Renal sympathetic denervation for resistant hypertension: where do we stand after more than a decade / Denervação simpática renal para hipertensão resistente: situação depois de mais de uma década

Abstract Despite the current availability of safe and efficient drugs for treating hypertension, a substantial number of patients are drug-resistant hypertensives. Aiming this condition, a relatively new approach named catheter-based renal denervation was developed. We have now a clinically relevant time window to review the efficacy of renal denervation for treating this form of hypertension. This short review addresses the physiological contribution of renal sympathetic nerves for blood pressure control and discusses the pros and cons of renal denervation procedure for the treatment of resistant hypertension.

Resumo Em que pese a atual disponibilidade de medicamentos seguros e eficientes para o tratamento da hipertensão, um número significativo de pacientes sofre de hipertensão arterial resistente a tratamento medicamentoso. Em vista dessa condição, foi desenvolvida uma abordagem relativamente nova, denominada denervação renal por cateter. Dispomos atualmente de uma janela de tempo clinicamente relevante para analisar a eficácia da denervação renal no tratamento dessa modalidade de hipertensão. A presente revisão aborda a contribuição fisiológica dos nervos renais simpáticos no controle da pressão arterial e discute os prós e contras do procedimento de denervação renal no tratamento da hipertensão resistente.

Effects and Mechanisms of Radiofrequency Ablation of Renal Sympathetic Nerve on Anti-Hypertension in Canine / Efeitos e Mecanismos da Denervação Simpática Renal por Radiofrequência na Anti-Hipertensão em Cães

Abstract Background: Radiofrequency ablation of renal sympathetic nerve (RDN) shows effective BP reduction in hypertensive patients while the specific mechanisms remain unclear. Objective: We hypothesized that abnormal levels of norepinephrine (NE) and changes in NE-related enzymes and angiotensinconverting enzyme 2 (ACE2), angiotensin (Ang)-(1-7) and Mas receptor mediate the anti-hypertensive effects of RDN. Methods: Mean values of systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) were assessed at baseline and follow-up. Plasma and renal norepinephrine (NE) concentrations were determined using highperformance liquid chromatography with electrochemical detection, and levels of NE-related enzyme and ACE2-Ang(1-7)- Mas were measured using real time PCR, Western blot and immunohistochemistry or Elisa in a hypertensive canine model fed with high-fat diet and treated with RDN. The parameters were also determined in a sham group treated with renal arteriography and a control group fed with normal diet. Results: RDN decreased SBP, DBP, MAP, plasma and renal NE. Compared with the sham group, renal tyrosine hydroxylase (TH) expression was lower and renalase expression was higher in the RDN group. Compared with the control group, renal TH and catechol-o-methyl transferase (COMT) were higher and renalase was lower in the sham group. Moreover, renal ACE2, Ang-(1-7) and Mas levels of the RDN group were higher than those of the sham group, which were lower than those of the control group. Conclusion: RDN shows anti-hypertensive effect with reduced NE and activation of ACE2-Ang(1-7)-Mas, indicating that it may contribute to the anti-hypertensive effect of RDN.

Resumo Fundamentos: A denervação simpática renal por radiofrequência (DSR) mostra redução eficaz da pressão arterial (PA) de pacientes hipertensos, ainda que os mecanismos específicos permaneçam obscuros. Objetivo: Fizemos a hipótese de que níveis alterados de noradrenalina (NA) e mudanças nas enzimas relacionadas à NA e enzima conversora de angiotensina 2 (ECA-2), angiotensina (Ang)-(1-7) e receptor Mas são mediadores dos efeitos antihipertensivos da DSR. Métodos: Foram avaliados os valores médios de pressão arterial sistólica (PAS), pressão arterial diastólica (PAD) e pressão arterial média (PAM) no início e durante o seguimento. Foram medidas as concentrações plasmática e renal de noradrenalina (NA) por cromatografia líquida de alta eficiência com detecção eletroquímica, e os níveis de enzima relacionada à NA e ECA2-Ang-(1-7)-Mas através de PCR em tempo real, Western blot e imunohistoquímica ou Elisa em um modelo canino de hipertensão que recebeu ração rica em gordura e foi tratado com DSR. Os parâmetros também foram determinados em um grupo de cirurgia simulada submetido à arteriografia renal e em um grupo controle que recebeu dieta normal. Resultados: DSR causou diminuição da PAS, PAD, PAM e das concentrações plasmática e renal de NA. Em comparação ao grupo placebo, a expressão da tirosina hidroxilase (TH) renal foi menor e a da renalase foi maior no grupo DSR. Em comparação ao grupo controle, os níveis de TH renal e de catecol-o-metil-transferase (COMT) foram maiores e os de renalase foram menores no grupo cirurgia simulada. Além disso, os níveis renais de ECA2, Ang-(1-7) e Mas foram maiores no grupo DSR do que no grupo cirurgia simulada, que, por sua vez, foram menores do que no grupo controle. Conclusões: A DSR mostra efeitos anti-hipertensivos com redução da NA e ativação da ECA2-Ang-(1-7)-Mas, o que indica que pode contribuir com o efeito anti-hipertensivo da DSR.

