The primary consideration for managing NH is to prevent end-organ damage [86,87]. Before drug therapy is initiated, non-pharmacological measures are recommended to reduce BP. Lifestyle modifications such as exercising, reducing alcohol and sodium consumption, and ceasing cigarette smoking improve BP control [88,89]. In addition, some dietary components, such as bamboo shoot extract, have shown significant inhibition of ACE and could have a beneficial effect in lowering BP [90,91]. Monotherapy is the recommended therapeutic approach for managing early-stage hypertension. Yet, the lack of sufficient guidance to clinicians on options for individualizing therapies makes drug choice a significant concern, especially in managing NH. In addition, current knowledge cannot confirm if the available therapeutics for hypertension management can impact central sympathetic outflow associated with NH.

Despite the abovementioned fact, combination therapies have become the primary practice for controlling elevated BP in NH patients [92,93]. Usually, a combination of three drug classes (and a stepwise addition of a fourth antihypertensive if BP remains elevated) is often prescribed, which include at least a diuretic, an angiotensin receptor blocker (ARB), and/or ACE inhibitor [92]. However, studies of ARBs show they do not reduce sympathetic nervous outflow in NH when administered alone. Even in some cases, they may augment central neural vasoconstrictor outflow with increased plasma norepinephrine levels [94,95]. On the contrary, a study found that adding valsartan (an ARB) to an ACE inhibitor improves cardiac SNA [96]. However, the current treatment guideline does not recommend combining an ARB with an ACE for hypertension management due to the likelihood of causing renal failure [97]. The American heart association makes several recommendations for managing hypertension resistant to monotherapy, including dose augmentation with the addition of beta blockers, hydralazine, and minoxidil. However, most NH patients are elderly and often have associated cardiovascular (e.g., heart failure, cardiac arrhythmia) and non-cardiovascular comorbidities (e.g., diabetes) that can interfere with current treatment choices. Therefore, NH patients should be treated case by case instead of through a generalized treatment regimen [98].

Table 1 provides a list of current antihypertensive drugs that can be used in combination to manage NH.

Most of the clinically used BP-reducing drugs function outside the CNS. However, a few antihypertensive agents are known to have central activity, reducing overall vasomotor tone by activating receptors within the ventrolateral medulla. Centrally acting drugs either stimulate imidazoline receptors (rilmenidine, moxonidine) or α-2 (Clonidine) within the central nervous system [101]. Although the central actions of these drugs could be useful in NH, their benefits are marred with several adverse effects that limit their suitability for clinical use. Therefore, dose adjustment is proposed as a strategy to circumvent the harsh side effects of these chemotherapeutics; regardless, this approach has not seen much success. A more promising approach has been the development of second-generation imidazoline binding agents. An example of such an agent is rilmenidine, whose beneficial sympatholytic and BP-lowering effects are augmented by its ability to protect from postural hypotension [102]. In addition to its protective effects, rilmenidine is well tolerated and effective in reducing left ventricular hypertrophy associated with essential hypertension [103,104].

In the early 19th century, “Serious hypertension” was treated by surgically removing the splanchnic nerves [105,106]. The successful surgical interventions developed by Keith Grimson and Reginald Smithwick facilitated the development of chemical sympathectomy agents. However, the major backlashes of earlier surgical approaches were that it was invasive, time-consuming, and unsafe [107,108]. Over the past few decades, a return to surgical procedures has received much attention with the development of a brief (typically performed in 40 minutes) and less deleterious catheter-based renal denervation technique. The procedure only requires the insertion of a catheter into the femoral artery at the groin and advancing it to the renal artery. Radio frequencies are applied at the renal artery to ablate afferent and efferent sympathetic nerves connected to the kidneys [104,109].

