Treatment-Resistant Hypertension:
Pathophysiology
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Perceptions of hypertension
have changed over time
High BP Is Good!
Arterial pressure is elevated to
overcome mechanical resistance against
blood flow in renal disease.1 (Traube)
(Theory generalized to include
hypertension due to various etiologies).1
Efficiency of the kidney is not altered by
marked fall in BP, occurring
spontaneously or induced.1 (Page)
In patients with chronic kidney disease, a
fall in BP occurring spontaneously or as a
result of surgical renal denervation caused
no change in renal efficiency.1
Is High BP Good?
High BP Is Bad!
Landmark study demonstrated a 96%
reduction in CV events over 18 months with
the use of a triple antihypertensive regimen
compared with placebo in patients with
severe hypertension (P<0.001).3,4
The widespread opinion in the 1950s
was that lowering BP could be harmful.2
Lowering BP would impair perfusion of
vital organs, increasing CV risk and
renal disease.2
Low BP Is Bad!
BP = blood pressure; CV = cardiovascular.
1. Page IH. J Clin Invest. 1934;13:909-915. 2. Chobanian AV. N Engl J Med. 2009;361:878-887. 3. Veterans Administration
Cooperative Study Group. JAMA. 1967;202:1028-1034. 4. Calhoun DA, et al. Circulation. 2008;117(25):e510-e526.
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The kidney is a central regulator of the
electrical, chemical, and mechanical,
forces that control BP
SNS
Electrical
Brain
RAAS
Kidney: BP
Regulation
Chemical
Cytokines
Neurohormones
Heart rate
Mechanical
Vasodilation/
Vasoconstriction
Volume control
SNS = sympathetic nervous system.
RAAS = renin-angiotensin-aldosterone/system.
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 p. 535-547. Cowley A. Nat Rev Genetics. 2006;7:829-840. Kaplan NM, Victor R.
Kaplan's Clinical Hypertension. 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010. Schlaich M, et al. Hypertension.
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2009;54:1195-1201. Guyton AC. Science. 1991;252:1813-1816.
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Primary electrical component of
BP control is the sympathetic
nervous system (SNS)
• The SNS connects the
brain, heart, blood vessels,
and kidneys, each of which
plays an important role in
the regulation of BP
Relaxes bronchi
Accelerates heart
Inhibits digestive activity
Stimulates glucose
release by liver
Epinephrine—adrenal glands
Norepinephrine—kidney
Relaxes bladder
Cervical
Inhibits salivation
Thoracic
– Operates without
conscious control
Dilates pupils
Lumbar
• The SNS is part of the
body’s autonomic nervous
system
Contracts rectum
Campbell W. The Autonomic and Peripheral Nervous Systems. In: Campbell, WW, editor. DeJong's The Neurologic Examination.
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6th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2005 p. 535-547.
The kidneys are the most central
contributors to BP, playing electrical,
mechanical, and hormonal roles
 Neurohormones
 Blood Pressure
 Vasoconstriction
 Contractility/Rate
 RBF/GFR
 Renin
 Na+/Volume
Ang II
Ang II = Angiotensin II.
Aldo = Aldosterone.
RBF = Renal blood flow.
GFR = Glomerular filtration rate.
Aldo
Adapted from Schlaich MP, et al. Hypertension. 2009;54:1195-1201.
Hall JE, Guyton AC. Textbook of Medical Physiology. 12th ed. Philadelphia, PA: Saunders Elsevier, 2011.
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Kidneys are the most central
contributors to BP, playing electrical,
mechanical, and hormonal roles
 Neurohormones
 Blood Pressure
 Vasoconstriction
 Contractility/Rate
Kidney impairment or
dysfunction =  afferent activity
 RBF/GFR
 Renin
 Na+/Volume
Ang II
Aldo
Adapted from Schlaich MP, et al. Hypertension. 2009;54:1195-1201.