Declaración ante los resultados del ensayo clínico Symplicity HTN 3. Grupo de estudio de la hipertensión arterial resistente / Position paper on the results of Symplicity HTN-3 trial. Grupo de estudio de la hipertensión arterial resistente

La denervación de las arterias renales ha sido una alternativa para el tratamiento de la hipertensión arterial resistente. Los estudios Symplicity HTN 1 y 2 mostraron en grupos pequeños y no controlados disminuciones de la presión sistólica hasta de 30 mm Hg. Este entusiasmo ha sido opacado por el estudio Symplicity HTN 3, ensayo clínico aleatorizado y controlado con un procedimiento placebo. Sorprendentemente, los resultados sugirieron que la denervación renal tuvo un efecto similar al del placebo, aunque en el análisis de subgrupos preespecificados los pacientes que no eran de raza negra, los menores de 65 años y los que tenían función renal normal tuvieron una reducción de la presión arterial sistólica estadísticamente significativa. Esta es una evaluación crítica de los resultados del Symplicity HTN 3 y propone posibles explicaciones para estos. Además, declara la postura de nuestro grupo y las acciones futuras.

Renal artery denervation has shown to be an effective treatment for resistant hypertension. Symplicity HTN 1 and 2 trials showed in small and uncontrolled groups, significant systolic blood pressure reductions down to 30 mm Hg. Symplicity HTN-3, a double blind, randomized, placebo controlled clinical trial shaded this initial enthusiasm. Surprisingly, their results showed that renal denervation has a similar effect to placebo. Pre-specified subgroup analysis showed that non-black race individuals, younger than 65 years and with normal renal function, had a statistically significant systolic blood pressure decrease. This manuscript critically appraises the Symplicity HTN-3 trial, proposing possible explanations for the results. Also declares our group position and future actions regarding renal denervation.

Effects of acute administration of selective serotonin reuptake inhibitors on sympathetic nerve activity

Serotonergic mechanisms have an important function in the central control of circulation. Here, the acute effects of three selective serotonin (5-HT) reuptake inhibitors (SSRIs) on autonomic and cardiorespiratory variables were measured in rats. Although SSRIs require 2-3 weeks to achieve their full antidepressant effects, it has been shown that they cause an immediate inhibition of 5-HT reuptake. Seventy male Wistar rats were anesthetized with urethane and instrumented to record blood pressure, heart rate, renal sympathetic nerve activity (RSNA), and respiratory frequency. At lower doses, the acute cardiovascular effects of fluoxetine, paroxetine and sertraline administered intravenously were insignificant and variable. At middle and higher doses, a general pattern was observed, with significant reductions in sympathetic nerve activity. At 10 min, fluoxetine (3 and 10 mg/kg) reduced RSNA by -33±4.7 and -31±5.4%, respectively, without changes in blood pressure; 3 and 10 mg/kg paroxetine reduced RSNA by -35±5.4 and -31±5.5%, respectively, with an increase in blood pressure +26.3±2.5; 3 mg/kg sertraline reduced RSNA by -59.4±8.6%, without changes in blood pressure. Sympathoinhibition began 5 min after injection and lasted approximately 30 min. For fluoxetine and sertraline, but not paroxetine, there was a reduction in heart rate that was nearly parallel to the sympathoinhibition. The effect of these drugs on the other variables was insignificant. In conclusion, acute peripheral administration of SSRIs caused early autonomic cardiovascular effects, particularly sympathoinhibition, as measured by RSNA. Although a peripheral action cannot be ruled out, such effects are presumably mostly central.

