by either drug alone. These findings suggest that low level RNS results in renin release which is not dependent on prostaglandins. High level RNS results in renin release which is partly mediated by beta-1-adrenoceptors and partly related to alpha-adrenoceptor mediated renal vasoconstriction. Prostaglandins are not involved in the beta-adrenoceptor mediated renin release but are involved in the renin release deriving from alpha-adrenoceptor mediated renal vasoconstriction. [ABSTRACT FROM AUTHOR]

The contribution of beta-adrenoceptor activation to renin release was examined in anaesthetized dogs using renal nerve stimulation (RNS) at different discharge rates in the presence of i.v. beta-adrenoceptor blockade. The animals were divided into 2 groups, which received either low or high level of RNS, defined by the frequency of stimulation producing decrease in renal blood flow of 5 and 50%, respectively. Low level RNS increased renin release tenfold. The renin release response was almost abolished by 0.5 mg/kg of metoprolol or dl-propranolol but unaffected by 0.5 mg/kg of d-propranolol. The increase in renin release to high level RNS was equally reduced by 33% by 0.5 mg/kg and 2.0 mg/kg of metoprolol. dl-propranolol, 0.5 mg/kg, reduced the renin release response to about the same extent, 44%, while 2.0 mg/kg reduced it somewhat more, 59%. This was probably due to its membrane stabilizing properties as d-propranolol, 2.0 mg/kg and lidocaine 2.0 mg/kg+0.1 mgxkgxmin, also reduced the renin release response. These data suggest that the renin release response to low level RNS is almost completely mediated by beta-adrenoceptors which are of the beta-1 subtype. High level RNS results in a renin release, which is only partly mediated by beta-1-adrenoceptors. The remainder is apparently related to other mechanisms activated by high level RNS and is probably a consequence of the associated renal vasoconstriction. [ABSTRACT FROM AUTHOR]

A strong evidence of outcomes for vasovagal syncope is not easily identified. It would seem reasonable that the proposed Mayo Clinic technology would be reserved for cases with severe recurrent or refractory syncope. However, recurrence levels are relatively low, and while some predictive methods have been proposed, recurrence is also influenced by the interaction that occurs during screening and examinations, i.e. recurrence diminishes once an initial diagnosis has been made. Finally, a key factor in being able to identify suitable patients relates to understanding the relative significance of the vasodepression and cardioinhibitory components-the therapy is best suited to patients that have a significant level of both components. It is probably not needed in patients with mainly cardioinhibitory involvement-data from ISSUE 2 and ISSUE 3 studies suggest that this is a relatively large proportion, particularly with asystolic involvement. The challenge remains in having suitable screening tests to identify the best patients. Tilt table testing has questions concerning its ability to replicate clinical syncope-implantable loop recorders (ILRs) may provide more accurate data but their usage is not yet widely accepted given the costs and invasive nature of the monitor.