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.

Evidence that blood pressure remains under the control of arterial baroreceptors in renal hypertensive rats

The purpose of the present study was to determine the range of the influence of the baroreflex on blood pressure in chronic renal hypertensive rats. Supramaximal electrical stimulation of the aortic depressor nerve and section of the baroreceptor nerves (sinoaortic denervation) were used to obtain a global analysis of the baroreceptor-sympathetic reflex in normotensive control and in chronic (2 months) 1-kidney, 1-clip hypertensive rats. The fall in blood pressure produced by electrical baroreceptor stimulation was greater in renal hypertensive rats than in normotensive controls (right nerve: -47 ± 8 vs -23 ± 4 mmHg; left nerve: -51 ± 7 vs -30 ± 4 mmHg; and both right and left nerves: -50 ± 8 vs -30 ± 4 mmHg; P < 0.05). Furthermore, the increase in blood pressure level produced by baroreceptor denervation in chronic renal hypertensive rats was similar to that observed in control animals 2-5 h (control: 163 ± 5 vs 121 ± 1 mmHg; 1K-1C: 203 ± 7 vs 170 ± 5 mmHg; P < 0.05) and 24 h (control: 149 ± 3 vs 121 ± 1 mmHg; 1K-1C: 198 ± 8 vs 170 ± 5 mmHg; P < 0.05) after sinoaortic denervation. Taken together, these data indicate that the central and peripheral components of the baroreflex are acting efficiently at higher arterial pressure in renal hypertensive rats when the aortic nerve is maximally stimulated or the activity is abolished.

New nitric oxide donors based on ruthenium complexes

Nitric oxide (NO) donors produce NO-related activity when applied to biological systems. Among its diverse functions, NO has been implicated in vascular smooth muscle relaxation. Despite the great importance of NO in biological systems, its pharmacological and physiological studies have been limited due to its high reactivity and short half-life. In this review we will focus on our recent investigations of nitrosyl ruthenium complexes as NO-delivery agents and their effects on vascular smooth muscle cell relaxation. The high affinity of ruthenium for NO is a marked feature of its chemistry. The main signaling pathway responsible for the vascular relaxation induced by NO involves the activation of soluble guanylyl-cyclase, with subsequent accumulation of cGMP and activation of cGMP-dependent protein kinase. This in turn can activate several proteins such as K+ channels as well as induce vasodilatation by a decrease in cytosolic Ca2+. Oxidative stress and associated oxidative damage are mediators of vascular damage in several cardiovascular diseases, including hypertension. The increased production of the superoxide anion (O2-) by the vascular wall has been observed in different animal models of hypertension. Vascular relaxation to the endogenous NO-related response or to NO released from NO deliverers is impaired in vessels from renal hypertensive (2K-1C) rats. A growing amount of evidence supports the possibility that increased NO inactivation by excess O2- may account for the decreased NO bioavailability and vascular dysfunction in hypertension.

Acute effect of amiodarone on cardiovascular reflexes of normotensive and renal hypertensive rats

The aim of the present study was to evaluate the effect of amiodarone on mean arterial pressure (MAP), heart rate (HR), baroreflex, Bezold-Jarisch, and peripheral chemoreflex in normotensive and chronic one-kidney, one-clip (1K1C) hypertensive rats (N = 9 to 11 rats in each group). Amiodarone (50 mg/kg, iv) elicited hypotension and bradycardia in normotensive (-10 ± 1 mmHg, -57 ± 6 bpm) and hypertensive rats (-37 ± 7 mmHg, -39 ± 19 bpm). The baroreflex index (deltaHR/deltaMAP) was significantly attenuated by amiodarone in both normotensive (-0.61 ± 0.12 vs -1.47 ± 0.14 bpm/mmHg for reflex bradycardia and -1.15 ± 0.19 vs -2.63 ± 0.26 bpm/mmHg for reflex tachycardia) and hypertensive rats (-0.26 ± 0.05 vs -0.72 ± 0.16 bpm/mmHg for reflex bradycardia and -0.92 ± 0.19 vs -1.51 ± 0.19 bpm/mmHg for reflex tachycardia). The slope of linear regression from deltapulse interval/deltaMAP was attenuated for both reflex bradycardia and tachycardia in normotensive rats (-0.47 ± 0.13 vs -0.94 ± 0.19 ms/mmHg and -0.80 ± 0.13 vs -1.11 ± 0.13 ms/mmHg), but only for reflex bradycardia in hypertensive rats (-0.15 ± 0.02 vs -0.23 ± 0.3 ms/mmHg). In addition, the MAP and HR responses to the Bezold-Jarisch reflex were 20-30 percent smaller in amiodarone-treated normotensive or hypertensive rats. The bradycardic response to peripheral chemoreflex activation with intravenous potassium cyanide was also attenuated by amiodarone in both normotensive (-30 ± 6 vs -49 ± 8 bpm) and hypertensive rats (-34 ± 13 vs -42 ± 10 bpm). On the basis of the well-known electrophysiological effects of amiodarone, the sinus node might be the responsible for the attenuation of the cardiovascular reflexes found in the present study.