Denervação Renal com Cateter Irrigado em Hipertensos Resistentes: Uma Estratégia Promissora? / Renal Denervation Using an Irrigated Catheter in Patients with Resistant Hypertension: A Promising Strategy?

Fundamento: A hipertensão arterial sistêmica constitui importante problema de saúde pública e significativa causa de mortalidade cardiovascular. A elevada prevalência e as reduzidas taxas de controle tensional despertaram o interesse por estratégias terapêuticas alternativas. A denervação simpática renal percutânea surgiu como perspectiva no tratamento de hipertensos resistentes. Objetivo: Avaliar a factibilidade e a segurança da denervação renal com cateter irrigado. Métodos: Dez hipertensos resistentes foram submetidos ao procedimento. O desfecho primário foi a segurança, avaliada por eventos adversos periprocedimento, função renal e anormalidade vascular renal aos 6 meses. Os desfechos secundários constituíram mudanças na pressão arterial (consultório e monitorização ambulatorial) e no número de anti-hipertensivos aos 6 meses. Resultados: A média de idade foi de 47,3 (± 12) anos, 90% eram mulheres. No primeiro caso, houve dissecção de artéria renal causada por trauma da bainha, fato que não se repetiu após ajuste técnico, demonstrando efeito da curva de aprendizado. Nenhum caso de trombose/infarto renal ou óbito foi reportado. Não se observou elevação dos níveis séricos de creatinina durante o seguimento. Aos 6 meses, diagnosticou-se um caso de estenose significativa de artéria renal, sem repercussão clínica. A denervação renal reduziu a pressão arterial de consultório, em média, em 14,6/6,6 mmHg (p = 0,4 tanto para pressão arterial sistólica como para a diastólica). A redução média da pressão arterial pela monitorização ambulatorial foi de 28/17,6 mmHg (p = 0,02 e p = 0,07 para pressão arterial sistólica e diastólica, ...

Background: Systemic hypertension is an important public health problem and a significant cause of cardiovascular mortality. Its high prevalence and the low rates of blood pressure control have resulted in the search for alternative therapeutic strategies. Percutaneous renal sympathetic denervation emerged as a perspective in the treatment of patients with resistant hypertension. Objective: To evaluate the feasibility and safety of renal denervation using an irrigated catheter. Methods: Ten patients with resistant hypertension underwent the procedure. The primary endpoint was safety, as assessed by periprocedural adverse events, renal function and renal vascular abnormalities at 6 months. The secondary endpoints were changes in blood pressure levels (office and ambulatory monitoring) and in the number of antihypertensive drugs at 6 months. Results: The mean age was 47.3 (± 12) years, and 90% of patients were women. In the first case, renal artery dissection occurred as a result of trauma due to the long sheath; no further cases were observed after technical adjustments, thus showing an effect of the learning curve. No cases of thrombosis/renal infarction or death were reported. Elevation of serum creatinine levels was not observed during follow-up. At 6 months, one case of significant renal artery stenosis with no clinical consequences was diagnosed. Renal denervation reduced office blood pressure levels by 14.6/6.6 mmHg, on average (p = 0.4 both for systolic and diastolic blood pressure). Blood pressure levels on ambulatory monitoring decreased by 28/17.6 mmHg (p = 0.02 and p = 0.07 for systolic and diastolic blood pressure, respectively). A mean reduction of 2.1 antihypertensive drugs was observed. Conclusion: Renal denervation is feasible and safe in the treatment of resistant systemic arterial hypertension. Larger studies are required to confirm our findings. .

