**11. Vascular NAD(P)H oxidase inhibitors**

The involvement of oxidative stress in hypertension is well known. There is strong evidence that oxidative stress is increased in essential hypertension, renovascular hypertension, preeclampsia and hypertension induced by cyclosporine.

Hypertensive patients have significantly higher levels of hydrogen peroxide (H202) in plasma than the normotensive ones. Besides the normotensive ones which have a family history of hypertension have an increased production of H202 than those who have no family history of hypertension, suggesting that there may be a genetic component in the high production of H202. (Stocker & Keaney, 2004)

The NAD(P)H oxidase is the largest supplier of superoxide (O2-) in blood vessels and its expression and actions are regulated by Ang II through AT1 receptor. It has been shown that NAD(P)H oxidase contributes to the pathogenesis of hypertension. (Matsuno et al., 2005, Gavazzi et al., 2006)

The NAD(P)H oxidase is found in neutrophils and has five subunits: p67phox, p40phox, p22phox, and gp91phox catalytic subunit (also known as "NOX/DUOX family"), with 7 counterparts known to date, with diverse biological functions in different tissues such as: the colon, the blood vessels, the lungs, the heart, the kidneys, the nervous system, the ear, the bones, the testicles, the thyroid and lymphoid tissues. (S Wind et al., 2010)

Though the interaction of subunits in cardiovascular cells and its regulation and function of each NOX/DUOX is still uncertain, it is clear that NOX/DUOX enzymes are very important in normal biological response and contribute to cardiovascular and renal disease, including atherosclerosis and hypertension.

The development of specific inhibitors of these enzymes has attracted attention for its potential therapeutic use in hypertension. Experiments have shown that inhibitors of NAD(P)H decrease the release of O2- and increase the synthesis of NO, thus lowering BP. So far, two specific inhibitors: gp91ds-tat and apocynin have been proven to reduce BP in animals in labs. Other inhibitors such as diphenylene iodonium, aminoethyl benzenesulfono fluoride, S17834, PR39 and VAS2870, have proven to be effective in vitro, its effectiveness, pharmacokinetics and specificity is to be determined in vivo. (S Wind et al., 2010)

Many of these drugs not only inhibit the NAD(P)H oxidase but also other enzyme systems and cannot be administered orally, so its clinical use is limited. In addition, reactive oxygen species are so important to the immune and vascular health of human beings as for the disease, so not discriminating against the inhibition of NAD(P)H oxidase derived from reactive oxygen species could produce dangerous side effects.

Other drugs such as ACE inhibitors, ARBs and drugs lowering cholesterol like statins have also shown that they attenuate the activation of NAD(P)H oxidase, so this could be a promising avenue in the search for molecules with specific activities over enzymatic systems involved in cardiovascular diseases.

New Therapeutics in Hypertension 15

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

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

Fig. 1. Percutaneous renal denervation procedure. Graphic of catheter tip in distal renal

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

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

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.

denervation in patients with uncontrolled hypertension.

artery. Reproduced from Krum, H. et al. (2009)

renal denervation. (Witkowski et al., 2011)

emitting radio frequency motions to suppress nerve activity. (Fig.1)

the control group had a mean of 179/98 mmHg. (Krum et al., 2009)