Hipertensäo e doenças primárias renais / Hypertension and nephropathy

A hipertensão nas doenças renais primárias possui múltiplas causas. Num extremo, quando a perda de função é mais presente, estão as causas relacionadas ao volume e sódio, caracterizando hipertensão sal-sensível. No outro extremo, onde a função está ainda mantida próxima ao normal, estão mais presentes as causas relacionadas à vasoconstrição periférica. No texto descrevemos as várias causas aventadas e sua inter-relação nos pacientes com doença renal.

Baroreflex control of sympathetic activity in experimental hypertension

The arterial baroreceptor reflex system is one of the most powerful and rapidly acting mechanisms for controlling arterial pressure. The purpose of the present review is to discuss data relating sympathetic activity to the baroreflex control of arterial pressure in two different experimental models: neurogenic hypertension by sinoaortic denervation (SAD) and high-renin hypertension by total aortic ligation between the renal arteries in the rat. SAD depresses baroreflex regulation of renal sympathetic activity in both the acute and chronic phases. However, increased sympathetic activity (100 percent) was found only in the acute phase of sinoaortic denervation. In the chronic phase of SAD average discharge normalized but the pattern of discharges was different from that found in controls. High-renin hypertensive rats showed overactivity of the renin angiotensin system and a great depression of the baroreflexes, comparable to the depression observed in chronic sinoaortic denervated rats. However, there were no differences in the average tonic sympathetic activity or changes in the pattern of discharges in high-renin rats. We suggest that the difference in the pattern of discharges may contribute to the increase in arterial pressure lability observed in chronic sinoaortic denervated rats.

Mecanismos de lesao glomerular cronica / Mechanisms of glomerular chronic injury

Nos anos 80, Brenner e colaboradores demonstraram uma associacao estreita entre anomalias da hemodinamica glomerular, especialmente a hipertensao intracapilar, e o desenvolvimento de esclerose glomerular em varios modelos de lesao cronica. Essa relacao e analoga a conhecida associacao entre hipertensao sistemica e macrovasculopatias. Varios mecanismos, tais como a proliferacao celular, a lesao endotelial e a microtrombose intracapilar, podem ligar a hipertensao intracapilar ao processo de esclerose glomerular, estimulando por exemplo a proliferacao de celulas mesangiais e a producao de matriz mesangial. Futuros estudos sobre a interacao entre eventos mecanicos e celulares devem contribuir para a elucidacao desse complexo processo

Efeito do urapidil sobre a pressão arterial, hemodinâmica renal, metabolismo lipídico e glicídico / The effect of urapidil on blood pressure, renal hemodynamics, lipid and glucose metabolism

PURPOSE--To evaluate the effects of urapidil on blood pressure (BP), renal hemodynamics and lipid and glucose metabolism, in patients with mild-to-moderate uncomplicated essential hypertension. METHODS--Fifteen hypertensive patients, aged 38-64 year-old were studied by ambulatory blood pressure monitoring system (ABPM). It was also evaluated: 1) the creatinine clearance; 2) the effective renal plasma flow by use of a single plasma sample after injection of orthoiodohippurate; 3) the serum triglycerides, cholesterol, and HDL-cholesterol; 4) blood levels of glucose and insulin. The urapidil dose ranged from 60 to 180 mg/day, according to the individual response. RESULTS--The values after four weeks washout-placebo and active treatment with urapidil showed: the systolic/diastolic BP was reduced from 157.7 +/- 6/108.0 +/- 2 on placebo to 140.4 +/- 4/97.3 +/- 3 mmHg (p < 0.05/p < 0.01) after urapidil, respectively, whereas heart rate was unchanged. The percentage of elevated systolic and diastolic BP values during 24h (BP load) was reduced from 60.9 to 54.4 and from 60.8 to 50.3, respectively. Effective renal plasma flow, glomerular filtration rate, filtration fraction and renal vascular resistance were unaltered by treatment. Significant increase in HDL-cholesterol was observed (from 39.5 +/- 3.6 on placebo vs 49.2 +/- 4.8 mg/dl (p < 0.01) after urapidil. Total cholesterol, LDL-cholesterol and triglycerides levels were not modified with treatment. Circulating plasma glucose and insulin remained unchanged. CONCLUSION--Urapidil is an effective antihypertensive agent without deleterious effect on renal hemodynamics, lipid and glucose metabolism.

