The Pathophysiology of Treatment-Resistant Hypertension

Regulation of arterial blood pressure

Blood pressure (BP) is controlled by a complex interaction of electrical, mechanical, and hormonal forces in the body. At any moment, arterial pressure may be defined as the product of cardiac output and total peripheral resistance. Cardiac output is controlled by a combination of several factors:

  • Extracellular fluid volume
  • Blood volume
  • Arterial and venous compliance*
  • Resistance of the blood flow to venous return

The kidneys play a key role in controlling both extracellular fluid volume and arterial pressure. The efficiency of the kidneys may be influenced by several factors, including the many intrinsic mechanisms that regulate renal blood flow and glomerular filtration.1

The sympathetic nervous system (SNS)

The main electrical component of BP control is the SNS, which is part of the body’s autonomic nervous system (ANS) and operates without conscious control. The SNS connects the brain, heart, blood vessels, and kidneys, each of which plays an important role in the regulation of the body’s blood pressure. The ANS has 2 parts – the SNS and the parasympathetic nervous system (Figure 1)2:


POP - Sympathtic_Parasympathetic

Adapted from: Campbell W. The Autonomic and Peripheral Nervous Systems. In: Campbell WW, editor. DeJong's The Neurologic Examination 6th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2005:535-547.

The renal sympathetic nerves play a key role in BP regulation and hypertension.3
Efferent renal sympathetic nerves3:

  • Carry signals from the central nervous system (CNS) to the kidneys
  • Increase renin release
  • Promote sodium retention
  • Reduce renal blood flow

In hypertensive patients, the efferent sympathetics are hyperstimulated and contribute to the rise in BP.3  Afferent renal sympathetic nerves3:

  • Carry signals from the kidneys to the central nervous system
  • Influence sympathetic outflow by the efferent sympathetics, affecting:
    • Kidneys
    • Heart
    • Peripheral blood vessels
    • Other organs involved in cardiovascular control

Increased sympathetic drive creates a feedback loop that adversely affects the vasculature, heart, and kidneys, and plays a vital role in the pathophysiology of hypertension (Figure 2).3


POP - Neurohormones1

RBF = Renal blood flow

GFR = Glomerular filtration rate

Ang ll = Angiotensin ll

Aldo = Aldosterone

Adapted from: Schlaich MP, et al. Hypertension. 2009;54:1195-1201.

Most patients with treatment-resistant hypertension and no apparent secondary causes display chronic SNS overactivity. Increased sympathetic tone (Figure 3)3,4:

  • Increases peripheral vascular resistance
  • Reduces renal blood flow
  • Increases sodium retention
  • Impairs glucose handling
  • Causes adverse cardiac and vascular remodeling

POP - Neurohormones2

Adapted from: Schlaich MP, et al. Hypertension. 2009;54:1195-1201. 

The renin-angiotensin-aldosterone system

The kidneys produce hormones including renin, cytokines, and other neurohormones. Renin starts a cascade of events called the renin-angiotensin-aldosterone system (RAAS), which causes vasoconstriction (contraction of the blood vessels), elevated heart rate, and salt and water retention. This cascade, which can be triggered by electrical means or automatically by the kidneys, operates normally in nonhypertensive patients but can become hyperactive in hypertensive patients.5

The kidney also produces cytokines and other neurohormones in response to elevated sympathetic activation. These hormones, though also active in blood pressure regulation, can be toxic to the body tissues, particularly the blood vessels, heart, and kidneys. As such, they may be responsible for much of the damage caused by chronic high blood pressure.3,5 

Under normal circumstances, components of the RAAS maintain salt and water homeostasis and BP regulation. The system forms a feedback loop whose activity can be regulated at multiple steps (Figure 4). Dysfunction of the RAAS leads to aberrant fluid and electrolyte metabolism and alterations of BP.3,5


POP - angiotensin

Schrier RW, ed. Renal and Electrolyte Disorders. 5th ed. 1997. 

The exact causes of treatment-resistant hypertension are not known

While treatment-resistant hypertension is a well-recognized phenomenon, the diagnosis of this condition is based on a process of elimination, and the pathophysiology of treatment-resistant hypertension is not well understood. Some studies have suggested that genetic factors may play a role in treatment-resistance; however, information is currently limited.6 It is clear that treatment-resistant hypertension, like other types of hypertension, is associated with elevated SNS activity,3 but the exact causes of treatment-resistance are not known at this time.

*Compliance is the ratio of the increase in intraluminal volume relative to an increase in pressure within the blood vessel.


  1. Cowley AW, Jr. Nat Rev Genet. 2006;7:829-840.
  2. Campbell W. The Autonomic and Peripheral Nervous Systems. In: Campbell WW, editor. DeJong's The Neurologic Examination, 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:535-547.
  3. Schlaich MP, Sobotka PA, Krum H, Whitbourn R, Walton A, Esler MD. Hypertension. 2009;54:1195-1201.
  4. Papademetriou V, Doumas M, Tsioufis K. Int J Hypertens. 2011;2011:196518.
  5. Conlin PR, Dluhy R, Williams GH. Disorders of the renin-angiotensin-aldosterone system. In: Schrier R, editor. Renal and Electrolyte Disorders, 5th ed. Lippincott-Raven Publishers; 1997:349-392.
  6. Calhoun DA, Jones D, Textor S, et al. Circulation. 2008;117:e510-e526. 

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