**13. Renal sympathetic denervation**

The role of afferent renal nerves in the pathogenesis of hypertension has been well studied in animal models. Renal denervation in animal models with renal chronic or renovascular failure result in attenuation of the BP. The depressing effect of renal denervation in these models is not caused by changes in renin activity or sodium excretion, but with reduced adrenal sympathetic activity. These findings suggest that afferent renal nerves contribute to the pathogenesis of renovascular hypertension and renal failure, due to the increase of the sympathetic nervous system activity. Moreover, selective afferent renal denervation by dorsal rhizotomy has confirmed that the depressing effect of renal denervation in these models is due to the interruption of renal afferent activity. Similar reductions of muscle sympathetic nerve activity recorded in the peroneal nerve was observed after therapeutic nephrectomy in patients with advanced renal disease, confirming the relationship between afferent sensory fibers of the kidney and central sympathetic activity. (Fisher & Paton, 2011)

The first attempts to produce a vaccine for hypertension was conducted in the early 50s of the twentieth century and were focused on the RAAS. At that time immunogen renin was employed, demonstrating an antihypertensive action. However, its development was abandoned when observing the appearance of an autoimmune disease characterized by the deposition of antibodies antirenin in the juxtaglomerular apparatus and progressive interstitial inflammatory lesion in the kidney in animal models studied. (Goldblatt, Haas &

Years later in the 60s, interest is focused on vaccines used against Ang I, but these had no antihypertensive effect. (Downham et al., 2003) At present, interest is focused on Ang II as an immunogen agent using a new immunization technology that combines antigens on the surface of a structure of virus like particles (VLP) generating a B cell response against autoantigens. VLPs conjugated to Ang II (CYT006-AngQb vaccine) have been tested in preclinical and clinical trials and have been observed to be well tolerated, immunogenic and

In Phase I studies, the tolerability, safety and immunogenicity of the vaccine was assessed after injection of the vaccine in 12 healthy subjects. They noted that the vaccine was well tolerated, safe and rapidly produced levels of specific antibodies to Ang II, which descended over time. (Ambühl et al., 2007) In Phase II B trials, in order to evaluate the effective response dose, the effect of the administration of 100 or 300 micrograms of the vaccine (CYT006-AngQb) or placebo to 72 patients (65 men and seven women with a average age 51.5 years) with moderate hypertension had been analyzed. The administration of the vaccine or placebo was performed at zero, four and twelve weeks. After twelve weeks of follow up, we observed that vaccination with CYT006-AngQb induced a dose dependent response, so that the title of antibodies to Ang II was greater in patients who received doses of 300 micrograms. The BP changes were evaluated at week 14. It was observed that patients who received 300 micrograms of vaccine significantly reduced the daytime systolic BP by 5.6 mmHg and diastolic by 2.8 mmHg compared with placebo recipients. (Tissot et al., 2008) However, more studies on the beneficial effects of vaccination against hypertension are still

needed, its long term effects, its influence on target organ damage and mortality.

The role of afferent renal nerves in the pathogenesis of hypertension has been well studied in animal models. Renal denervation in animal models with renal chronic or renovascular failure result in attenuation of the BP. The depressing effect of renal denervation in these models is not caused by changes in renin activity or sodium excretion, but with reduced adrenal sympathetic activity. These findings suggest that afferent renal nerves contribute to the pathogenesis of renovascular hypertension and renal failure, due to the increase of the sympathetic nervous system activity. Moreover, selective afferent renal denervation by dorsal rhizotomy has confirmed that the depressing effect of renal denervation in these models is due to the interruption of renal afferent activity. Similar reductions of muscle sympathetic nerve activity recorded in the peroneal nerve was observed after therapeutic nephrectomy in patients with advanced renal disease, confirming the relationship between afferent sensory fibers of the kidney and central sympathetic activity. (Fisher & Paton, 2011)

**12. Vaccines**

Lamfrom, 1951, Michel et al., 1987)

with a high proportion of respondent individuals.

**13. Renal sympathetic denervation**

In a study coordinated by researchers at Monash University in Melbourne (Australia) and published in The Lancet, the use of renal denervation, a technique based on the use of a catheter to clear the neural activity of the kidneys, could be useful in the approach of people with resistant hypertension. The Symplicity HTN-2 trial was a multicenter, prospective, randomized, and controlled study about safety and efficacy of renal sympathetic denervation in patients with uncontrolled hypertension.