Desnervação simpática renal no tratamento da hipertensão arterial resistente : perspectivas atuais / Renal sympathetic denervation for resistant hypertension treatment : current perspectives

Os autores revisam o conceito de hipertensão arterial resistente e o envolvimento do sistema nervoso simpático na hipertensão arterial como base racional para a técnica de desnervação simpática renal (DSR), realizada por via percutânea. A presente revisão é resultado de uma busca ativa de artigos científicos com o nome "renal denervation" na base de dados Medline e PubMed. A técnica e os dispositivos empregados no procedimento são apresentados, bem como os resultados clínicos em seis, 12 e 24 meses após a intervenção com o cateter Symplicity. Observam-se reduções expressivas e progressivamente maiores da PAS e PAD após a DSR. A taxa de complicações foi mínima. Novos dispositivos para a DSR e respectivos estudos clínicos em andamento são citados. Em conclusão, a DSR apresenta-se como um procedimento efetivo e seguro para a abordagem da hipertensão arterial resistente. Resultados de estudos em andamento e tempo maior de seguimento desses pacientes são aguardados para confirmar os resultados iniciais e colocar em perspectiva a ampliação da utilização do procedimento na abordagem da hipertensão arterial.

The authors review the concept of resistant hypertension and the involvement of the sympathetic nervous system in hypertension as a rational basis for the technique of renal sympathetic denervation (RSD) performed percutaneously. This revision is the result of an active search for scientific articles with the term "renal denervation" in the Medline and PubMed databases. The techniques and devices used in the procedure are presented, as well as clinical outcomes at six, 12 and 24 months after the intervention with the Symplicity catheter. Significant decreases and progressively higher reductions of systolic and diastolic blood pressure were observed after RSD. The complication rate was minimal. New devices for RSD and its ongoing clinical studies are cited. In conclusion, the RSD presents itself as an effective and safe approach to resistant hypertension. Results from ongoing studies and longer follow-up of these patients are expected to confirm the initial results and put into perspective the expansion of the procedure use in hypertension approach.

Roles of estrogen and progesterone in modulating renal nerve function in the rat kidney

The maintenance of extracellular Na+ and Cl- concentrations in mammals depends, at least in part, on renal function. It has been shown that neural and endocrine mechanisms regulate extracellular fluid volume and transport of electrolytes along nephrons. Studies of sex hormones and renal nerves suggested that sex hormones modulate renal function, although this relationship is not well understood in the kidney. To better understand the role of these hormones on the effects that renal nerves have on Na+ and Cl- reabsorption, we studied the effects of renal denervation and oophorectomy in female rats. Oophorectomized (OVX) rats received 17β-estradiol benzoate (OVE, 2.0 mg·kg-1·day-1, sc) and progesterone (OVP, 1.7 mg·kg-1·day-1, sc). We assessed Na+ and Cl- fractional excretion (FENa+ and FECl- , respectively) and renal and plasma catecholamine release concentrations. FENa+ , FECl- , water intake, urinary flow, and renal and plasma catecholamine release levels increased in OVX vs control rats. These effects were reversed by 17β-estradiol benzoate but not by progesterone. Renal denervation did not alter FENa+ , FECl- , water intake, or urinary flow values vs controls. However, the renal catecholamine release level was decreased in the OVP (236.6±36.1 ng/g) and denervated rat groups (D: 102.1±15.7; ODE: 108.7±23.2; ODP: 101.1±22.1 ng/g). Furthermore, combining OVX + D (OD: 111.9±25.4) decreased renal catecholamine release levels compared to either treatment alone. OVE normalized and OVP reduced renal catecholamine release levels, and the effects on plasma catecholamine release levels were reversed by ODE and ODP replacement in OD. These data suggest that progesterone may influence catecholamine release levels by renal innervation and that there are complex interactions among renal nerves, estrogen, and progesterone in the modulation of renal function.

Effect of renal denervation procedure on left ventricular hypertrophy of hypertensive rats and its mechanisms / Efeito da denervação renal na hipertrofia do ventrículo esquerdo de ratos hipertensos e seu mecanismo

PURPOSE: To investigate the effect of renal denervation (RDN) on the blood pressure, left ventricular hypertrophy and myocardial expression of TLR4/NF-κB in spontaneously hypertensive rats (SHR). METHODS: A total of 36 SHR were randomly assigned into control group (D0), RDN group (D) and sham group (S). 12 WKY rats of same age served as controls (WKY group). Rats in the D0 and WKY groups were sacrificed, but rats in the D and S group were sacrificed at one week and six weeks after surgery. The heart was collected and the left ventricle weighted followed by calculation of left ventricular mass index (LVMI). RESULTS: In the D0 group, the blood pressure, LVMI and protein expression of TLR4, NF-κB, TNF-α and IL-6 in the myocardium were markedly higher than that in the WKY group (p<0.05). In the D1 and D2 group, the LVMI, NE and protein expression of TLR4, NF-κB, TNF-α and IL-6 in the myocardium were significantly reduced (p<0.05). CONCLUSION: Renal denervation can significantly delay the progression of left ventricular hypertrophy in spontaneously hypertensive rats, which may be attributed to the not only the suppression of sympathetic activity and attenuation of pressure load but the improvement of myocardial immuno-inflammation.