Hall JE, Guyton AC. Textbook of Medical Physiology. 12th ed. Philadelphia, PA: Saunders Elsevier, 2011.
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Kidneys are the most central
contributors to BP, playing electrical,
mechanical, and hormonal roles
 Neurohormones
 Blood Pressure
 Vasoconstriction
 Contractility/Rate
Kidney impairment or
dysfunction =  afferent activity
Amplifies central, or systemic,
sympathetic outflow
 RBF/GFR
 Renin
 Na+/Volume
Ang II
Aldo
Adapted from Schlaich MP, et al. Hypertension. 2009;54:1195-1201.
Hall JE, Guyton AC. Textbook of Medical Physiology. 12th ed. Philadelphia, PA: Saunders Elsevier, 2011.
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Kidneys are the most central
contributors to BP, playing electrical,
mechanical, and hormonal roles
 Neurohormones
 Blood Pressure
 Vasoconstriction
 Contractility/Rate
Kidney impairment or
dysfunction =  afferent activity
Amplifies central, or systemic,
sympathetic outflow
 RBF/GFR
 Renin
 Na+/Volume
Ang II
Aldo
Adapted from Schlaich MP, et al. Hypertension. 2009;54:1195-1201.
Hall JE, Guyton AC. Textbook of Medical Physiology. 12th ed. Philadelphia, PA: Saunders Elsevier, 2011.
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Renin-angiotensin-aldosterone
system (RAAS) is central to the
pathogenesis of hypertension
Increased sympathetic activity
Tubular Na+
reabsorption,
K+ excretion and
water retention
Pulmonary and renal
epithelium:
ACE
Aldosterone
secretion
Angiotensinogen
Angiotensin I
Angiotensin II
Water and salt
retention.
Effective
circulating
volume
increases.
Perfusion
of the
juxtaglomerular
apparatus
increases
Renin
Decrease
in renal
perfusion
Vasoconstriction
and increased BP
Antidiuretic hormone
secreted from pituitary,
leading to water absorption
Schrier RW, ed. Renal and Electrolyte Disorders 5th ed.1997.
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Sympathetic drive plays a
critical role in hypertension
Efferent Renal Sympathetics
Afferent Renal Sympathetics
Sympathetic signals from the
CNS modulate the physiology of
the kidneys
The kidney is a source of central
sympathetic activity, sending
signals to the CNS
CNS = central nervous system.
Adapted from Schlaich MP, et al. Hypertension. 2009;54:1195-1201.
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Sympathetic drive is elevated in
multiple types of hypertension
Sympathetic Activity per Minute
80
Single-unit efferent sympathetic
†
nerve activity (s-MSNA)
‡
§
60
40
*
†
20
*
†
‡
*
*
‡
§
¶
†
‡
§
#
Baseline activity
(normotensives)
0
LVH=left ventricular hypertrophy.
*P<0.05 Compared with borderline hypertension. / †P<0.05 Compared with white-coat hypertension. / ‡P<0.05 Compared with normal pressure.
§P<0.05 Compared with high-normal pressure. / ¶P<0.05 Compared with essential hypertension–stage 1. / #P<0.05 Compared with essential
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hypertension–stages 2 and 3.
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Adapted from Smith P, et al. Am J Hypertens. 2004; 217-222.
Summary: pathophysiology of
treatment-resistant hypertension
• While treatment-resistant hypertension is a well-recognized
phenomenon, perceptions of hypertension have changed over time
• BP is controlled by the complex interaction of several forces
– Electrical: SNS, brain
– Hormonal: RAAS, cytokines, neurohormones
– Mechanical: heart rate, vasodilation/vasoconstriction, volume control
• The kidneys play a major role in BP control due to their intrinsic
SNS connection
• Salt and water homeostasis along with BP regulation are controlled
by RAAS
• Efferent and afferent signaling between the CNS and kidneys play a
critical role in hypertension
• Elevated SNS activity is found in patients with multiple types
of hypertension
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