The device (Simplicity Catheter; Ardian Inc, Palo alto, California) is a catheter that is inserted through the end of the renal artery and then the tip is removed slowly, rotating and emitting radio frequency motions to suppress nerve activity. (Fig.1)

Fig. 1. Percutaneous renal denervation procedure. Graphic of catheter tip in distal renal artery. Reproduced from Krum, H. et al. (2009)

The study included a total of 106 patients from 24 hospitals in Australia and Europe. Both the treatment and control groups at baseline had high levels of BP (178/97 mmHg and 178/98 mmHg respectively), despite receiving intensive antihypertensive treatment, with an average of five drugs. After six months of beginning the trial, the average number of BP of the group that received renal denervation treatment was reduced to 146/85 mmHg, while the control group had a mean of 179/98 mmHg. (Krum et al., 2009)

Witkowski and colleagues evaluated the effects of renal denervation on BP and sleep apnea severity in patients with resistant hypertension and sleep apnea. They studied 10 patients with resistant hypertension and sleep apnea, who underwent renal denervation and completed 3 month and 6 month follow-up evaluations, including polysomnography and selected blood chemistries, and BP measurements. Antihypertensive regimens were not changed during the 6 months of follow up. Three and 6 months after the denervation, decreases systolic and diastolic BPs were observed. Significant decreases were also observed in plasma glucose concentration 2 hours after glucose administration and in hemoglobin A1C level at 6 months, as well as a decrease in apnea-hypopnea index at 6 months after renal denervation. (Witkowski et al., 2011)

In another study, a total of 11 patients received renal denervation treatment. Patients were followed up for 1 month after treatment. No periprocedural complications or adverse events during follow up were noted. A significant reduction of BP was seen at 1 month follow up.

New Therapeutics in Hypertension 17

follow up. Both systolic and diastolic BP decreased significantly with 35 ± 8 mmHg and 24 ± 6 mmHg, respectively. In 75% of patients, a decrease in BP of 20 mmHg in systolic BP was

In the European and North American study, Rheos system was applied to 16 patients with resistant hypertension which demonstrated a statistically significant decrease in BP in 3 months, along with reduction of left ventricular mass index (-24.1 ± 18.7 g/m2), of the thickness of the septum (- 1.3 ± 1.8 mm), and of the thickness of the left ventricular posterior wall (-1.4 ± 1.1 mm). These results are also accompanied by reduction in the number of antihypertensive drugs used per patient. (de Leeuw et al., 2008) Another study of 12 patients with Rheos system in patients with resistant hypertension showed no deterioration of renal function after 1 year follow up. (Scheffers, Kroon & de Leeuw., 2008) In another 12 patients with resistant hypertension studied by Heusser, showed that electrical stimulation of the baroreceptors decreased systolic BP in 32 ± 10 mmHg, and this one correlated with a reduction in the muscle sympathetic nerve activity, the heart rate and the concentration of

Fig. 2. Rheos System. From CVRx, Rheos, Baroreflex Hypertension Therapy are trademarks

At the present time the company CVRx, Inc., the proprietress of this system has announced the introduction of a second generation with an implantable device: The Barostim neo™, with the characteristic to have a smaller generator and a 1 mm unilateral electrode, which

Without misgivings another investigating step to explain details of efficacy to brief, middle and long term of these devices, their possible interactions with other drugs or surgical procedures, their medical indications, etc., what will permit in the future its use on a wider

The abnormal collagen cross links due to the formation of the end products of advanced glycation (AGEs) contribute to increase cardiovascular stiffness, which is a predictor of adverse cardiovascular events in old age, hypertension and diabetes. (Vlassara & Palace,

should be utilized in resistant hypertension and the HF. (Hasenfuss, 2011)

**15. Crosslink breakers of the end products of advanced glycation** 

shown and 31% achieved BP control. (Scheffers et al., 2008)

plasma renin. (Heusser et al., 2010)

of CVRx, Inc. © CVRx, Inc. 2009

scale in the resistant hypertension.

2002, Susic et al., 2004)

Also, They noted a significant decrease in aldosterone level,while there was no decrease in plasma renin activity and in the renal function. (Voskuil et al.,2011)

Although the treatment is minimally invasive and presented no apparent complications, it is reserved only for patients with resistant hypertension unresponsive to adequate medical treatment. However randomized studies should be conducted with a larger population and a longer follow up term.