OBJETIVO: Investigar o efeito da denervação renal na pressão sanguínea, na hipertrofia do ventrículo esquerdo e a expressão miocárdica de TLR4/NF-kB em ratos espontaneamente hipertensos. MÉTODOS: Trinta e seis SHR ratos foram aleatoriamente distribuídos em grupo controle, grupo denervação renal (D) e grupo sham(S). 12 WKY ratos de mesma idade serviram de controle. Os ratos controles foram sacrificados, mas os ratos com denervação renal e sham foram sacrificados uma semana e seis semanas após a cirurgia. O coração foi retirado e o ventrículo esquerdo pesado seguido pelo cálculo da massa ventricular (LVMI). RESULTADOS: No grupo DO, a pressão sanguínea, LVMI e a expressão proteica de TLR4, NF-κB, TNF-α e IL-6, no miocárdio foram marcadamente maiores do que o grupo WKY (p<0,05). Nos grupos D1 e D2, o LVMI, NE e a expressão proteica de TLR4, NF-κB, TNF-α e IL-6 no miocárdio foi significantemente reduzido (p<0,05). CONCLUSÃO: A denervação renal pode significantemente retardar a progressão da hipertrofia ventricular esquerda em ratos espontaneamente hipertensos, o que pode ser atribuído não apenas pela supressão da atividade simpática e atenuação da pressão, mas pela melhora na imunoinflamação miocárdica.

Renal functional & haemodynamic changes following acute unilateral renal denervation in Sprague Dawley rats.

Background & objectives: Regulation of renal function and haemodynamics are under a direct control from the renal sympathetic nerves and renal denervation produces overt diuresis and natriuresis in several mammalian species. However, the inter-related series of changes in renal function and haemodynamics following acute renal denervation (ARD) is not fully understood. Thus, we aimed to investigate and relate the changes in renal function and haemodynamics following acute unilateral renal denervation in anaesthetized Sprague Dawley (SD) rats. Methods: Male SD rats were fasted overnight, anaesthetized with sodium pentobarbitone (60 mg/kg ip), denervated by application of phenol to the left renal artery and maintained on an intravenous (iv) infusion of isotonic saline for 2 h. Throughout this period, six urine and plasma samples were taken at 20-min intervals to study kidney function parameters. In a different set of experiments, renal nerve stimulation (RNS) was carried out to characterize the changes in renal vasoconstrictor responses following ARD. Results: Denervated animals showed significantly (P<0.05 vs. control innervated rats) higher urine flow rate (UFR), absolute sodium excretion (UNaV), fractional sodium excretion (FENa) and glomerular filtration rate (GFR). The renal vasoconstrictor responses to RNS were significantly (P<0.05) lower in denervated rats as compared to the innervated counterparts. However, no appreciable differences were seen in the mean arterial pressure (MAP), plasma sodium (PNa), basal renal blood flow (RBF) and basal renal vascular resistance (RVR) in both innervated and denervated SD rats. Interpretation & conclusions: Natriuresis, diuresis, enhanced GFR and impaired vasoconstriction in response to RNS are typical and instant responses to ARD in SD rats. Renal sympathetic nerves serve more important role in salt and water conservation than in dynamic autoregulation of RBF under normal sympathetic tone; yet, their effects on renal haemodynamics become more evident in the presence of augmented renal sympathetic nerve activity (RSNA).