In a proof-of-concept study, the SYMPLICITY HTN-1 study, Krum et. al [110] found that catheter-based renal denervation causes substantial and sustained BP reduction. However, they did not deem their findings decisive for managing resistant hypertension and called for more trials [111]. In a follow-up trial, SYMPLICITY HTN-2, similar outcomes were observed. Although both SYMPLICITY HTN-1 and HTN-2 trials had positive outcomes, they lacked sham controls, making the observations inconclusive [111,112,113]. To correctly affirm the suitability of renal denervation, well-designed randomized clinical trials are essential. In the third study with sham control (SYMPLICITY HTN-3), no significant difference was observed between the sham and treated groups. However, procedural insufficiencies such as fewer desirable ablations in the SYMPLICITY HTN-3 trial might be responsible for the unsuccessful findings. The failed attempt of the SYMPLICITY HTN-3 trial has left the fate of what appeared to be a promising treatment with unanswered questions.

Regardless, the idea of this technique being relatively safer has caused it to receive much attention with a significant number of clinical trials been performed. Table 2 provides a list of some of the registered clinical trials involving renal denervation, their status, and the measured outcomes of their study.

In 2019, the US Food and Drugs Administration approved the Barostim Neo^® System to improve symptoms in patients with heart failure [114]. The Barostim Neo system comprises an implantable pulse generator connected to a lead generator that is attached to the carotid artery in the neck. The device is programmed to deliver electrical impulses called baroreceptors which sense blood flow rate and relay them to the brain. The brain relying on this input transmits signals that regulate the heart and blood vessels to ensure optimum BP [114,115]. Although approved for managing heart failure, the technique employed in the device has previously been proposed for managing resistant hypertension since its first description over half a century ago [116,117]. Despite this promising feature, baroreceptor reflex activation has its pitfalls. Firstly, baroreceptor denervation significantly increases the short-term lability of arterial pressure but does not reduce arterial hypertension chronically. Also, in a phase III trial, the prototype device was associated with questionable efficacy and induced facial nerve palsy [104]. Fortunately, the production of a miniaturized second-generation pacing electrode allows the possibility of avoiding the significant side effect of facial nerve palsy [116].

Recent studies show nitric oxide biosynthesis is impaired in hypertension, and its acute inhibition further exaggerates hypertension. Incidentally, nitric oxide levels are known to influence SNA (sympathoexcitation at a low level and inhibition at a high level). Although the mechanism behind this pathophysiology is not fully understood, stimulating nitric oxide synthesis has been proposed as a possible target for the treatment of NH. [104,118,119,120,121]. Although a conclusion of this potential therapy is not yet presented, a study confirmed that inhaled nitric oxide treatment could improve systemic oxygenation in infants with persistent pulmonary hypertension [122], further strengthening this claim.

Another unconventional therapy proposed is statins, a class of drugs more frequently prescribed for their potent cholesterol-lowering properties. Additionally, statins are known to stimulate nitric oxide production and possess anti-inflammatory and antioxidant properties [123,124,125,126]. In animal models of heart failure, statins were identified to lower renal SNA and cause marked improvements in heart rate variability indices of cardiac autonomic balance [104,123,127,128]. Although there is not enough data to claim statins’ suitability for hypertension, their potential to impact SNA requires further investigation.

Inflammatory molecules generated by vascular endothelial cells and leukocytes can infiltrate the brain parenchyma via disrupting the BBB. When these inflammatory chemicals interact with microglia, they release more ROS and chemokines/cytokines, which can have an immediate impact on neuronal function. As a result, the role of inflammation and oxidative stress in NH pathophysiology is another area of active research. Further, substantial evidence suggests that diets rich in antioxidants cause significant reductions in blood pressure [129]. Thus, food components such as oatmeal which are rich in antioxidants and can regulate metabolic syndrome, hold potential as a dietary approach to managing NH [130,131,132,133].

Also, neurosteroid allopregnanolone is identified as a potential treatment for NH. Allopregnanolone facilitates high-affinity extra-synaptic γ-aminobutyric acid A receptors through allosteric modulation and transcriptional upregulation.