Objetivo − Avaliar os efeitos do urapidil sobre a pressão arterial, hemodinâmica renal, metabolismo lipídico e glicídico em portadores de hipertensão arterial sistêmica primária leve a moderada. Métodos − Foram analisados 15 pacientes hipertensos, com idades entre 38 e 64 anos, utilizando-se a técnica da monitorização ambulatorial da pressão arterial (MAPA) em 24h, avaliando-se, também, os clearances de creatinina e do hipuran radioativo, espectrofotometria de cristal sólido e as dosagens do colesterol e triglicérides séricos, do HDL-colesterol, da glicemia e insulina. As doses de urapidil variaram de 60 a 180mg/dia, administradas 2 ou 3 vezes, de acordo com cada caso. A avaliação durou pelo menos 6 semanas. Resultados − Os parâmetros analisados após 4 semanas de washout-placebo e tratamento com urapidil revelaram: 1) redução significante das pressões sistólica e diastólica (157,7±6 e 108±2 na fase placebo para 140,4±4 e 97,3±3mmHg, p<0,05; p<0,01, respectivamente); 2) o fluxo plasmático renal efetivo, ritmo de filtração glomerular, fração de filtração e resistência vascular renal não sofreram mudanças significantes; 3) aumento significante na concentração sérica das HDLcolesterol (39,5±3,6 para 49,2±4,8mg/dl, p<0,01), sem modificações nos níveis séricos do colesterol total, LDL colesterol e triglicérides; 4) as curvas glicêmicas e insulínicas não se alteraram. Conclusão − O urapidil reduziu a pressão arterial sem promover alterações na hemodinâmica renal, metabolismo lipídico e glicídico

Suprapontine ablation in normal and Doc-salt or one-kidney, one-clip hypertensive rats

Se estududió, en ratas no anestesiadas, el papel de las áreas supraprotuberanciales en el mantenimiento agudo de la hipertensión producida por tratamiento con Doca-sal (4 semanas) o en el modelo 1 riñon, 1-clip (1R-1C) (4 semanas post-cirugia). Se midió la presión arterial media (PA) y la fecuencia cardíaca (FC) 15 minutos antes y 2 horas después de aspirar todos los tejidos rostrales a la protuberancia. Este procedimiento no modificó la PA de las ratas normales o 1R-1C. En las ratas tratadas con Doca-sal la PA cayo (154 ñ 4 vs. 110 ñ 5 mmHg; p < 0.001). La FC aumentó en las ratas normales (351 ñ 10 a 446, ñ20 1pm; p < 0.01) y en las 1R-1C. (350 ñ 10 a (351 ñ 12 1 pm; p < 0.001). Las clonidinas inyectada en la cisterna magna de las ratas 1R-1C luego de la aspiración de las áreas supraprotuberanciales baja la PA (146 ñ6 a 118 ñ 11 mmHg; p < 0.05) y la FC (515 ñ17 a 400 ñ 33; p < 0.05). El pentolinium, luego de la aspiración supraprotuberancial, baja la PA de las ratas normales (116 ñ 4 a 63 ñ 5 mmHg; p < 0.001), Doca-sal (111 ñ 5; p < 0.001) y 1R-1C (163 ñ 8 a 59 ñ 6 mmHg; P < 0.001). Estos resultados sugieren que las estructuras supraprotuberanciales tienen un papel importante en el mantenimiento agudo de la hipertensión por Doca-sal. En las ratas 1R-1C el mantenimiento agudo de la hipertensión depende de una actividad simpática originada en áeas caudales a la ablación

Receptores beta adrenergicos miocardicos durante el desarrollo de la hipertension renal experimental, tipo Goldblatt II / Myocardial beta adrenergic receptors during experimental renal hypertension, type Goldblatt II

En la hipertensión se ha observado que la capacidad del miocardio para responder a la estimulación adrenérgica se halla disminuida. Esta alteración de la reactividad a las catecolaminas puede ser atribuida a cambios en la densidad y/o la afinidad de los receptores ß adrenérgicos, a modificaciones en la célula efectos que ocurren posteriormente a la unión del agonista con su receptor, o a una disminución de la reserva capilar coronaria. Con la finalidad de determinar si modificaciones en los receptores ß contribuyen o no a la menor respuesta miocárdica a las catecolaminas, estudiamos las propiedades de los receptores ß miocárdios en ratas hipertensas renales 2 riñones - 1 "clip" (Goldblatt II). La densidad y la afinidad de los receptores ß miocárdicos fueron determinadas mediante la técnica de fijación de dihidroalprenolol tritiado (-3H-DHA) en una fracción enriquecida de sarcolema ventricular, obtenida de los corazones de ratas con 3 y 4 semanas de desarrollo de la hipertensión experimental. En las ratas con 3 semanas de evolución de la hipertensión no se detectaron diferencias significativas ni en el número ni en la afinidad de los receptores (30.9 + ou - 5.3fmol/mg proteína, KD: 1.62 + ou - 0.43 nM) en comparación con los controles (33.3 + ou - 6.3 fmol/mg proteína, KD: 2.21 + ou - 0.59 nM). En las ratas con 4 semanas de desarrollo de la hipertensión se detectó un aumento del número de receptores ß miocárdicos (54.7 + ou - 3.7 fmol/mg proteína, KD: 1.41 + ou - 0.17 nM) comparado con las ratas controles (40.0 + ou - 2.3 fmol/mg proteína, KD: 1.13 + ou - 0.12 nM). Los resultados obtenidos sugierem que la menor respuesta a las catecolaminas descripta en este modelo de hipertensión no se debería a alteraciones directas de los receptores ß miocárdicos, observándose en contraposición un aumento en el número de los receptores ß que podría ser la expresión de un mecanismo compensatorio durante el desarrollo de la hipertensión