Análisis multivariado aplicado a la etapa de deshidratación en la técnica de plastinación del riñón de caballo / Multivaried analysis applied at the stage of dehydration in the plastination technique in horse´s kidney

La Plastinación es la técnica más moderna para la conservación de piezas anatómicas y especímenes. Esta técnica consta de cuatro etapas: fijación, deshidratación, impregnación forzada y curado. Este trabajo pretende mejorar la eficiencia en la producción de órganos plastinados mediante la técnica de Plastinación estándar denominada S 10. Se utilizaron riñones de equinos mestizos criollos provenientes del Frigorífico Aimar S/A, ubicado en la zona rural de Río Cuarto. Luego de realizar la fijación del órgano con formalina se procedió a deshidratarlo. La deshidratación se llevó a cabo en tres sub-etapas donde en cada una de ellas se trabajó a la misma temperatura y se utilizó como solvente una solución de acetona en diferentes concentraciones. Las mediciones se realizaron con acetómetro registrándose el tiempo insumido para lograr la deshidratación. Los datos se analizaron estadísticamente por medio de: análisis de la varianza multivariada y análisis de correlación simple utilizando el paquete estadístico InfoStat. Los resultados muestran que los tiempos de deshidratación se ven influenciados por la edad del animal pero no por la posición ni por el peso del órgano.

Plastination is the most modern technique for the preservation of anatomical pieces and specimens. This technique consists of four stages: fixation, dehydration, forced impregnation, and cured. This research aims at improving the efficiency of production plastinated organs through the standard technique known as S10. Kidneys of criole mestizo equines from Frigorifico Aimar S.A placed in the rural area of Rio IV were used. After binding the organ with formalin, it was dehydrated. The dehydration was carried out in three sub-stages working at the same temperature, and a solvent composed of solution of acetone of different concentrations was used. The measurements were analysed with acetometer, keeping register of the time consumption to reach dehydration. The resulting data was statistically analysed using Infostat program. Results showed that the time consumed to reach dehydration was influenced by the horses age but not by the kidney's weight, there were no significant differences between right and left kidneys neither.

Influence of renal denervation on blood pressure, sodium and water excretion in acute total obstructive apnea in rats

Obstructive apnea (OA) can exert significant effects on renal sympathetic nerve activity (RSNA) and hemodynamic parameters. The present study focuses on the modulatory actions of RSNA on OA-induced sodium and water retention. The experiments were performed in renal-denervated rats (D; N = 9), which were compared to sham (S; N = 9) rats. Mean arterial pressure (MAP) and heart rate (HR) were assessed via an intrafemoral catheter. A catheter was inserted into the bladder for urinary measurements. OA episodes were induced via occlusion of the catheter inserted into the trachea. After an equilibration period, OA was induced for 20 s every 2 min and the changes in urine, MAP, HR and RSNA were recorded. Renal denervation did not alter resting MAP (S: 113 ± 4 vs D: 115 ± 4 mmHg) or HR (S: 340 ± 12 vs D: 368 ± 11 bpm). An OA episode resulted in decreased HR and MAP in both groups, but D rats showed exacerbated hypotension and attenuated bradycardia (S: -12 ± 1 mmHg and -16 ± 2 bpm vs D: -16 ± 1 mmHg and 9 ± 2 bpm; P < 0.01). The basal urinary parameters did not change during or after OA in S rats. However, D rats showed significant increases both during and after OA. Renal sympathetic nerve activity in S rats increased (34 ± 9 percent) during apnea episodes. These results indicate that renal denervation induces elevations of sodium content and urine volume and alters bradycardia and hypotension patterns during total OA in unconscious rats.

Mechanisms of depressor effect of norepinephrine injected into subnucleus commissuriu of nucleus solitarius tractus in rabbits / 华中科技大学学报（医学）（英德文版）

This experiment aimed to investigate the effect of adrenergic system in the subnucleus commissuriu of nucleus solitrius tractus (CNTS) on renal nerve discharges. Norepinephrine (NE) was microinjected into the CNTS of rabbits and mean arterial blood pressure (MAP) and renal nerve discharges (FRND) were synchronously recorded. The results indicated that (1) microinjection of norepinephine into the CNTS of rabbit could significantly attenuate the frequency of renal nerve discharge, and at the same time decrease markedly the mean arterial pressure. (2) Microinjection of 0.3 nmol yohimbin into CNTS had no significant influence on FRND and MAP, but could attenuate and even reverse the effects of NE on FRND and MAP. These results suggest that microinjection of NE into CNTS may activate the alpha-adrenorecptor located in CNTS and secondarily produce a depressor effect by attenuating the activity of periphenal sympathetic nervous system.

Effect of inhibition of nitric oxide synthase on blood pressure and renal sodium handling in renal denervated rats

The role of sympathetic nerve activity in the changes in arterial blood pressure and renal function caused by the chronic administration of NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthesis, was examined in sham and bilaterally renal denervated rats. Several studies have demonstrated that sympathetic nerve activity is elevated acutely after L-NAME administration. To evaluate the role of renal nerve activity in L-NAME-induced hypertension, we compared the blood pressure response in four groups (N = 10 each) of male Wistar-Hannover rats weighing 200 to 250 g: 1) sham-operated vehicle-treated, 2) sham-operated L-NAME-treated, 3) denervated vehicle-treated, and 4) denervated L-NAME-treated rats. After renal denervation or sham surgery, one control week was followed by three weeks of oral administration of L-NAME by gavage. Arterial pressure was measured weekly in conscious rats by a tail-cuff method and renal function tests were performed in individual metabolic cages 0, 7, 14 and 21 days after the beginning of L-NAME administration. L-NAME (60 mg kg-1 day-1) progressively increased arterial pressure from 108 + or - 6.0 to 149 + or - 12 mmHg (P<0.05) in the sham-operated group by the third week of treatment which was accompanied by a fall in creatinine clearance from 336 + or - 18 to 222 + or - 59 µl min-1 100 g body weight-1 (P<0.05) and a rise in fractional urinary sodium excretion from 0.2 + or - 0.04 to 1.62 + or - 0.35 per cent (P<0.05) and in sodium post-proximal fractional excretion from 0.54 + or - 0.09 to 4.7 + or - 0.86 per cent (P<0.05). The development of hypertension was significantly delayed and attenuated in denervated L-NAME-treated rats. This was accompanied by a striking additional increase in fractional renal sodium and potassium excretion from 0.2 + or - 0.04 to 4.5 + or - 1.6 per cent and from 0.1 + or - 0.015 to 1.21 + or - 0.37 per cent, respectively, and an enhanced post-proximal sodium excretion compared to the sham-operated group. These differences occurred despite an unchanged creatinine clearance and Na+ filtered load. These results suggest that bilateral renal denervation delayed and attenuated the L-NAME-induced hypertension by promoting an additional decrease in tubule sodium reabsorption in the post-proximal segments of nephrons. Much of the hypertension caused by chronic NO synthesis inhibition is thus dependent on renal nerve activity.

Diverse effects of renal denervation on ventricular hypertrophy and blood pressure in DOCA-salt hypertensive rats

Cardiac hypertrophy that accompanies hypertension seems to be a phenomenon of multifactorial origin whose development does not seem to depend on an increased pressure load alone, but also on local growth factores and cardioadrenergic activity. The aim of the present study was to determine if sympathetic renal denervation and its effects on arterial pressure level can prevent cardiac hypertrophy and if it can also delay the onset and attenuate the severity of deoxycorticosterone acetate (DOCA)-salt hypertension. DOCA-salt treatment was initiated in rats seven days after uninephrectomy and contralateral renal denervation or sham renal denervation. DOCA (15 mg/kg, sc) or vehicle (soybean oil, 0.25 ml per animal) was administered twice a week for two weeks. Rats treated with DOCA or vehicle (control) were provided drinking water containing 1 percent NaCl and 0.03 percent KCl. At the end of the treatment period, mean arterial pressure (MAP) and heart rate measurements were made in conscious animals. Under ether anesthesia, the heart was removed and the right and left ventricles (including the septum) were separated and weighed. DOCA-salt treatment produced a significant increase in left ventricular weight/body weight (LVW/BW) ratio (2.44 + 0.09 mg/g) and right ventricular weight/body weight (RVW/BW) ratio (0.53 + 0.01 mg/g) compared to control (1.92 + 0.04 and 0.48 + 0.01 mg/g, respectively) rats. MAP was significantly higher (39 percent) in DOCA-salt rats. Renal denervation prevented (P>0.05) the development of hypertension in DOCA-salt rats but did not prevent the increase in LVW/BW (2.27 + 0.03 mg/g) and RVW/BW (0.52 + 0.01 mg/g). We have shown that the increase in arterial pressure level is not responsible for cardiac hypertrophy, which may be more related to other events associated with DOCA-salt hypertension, such as an increase in cardiac sympathetic activity.

Mechanism of transmission and modulation of renal pain in cats: effects of transcutaneous electrical nerve stimulation on renal pain

Transcutaneous electrical nerve stimulation (TENS) has widely been employed as a method of obtaining analgesia in medical practice. The mechanisms of pain relief by TENS are known to be associated with the spinal gate control mechanism or descending pain inhibitory system. However, most of the studies concerning the analgesic effects and their mechanisms for TENS have dealt with somatic pain. Thus, in this experiment, we investigated the analgesic effects of TENS on renal pain as a model of visceral pain, and the characteristics of the dorsal horn cells with renal inputs. The renal pain was induced by acute occlusion of the ureter or renal artery. The main results are summarized as follows: 1) The renal nerve was composed of A beta, A delta and C fiber groups; the thresholds for each group were 400-800 mV, 1.1-1.5 V, and 2.1-5.8 V, respectively. 2) The dorsal horn cells tested received A and/or C afferent fibers from the kidney, and the more C inputs the dorsal horn cells had, the greater was the response to the stimuli that elicited the renal pain. 3) 94.9% of cells with renal input had the concomitant somatic receptive fields on the skin; the high threshold (HT) and wide dynamic range (WDR) cells exhibited a greater responses than low threshold (LT) cells to the renal pain-producing stimuli. 4) TENS reduced the C-responses of dorsal horn cells to 38.9 +/- 8.4% of the control value and the effect lasted for 10 min after the cessation of TENS. 5) By TENS, the responses evoked by acute occlusion of the ureter or renal artery were reduced to 37.5 +/- 9.7% and 46.3 +/- 8.9% of the control value, respectively. This analgesic effects lasted 10 min after TENS. 6) The responses elicited by squeezing the receptive fields of the skin were reduced to 40.7 +/- 7.9% of the control value and the effects lasted 15 min after TENS. These results suggest that most of dorsal horn cells with renal inputs have the concomitant somatic inputs and TENS can alleviate the renal pain as well as somatic pain.

Mechanism of transmission and modulation of renal pain in cats; effect of nucleus raphe magnus stimulation on renal pain

Initially, when periaqueductal gray (PAG) is electrically stimulated, analgesia is induced, and this phenomenon is called stimulation-produced analgesia. Nucleus raphe magnus (NRM) as well as PAG are known to be the potent analgesic centers. NRM could modulate the nociceptive response of spinal cord neurons through spinally projecting fibers. However, as well as the above analgesic effects have been confined to the somatic pain, it was variable according to species, and the analgesic effect by NRM stimulation on the visceral pain was not yet clarified. In this study the analgesic effect by NRM stimulation on the visceral pain was examined through recording the activities of the dorsal horn neurons with renal input and renal pain, as a type of visceral pain. The renal pain was induced by ureteral occlusion or renal arterial occlusion, which in turn activated the renal mechanoreceptor or chemoreceptor. These cells had concomitant somatic input. In order to compare the effects of NRM stimulation on the renal pain with somatic pain, the somatic stimulation such as squeezing was conducted on the peripheral receptive field. The main results are summarized as follows: 1) After an electrical stimulation of NRM, spontaneous activities of dorsal horn neurons with renal input were reduced to 73.3 +/- 9.7% of the control value. 2) After an electrical stimulation of NRM, activities of dorsal horn neurons with renal input evoked by a brush, a type of non-noxious stimuli, did not change significantly. But the activities by a squeeze, a type of noxious stimuli, the activities were reduced to 63.2 +/- 7.2% of the control value. 3) After an electrical stimulation of NRM, activities of dorsal horn neurons with renal input evoked by occlusion of ureter or renal artery were reduced to 46.7 +/- 8.8% and 49.0 +/- 8.0% of the control value respectively. 4) The inhibitory effect of NRM on the dorsal horn neurons with renal input did not show any difference between renal A delta fiber and C fiber group. 5) By the electrical stimulation of NRM, the activities evoked by ureteral occlusion showed more reduction in the high threshold cell group than in the wide dynamic range cell group. These results suggest that activation of NRM can alleviate the renal pain as well as the somatic pain by modulating the dorsal horn neurons activities.